Allosteric EGFR inhibitors and methods of use thereof

Abstract

To provide potent small molecule epidermal growth factor receptor (EGFR) inhibitors with alternative mechanisms of action targeting mutant EGFR.SOLUTION: The invention relates to: compounds that act as allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.SELECTED DRAWING: None

Description

Technical Field

[0001] Description of Research or Development Receiving Federal Government Funding 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 the benefit of 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 hereby incorporated by reference in their entirety.

Background Art

[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, C. L., J. Clin. Oncol. 19, 2001, pp. 32-40). Dysregulation of EGFR has been implicated in many types of human cancers, and the receptor is overexpressed in at least 70% of human cancers (Seymour, L. K., 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 41-2; Salomon, D. S. et al., Crit. Rev. Oncol. Hematol. 19, 1995, pp. 183-232; Voldborg B. R. et al., Ann. Oncol. 8, 1997, pp. 1197-1206). Thus, EGFR has become an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind within cancer cells and inhibit the tyrosine kinase activity and signaling pathways of the receptor. For example, TARCEVA RTM, a reversible inhibitor of EGFR tyrosine kinase (EGFR-TK), has been approved by the FDA for the treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR targeting molecules, including lapatinib RTM and IRESSA RTM, have also been approved.

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

[0005] Pan-associative EGFR inhibitors have come to be known as inhibitors of cancers containing EGFR T790M. However, in lung cancer patients, only afatinib is effective in EGFR-mutation naïve EGFR mutant cancers, and the response rate (RR) is less than 10% in patients with NSCLC who have acquired resistance to gefitinib or erlotinib (Miller, V. A. 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 increase the dose of afatinib in patients to the levels required to inhibit EGFR T790M. Irreversible pyrimidine EGFR inhibitors, including the tool compound WZ4002 and the clinical compounds CO-1686 and AZD9291, have overcome many of the limitations of afatinib (Zhou, W. et al., Nature 462, 2009, pp. 1070-4; Walter, A. O. et al., Cancer Discov. 3, 2013, pp. 1404-15; Cross, D. A. E. et al., Cancer Discov. 4, 2014, pp. 1046-61). They are not only more potent against EGFR T790M, but also selectively inhibit the mutant over WT EGFR, leading to higher clinical efficacy and lower toxicity compared to afatinib (Zhou, W. et al.; Walter A. O. et al., Cross, D. A. E. et al.).

PRIOR ART DOCUMENTS

NON-PATENT DOCUMENTS

[0006]

NON-PATENT DOCUMENT 1

NON-PATENT DOCUMENT 2

NON-PATENT DOCUMENT 3

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-Patent Document 25

Summary of the Invention

Problems to be Solved by the Invention

[0007] However, all current EGFR TKIs target the ATP site. While third-generation irreversible inhibitors can overcome T790M, they are all rendered ineffective by the already-occurring C797S mutation in the patients being treated. Since kinase mutation activation is effectively "downstream" of receptor dimerization, the anti-EGFR antibody cetuximab, which interferes with receptor dimerization, is not effective in EGFR-mutant NSCLC. Therefore, an alternative strategy for inhibiting EGFR is needed. At present, suitable compounds with alternative mechanisms of action targeting mutant EGFR are not available. Accordingly, there is a need for a potent small-molecule EGFR inhibitor with an alternative mechanism of action that targets mutant EGFR.

Means for Solving the Problems

[0008] In one aspect, provided herein is a compound of formula I:

[0009]

Chemical Formula

[0010] or a pharmaceutically acceptable salt thereof (wherein, A and A' are each independently CH, CR 8 or N, W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy), X and Y are each independently N, CH or CR 3 and However, 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 are optionally substituted with one, two, or three R 8 groups, 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 are optionally substituted with one, two, or three R 6 groups, R 3 is, each occurrence independently, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, where the alkyl, alkenyl, or alkynyl is each optionally substituted with one, two, or three R 4 groups, and the aryl, heteroaryl, or heterocyclyl is each optionally substituted with one, two, or three R 5 groups, R 4 is, each occurrence independently, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl), and (CH2) 0~3-Selected from the group consisting of (5-7 membered heterocyclyl), wherein aryl, heteroaryl or heterocyclyl is each optionally R 5 is substituted one, two or three times with, R 5 is, independently at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5-7 membered heterocyclyl), wherein aryl, heteroaryl or heterocyclyl is each optionally R 7 is substituted one, two 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 NH2 or CN, or two Rs 6 together with the atoms to which they are attached may form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 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 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 Rs 7 together with the atoms to which they are attached may form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl, R 8 is, each occurrence independently, 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 (selected from the group consisting of).

[0011] In another aspect, provided herein is a compound of formula II:

[0012]

Chemical formula

[0013] or a pharmaceutically acceptable salt thereof (wherein W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl), or C-(C1-C3 alkoxy), X and Y are each independently N, CH, or CR 3 wherein 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 are optionally substituted with one, two, or three Rs 8 and 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 are optionally substituted by one, two or three R 6 and R 3 is, independently at each occurrence, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl and 5- to 7-membered heterocyclyl, where the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 and the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times by R 5 , R 4 is, independently at each occurrence, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), where the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times by R 5 , R 5 is, independently at each occurrence, 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 -(5-7 membered heterocyclyl), where aryl, heteroaryl or heterocyclyl are each optionally substituted one, two or three times by R 7 and R 6 is, each occurrence independently, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN, or two R 6 together with the atoms to which they are attached may form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl, R 7 is, each occurrence independently, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1~2 -OH, C(O)(CH2) 1~2 -OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl), or two R 7 together with the atoms to which they are attached may form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl, R 8Each occurrence is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN, and n is 1 or 2).

[0014] In yet another aspect, provided herein is a compound of Formula III:

[0015]

Chemical formula

[0016] or a pharmaceutically acceptable salt thereof (wherein

[0017]

Chemical formula

[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 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two or three R 8 and 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 are optionally substituted with one, two or three R 6 and R 3 is, each occurrence independently, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl and 5- to 7-membered heterocyclyl, where the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times with R 4 and the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times with R 5 , R 4 is, each occurrence independently, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), where the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times with R 5 , R 5 is, each occurrence independently, 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 -(5-7 membered heterocyclyl), where aryl, heteroaryl or heterocyclyl are each optionally substituted one, two or three times by R 7 and 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 NH2 or CN, or two R 6 together with the atoms to which they are attached may form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 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 -OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl), and is selected from the group consisting of substituents independently selected therefrom, or two R 7 together with the atoms to which they are attached may form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl, R 8Each occurrence is independently C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN).

[0019] In one aspect, provided herein is a method of treating cancer or a proliferative disorder comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound disclosed herein or 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 dimerization of EGFR. In another embodiment, the subject is human.

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

Mode for Carrying Out the Invention

[0021] Definitions The following are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms used throughout this specification and the claims, 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, as well as the experimental 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 more than one (i.e., at least one) of the grammatical objects of the article. By way of example, “an element” means one element or more than one element. Further, 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” is 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 to refer to a measurable value such as an amount, a temporal duration, etc., the term “about” means a variation of ±20% or ±10%, including ±5%, ±1% and ±0.1% from the specified value, as long as such variation is appropriate for carrying out the disclosed method.

[0025] Terms such as “administer” used herein refer to giving a therapeutic agent to a subject. There are multiple techniques in the art for administering therapeutic agents, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, eye drops, pulmonary administration and topical administration.

[0026] The terms “treating”, “treated”, “being treating” or “treatment” include the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder or disease being treated. In certain embodiments, treatment includes contacting wild-type or mutant EGFR with an effective amount of a compound disclosed herein for a subject in a cancer-related condition.

[0027] As used herein, the terms "prevent" or "prevention" mean, in the case where nothing is occurring, the absence of the onset of a disorder or disease, or in the case where the onset of a disorder or disease is already present, the absence of the onset of a further disorder or disease. It is also considered its 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" mean a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as ovine species, bovine species, porcine species, canine species, feline species 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 non-toxic but sufficient amount of a drug that produces the desired biological result. This result may be a reduction or alleviation of the signs, symptoms or causes of a disease, or any other desired modification of a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using standard experimental methods.

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

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, 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 a mixture of the two (generally a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred). The phrase "pharmaceutically acceptable salt" is not limited to mono-salts, i.e., 1:1 salts. For example, "pharmaceutically acceptable salts" include bis-salts such as bis-hydrochloride salts. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 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 will result in an active drug upon metabolic activation in vivo. Thus, for example, a prodrug of a compound provided herein will, when administered to a subject, result in the production of the compound upon metabolic activation.

[0033] As used herein, the terms "composition" or "pharmaceutical composition" refer to a mixture of at least one compound useful within the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. There are a plurality of techniques in the art for administering the compound, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic instillation, pulmonary administration, and topical administration.

[0034] As used herein, the term "combination medicament" means a product obtained by mixing or combining more than one active ingredient, and includes both fixed combinations and non-fixed combinations of active ingredients. The term "fixed combination" means administering both an active ingredient, such as a disclosed compound, and a co-agent, to a patient simultaneously in the form of a single entity or a single dosage. The term "non-fixed combination" means administering both an active ingredient, such as a disclosed compound, and a co-agent, to a patient as separate entities, simultaneously, concurrently, or sequentially without a specific time limit, such that such administration results in therapeutic effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapies, such as 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 filler or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, that is involved in transporting or delivering a compound useful within the present disclosure into or to a patient so that its intended function can be performed. Typically, such a construct is transported or delivered from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation, including the compounds 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 carboxymethyl cellulose sodium, ethyl cellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0036] As used herein, "pharmaceutically acceptable carrier" also includes any coating agent, antibacterial and antifungal agent, absorption delaying agent, etc. that is compatible with the activity of the compounds useful within the disclosure and is physiologically acceptable to the patient. Auxiliary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" 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 (also referred to as ErbB-1 or HER1), and can 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. The "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 amino acid residues of the epidermal growth factor receptor (EGFR): Lys745, Leu788, Ala743, Cys755, Leu777, Phe856, Asp855, Met766, Ile759, Glu762, and / or Ala763.

[0040] As used herein, the term "agent that prevents dimer formation of EGFR" or iterations thereof refers to an agent that prevents dimer formation, where the C-lobe of the "activator" subunit collides with the N-lobe of the "receptor" subunit. Examples of agents that prevent dimer formation of EGFR include, but are not limited to, cetuximab, trastuzumab, panitumumab, and Mig6.

[0041] As used herein, the term "alkyl", whether by itself or as part of another substituent, means a straight-chain or branched-chain hydrocarbon having the indicated number of carbon atoms (i.e., C1-C6 alkyl means alkyl having from 1 to 6 carbon atoms), including straight and branched chains, unless otherwise stated. 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 as defined herein. Examples of haloalkyl include chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, etc.

[0043] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, etc.

[0044] As used herein, the term "alkylamine" refers to an -NH-alkyl group, where alkyl is as defined herein. Examples of alkylamines include 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. Examples of haloalkoxys include 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 having at least one carbon-carbon double bond. The alkenyl group may or may not be a point of attachment to another group. The term "alkenyl" includes, but is not limited to, 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 having at least one carbon-carbon triple bond. The alkynyl group may or may not be a point of attachment to another group. The term "alkynyl" includes, but is not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0048] As used herein, the term "halo" or "halogen", alone or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine, unless otherwise stated.

[0049] As used herein, the term "cycloalkyl" means a fully saturated non-aromatic carbocyclic system having 1, 2 or 3 rings, where such rings may be fused. The term "fused" means that a second ring is present (i.e., attached or formed) by having two adjacent atoms common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be essentially bridged or spirocyclic, where the individual rings within the bicyclic vary in 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 system having 1, 2 or 3 rings, where such rings may be fused, and where at least one ring contains a sp 2 carbon-carbon bond. The term "cycloalkenyl" includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, bicyclo[3.1.0]hexenyl, spiro[3.3]heptenyl and bicyclo[1.1.1]pentenyl.

[0051] As used herein, the terms "heterocyclyl" or "heterocycloalkyl" mean a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, where such rings may be fused, and where the fusion is defined above. Heterocyclyl also includes bicyclic structures that may be essentially crosslinked or spirocyclic, where the individual rings within the bicyclic vary in the range of 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), and specifically includes, but is not limited to, epoxyxyl, 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-[2.2.1]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 having one or more polyunsaturated rings, having aromatic characteristics, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

[0053] As used herein, the term "aryl" means an aromatic carbocyclic system containing 1, 2, or 3 rings, where such rings may be fused, and where the fusion is defined as above. When the rings are fused, one of the rings must be completely unsaturated, and the fused rings may be completely saturated, partially unsaturated, or completely unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group has 6 to 16 carbon atoms.

[0054] As used herein, the term "heteroaryl" means an aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, where such rings may be fused, and where the fusion is defined as above. The term "heteroaryl" includes, but is not limited 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, 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] When an aryl, heteroaryl, cycloalkyl or heterocyclyl moiety can be attached to the moiety indicated via a different ring atom or otherwise attached (i.e., shown or described without indicating a specific point of attachment), it should be understood that all possible points are intended, whether via a carbon atom or, for example, via a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3- or 4-pyridinyl, the term "thienyl" means 2- or 3-thienyl, and the like.

[0056] As used herein, the term "substituted" means that an atom or group of atoms has been replaced with a substituent in place of hydrogen as a group bonded to another group.

[0057] As used herein, the term "optionally substituted" means that the recited group may or may not be substituted. In one embodiment, the recited group is optionally substituted with 0 substituents, i.e., the recited group is unsubstituted. In another embodiment, the recited 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 cancers and other proliferative diseases.

[0059] In one aspect, provided herein is Formula I:

[0060]

Chemical formula

[0061] a compound of or a pharmaceutically acceptable salt thereof (wherein, A and A' are each independently CH, CR 8 or N, W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy), X and Y are each independently N, CH or CR 3 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 are optionally substituted with 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 are optionally substituted with one, two, or three Rs 6 is replaced by R 3 is, each occurrence independently, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, where the alkyl, alkenyl, or alkynyl is each optionally substituted with one, two, or three Rs 4 and the aryl, heteroaryl, or heterocyclyl is each optionally substituted with one, two, or three Rs 5 is replaced by R 4 is, each occurrence independently, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), where the aryl, heteroaryl, or heterocyclyl is each optionally substituted with one, two, or three Rs 5 and is replaced by R 5Independently at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3- to 10-membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl) and (CH2) 0~3 -(5- to 7-membered heterocyclyl), where aryl, heteroaryl or heterocyclyl may each be optionally substituted one, two or three times with R 7 and R 6 is independently at each occurrence selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN, or two R 6 may together with the atoms to which they are attached form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl, R 7 is independently at each occurrence selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1~2 -OH, C(O)(CH2) 1~2 -OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl), or two R 7may, together with the atoms to which they are attached, form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl, R 8 is, independently at each occurrence, 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 is a compound of formula I or a pharmaceutically acceptable salt 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), wherein all other variable groups are as defined above).

[0063] In certain embodiments, the compound of formula I is of formula Ia:

[0064]

Chemical formula

[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 substituted once with R 5 In another embodiment of formula Ia, R 3 is C6-C 5 aryl optionally substituted once with R 10 wherein R 5 is 5- to 7-membered heterocyclyl, C6-C 10Aryl, 3- to 10-membered cycloalkyl or 5- to 6-membered heteroaryl, all of which are optionally R 7 substituted once. In yet another embodiment of formula Ia, R 3 is phenyl optionally substituted once with R 5 where R 5 is 5- to 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 substituted once. In yet another further embodiment of formula Ia, R 3 is C6-C 5 aryl optionally substituted once with R 10 where R 5 is 5-membered heterocyclyl optionally substituted once with R 7 . In one embodiment of formula Ia, R 3 is phenyl optionally substituted once with piperidine, where piperidine is substituted once with R7.

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

[0068]

Chemical formula

[0069] or a pharmaceutically acceptable salt thereof.

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

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

[0072] [Chemical]

[0073] selected from the group consisting of, all of which are optionally substituted with one, two or three Rs 8 is substituted.

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

[0075] In one embodiment, the compound of formula I is Table 1 (Table 1)

[0076] [Table 1A]

[0077] [Table 1B]

[0078]

Table 1C

[0079] is selected from the group consisting of the compounds or their pharmaceutically acceptable salts in

[0080] In another embodiment, the compound of formula I is Table 2 (Table 2):

[0081]

Table 2A

[0082]

Table 2B

[0083]

Table 2C

[0084]

Table 2D

[0085]

Table 2E

[0086]

Table 2F

[0087] is selected from the group consisting of the compounds or their pharmaceutically acceptable salts in

[0088] In embodiments, Compounds 112-117 provided herein have an isotope 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) for each designated deuterium atom.

[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 is a compound of Formula II:

[0091]

Chemical formula

[0092] or a pharmaceutically acceptable salt thereof (wherein, W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy), X and Y are each independently 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 are optionally substituted with one, two or three R 8 and 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 are optionally substituted with one, two, or three R 6 and R 3 is, independently at each occurrence, halogen, OR 4 , NR 4 R 4 , SO2R 4 , SO2NHR 4 , NHSO2R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10 aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, where the alkyl, alkenyl, or alkynyl is each optionally substituted one, two, or three times with R 4 and the aryl, heteroaryl, or heterocyclyl is each optionally substituted one, two, or three times with R 5 , R 4 is, independently at each occurrence, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), where the aryl, heteroaryl, or heterocyclyl is each optionally substituted one, two, or three times with R 5 , R 5 is, independently at each occurrence, 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 -(5-7 membered heterocyclyl), where aryl, heteroaryl or heterocyclyl may each be optionally substituted one, two or three times by R 7 and 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 NH2 or CN, alternatively, two R 6 may together with the atoms to which they are attached form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 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 -OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl), alternatively, two R 7 may together with the atoms to which they are attached form a 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl, R 8independently at each occurrence, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 selected from the group consisting of NH2 or CN, n is 1 or 2).

[0093] In certain embodiments of Formula II, R 5 independently at each occurrence, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5-6 membered heteroaryl), O(CH2) 0~3 -(4-7 membered heterocyclyl) and (CH2) 0~3 -(4-7 membered heterocyclyl) selected from the group consisting of, wherein alkyl, alkoxy, aryl, heteroaryl or heterocyclyl are each optionally R 7 substituted one, two or three times with, wherein all other variable groups are as defined above.

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

[0095]

Chemical formula

[0096] or a pharmaceutically acceptable salt thereof.

[0097] In yet another aspect, provided herein is a compound of formula X:

[0098] [Chemical formula]

[0099] or a pharmaceutically acceptable salt thereof (wherein, A is O or S, W and Z are each independently N, CH, C-halo, C-(C1-C3 alkyl) or C-(C1-C3 alkoxy), X and Y are each independently N, CH or CR 3 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 are optionally substituted with one, two or three R 8 groups, 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 are optionally substituted with one, two or three R 6 groups, R 3 is independently at each occurrence halogen, OR 4 NR 4 R 4 SO2R 4 SO2NHR 4 NHSO2R 4 C(O)OR 4 C(O)NHR 4 C(O)R 4 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 7-membered cycloalkyl, C4-C7 cycloalkenyl, C6-C 10Selected from the group consisting of aryl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocyclyl, where alkyl, alkenyl, or alkynyl is each optionally substituted one, two, or three times by R 4 and aryl, heteroaryl, or heterocyclyl is each optionally substituted one, two, or three times by R 5 ; R 4 is, each occurrence independently, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl), and (CH2) 0~3 -(5- to 7-membered heterocyclyl), where aryl, heteroaryl, or heterocyclyl is each optionally substituted one, two, or three times by R 5 ; R 5 is, each occurrence independently, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3- to 10-membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5- to 6-membered heteroaryl), O(CH2) 0~3 -(4- to 7-membered heterocyclyl), and (CH2) 0~3 -(4- to 7-membered heterocyclyl), where alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl is each optionally substituted one, two, or three times by R 7 ; R 6Each occurrence is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, (CH2) 1~4 OH, S(O) 0~2 H, S(O) 0~2 NH2 or CN, and alternatively, two Rs 6 together with the atom to which they are attached may form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; R 7 Each occurrence is independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, (CH2) 1~2 -OH, C(O)(CH2) 1~2 -OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl), and is independently selected from the group consisting of substituents; alternatively, two Rs 7 together with the atom to which they are attached may form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl; R 8 Each occurrence is independently selected from the group consisting 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, and 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 substituted by R 5 once. In another embodiment of formula IIa, R 3 is C6-C 5 aryl optionally substituted once by R 10 , where R 5 is 5- to 7-membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl or 5- to 6-membered heteroaryl, all of which are optionally substituted by R 7 once. In yet another embodiment of formula IIa, R 3 is phenyl optionally substituted once by R 5 , where R 5 is 5- to 7-membered heterocyclyl, C6-C 10 aryl, 3- to 10-membered cycloalkyl or 5- to 6-membered heteroaryl, all of which are optionally substituted by R 7 once. In still yet another embodiment of formula IIa, R 3 is C6-C 5 aryl optionally substituted once by R 10 , where R 5 is 5-membered heterocyclyl optionally substituted once by R 7 . In one embodiment of formula IIa, R 3 is phenyl optionally substituted once by piperidine, where piperidine is substituted once by R7.

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

[0102]

Chemical formula

[0103] or a pharmaceutically acceptable salt thereof.

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

[0105] [Chemical formula]

[0106] is a compound of formula (I) 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 atoms to which they are attached form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl. In another embodiment, R 6 is hydroxy, fluoro, or two R 6 together with the atoms to which they are attached form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl. In yet another embodiment, R 6 is hydroxy. In yet another embodiment, R 6 is fluoro. In another embodiment, R 6 is chloro. In one embodiment, two R 6 which are hydroxy and fluoro are present. In another embodiment, two R 6 which are hydroxy and chloro are present. In yet another embodiment, two R 6 together with the atoms to which they are attached form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered cycloalkyl.

[0108] In certain embodiments of Formulas II, IIa, and IIb, R 1 is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole, and imidazopyridine. In one embodiment, R1 is

[0109] [Chemical formula]

[0110] Selected from the group consisting of, all of which are optionally substituted with one, two or three R 8 s.

[0111] In another embodiment, R 3 is phenyl or C2-C3 alkynyl, where phenyl is optionally substituted one or two times with R 5 s, and alkynyl is optionally substituted one or two times with R 4 s. In yet another embodiment, R 3 is phenyl optionally substituted one or two times with R 5 s. In still yet another embodiment, R 3 is C2-C3 alkynyl optionally substituted one or two times with R 4 s. In one embodiment, R 3 is phenyl substituted with one or two R 5 s, and R 5 is selected from the group consisting of piperidine, pyridine and thiomorpholine dioxide, all of which are optionally substituted with one or two R 7 s.

[0112] In another embodiment, the compound of formula II is shown in Table 3 (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] is selected from the group consisting of the compounds or their pharmaceutically acceptable salts in

[0123] In yet another embodiment, the compound of Formula II is Table 4 (Table 4):

[0124]

Table 4

[0125] is selected from the group consisting of the compounds or their pharmaceutically acceptable salts in

[0126] In embodiments, Compounds 036 - 039 provided herein have an isotope 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) for each designated deuterium atom.

[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 shown in Table 5:

[0129] [Table 5A]

[0130] [Table 5B]

[0131] [Table 5C]

[0132] [Table 5D]

[0133] [Table 5E]

[0134] It is selected from the group consisting of a compound or a pharmaceutically acceptable salt thereof.

[0135] In yet another aspect, provided herein is a compound of formula III:

[0136]

Chemical formula

[0137] or a pharmaceutically acceptable salt thereof (wherein,

[0138]

Chemical formula

[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 are optionally substituted with one, two or three R 8 and 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 are optionally substituted with one, two or three R 6 and R 3 is independently at each occurrence halogen, OR 4 NR 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, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, wherein the alkyl, alkenyl or alkynyl is each optionally substituted one, two or three times by R 4 , and the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times by R 5 , R 4 is, each occurrence independently, H, (CH2) 0~3 -(C3-C7 cycloalkyl), (CH2) 0~3 -(C4-C7 cycloalkenyl), (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5-7 membered heterocyclyl), wherein the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times by R 5 , R 5 is, each occurrence independently, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C1-C6 alkyl), O(CH2) 1~3 -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, CN, (CH2) 0~3 -(C6-C 10 aryl), (CH2) 0~3 -(5-6 membered heteroaryl) and (CH2) 0~3 -(5-7 membered heterocyclyl), wherein the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times by R 7is substituted one, two or three times, R 6 is, independently for 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 NH2 or CN, or two Rs 6 together with the atoms to which they are attached, may form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl, R 7 is, independently for 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 -OH, C(O)(C1-C6 alkyl) and C(O)O(C1-C6 alkyl), or two Rs 7 together with the atoms to which they are attached, may form a 5- to 10-membered heteroaryl, 6- to 10-membered aryl, 3- to 10-membered heterocycloalkyl or 3- to 10-membered cycloalkyl, R 8 is, independently for each occurrence, 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, selected from the group consisting of 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 -(5-7 membered heterocyclyl), wherein the aryl, heteroaryl or heterocyclyl is each optionally substituted one, two or three times with R 5 ; and all other variable groups are as defined above). wherein all other variable groups are as defined above).

[0141] In certain embodiments, the compound of formula III is a compound of formula IIIa:

[0142]

Chemical formula

[0143] or a pharmaceutically acceptable salt thereof.

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

[0145] In another embodiment, the compound of Formula III is a compound of Formula IIIb:

[0146]

Chemical formula

[0147] or a pharmaceutically acceptable salt thereof.

[0148] In yet another embodiment, the compound of Formula III is a compound of Formula IIIc:

[0149]

Chemical formula

[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. In one embodiment, R 1 is

[0152] [Chemical]

[0153] selected from the group consisting of, all of which are optionally substituted with one, two or three Rs 8 is substituted.

[0154] In another embodiment, Y is CR 3 and R 3 is a 6- to 10-membered aryl substituted with one or two Rs 5 . In yet another embodiment, Z is CF. In still yet another embodiment, Z is CH. In one embodiment, Z is N.

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

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

[0157]

Table 6A

[0158]

Table 6B

[0159]

Table 6C

[0160] selected from the group consisting of compounds from

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

[0162] The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, mixtures of diastereomers, racemic mixtures, etc.).

[0163] In the context of the present disclosure, it is generally known in the art that any compound that is converted in vivo to yield a compound disclosed herein is a prodrug.

[0164] ​The compounds provided herein can also include all isotopes of atoms present in the intermediate or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds of the invention can be replaced, i.e., substituted, with isotopes of the atoms in natural abundance or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced, i.e., substituted, with deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, pages 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Compounds labeled with isotopes can be used in various tests, such as NMR spectroscopy, metabolic experiments and / or assays.

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

[0166] In one aspect, 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 certain embodiments, the composition further comprises a second active agent. In another embodiment, the second active agent is selected from the group consisting of MEK inhibitors, PI3K inhibitors, and mTor inhibitors. In yet another embodiment, the second active agent prevents dimer formation of EGFR in a subject. In still 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 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 dimer formation and a pharmaceutically acceptable carrier. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab.

[0169] Compounds that bind to allosteric sites within EGFR, such as compounds of the disclosure (e.g., compounds of the formulas disclosed herein), may optionally be combined with a second active agent that prevents EGFR dimer formation and can modulate the activity of EGFR. In some embodiments, the compounds of the disclosure can inhibit or reduce the activity of EGFR without using a second active agent (e.g., an antibody such as cetuximab, trastuzumab or panitumumab). In other embodiments, the compounds of the disclosure are combined with a second active agent. In certain embodiments, the second active agent can prevent EGFR dimer formation and / or inhibit or reduce the activity of EGFR. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. 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] Method of treatment In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound disclosed herein. In certain embodiments, 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 of inhibiting a kinase in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound provided herein. In certain embodiments, the kinase is EGFR.

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

[0173] In some embodiments, the 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, where 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, where the combination of mutations is selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M, Del / T790M / C797S, and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations, where the combination of mutations is selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M.

[0174] In some embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation 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, where 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, where the combination of mutations is selected from Del / L844V, L858R / L844V, L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In other embodiments, the mutant EGFR contains a combination of mutations, where the combination of mutations is selected from L858R / T790M, L858R / T790M / I941R, L858R / T790M / C797S, Del / T790M, Del / T790M / C797S, and L858R / T790M. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib.

[0175] In some embodiments, the 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, the compounds 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 do 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 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.

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

[0178] In some embodiments, the compounds of the present disclosure exhibit greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit up to 1000-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit up to 10,000-fold greater inhibition against EGFR having a combination of the mutations 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit up to 1000-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit up to 10,000-fold greater inhibition against EGFR having a combination of the mutations 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 dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0180] In some embodiments, the compounds of the present disclosure exhibit from about 2-fold to about 10-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit from about 10-fold to about 100-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit from about 100-fold to about 1000-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In various embodiments, the compounds of the present disclosure exhibit from about 1000-fold to about 10000-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR.

[0181] In other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit from about 2-fold to about 10-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit from about 10-fold to about 100-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit from about 100-fold to about 1000-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In other embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit from about 1000-fold to about 10000-fold greater inhibition against EGFR containing one or more of the mutations described herein compared to wild-type EGFR. In other embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0182] In certain embodiments, the compounds of the present disclosure exhibit at least 2-fold greater inhibition against EGFR 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, the compounds of the present disclosure exhibit at least 3-fold greater inhibition against EGFR 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, the compounds of the present disclosure exhibit at least 5-fold greater inhibition against EGFR 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, the compounds of the present disclosure exhibit at least 10-fold greater inhibition against EGFR 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, the compounds of the present disclosure exhibit at least 25-fold greater inhibition against EGFR 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, the compounds of the present disclosure exhibit at least 50-fold greater inhibition against EGFR 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, the compounds of the present disclosure exhibit at least 100-fold greater inhibition against EGFR 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.

[0183] In certain embodiments, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 2-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 3-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 5-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 10-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 25-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 50-fold greater inhibition against EGFR 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, the compounds of the present disclosure in combination with a second active agent that prevents EGFR dimer formation exhibit at least 100-fold greater inhibition against EGFR 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 some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

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

[0185] In some embodiments, the inhibition of EGFR activity is EC 50 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 examples, using the conditions and experimental parameters disclosed herein, a homogenous time-resolved fluorescence (HTRF) assay can be used to determine inhibition of EGFR activity. In the HTRF assay, for example, a substrate concentration of about 1 μM (e.g., biotin-Lck-peptide substrate), an EGFR (variant 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 can be employed. The disclosed compounds screened under these conditions have, for example, an IC 50 value of from about 1 nM to >1 μM, from about 1 nM to about 400 nM, from about 1 nM to about 150 nM, from about 1 nM to about 75 nM, from about 1 nM to about 40 nM, from about 1 nM to about 25 nM, from about 1 nM to about 15 nM, or from about 1 nM to about 10 nM. In certain embodiments, for inhibition of EGFR having a mutation or combination of mutations selected from L858R / T790M, L858R, and T790M, the disclosed compounds screened under the above conditions have, for example, an IC 50 value of from about 1 nM to >1 μM, from about 1 nM to about 400 nM, from about 1 nM to about 150 nM, from about 1 nM to about 75 nM, from about 1 nM to about 40 nM, from about 1 nM to about 25 nM, from about 1 nM to about 15 nM, or from about 1 nM to about 10 nM.

[0187] In some embodiments, the compounds of the present disclosure bind to allosteric sites within EGFR. In some embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and Ala743. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Cys755, Leu777, Phe856, and Asp855. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Met766, Ile759, Glu762, and Ala763. In other embodiments, the compounds of the present disclosure interact with at least one amino acid residue of epidermal growth factor receptor (EGFR) selected from Lys745, Leu788, and 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, the compounds of the present disclosure do not interact with any amino acid residues of epidermal growth factor receptor (EGFR) selected from Met793, Gly796, and Cys797.

[0188] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor that is a more potent inhibitor against drug-resistant EGFR variants compared to wild-type EGFR. For example, the compound can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the kinase activity of drug-resistant EGFR variants compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR variant is 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 variants include sensitizing mutations such as Del and L858R.

[0190] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimer formation, which is a more potent inhibitor against drug-resistant EGFR variants compared to wild-type EGFR. For example, the present compound in combination with a second active agent that prevents EGFR dimer formation can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the kinase activity of drug-resistant EGFR variants compared to wild-type EGFR. In some embodiments, the drug-resistant EGFR variant is resistant to one or more known EGFR inhibitors including, but not limited to, gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib. In some embodiments, drug-resistant EGFR variants include sensitizing mutations such as Del and L858R. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0191] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor, wherein the kinase activity of a drug-resistant EGFR variant carrying a sensitizing mutation (e.g., Del and L858R) and a drug-resistant mutation (e.g., T790M, L718Q, C797S, and L844V) is compared to that of an EGFR variant carrying the sensitizing mutation but not the drug-resistant mutation in terms of efficacy (e.g., IC 50To provide a compound that inhibits with a difference of less than 10-fold in (measured by). 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.

[0192] In other embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimer formation, the kinase activity of a drug-resistant EGFR variant carrying a sensitizing mutation (e.g., Del and L858R) and a drug-resistant mutation (e.g., T790M, L718Q, C797S and L844V) being compared to an EGFR variant that carries a sensitizing mutation but does not carry a drug-resistant mutation, with a difference in potency (e.g., IC 50 To provide a compound in combination with a second active agent that inhibits with a difference of less than 10-fold in (measured by). 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 dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0193] In some embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor that is more potent in inhibiting the activity of EGFR containing one or more mutations described herein, such as 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 present compound is at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the activity of EGFR containing one or more mutations described herein than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., as measured by IC 50 ).

[0194] In other embodiments, the present disclosure provides a compound comprising an allosteric kinase inhibitor in combination with a second active agent that prevents EGFR dimer formation, which is more potent in inhibiting the activity of EGFR containing one or more mutations described herein, such as 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 present compound in combination with a second active agent that prevents EGFR dimer formation is at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent in inhibiting the activity of EGFR containing one or more mutations described herein than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387785, and osimertinib (e.g., as measured by IC 50(measured by). In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

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

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

[0197] The potency of the inhibitor can be determined by the EC 50 value. A compound with a lower EC 50 value determined under substantially similar conditions is a more potent inhibitor compared to a compound with a higher EC 50 value. In some embodiments, substantially similar conditions include determining EGFR-dependent phosphorylation levels 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 IC 50It can also be determined by a value. ICs determined under substantially similar conditions 50 Compounds with low values are more potent inhibitors compared to compounds with high IC 50 values. In some embodiments, substantially similar conditions include determining EGFR-dependent phosphorylation levels 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, deletions in exon 19 and / or insertions in exon 20. Drug-resistant EGFR variants can have drug-resistant mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y.

[0200] The selectivity between wild-type EGFR and EGFR containing one or more of the mutations described herein can also be measured using a cell proliferation assay in which cell proliferation is dependent on kinase activity. For example, mouse 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. The proliferation assay is performed at various inhibitor concentrations (10 μΜ, 3 μΜ, 1.1 μΜ, 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 the phosphorylation of EGFR. 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 normally do not express endogenous EGFR), and the ability of an inhibitor to inhibit the phosphorylation of EGFR can be assayed (using the concentrations described above). The cells are exposed to the inhibitor for 6 hours while increasing the concentration of the inhibitor and then stimulated with EGF for 10 minutes. The effect on the phosphorylation of EGFR is assayed by Western blot using a phosphorylation-site (Y1068)-specific EGFR antibody.

[0202] In another aspect, the disclosure relates to a compound that binds to an allosteric site within EGFR and that exhibits an inhibition that is 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold or 1000-fold greater against an EGFR containing one or more of the 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 present disclosure provides a compound that binds to an allosteric site within EGFR, in combination with a second active agent that prevents dimerization of EGFR, the compound showing inhibition greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold or 1000-fold greater than that of wild-type EGFR, against EGFR containing one or more of the 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), in combination with a second active agent. In some embodiments, the second active agent that prevents dimerization of EGFR is an antibody. In further embodiments, the second active agent that prevents dimerization of EGFR is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents dimerization of EGFR 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 present disclosure provides a method of inhibiting epidermal growth factor receptor (EGFR), the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the method further comprises administering a second active agent that prevents dimerization of EGFR. In some embodiments, the second active agent that prevents dimerization of EGFR is an antibody. In further embodiments, the second active agent that prevents dimerization of EGFR is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents dimerization of EGFR 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.

[0205] In another aspect, provided herein is a method of treating or preventing a disease, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. 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 within EGFR, and such positions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec and Txk are included. In some embodiments, the method further comprises administering a second active agent that prevents dimer formation of the kinase. In some embodiments, the second active agent that prevents dimer formation of the kinase is an antibody. In further embodiments, the second active agent prevents dimer formation of EGFR. In further embodiments, the second active agent that prevents dimer formation of EGFR is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents dimer formation of EGFR 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 causation 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 an EGFR that bears an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. Drug-resistant EGFR variants can have drug-resistant mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those of skill in the art 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 solid tumor. In further embodiments, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In even 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 an EGFR that bears an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. The drug-resistant EGFR variant may have a drug-resistant mutation including, but not limited to, T790M, T854A, L718Q, C797S or D761Y. The diagnostic test may include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those of skill in the art capable of detecting nucleotide sequences.

[0211] In yet another aspect, provided herein is a method of treating a kinase-mediated disorder comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. 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 present disclosure provides a method for treating a kinase-mediated disorder, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a second active agent that prevents EGFR dimer formation. In some embodiments, the compound is an inhibitor of HER1, HER2, or HER4. In other embodiments, an additional therapeutic agent is administered to the subject. In other embodiments, the compound, the second active agent that prevents EGFR dimer formation, and the additional therapeutic agent are administered simultaneously or sequentially. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In a further embodiment, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0213] In other embodiments, the disease is cancer. In a further embodiment, 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 solid tumor. In a further embodiment, the disease is lung cancer, breast cancer, glioma, squamous cell carcinoma, or prostate cancer. In an even further embodiment, the disease is non-small cell lung cancer.

[0214] In another aspect, provided herein is a method for treating cancer in which activated EGFR is contained in cancer cells, the method 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 is a method of treating cancer in which activated EGFR is included in cancer cells, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a second active agent that prevents dimerization of EGFR. In some embodiments, the second active agent that prevents dimerization of EGFR is an antibody. In further embodiments, the second active agent that prevents dimerization of EGFR is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents dimerization of EGFR 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.

[0216] In certain embodiments, the activation of EGFR is selected from mutations of EGFR, amplifications of EGFR, expression of EGFR, and ligands that mediate the activation of EGFR.

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

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

[0219] In certain embodiments, a subject identified as in need of EGFR inhibition is resistant to known EGFR inhibitors including, but not limited to, gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002. In certain embodiments, a diagnostic test is performed to determine whether the subject has an activating mutation in EGFR. In certain embodiments, a diagnostic test is performed to determine whether the subject has an EGFR that harbors an activating mutation and / or a drug-resistant mutation. Activating mutations include, but are not limited to, L858R, G719S, G719C, G719A, L718Q, L861Q, deletions in exon 19 and / or insertions in exon 20. Drug-resistant EGFR variants can have drug-resistant mutations including, but not limited to, T790M, T854A, L718Q, C797S, or D761Y. Diagnostic tests can include sequencing, pyrosequencing, PCR, RT-PCR, or similar analytical techniques known to those of skill in the art capable of detecting nucleotide sequences.

[0220] In one aspect, provided herein is a method of preventing resistance to known EGFR inhibitors (including, but not limited to, gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002) in a subject, the method comprising administering to the 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 to known EGFR inhibitors (including, but not limited to, gefitinib, erlotinib, osimertinib, CO-1686, or WZ4002) in 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, and a second active agent that prevents EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab.

[0222] In certain embodiments of the methods disclosed herein, the subject is 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 caused, in part, by EGFR.

[0224] In one aspect, provided herein is a method of treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In other embodiments, the condition is selected from proliferative disorders and neurodegenerative disorders.

[0225] One aspect of the present disclosure provides compounds useful for the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell growth. 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 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, myelodysplasia, lymphatic disorders, Hodgkin's disease, hairy cell, buccal oral and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, colorectal cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myelogenous leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, cancers selected from the following cancers: myeloma, lymphoma, or gastric cancer, kidney cancer, head and neck cancer, oral pharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin lymphoma, and lung cancer.

[0226] The term "cancer" refers to any cancer resulting from the growth of malignant neoplastic cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include mesotheliomas, leukemias and lymphomas, such as lymphomas associated with human T cell lymphotropic virus (HTLV) like cutaneous T cell lymphoma (CTCL), non-cutaneous peripheral T cell lymphoma, adult T cell leukemia / lymphoma (ATLL), B cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma, but are not limited thereto. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastomas, retinoblastomas, Wilms tumors, bone tumors, and soft tissue sarcomas, solid tumors commonly seen in adults such as head and neck cancers (e.g., oral cavity, larynx, nasopharynx, and esophagus), genitourinary cancers (e.g., prostate, bladder, kidney, uterus, ovary, testis), lung cancers (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Further exemplary forms of cancer that can be treated by the subject compound include, but are not limited to, cancers of the skeleton or smooth muscle, stomach cancer, cancer of the small intestine, rectal cancer, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0227] Additional cancers for which the compounds described herein may be useful in prevention, treatment, and research include, for example, colon cancer, familial adenomatous polyposis cancer, and hereditary non-polyposis colorectal cancer, or melanoma. Further cancers include vulvar cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), renal cancer, renal parenchymal cancer, cervical cancer, corpus 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 cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma, but are not limited thereto. In one aspect of the disclosure, the disclosure provides for the use of one or more compounds of the disclosure in the manufacture of a medicament for the treatment of cancers including, but not limited to, the various types of cancers disclosed herein.

[0228] In some embodiments, the compounds of the disclosure are useful for the treatment of cancers 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, the compounds of the disclosure are useful for the treatment of hematopoietic disorders, specifically, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

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

[0230] The present disclosure further provides a method for treating or preventing cell proliferative disorders such as hyperplasia, dysplasia, and pre-cancerous lesions. Dysplasia is the earliest form of pre-cancerous lesions recognizable by pathologists in biopsies. The subject compound can be administered for the purpose of preventing the hyperplasia, dysplasia, or pre-cancerous lesions from continuing to expand or becoming cancerous. Examples of pre-cancerous lesions can occur in the skin, esophageal tissues, breast, and cervical intraepithelial tissues.

[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 dementia, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Lewy body dementia, Lyme borreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease), spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord syrinx, and toxic encephalopathy, but are not limited thereto.

[0232] Another aspect of the present disclosure provides a method of treating or alleviating 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 dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab, or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib, or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[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 the inhibition of either the kinase activity or the ATPase activity of the activated kinase. Alternative in vitro assays quantify the ability of an inhibitor to bind to a protein kinase, either by radiolabeling before binding the inhibitor and separating the inhibitor / kinase complex to determine the amount of bound radiolabel, or by performing a competition experiment in which a novel inhibitor is incubated with a kinase bound to a known radioligand. The detailed conditions for assaying the compounds utilized in the present disclosure as inhibitors of various kinases are set forth in the examples below.

[0234] According to 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, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and optionally a second active agent that prevents dimerization of EGFR. For any of the above uses, the required dosage will vary depending on the mode of administration, the individual condition being treated, and the desired effect.

[0235] In other embodiments, the compound and the second active agent that prevents dimerization of EGFR 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, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically 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 the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and perfuming agents.

[0237] Injectable preparations (for example, sterile aqueous or oily suspensions for injection) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as for example a solution of 1,3 - butanediol. Among the acceptable media and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic saline solution. Further, sterile fixed oils have conventionally been employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic monoglycerides or diglycerides. Further, fatty acids such as oleic acid are used in the preparation of injectable substances.

[0238] In order to extend the action of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a poorly water-soluble crystalline or amorphous liquid suspension. In that case the rate of absorption of the drug depends on its rate of dissolution, and the rate of dissolution can depend on the crystal size and crystal form. Alternatively, by dissolving or suspending the drug in an oily medium, a delay in the absorption of the parenterally administered drug form is achieved.

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

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

[0241] The active compound may also be in microencapsulated form with one or more of the excipients mentioned above. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings, release control coatings and other coatings known in the pharmaceutical 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 additional substances other than the inert diluent, for example, tableting lubricants such as magnesium stearate and microcrystalline cellulose and other tableting aids, as is customary. In the case of capsules, tablets and pills, the dosage form 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 aseptic conditions with a pharmaceutically acceptable carrier and, optionally, any required preservative or buffer. Ophthalmic preparations, otic preparations, eye ointments, powders and solutions are also contemplated as being within the scope of the present disclosure.

[0243] Ointments, pastes, creams and gels can contain, in addition to the active compound of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, 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 compound of the present disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can further contain conventional propellants such as chlorofluorohydrocarbons.

[0245] Transdermal patches have the further advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Penetration enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0246] In accordance with the treatment methods of the present disclosure, a disorder is 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 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 arts, a therapeutically effective amount of a compound of the present disclosure results in a reasonable benefit / risk ratio applicable to any medical treatment.

[0247] Generally, the compounds of the present disclosure will be administered in therapeutically effective amounts, alone or in combination with one or more therapeutic agents, by any of the conventional acceptable modes 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 efficacy of the compound being used, and other factors. Generally, good results have been shown to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg body weight. The daily dosage shown for larger mammals, such as humans, ranges from about 0.5 mg to about 100 mg, for example in divided doses up to four times a day, or in retard form, as convenient. Unit dosage forms suitable for oral administration contain from about 1 to 50 mg of the active ingredient.

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

[0249] When the condition of the subject improves, a maintenance dose of a compound, composition or formulation of the present disclosure can be administered, if necessary. Thereafter, the dosage or frequency of administration, or both, can be reduced to a level at which the improved condition is maintained as a function of the symptoms, and treatment must be discontinued when the symptoms have been reduced to the desired level. However, the subject may require intermittent treatment on a long-term basis upon recurrence of symptoms of any disease.

[0250] However, it will be understood that the total daily usage 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 dosage for any particular patient will depend on the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; the age, weight, general health, sex and diet of the patient; the timing, route of administration and excretion rate of the particular compound employed; the duration of the treatment; drugs used in combination with or simultaneously with the particular compound employed; and various factors including similar factors known in the medical arts.

[0251] The present disclosure also provides a combination medicament, such as a kit, comprising a) a first agent which is a compound of the disclosure disclosed herein, in free form or in a pharmaceutically acceptable salt form, and b) at least one co-administered agent. The kit can include instructions for its use in administration.

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

[0253] Some examples of materials that can function as pharmaceutically acceptable carriers include ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffering 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; polyacrylate; wax; polyethylene polyoxypropylene block polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, but are not limited thereto. Further, not only non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, but also colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants can be present in the composition at the discretion of the formulator. The protein kinase inhibitor or a pharmaceutical salt thereof can be formulated into a pharmaceutical composition for administration to animals or humans. These pharmaceutical compositions containing an effective amount of the protein inhibitor for treating or preventing a protein kinase-mediated condition and a pharmaceutically acceptable carrier are other embodiments of the present disclosure.

[0254] Kit In one aspect, provided herein is a kit comprising a compound capable of inhibiting kinase activity, or a pharmaceutically acceptable salt thereof, selected from one or more of the compounds disclosed herein, and instructions for use for use in the treatment of 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.

[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, or a pharmaceutically acceptable salt thereof, selected from one or more of the compounds disclosed herein, a second active agent that prevents dimer formation of EGFR, and instructions for use for use in the treatment of 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 dimer formation of EGFR is an antibody. In further embodiments, the second active agent that prevents dimer formation of EGFR is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents dimer formation of EGFR is cetuximab.

[0257] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting EGFR activity, which is selected from the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a second active agent that prevents EGFR dimer formation. In some embodiments, the second active agent that prevents EGFR dimer formation is an antibody. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab, trastuzumab or panitumumab. In further embodiments, the second active agent that prevents EGFR dimer formation is cetuximab. In one embodiment, the second active agent is an ATP-competitive EGFR inhibitor. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib. In another embodiment, the ATP-competitive EGFR inhibitor is osimertinib.

[0258] The present disclosure is further illustrated by the following examples and synthetic schemes, but it should not be construed that the present disclosure is limited to the specific procedures described herein in terms of scope or spirit. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of the present disclosure. Further, it should be further understood that various other embodiments, modifications and their equivalents that may be suggested to those skilled in the art without departing from the spirit and / or scope of the present disclosure and the appended claims may be relied upon.

Examples

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

[0260] Abbreviations ACN Acetonitrile dba Dibenzylideneacetone DCM Dichloromethane DIPEA Diisopropylethylamine DMF N,N-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] [Chemical formula]

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

[0264] [Chemical formula]

[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, 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 and 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-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-2-yl]acetate

[0266] [Chemical formula]

[0267] 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), a 1.0 M sodium carbonate solution (21.8 mL, 21.8 mmol) and dioxane (109 mL) were degassed twice with nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) was added, and then the reaction mixture was degassed once more with nitrogen. The reaction mixture was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0 - 80% 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]

Chemical formula

[0269] 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), a 1.0 M sodium carbonate solution (21.8 mL, 21.8 mmol) and dioxane (109 mL) were degassed twice with nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.534 g, 0.654 mmol) and XPhos (0.519 g, 1.09 mmol) was added, and then the reaction mixture was degassed once more with nitrogen. The reaction mixture was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 column chromatography eluting with 0 - 80% 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]

Chemical Structure

[0271] 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 with 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, washed with water to obtain the amide intermediate, which was used in the next reaction without further purification. MS m / z: 549.3 [M+1]+.

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

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

[0278] [Chemical formula]

[0279] To a solution of 2-bromo-4-fluoro-phenol (100 g, 523 mmol) in THF (1 L) was added sodium hydride (23.0 g, 575 mmol, 60% in mineral oil) at 0 °C over 4 h, followed by 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-oxo-acetate

[0280]

Chem.

[0281] To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (80.0 g, 340 mmol) in THF (1 L) at -78 °C was added dropwise n-butyllithium (2.5 M in hexane, 142 mL, 357 mmol). After stirring at -78 °C for 1 hour, the reaction mixture was added via cannula to 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 warmed 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 afford 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]

Chem.

[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 h, 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]

Chemical Structure

[0285] To a solution of Raney nickel (1.46 g, 25.0 mmol) in EtOH / THF (650 mL, 4 / 1) was added ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxyimino-acetate (34.0 g, 125 mmol). The flask was evacuated and refilled with hydrogen, and the reaction mixture was stirred at 70 °C for 24 h under a hydrogen atmosphere (50 psi). The reaction mixture was filtered through a pad of Celite washed several times with ethanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with 33% ethyl acetate in petroleum ether to give the title compound (30.6 g, 48%). 11H 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] [Chemical formula]

[0287] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (30.6 g, 118 mmol) in DMF (300 mL) was added DIPEA (58.4 mL, 354 mmol). The reaction mixture was stirred at room temperature for 5 minutes, 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 and 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 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, 1H), 7.63 (dd, 1H), 7.22 - 7.36 (m, 1H), 7.10 - 7.19 (m, 1H), 6.94 - 7.08 (m, 2H), 6.36 - 6.54 (m, 1H), 5.06 - 5.21 (m, 2H), 4.72 (d, 1H), 4.13 - 4.34 (m, 2H), 3.94 (d, 1H), 3.31 - 3.45 (m, 3H), 1.24 - 1.28 (m, 3H); MS m / z: 453.8 [M+1] + . Step 6. Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]acetate

[0288]

Chem.

[0289] A mixture of ethyl 2-(6-bromo-1-oxoisoindolin-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. A dichloromethane complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.44 g, 1.77 mmol) was added, and then the reaction mixture was degassed one more time 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-oxoisoindolin-2-yl]acetic acid

[0290]

Chem.

[0291] Ethyl 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-2-yl]acetate (4.91 g, 8.98 mmol) in a solution of 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-methylpiperidin-4-yl)phenyl]isoindolin-1-one

[0292]

Chemical formula

[0293] To a solution of 2-[5-fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methylpiperidin-4-yl)phenyl]-1-oxoisoindolin-2-yl]acetic acid (0.200 g, 0.385 mmol), 3,4-diaminopyridine (0.084 g, 0.770 mmol) and HATU (0.219 g, 0.577 mmol) in DMF (4 mL) was added DIPEA (0.265 mL, 1.53 mmol). After stirring 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] Acetic acid (3.66 mL) was added to the above amide intermediate (0.172 g, 0.282 mmol). After stirring at 80 °C for 30 minutes, 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] [Chemical formula]

[0296] 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 with HCl (4 M in dioxane, 0.6 mL, 2.40 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was 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 from ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate, and either methyl 5-bromo-2-(bromomethyl)benzoate or methyl 5-bromo-2-(bromomethyl)nicotinate, and the corresponding boronate and diaminoaryl starting materials by a method similar to Example 2.

[0298]

Table 8A

[0299]

Table 8B

[0300]

Table 8C

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

[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]

Chemical Structure

[0305] 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)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 using a Chiralpak IA column eluting at 10 MPa with 45% (0.3% TEA in MeOH) / 55% CO2 to separate the enantiomers. The absolute configuration of the chiral centers of each isolated enantiomer was unknown. First eluting peak (022) (120 mg, 22% yield, 94:6 er); [α] 20 D -34.2° (c = 0.12, MeOH); 1 1H NMR (400 MHz, methanol-d4) δ: 8.02 (s, 1H), 7.84 - 7.90 (m, 1H), 7.52 - 7.63 (m, 5H), 7.36 (d, 2H), 7.20 - 7.27 (m, 2H), 7.14 (s, 1H), 6.97 - 7.05 (m, 1H), 6.86 - 6.91 (m, 1H), 6.73 - 6.79 (m, 1H), 4.76 (d, 1H), 4.26 (d, 1H), 2.99 - 3.08 (m, 2H), 2.56 - 2.66 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.77 - 1.94 (m, 4H); MS m / z: 547.2 [M+1]+. Second eluting peak (023) (154 mg, 28% yield, 89:11 er); [α] 20 D +28.0° (c = 0.1, MeOH); 11H NMR (400 MHz, methanol-d4) δ: 8.02 (s, 1H), 7.84 - 7.89 (m, 1H), 7.52 - 7.64 (m, 5H), 7.36 (d, 2H), 7.20 - 7.27 (m, 2H), 7.14 (s, 1H), 6.96 - 7.06 (m, 1H), 6.86 - 6.92 (m, 1H), 6.74 - 6.79 (m, 1H), 4.76 (d, 1H), 4.27 (d, 1H), 3.00 - 3.09 (m, 2H), 2.56 - 2.68 (m, 1H), 2.36 (s, 3H), 2.23 (m, 2H), 1.78 - 1.94 (m, 4H); MS m / z: 547.3 [M+1] + .

[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] [Chemical Structure Diagram]

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

[0309] [Chemical Structure Diagram]

[0310] Ethyl 2-(6-bromo-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate (22.0 g, 48.6 mmol) in a solution of 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 obtain the title compound (18.2 g, 88%). 1 1H NMR (400 MHz, CDCl3) δ: 8.20 (br s, 1H), 7.90 (d, 1H), 7.56 (dd, 1H), 7.19 (s, 1H), 6.94 - 7.15 (m, 3H), 6.35 (s, 1H), 5.03 - 5.10 (m, 2H), 4.63 (d, 1H), 3.89 (d, 1H), 3.27 - 3.36 (m, 3H). Step 2. 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one

[0311]

Chemical Structure

[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 hours, 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%). 11H 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] Acetic acid (150 mL) was added to the above amide intermediate (15.5 g, 30.1 mmol). 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]

Chemical Structure

[0315] 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoin-dolin-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 a mixture of TEA / DMF (3 mL, 1 / 1) were 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]

Chemical formula

[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%). 11H NMR (400 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.68 - 7.78 (m, 2H), 7.59 - 7.64 (m, 1H), 7.44 - 7.56 (m, 3H), 7.11 - 7.19 (m, 2H), 7.00 - 7.09 (m, 1H), 6.77 - 6.97 (m, 3H), 6.43 - 6.48 (m, 3H), 4.70 - 4.86 (m, 1H), 4.20 - 4.36 (m, 1H); MS m / z: 490.2 [M+1] + .

[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 by a method similar to that in 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]

Chemical Structure

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

[0323]

Chemical Structure

[0324] A solution of 1-chloro-2-fluoro-4-methyl-benzene (10.0 g, 69.1 mmol) in THF (100 mL) at -70 °C was added dropwise with LDA (2 M in THF, 36.2 mL, 72.5 mmol). After stirring at -70 °C for 0.5 h, CO2 (9.10 g) was added to the reaction mixture and stirred at the same temperature for 1 h. After warming to room temperature, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was washed 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 obtain 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]

Chemical formula

[0326] Oxalyl chloride (4.69 g, 37.0 mmol) was added to a solution of 3-chloro-2-fluoro-6-methyl-benzoic acid (3.50 g, 18.5 mmol) in dichloromethane (50 mL) 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 obtain the title compound (1.9 g, 51%). 1 1H 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: Methyl 6-(bromomethyl)-3-chloro-2-fluoro-benzoate

[0327] [Chemical]

[0328] To a solution of methyl 3-chloro-2-fluoro-6-methyl-benzoate (1.90 g, 9.37 mmol) in carbon tetrachloride (20 mL) were added N-bromosuccinimide (1.66 g, 9.37 mmol) and benzoyl peroxide (0.452 g, 1.87 mmol). After stirring at 80 °C for 12 h, 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: Ethyl 2-(6-chloro-7-fluoro-1-oxo-isoindolin-2-yl)-2-[5-fluoro-2-(methoxymethoxy)-phenyl]acetate

[0329] [Chemical]

[0330] To a solution of ethyl 2-amino-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (1.06 g, 4.14 mmol) in DMF (15 mL) was added DIPEA (1.23 g, 9.57 mmol). The reaction mixture was stirred at room temperature for 5 min, then methyl 6-(bromomethyl)-3-chloro-2-fluoro-benzoate (0.900 g, 3.19 mmol) was added. The reaction mixture was heated at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 33% ethyl acetate 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]

Chem.

[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 obtained 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]

Chem.

[0334] 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) solution were added with DIPEA (0.728 g, 5.64 mmol). After stirring overnight at room temperature, the reaction mixture was separated 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 obtain the amide intermediate (800 mg, 87%), which was used in the next reaction without further purification. MS m / z: 488.3 [M+1]+.

[0335] Acetic acid (15 mL) was added to the above amide intermediate. After stirring at 80 °C for 0.5 h, the solvent was removed under reduced pressure. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to obtain 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]

Chemical formula

[0337] 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-chloro-7-fluoro-isoindolin-1-one (0.550 g, 1.17 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (0.385 g, 1.28 mmol), sodium carbonate (0.487 g, 3.51 mmol), SPhos (0.192 g, 0.468 mmol), Pd2(dba)3 (0.321 g, 0.351 mmol) and dioxane (10 mL) were degassed twice with nitrogen. The reaction mixture was heated at 105 °C for 4 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10% methanol 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]

Chemical Structure

[0339] 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 with HCl (4 M in dioxane, 0.985 mL, 3.94 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was 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 (034) Scheme 5

[0341] [Chemical formula]

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

[0343]

Chem.

[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 h, the solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate, washed three times with saturated sodium hydrogen carbonate, 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-methoxyphenyl)acetate

[0345]

Chem.

[0346] To a solution of methyl 2-(5-fluoro-2-methoxyphenyl)acetate (0.900 g, 5.44 mmol) in carbon tetrachloride (20 mL) were added N-bromosuccinimide (0.968 g, 5.44 mmol) and benzoyl peroxide (0.109 g, 0.454 mmol). After stirring at 80 °C for 16 h, the solvent was removed under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 12% ethyl acetate 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]

Chem.

[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). The mixture was stirred 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 obtain 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 hour, the solvent was removed under reduced pressure. 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] [Chem.]

[0351] To a solution of 2-(6-bromo-7-fluoro-indazol-2-yl)-2-(5-fluoro-2-methoxyphenyl)acetic acid (0.280 g, 0.704 mmol), 1,2-diaminobenzene (0.091 g, 0.844 mmol) and TBTU (0.270 g, 0.844 mmol) in DMF (10 mL) was added DIPEA (0.091 g, 0.704 mmol). After stirring at room temperature for 16 h, the reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 35% ethyl acetate 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 min, the solvent was removed under reduced pressure. The reaction mixture was diluted with ethyl acetate and washed three times with saturated sodium hydrogen carbonate. 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-methoxyphenyl)methyl]-7-fluoro-6-[4-(1-methyl-4-piperidyl)phenyl]indazole (Compound 035)

[0353] [Chem.]

[0354] 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-methoxy-phenyl)methyl]-6-bromo-7-fluoro-indazole (0.200 g, 0.426 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (0.140 g, 0.468 mmol), sodium carbonate (0.146 g, 1.06 mmol), dichloromethane complex of [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (0.047 g, 0.064 mmol) and a mixture of dioxane / water (8 mL, 4 / 1) were 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 (Compound 034)

[0355] [Chemical formula]

[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 hours, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0 - 100% ACN / water (adjusted with 0.05% HCl) 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, 1H), 6.90 (m, 1H), 3.48 - 3.57 (m, 2H), 3.00 - 3.14 (m, 2H), 2.76 - 2.93 (m, 4H), 1.92 - 2.10 (m, 4H); MS m / z: 550.3 [M+1] + .

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

[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]

Chemical Structure

[0363] 2-[(rac)-1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)-phenyl]isoquinolin-1-one; dihydrochloride (069, 0.050 g, 0.079 mmol) was purified by prep SFC using a Chiralpak IG (5 micron 250×10 mm) column from Chiral Technologies at 40 °C with elution at 10 MPa BPR with 55% (0.3% TEA in MeOH) / 45% CO2 to separate the enantiomers. The absolute configuration of the chiral centers of the isolated enantiomers 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] + . The 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, 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] + . 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] [Chemical formula]

[0365] 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)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 using a Phenomenex Lux Cellulose-4 column with elution at 10 MPa with 55% (0.3% TEA in MeOH) / 45% CO2 to separate the enantiomers. The absolute configuration of the chiral centers of the isolated enantiomers is unknown. The first eluted peak (065) (3 mg, 27% yield, 100:0 er); [α] 20 D -13.3 (c = 0.37, MeOH); 1 1H NMR (DMSO-d6) δ: 12.69 (br s, 1H), 9.95 (br s, 1H), 7.68 - 7.73 (m, 3H), 7.37 - 7.58 (m, 4H), 7.32 (d, 2H), 7.22 (d, 1H), 7.08 - 7.16 (m, 2H), 6.99 - 7.07 (m, 1H), 6.80 - 6.86 (m, 1H), 6.56 - 6.63 (m, 2H), 2.81 (d, 2H), 2.45 - 2.50 (m, 1H), 2.13 (s, 3H), 1.85 - 1.96 (m, 2H), 1.57 - 1.73 (m, 4H); MS m / z: 577.3 [M+1]+ . Second elution peak (066) (4 mg, 36% yield, 100:0 er); [α] 20 D +14.8 (c = 0.27, MeOH); 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]

Chem.

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

[0369]

Chem.

[0370] 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) were added to a solution of triethylamine (7.85 g, 77.6 mmol) in THF (80 mL). After stirring at 40 °C for 3 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 25% ethyl acetate 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]

Chemical formula

[0372] A solution of ethyl 2-[(2-amino-5-bromobenzoyl)amino]-2-[5-fluoro-2-(methoxymethoxy)phenyl]acetate (5.25 g, 11.5 mmol) in triethoxymethane (20 mL) was stirred at 110 °C for 22 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 10 - 33% ethyl acetate in petroleum ether to give the title compound (2.2 g, 41%). 11H 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]

Chemical formula

[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. A complex of [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) with dichloromethane (0.690 g, 0.944 mmol) was added and then the reaction mixture was degassed one more time under nitrogen. The reaction mixture was heated at 105 °C for 3 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 (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]

Chem.

[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 h, the solvent was removed under reduced pressure, and the resulting residue was adjusted to pH 3 with HCl (1 M). The obtained 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]

Chem.

[0378] 2-[5-Fluoro-2-(methoxymethoxy)phenyl]-2-[6-[4-(1-methyl-4-piperidyl)phenyl]-4-oxoquinazolin-3-yl]acetic acid (0.900 g, 1.69 mmol), 1,2-diaminobenzene (0.218 g, 2.02 mmol), and HATU (0.962 g, 2.53 mmol) in DMF (10 mL) were added to DIPEA (0.545 g, 4.22 mmol). After stirring at room temperature for 10 hours, 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 obtain the amide intermediate. MS m / z: 622.3 [M+1]+.

[0379] Acetic acid (8 mL) was added to the above amide intermediate. 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 obtain 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]

Chemical formula

[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 (4 M in dioxane, 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 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, by a method similar to Example 7.

[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]

Chem.

[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]

Chem.

[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) were 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]

Chem.

[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 an aqueous potassium hydroxide solution (2 M, 4.85 mL, 9.70 mmol). After stirring at 100 °C for 2 h, the reaction mixture was diluted with water and adjusted to pH 5 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]

Chemical Structure

[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 h, saturated sodium chloride was added to the reaction mixture. The resulting solid was collected by filtration, 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] Acetic acid (8 mL) was added to the above amide intermediate. 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]

Chemical formula

[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), and sodium carbonate (0.024 g, 0.222 mmol) in dioxane / water (4.5 mL, 7 / 2) was degassed twice with nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.028 g, 0.035 mmol) was added, and then the reaction mixture was degassed one more time 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]

Chem.

[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 similar manner to 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] [Chemical formula]

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

[0403] [Chemical formula]

[0404] A mixture of methyl 3-aminopicolinate (650 mg, 4.27 mmol) in a solution of H2SO4 (207 mL, 4 mmol), water (13 mL), was treated by dropwise addition over 1 minute of a solution of bromine (200 mL, 4.27 mmol) in acetic acid (800 mL). The reaction mixture was stirred at room temperature for 15 minutes and basified to pH 6 with 10N NaOH. The mixture was extracted three times with EtOAc. The combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 - 60% EtOAc in hexane 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]

Chemical formula

[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] [Chemical formula]

[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 Na2SO4, 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. Ethyl 2-(6-bromo-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate

[0409] [Chemical formula]

[0410] A mixture of ethyl 2-(3-amino-6-bromopicolinamide)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (315 mg, 0.68 mmol) in triethyl orthoformate (4 mL) in a sealed vial was heated in a microwave at 210 °C for 2 h. After cooling, the excess triethyl orthoformate was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 - 65% EtOAc in hexane to give the title compound (310 mg, 98%). 11H NMR (500 MHz, DMSO-d6) δ ppm 8.37 (s, 1H) 8.06 - 8.09 (m, 2H) 7.36 (dd, 1H) 7.25 - 7.32 (m, 1H) 7.17 - 7.23 (m, 1H) 6.71 (s, 1H) 5.19 - 5.25 (m, 2H) 4.27 (q, 2H) 3.29 (s, 3H) 1.19 - 1.23 (m, 3H); MS m / z: 468.0 [M+1] + . 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]

Chemical formula

[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)Cl2·DCM (119 mg, 0.146 mmol) and sodium carbonate (232 mg, 2.19 mmol) in dioxane:water (4:1, 7.5 mL) was heated at 100 °C for 24 h under nitrogen. After cooling, the reaction mixture was filtered, the filtrate was concentrated and purified by reverse-phase HPLC eluting with 0 - 80% ACN / water (adjusted with 0.035% TFA) to give the title compound (151 mg, 39%). 11H NMR (500 MHz, DMSO-d6) δ 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]

Chem.

[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), o - phenylenediamine (31 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), and DIPEA (156 μL, 0.90 mmol) in degassed DMF (3 mL) was stirred at 60 °C for 1.5 h. The reaction mixture was purified by reverse - phase HPLC eluting with 0 - 80% ACN / water (adjusted with 0.035% TFA) to afford 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 hour. Excess acetic acid was removed under reduced pressure to obtain the title compound, which was used without further purification. MS m / z: 605.4 [M+1]+. Step 7. 3-((1H-Benzimidazol-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]

Chemical formula

[0417] 3-((1H-Benzimidazol-2-yl)(5-fluoro-2-(methoxymethoxy)-phenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one of the above materials 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 (adjusted with 0.035% TFA) to obtain 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 by a method similar to Example 9.

[0419] [Table 14]

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

[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 Scheme 9

[0423] [Chemical formula]

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

[0425] [Chemical formula]

[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 (adjusted with 0.035% TFA) 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 (m, 4H), 6.83 (d, 1H), 6.46 (d, 1H), 6.11 (s, 2H), 5.24 (d, 1H), 5.17 (d, 1H), 3.62 (s, 3H), 3.26 (s, 3H); MS m / z: 529.1 [M+1] + . Step 2. 3-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-5-methoxy-quinazolin-4-one

[0427]

Chemical formula

[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 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by reverse-phase HPLC eluting with 0–100% ACN / water (adjusted with 0.035% TFA) to give the title compound (0.14 g, 69%). 11H NMR (DMSO-d6) δ: 12.88 (br s, 1H), 8.18 - 8.32 (m, 1H), 7.94 - 8.14 (m, 1H), 7.59 - 7.75 (m, 2H), 7.47 - 7.56 (m, 1H), 7.38 - 7.47 (m, 1H), 7.23 (d, 4H), 6.76 - 6.96 (m, 1H), 5.10 - 5.26 (m, 2H), 3.82 (s, 3H), 3.13 (s, 3H); MS m / z: 539.1 [M+1] + . 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]

Chem.

[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)Cl2 (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 h under nitrogen. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by reverse - phase HPLC eluting with 0 - 100% ACN / water (adjusted with 0.035% TFA) to give the title compound (0.085 g, 73%). 11H 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]

Chemical formula

[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 (adjusted with 0.05% HCl) to give the title compound (0.026 g, 37%). 11H NMR (400 MHz, methanol-d4) δ: 8.41 (s, 1H), 7.92 (d, 1H), 7.73 - 7.82 (m, 2H), 7.52 - 7.69 (m, 6H), 7.37 - 7.45 (m, 2H), 7.21 - 7.35 (m, 2H), 6.99 - 7.07 (m, 1H), 3.60 - 3.68 (m, 2H), 3.53 (s, 3H), 3.15 - 3.26 (m, 2H), 2.89 - 3.05 (m, 4H), 1.98 - 2.20 (m, 4H); MS m / z: 590.7 [M+1] + . Compound 078: 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindoline-1-thione; dihydrochloride Scheme 10

[0433]

Chem.

[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]

Chem.

[0436] To a solution of 2-[1H-benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (1.00 g, 1.82 mmol) in toluene (20 mL) was added Lawesson's reagent (3.68 g, 9.10 mmol). After stirring at 120 °C for 72 hours, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0 - 100% ACN / water (adjusted with 0.05% HCl) 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 (m, 2H), 5.08 - 5.26 (m, 1H), 4.40 - 4.57 (m, 1H), 3.00 - 3.14 (m, 3H), 2.86 - 2.98 (m, 2H), 2.80 (s, 3H), 1.96 - 2.19 (m, 4H); MS m / z: 563.1 [M+1] + . 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]

Chemical Structure

[0438] 2-[1H-Benzimidazol-2-yl-(5-fluoro-2-hydroxy-phenyl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindoline-1-thione; dihydrochloride (0.013 g, 0.020 mmol) was purified by prep SFC using a Phenomenex Lux Cellulose-4 column eluting at 10 MPa with 45% (0.3% TEA in MeOH) / 55% CO2 to separate the enantiomers. The absolute configuration of the chiral centers of each isolated enantiomer is unknown. 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); 11H NMR (DMSO-d6) δ: 12.74 (broad singlet, 1H), 10.08 (broad singlet, 1H), 8.06 (singlet, 1H), 7.93 (doublet, 1H), 7.73 (doublet, 1H), 7.44 - 7.69 (multiplet, 5H), 7.39 (doublet, 2H), 7.08 - 7.24 (multiplet, 3H), 6.89 - 7.00 (multiplet, 1H), 6.60 - 6.71 (multiplet, 1H), 5.07 - 5.20 (multiplet, 1H), 4.37 - 4.51 (multiplet, 1H), 2.84 - 2.95 (multiplet, 2H), 2.53 - 2.58 (multiplet, 1H), 2.21 (singlet, 3H), 1.93 - 2.06 (multiplet, 2H), 1.64 - 1.84 (multiplet, 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]

Chem.

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

[0441]

Chem.

[0442] 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 with tetraethyl orthotitanate (15.5 g, 68.1 mmol). After stirring at 75 °C for 16 h, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-100% ethyl acetate 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-methoxyphenyl)-(4-methyl-1H-imidazol-2-yl)methyl]-2-methylpropane-2-sulfinamide

[0443]

Chemical formula

[0444] 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 with a solution of 5-fluoromethoxyphenylmagnesium 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]

Chem.

[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 (4 M, 1.23 mL, 4.92 mmol) in dioxane 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]

Chem.

[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). After stirring the reaction mixture at room temperature for 5 min, methyl 5-bromo-2-(bromomethyl)benzoate (0.495 g, 1.61 mmol) was added. The reaction mixture was heated at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0 - 100% ethyl acetate in petroleum ether to give the title compound (0.28 g, 40%).1 1H 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]

Chem.

[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)Cl2 (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, the filtrate was concentrated under reduced pressure and purified by reverse phase HPLC eluting with 0 - 100% ACN / water (adjusted with 0.05% HCl) 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] [Chemical formula]

[0452] To a solution of 2-[(5-fluoro-2-methoxyphenyl)-(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 hours, the reaction mixture was diluted with dichloromethane and poured into ice water. The aqueous phase was extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. 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 compounds were prepared from (5-fluoro-2-methoxyphenyl)-(4-methyl-1H-imidazol-2-yl)methanamine and methyl 6-(bromomethyl)-3-chloro-2-fluorobenzoate in a similar manner 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]

Chemical Structure

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

Chemical Structure

[0459] The title compound was prepared in the same manner as compound 085 from 4,5-dimethyl-1H-imidazole-2-carbaldehyde and 2-methylpropane-2-sulfinamide. 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

[0460]

Chemical Structure

[0461] The title compound was prepared in the same manner as compound 085 from 2-methyl-1H-imidazole-5-carbaldehyde and 2-methylpropane-2-sulfinamide. 11H NMR (DMSO-d6) δ: 10.54 (broad singlet, 1H), 10.11 (broad singlet, 1H), 7.86 - 7.99 (multiplet, 2H), 7.62 - 7.75 (multiplet, 3H), 7.33 - 7.44 (multiplet, 3H), 7.05 - 7.15 (multiplet, 1H), 6.87 - 7.01 (multiplet, 2H), 6.75 (singlet, 1H), 4.54 (doublet, 1H), 4.22 (doublet, 1H), 3.49 - 3.52 (multiplet, 2H), 2.99 - 3.12 (multiplet, 2H), 2.70 - 2.91 (multiplet, 4H), 2.54 (singlet, 3H), 1.94 - 2.10 (multiplet, 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]

Chem.

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

[0464]

Chem.

[0465] Hydrazine (0.618 mL, 19.7 mmol) was added 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). After stirring at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give the title compound (0.75 g, 86%). 11H 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]

Chemical formula

[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 (1 M, 2.73 mL, 2.73 mmol) in THF. 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 and 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%). 11H 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]

Chemical formula

[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)Cl2 (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]

Chem.

[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-methylpiperidin-4-yl)phenyl]isoindolin-1-one in the same manner as in 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, 2H), 4.76 (d, 1H), 4.24 (d, 1H), 3.64 (d, 2H), 3.14 - 3.25 (m, 2H), 2.86 - 3.01 (m, 4H), 2.62 (s, 3H), 2.00 - 2.21 (m, 4H); MS m / z: 512.4 [M+1] + .

[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]

Chem.

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

[0475]

Chem.

[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 under reflux for 1 hour. After cooling, the solution was treated with 6N HCl to pH 4. The resulting precipitate was filtered, washed with water and dried to obtain 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]

Chemical formula

[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 hours. 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 MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0 - 35% EtOAc in hexane to obtain 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. Methyl 2-(6-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)-2-phenylacetate

[0479]

Chemical formula

[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 Cs2CO3 (1.20 g, 3.7 mmol) in DMF (3 mL), and the mixture was heated at 30 °C for 1 h. After cooling, the reaction mixture was poured into water (250 mL) and extracted three times with EtOAc. The combined organic extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0 - 30% EtOAc in hexane 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]

Chem.

[0482] The title compound was prepared in the same manner as in Step 5 of Example 9 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. 11H NMR (500 MHz, DMSO-d6) δ ppm 9.35 (br s, 1H) 8.11 (s, 1H) 7.94 - 7.99 (m, 1H) 7.60 (m, 3H) 7.52 - 7.56 (m, 2H) 7.43 - 7.51 (m, 3H) 7.40 (m, 2H) 6.49 (s, 1H) 3.56 (d, 2H) 3.06 - 3.16 (m, 2H) 2.84 (d, 4H) 2.05 - 2.13 (m, 2H) 1.80 - 1.93 (m, 2H); MS m / z: 472.2 [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]

Chem.

[0484] The title compound was prepared from 2 - (5 - fluoro - 6 - (4 - (1 - methylpiperidin - 4 - yl)phenyl) - 4 - oxoquinazolin - 3(4H) - yl) - 2 - phenylacetic acid in the same manner as in Step 6 of Example 9. 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.29 (br s, 1H) 8.32 (s, 1H) 7.94 - 8.03 (m, 1H) 7.56 - 7.64 (m, 5H) 7.54 (s, 1H) 7.44 - 7.49 (m, 3H) 7.35 - 7.42 (m, 4H) 7.17 - 7.29 (m, 2H) 3.50 - 3.59 (m, 2H) 3.04 - 3.16 (m, 2H) 2.84 (m, 4H) 2.04 - 2.13 (m, 2H) 1.79 - 1.93 (m, 2H); MS m / z: 544.3 [M+1] +

[0485] (Example 11) Preparation of Intermediate Scheme 14

[0486]

Chem.

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

[0488]

Chem.

[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 was added dropwise n-butyllithium (2.5 M in hexane, 31.9 mL, 79.7 mmol). After stirring at -70 °C for 30 minutes, 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 hour, 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]

Chem.

[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] [Chemical formula]

[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%). 11H 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]

Chem.

[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 at 30 °C for 16 h under a hydrogen atmosphere (30 psi). The reaction mixture was filtered through a Celite pad washed several times with methanol. The filtrate was concentrated under reduced pressure to give the title compound (2.7 g, 85%). 1 1H 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]

Chem.

[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]

Chem.

[0499] Diiodomethane (2.67 g, 10.0 mmol) was added to a 0 °C dichloromethane (5 mL) solution of diethylzinc (1 M in hexane, 10.0 mL, 10.0 mmol). After stirring at the same temperature for 0.5 h, a dichloromethane (5 mL) solution of 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylboronic acid pinacol ester (0.500 g, 1.67 mmol) 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]

Chem.

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

[0502]

Chem.

[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] [Chemical formula]

[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 D2O (1 mL) to obtain a heterogeneous mixture. Then, formic acid (40 μL, 1.07 mmol) was added, and the resulting solution was stirred overnight. After 16 hours, the 1 1H NMR (methanol-d4) showed about 50% deuterium incorporation based on the integration area of the methine peak at 7.16 ppm at the methine carbon. When the reaction was heated to 50 °C and stirred for an additional 8 hours, 1 1H NMR (methanol-d4) showed more than 90% deuterium incorporation. An additional 40 μL (1.07 mmol) of formic acid was added, and the reaction was stirred at 50 °C for an additional 6 hours while stirring under a nitrogen atmosphere. 11H NMR (methanol-d4) showed 100% deuterium incorporation at the methine carbon. A solution of DCl (100 μL, 35 wt% in D2O) was added to the reaction solution. After 10 minutes, 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 from 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 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]+.

[0508] Compounds 037 and 038 were prepared according to the procedure of Example 12. The crude product was then purified on a semi-prep SFC of JASCO using a Chiralpak IA (10×250 mm 5 micron) column eluting 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 to separate the enantiomers. The absolute configuration of the chiral centers of each isolated enantiomer is unknown. First eluting peak (27.4 mg, 27%); 11H NMR (400 MHz, methanol-d4) δ: 8.02 (s, 1H), 7.84 - 7.90 (m, 1H), 7.52 - 7.63 (m, 5H), 7.33 - 7.39 (m, 2H), 7.20 - 7.27 (m, 2H), 6.97 - 7.05 (m, 1H), 6.86 - 6.91 (m, 1H), 6.73 - 6.79 (m, 1H), 4.76 (d, 1H), 4.26 (d, 1H), 2.99 - 3.08 (m, 2H), 2.56 - 2.66 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.77 - 1.94 (m, 4H); MS m / z: 548.3 [M+1] + . The second elution peak (31 mg, 28%); 1 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), 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)isoindoline-1-one-3,3-d2 (Compound 039) Scheme 16

[0510] [Chemical formula]

[0511] 2-((1H-Benzimidazol-2-yl)(5-fluoro-2-hydroxyphenyl)methyl)-6-(4-(1-methylpiperidin-4-yl)phenyl)isoindolin-1-one (24.5 mg, 0.047 mmol) was stirred in CD3OD (1 g), D2O (0.5 mL), sodium carbonate (9.84 mg, 0.093 mmol) was added, and the mixture was stirred at 50 °C for 18 h in a sealed vial. The 1 1H NMR (methanol-d4) showed deuterium incorporation of more than 95% based on the integral area of the methine peak at 7.16 ppm at the methine carbon, and about 60% deuterium incorporation at the lactam methylene carbon. The reaction was stirred at 60 °C for an additional 48 h. The 1 1H NMR (methanol-d4) showed complete deuteration of both the methine carbon and the lactam methylene carbon. The reaction was cooled to room temperature, then a D2O solution of 35 wt% DCl (50 μL, 0.48 mmol) was added. After stirring for a few minutes, the reaction was concentrated and the residue was purified by silica chromatography eluting from 100% DCM to 100% (10% 7N NH3 in MeOH / DCM) to give the title compound as a white powder (18 mg, 70%). 1 1H 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-hydroxy-phenyl)methyl]-6-[4-[2-(dimethyl-amino)ethoxy]phenyl]isoindolin-1-one; hydrochloride (Compound 040) Scheme 17

[0513] [Chemical formula]

[0514] Step 1. N-(1H-Benzimidazol-2-ylmethylene)-2-methyl-propan-2-sulfinamide

[0515] [Chemical formula]

[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-propan-2-sulfinamide

[0517]

Chem.

[0518] To a solution of 2-bromo-4-fluoro-1-(methoxymethoxy)benzene (84.6 g, 360 mmol) in THF (600 mL) at -65 °C was added dropwise n-butyllithium (2.5 M in hexane, 158 mL, 396 mmol). After stirring at -65 °C for 20 minutes, the reaction mixture was added via cannula to a pre-cooled (-65 °C) solution of N-(1H-benzimidazol-2-ylmethylene)-2-methyl-propan-2-sulfinamide (45.0 g, 180 mmol) in THF (1100 mL). After stirring at -65 °C for 40 minutes, the reaction mixture was warmed to 15 °C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 33 - 100% ethyl acetate 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]

Chem.

[0520] To a solution of N-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-2-methyl-propan-2-sulfinamide (30.0 g, 73.9 mmol) in methanol (600 mL) was added HCl (4 M in dioxane, 55.2 mL, 221 mmol) at 0 °C. After stirring at room temperature for 15 h, the reaction mixture was diluted with water and adjusted to pH 8 with saturated sodium hydrogen carbonate 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]

Chemical formula

[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 min and then 5-bromo-2-(bromomethyl)benzoic acid methyl ester (28.1 g, 91.5 mmol) was added. The reaction mixture was heated at 90 °C for 16 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 (29.5 g, 78%). 11H NMR (400 MHz, DMSO-d6) δ: 12.69 (s, 1H), 7.87 (d, 1H), 7.80 (dd, 1H), 7.54 - 7.64 (m, 2H), 7.47 (d, 1H), 7.13 - 7.25 (m, 4H), 7.09 (s, 1H), 6.92 (dd, 1H), 5.10 - 5.22 (m, 2H), 4.74 (d, 1H), 4.17 (d, 1H), 3.14 - 3.23 (m, 3H); MS m / z: 496.1 [M+1] + . Step 5. 2-[1H - Benzimidazol - 2 - yl - [5 - fluoro - 2 - (methoxymethoxy)phenyl]methyl]-6-[4 - [2 - (dimethylamino)ethoxy]phenyl]isoindolin - 1 - one

[0523]

Chem.

[0524] A mixture of 2-[1H - Benzimidazol - 2 - yl - [5 - fluoro - 2 - (methoxymethoxy)phenyl]methyl]-6 - bromo - isoindolin - 1 - one (160 mg, 0.322 mmol), N - [2 - (dimethylamino)ethyl]-N - methyl - 4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)aniline (132 mg, 0.436 mmol), sodium carbonate (89.0 mg, 0.840 mmol) and dioxane / water (5 mL, 4 / 1) was degassed twice under nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (41.1 mg, 0.050 mmol) was added, and then the reaction mixture was degassed one more time under nitrogen. The reaction mixture was heated at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted 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%). 11H 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]

Chem.

[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 (4 M in dioxane, 0.462 mL, 1.85 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. Diethyl ether was added to the residue and the resulting solid was isolated by filtration to give the title compound (91 mg, 86%). 11H NMR (400 MHz, DMSO-d6) δ: 10.37 (br s, 1H), 10.22 (br s, 1H), 7.83 - 7.89 (m, 2H), 7.60 - 7.69 (m, 5H), 7.34 - 7.45 (m, 2H), 7.01 - 7.13 (m, 5H), 6.94 (dd, 1H), 4.71 (d, 1H), 4.35 (t, 2H), 4.19 (d, 1H), 3.42 - 3.49 (m, 2H), 2.79 (d, 6H); MS m / z: 537.3 [M+1] + .

[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]

Chemical Structure

[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]

Chemical Structure

[0531] 2-[1H-Benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one (191 mg, 0.384 mmol), tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-azetidinecarboxylate (158 mg, 0.441 mmol), sodium carbonate (105 mg, 0.990 mmol) and a mixture of dioxane / water (9 mL, 4 / 1) were degassed twice under nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (62.7 mg, 0.077 mmol) was added and then the reaction mixture was degassed one more time 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]

Chem.

[0533] To a solution of tert-butyl 3-[4-[2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-3-oxoisoindolin-5-yl]phenyl]azetidine-1-carboxylate (164 mg, 0.252 mmol) in dichloromethane (5 mL) were added ethanol (73.5 μL, 1.26 mmol) and zinc bromide (283 mg, 1.26 mmol). After stirring overnight at room temperature, the reaction mixture was added to a mixture of 1 N NaOH solution and methanol, and the resulting solid was 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-methylazetidin-3-yl)phenyl]isoindolin-1-one

[0534]

Chemical Structure

[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, 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 and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 10 - 100% ACN / water containing 0.1% formic acid to give the title compound (14 mg, 30%). 11H 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]

Chem.

[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 (4 M in dioxane, 62.0 μL, 0.248 mmol). After stirring overnight at room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 10 - 100% ACN / water containing 0.1% formic acid to give the title compound (3 mg, 23%). 11H NMR (400 MHz, methanol-d4) δ: 8.06 (s, 1H), 7.88 - 7.94 (m, 1H), 7.68 - 7.74 (m, 2H), 7.63 - 7.67 (m, 1H), 7.52 - 7.61 (m, 2H), 7.44 - 7.51 (m, 2H), 7.23 - 7.29 (m, 2H), 7.16 (s, 1H), 7.00 - 7.07 (m, 1H), 6.89 - 6.95 (m, 1H), 6.75 - 6.81 (m, 1H), 4.74 - 4.82 (m, 1H), 4.29 (d, 1H), 4.09 - 4.19 (m, 2H), 3.94 - 4.06 (m, 1H), 3.70 - 3.80 (m, 2H), 2.70 (s, 3H); MS m / z: 519.2 [M+1] + .

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

[0539] [Chemical formula]

[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] [Chemical formula]

[0542] A mixture of 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one (6.30 g, 12.6 mmol), bis(pinacolato)diboron (3.19 g, 12.6 mmol), potassium acetate (3.70 g, 37.8 mmol) and dioxane (160 mL) was degassed twice under nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.921 mg, 1.26 mmol) was added, and then the reaction mixture was degassed one more time under nitrogen. The reaction mixture was heated at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered through a pad of 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, 2H), 4.75-4.83 (m, 2H), 4.69 (d, 1H), 4.45 (d, 1H), 2.98 (s, 3H), 1.33 (d, 12H); MS m / z: 544.1 [M+1] + . Step 2. 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-[4-(1-methylazetidin-3-yl)oxyphenyl]isoindolin-1-one

[0543]

Chem.

[0544] 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 a mixture of dioxane / water (6 mL, 10 / 1) were degassed twice under nitrogen. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (75.3 mg, 0.259 mmol) was added and then the reaction mixture was degassed one more time 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]

Chemical formula

[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 (adjusted with 0.05% HCl) 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 from 2-[1H-benzimidazol-2-yl-[5-fluoro-2-(methoxymethoxy)phenyl]methyl]-6-bromo-isoindolin-1-one and the corresponding boronate starting materials by a method similar to Example 14.

[0548]

Table 17A

[0549]

Table 17B

[0550]

Table 17C

[0551] The following examples were prepared from the starting materials of phenol and boronate substituted with the corresponding halogen by a method similar to that of Example 14. The corresponding phenol was protected as a methoxymethyl derivative before reacting with sulfinamide.

[0552] [Table 18]

[0553] The following examples were prepared from the starting materials of the corresponding aldehyde and boronate by a method similar to that of Example 14.

[0554] [Table 19]

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

[0556] [Table 20A]

[0557] [Table 20B]

[0558] The following examples were prepared from methyl 2-bromo-2-(5-fluoro-2-methoxy-phenyl)acetate and the corresponding bicyclic starting materials by a method similar to that of Example 6.

[0559] [Table 21]

[0560] The following examples were prepared in a manner 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 materials.

[0561] [Table 22A]

[0562] [Table 22B]

[0563] The following examples were prepared in a manner similar 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 examples were prepared in a manner similar 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 halides as starting materials by a method similar to that of 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-methylpiperidine Scheme 20

[0570] [Chemical formula]

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

[0572] [Chemical formula]

[0573] 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 a mixture of dioxane / water (100 mL, 4 / 1) were 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 1H NMR (400 MHz, methanol-d4) δ: 7.51 - 7.59 (m, 1H), 7.25 - 7.31 (m, 1H), 7.13 - 7.23 (m, 1H), 6.21 - 6.24 (m, 1H), 3.10 - 3.16 (m, 2H), 2.67 - 2.75 (m, 2H), 2.52 - 2.61 (m, 2H), 2.39 (s, 3H); MS m / z: 271.8 [M+1] + . 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]

Chemical formula

[0575] A mixture of 4-(4-bromo-3-fluoro-phenyl)-1-methyl-3,6-dihydro-2H-pyridine (1.00 g, 3.70 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.40 g, 5.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.541 g, 0.740 mmol), potassium acetate (1.08 g, 11.1 mmol) and dioxane (20 mL) was degassed twice under nitrogen. The reaction mixture was heated at 100 °C for 3 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 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]

Chemical Structure

[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 at 30 °C for 48 h under a hydrogen atmosphere (50 psi). The reaction mixture was filtered through a pad of celite washed several 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]

Chemical formula

[0580] 7-Fluoro-2-[(5-fluoro-2-hydroxy-phenyl)-(5-methyl-1H-imidazol-2-yl)methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one (093, 0.020 g, 0.038 mmol) was purified by prep SFC using a Chiralpak IA (5 micron 250×10 mm) column from Chiral Technologies at 40 °C with elution at 10 MPa with 45% (0.3% TEA in MeOH) / 55% CO2 to separate the enantiomers. The absolute configuration of the chiral centers of each isolated enantiomer was unknown. The first eluting peak (094) (6 mg, 30% yield, 100:0 er); [α] 20 D -78.3 (c = 0.035, MeOH); 1 1H 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] + . The second eluting peak (095) (6 mg, 30% yield, 97.8:2.2 er); [α] 20 D +55.3 (c = 0.038, MeOH); 11H 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-hydroxy-phenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one; hydrochloride (103) Scheme 21

[0582]

Chemical Structure

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

[0584]

Chemical Structure

[0585] A solution of 5-(trifluoromethyl)-1H-imidazole-2-carbaldehyde (9.80 g, 59.7 mmol) and 2-methylpropan-2-sulfinamide (10.8 g, 98.5 mmol) in THF (300 mL) was added with 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 - 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]propan-2-sulfinamide

[0586]

Chemical Structure

[0587] To a solution of 2-methyl-N-[[5-(trifluoromethyl)-1H-imidazol-2-yl]methylene]propan-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%). 11H 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-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]methyl]-2-methyl-propan-2-sulfinamide

[0588]

Chem.

[0589] A solution of 5-fluorophenylmagnesium bromide in THF (0.5 M, 97.8 mL, 48.9 mmol) was added dropwise to a solution of 2-methyl-N-[[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methylene]propan-2-sulfinamide (6.50 g, 16.3 mmol) in THF (100 mL) 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%). 11H NMR (400 MHz, CDCl3) δ: 7.24 - 7.33 (m, 1H), 6.93 - 7.07 (m, 2H), 6.84 (dd, 1H), 6.15 (d, 1H), 5.17 - 5.26 (m, 2H), 4.92 (d, 1H), 3.85 (s, 3H), 3.24 - 3.45 (m, 2H), 1.21 (s, 9H), 0.74 - 0.89 (m, 2H), -0.06 - 0.00 (m, 9H); MS m / z: 524.1 [M+1] + . Step 4. (5-Fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]methanamine

[0590]

Chemical formula

[0591] To a solution of N-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilyl-ethoxymethyl)imidazol-2-yl]methyl]-2-methyl-propan-2-sulfinamide (1.90 g, 3.62 mmol) in methanol (80 mL) was added HCl (4 M in methanol, 9.05 mL, 36.2 mmol) at 0 °C. After stirring at room temperature for 2 h, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0 - 100% ACN / water containing 10 mM ammonium acetate to give the title compound (1.1 g, 73%). 1 1H NMR (400 MHz, CDCl3) δ: 7.24 - 7.33 (m, 1H), 6.90 - 6.98 (m, 1H), 6.79 - 6.89 (m, 2H), 5.63 (s, 1H), 5.02 - 5.13 (m, 2H), 3.85 (s, 3H), 3.24 - 3.41 (m, 2H), 0.70 - 0.86 (m, 2H), -0.03 (s, 9H); MS m / z: 420.0 [M+1] + . Step 5. Methyl 5-bromo-2-[[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]amino]methyl]benzoate

[0592]

Chem.

[0593] (5-Fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methanamine (1.05 g, 2.50 mmol) and methyl 5-bromo-2-(bromomethyl)benzoate (0.846 g, 2.75 mmol) in DMF (50 mL) were added dropwise with 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 and 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-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]isoindolin-1-one

[0594]

Chem.

[0595] To a solution of methyl 5-bromo-2-[[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]amino]methyl]benzoate (1.61 g, 2.49 mmol) in toluene (50 mL) was added trimethylaluminum (0.179 g, 2.49 mmol). The reaction mixture was heated at 90 °C for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse-phase HPLC eluting with 0 - 100% ACN / water containing 10 mM ammonium acetate to give the title compound (1.2 g, 78%). 1 H NMR (400 MHz, CDCl3) δ: 7.98 (d, 1H), 7.65 (dd, 1H), 7.29 - 7.35 (m, 2H), 7.26 (s, 1H), 7.18 (dd, 1H), 6.98 - 7.07 (m, 1H), 6.86 (dd, 1H), 5.59 (d, 1H), 5.22 (d, 1H), 4.96 (d, 1H), 4.06 (d, 1H), 3.75 - 3.84 (m, 3H), 3.21 - 3.44 (m, 2H), 0.53 - 0.78 (m, 2H), -0.12 - 0.00 (m, 9H); MS m / z: 614.1 [M+1] + . Step 7. 6-Bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]isoindolin-1-one

[0596]

Chem.

[0597] To a solution of 6-bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]isoindolin-1-one (0.540 g, 0.878 mmol) in methanol (5 mL) was added aqueous HCl solution (12 M, 10.0 mL, 120 mmol) at 0 °C. After stirring at room temperature for 4 hours, 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-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]-6-[4-(1-methyl-4-piperidyl)phenyl]isoindolin-1-one

[0598]

Chem.

[0599] 6-Bromo-2-[(5-fluoro-2-methoxyphenyl)-[5-(trifluoromethyl)-1H-imidazol-2-yl]methyl]isoindolin-1-one (0.425 g, 0.878 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.403 g, 1.34 mmol), Pd(dppf)Cl2 (0.032 g, 0.044 mmol) and potassium carbonate (0.372 g, 2.68 mmol) in dioxane:water (9:1, 10 mL) were heated at 100 °C for 2 h under nitrogen. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 0 - 15% methanol 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]

Chem.

[0601] To a solution of 2-[(5-fluoro-2-methoxyphenyl)-[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 hour, 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 (adjusted with 0.05% HCl) 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] [Chemical formula]

[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 using a Chiralpak IA (5 micron 250×10 mm) column from Chiral Technologies at 40 °C with elution at 12 MPa with 35% (0.3% TEA in MeOH) / 65% CO2 to separate the enantiomers. The absolute configuration of the chiral centers of the isolated enantiomers is unknown. First eluted 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] + . Second eluted peak (105) (7.3 mg, 37% yield, 97.7:2.3 er); [α] 20 D +67.3 (c = 0.049, MeOH); 11H NMR (DMSO-d6) δ: 11.74 - 12.20 (m, 1H), 10.08 (br s, 1H), 7.82 - 7.90 (m, 2H), 7.65 (br d, J = 8.2 Hz, 3H), 7.36 (d, J = 8.2 Hz, 2H), 7.02 (td, J = 8.6, 3.2 Hz, 1H), 6.52 - 6.91 (m, 4H), 4.72 (d, J = 17.9 Hz, 1H), 4.11 (d, J = 17.9 Hz, 1H), 2.88 (br d, J = 11.1 Hz, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (td, J = 11.3, 2.1 Hz, 2H), 1.59 - 1.84 (m, 4H); MS m / z: 511.3 [M+1] + .

[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] [Chemical formula]

[0607] 6 - [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 (028, 0.020 g, 0.037 mmol) was purified by prep SFC using a Chiralpak IA (5 micron 250×10 mm) column from Chiral Technologies at 40 °C with elution at 10 MPa with 55% (0.3% TEA in MeOH) / 45% CO2 to separate the enantiomers. The absolute configuration of the chiral centers 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 1H 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); 11H NMR (DMSO-d6) δ: 12.56 (broad singlet, 1H), 9.92 (broad singlet, 1H), 7.94 - 8.13 (multiplet, 4H), 7.46 - 7.57 (multiplet, 1H), 7.36 - 7.44 (multiplet, 1H), 7.33 (doublet, J = 8.3 Hz, 2H), 7.11 (broad singlet, 2H), 7.00 - 7.05 (multiplet, 1H), 6.99 (singlet, 1H), 6.84 (doublet of doublets, J = 8.9, 4.8 Hz, 1H), 6.75 (doublet of doublets, J = 9.3, 3.1 Hz, 1H), 4.73 (doublet, J = 17.9 Hz, 1H), 4.11 (doublet, J = 17.9 Hz, 1H), 2.73 - 2.88 (multiplet, 2H), 2.13 (singlet, 3H), 1.80 - 1.97 (multiplet, 2H), 1.53 - 1.78 (multiplet, 4H); MS m / z: 548.3 [M+1] + .

[0608] The following examples were prepared from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronate starting materials by a method similar to that of Compound 069.

[0609]

Table 26

[0610] The following examples were prepared from methyl 2-bromo-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate and the corresponding boronate starting materials by a method similar to that of Compound 070.

[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] [Chemical formula]

[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. Then, deuterium oxide (350 μL, 19.3 mmol) was added with stirring, followed by N,N-diisopropylethylamine (38.1 μL, 219 μmol) with stirring. The reaction vial was sealed and the reaction mixture was stirred at 70 °C for 60 hours. The 1 1H NMR (DMSO-d6) showed about 100% deuterium incorporation based on the disappearance of the methine peak at about 7.67 ppm at the methine carbon. The reaction mixture 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% of (7N NH3 in methanol) in DCM to give the title compound (14 mg, 68%). 1 1H NMR (DMSO-d6, 400 MHz) δ: 11.9 - 13.5 (m, 1H), 9.6 - 10.9 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.81 (d, 1H), 7.7 - 7.8 (m, 2H), 7.54 (br s, 2H), 7.3 - 7.4 (m, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.08 (dt, 1H), 6.88 (dd, 1H), 6.6 - 6.7 (m, 2H), 2.88 (br d, 2H), 2.5 - 2.7 (m, 1H), 2.20 (s, 3H), 1.9 - 2.0 (m, 2H), 1.6 - 1.8 (m, 4H); 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) by a method similar to that of 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] [Chemical formula]

[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. Then deuterium oxide (1000 μL, 55.4 mmol) was added with stirring, followed by N,N-diisopropylethylamine (62.2 μL, 358 μmol) with stirring. The reaction vial was sealed and then the reaction mixture was stirred at 70 °C for 60 hours. The 11H NMR (DMSO-d6) showed about 100% deuterium incorporation based on the disappearance of the methine peak at about 7.67 ppm at the methine carbon. The reaction mixture was cooled to room temperature and then evaporated to leave the crude product, which was dissolved in 5 mL of THF. Then 75 μL of a 35 wt% DCl in D2O solution was added dropwise with stirring. After 10 minutes, the reaction solution was concentrated and the residue was dried under vacuum overnight to obtain the crude product as the bis DCl salt. The crude product was purified by enantiomeric separation using a Chiralpak IG (10×250 mm 5 micron) column eluting with 55% (0.3% TEA in MeOH) / 45% CO2 at a back pressure regulator (BPR) value of 10 MPa and a flow rate of 7 mL / min on a semi-prep SFC from JASCO. The absolute configuration of the chiral centers of each isolated enantiomer was unknown. First eluted peak (114) (19.7 mg, 37%, 100:0 er); [α] 20 D -13.6 (c = 0.0515, MeOH); 1 1H NMR (DMSO-d6, 400 MHz) δ: 11.9 - 13.5 (m, 1H), 9.6 - 10.9 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.81 (d, 1H), 7.7 - 7.8 (m, 2H), 7.54 (br s, 2H), 7.3 - 7.4 (m, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.08 (dt, 1H), 6.88 (dd, 1H), 6.6 - 6.7 (m, 2H), 2.88 (br d, 2H), 2.5 - 2.7 (m, 1H), 2.20 (s, 3H), 1.9 - 2.0 (m, 2H), 1.6 - 1.8 (m, 4H); MS m / z: 560.3 [M+1] + . Second eluted peak (115) (18.8 mg, 36%, 99.7:0.3 er); [α] 20 D +14.2 (c = 0.0705, MeOH); 11H NMR (DMSO-d6, 400 MHz) δ: 11.9 - 13.5 (m, 1H), 9.6 - 10.9 (m, 1H), 8.28 (d, 1H), 7.94 (s, 1H), 7.81 (d, 1H), 7.7 - 7.8 (m, 2H), 7.54 (br s, 2H), 7.3 - 7.4 (m, 2H), 7.29 (d, 1H), 7.19 (br dd, 2H), 7.08 (dt, 1H), 6.88 (dd, 1H), 6.6 - 6.7 (m, 2H), 2.88 (br d, 2H), 2.5 - 2.7 (m, 1H), 2.20 (s, 3H), 1.9 - 2.0 (m, 2H), 1.6 - 1.8 (m, 4H); MS m / z: 560.3 [M+1] + .

[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 of Example 23. The absolute configuration of the chiral centers of each isolated enantiomer is unknown.

[0621]

Table 29

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

[0623]

Chemical Structure

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

[0625]

Chem.

[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 CH3CN (16 mL). The mixture was stirred at 0 °C for 1 hour and then at RT for 16 hours. 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 (Na2SO4), 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 1H NMR (CDCl3-d) δ: 8.00 (d, 1H), 7.92 (s, 1H), 7.31 (d, 1H), 7.20 (dd, 1H), 7.13 (m, 1H), 7.11 (d, 1H), 6.80 (s, 1H), 5.18 (d, 1H), 5.14 (d, 1H), 3.86 (s, 3H), 3.35 (s, 3H); MS m / z: 442.8 [M+1] + . 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]

Chem.

[0628] Methyl 2-(6-bromo-5-fluoro-2H-indazol-2-yl)-2-(5-fluoro-2-(methoxymethoxy)phenyl)acetate (205 mg, 0.47 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (147 mg, 0.49 mmol), Pd(dppf)Cl2.DCM (38 mg, 0.047 mmol) and sodium carbonate (149 mg, 1.41 mmol) in dioxane:water (3:1, 3 mL) were degassed and refilled with nitrogen three times. The mixture was heated at 100 °C for 4 h under nitrogen. After cooling, the reaction mixture was filtered and purified by reverse phase HPLC eluting with 0 - 80% ACN / water (adjusted with 0.035% TFA) 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]

Chemical Structure

[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 hour. The reaction mixture was purified by reverse-phase HPLC eluting with 0 - 80% ACN / water (adjusted with 0.035% TFA) 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-Benzimidazol-2-yl)(5-fluoro-6-(4-(1-methylpiperidin-4-yl)phenyl)-2H-indazol-2-yl)methyl)-4-fluorophenol (118)

[0631]

Chemical Structure

[0632] The material derived from Step 3 was heated in AcOH (5 mL) at 100 °C for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in 1:1 TFA:DCM (5 mL) over 5 hours. The reaction mixture was purified by reverse-phase HPLC eluting with 0 - 80% ACN / water (adjusted with 0.035% TFA) to afford the title compound (39 mg, 13% over 3 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 materials by a method similar to Example 24.

[0634]

Table 30

[0635] Scheme 25

[0636]

Chemical Structure

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

[0638]

Chemical Structure

[0639] To a solution of methyl 5-fluoro-2-(methoxymethoxy)benzoate (5.00 g, 21.9 mmol) in chloroform (80 mL) were 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 The biochemical activity of EGFR was measured using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio). First, inhibitors and DMSO standards (DMSO normalization) were dispensed into empty black low-volume 384-well plates (Corning) using a D300 digital liquid dispenser (HP). All reactions were carried out at room temperature, and solutions were added to the plates using a Multidrop Combi reagent dispenser (ThermoFisher). The reaction mixture (final volume 10 μl) contained 1 μM tyrosine kinase peptide-biotin substrate and mutant EGFR in reaction buffer (50 mM HEPES pH 7.0, 5 mM MgCl2, 1 mM MnCl2, 0.01% BSA, 2 mM TCEP, 0.1 mM NaVO4). The enzyme concentration was adjusted according to different kinase activities (L858R 0.1 nM, L858R / T790M 0.02 nM). To the 384-well plates containing the compounds, enzyme reaction solution (2x concentration, 5 μL) was added and incubated for 30 minutes. The enzyme reaction was initiated by adding 5 μL of ATP to a final concentration of 100 μM and reacted 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, then incubated at room temperature for 1 hour and read using a PHERAstar plate reader (excitation = 337 nm, emission = 620 nm and 665 nm). IC 50 values were determined by non-linear least squares fitting in GraphPad Prism 7.0d using inhibition curves in triplicate (11-point curve from 1.0 μM to 0.130 nM or 23-point curve from 1.0 μM to 0.130 pM). The obtained data are shown in Table 7 (Table 31) below.

[0641]

Table 31A

[0642]

Table 31B

[0643]

Table 31C

[0644]

Table 31D

[0645] (Example 26) Ba / F3 cell proliferation model For Ba / F3 cells with EGFR variants L858R and L858R / T790M, they have been described previously (Zhou, W. et al., Nature 462, 2009, pp. 1070 - 1074). All cell lines were maintained in RPMI 1640 (Cellgro; Mediatech, Inc., Herndon, VA) supplemented with 10% FBS, 100 units / mL penicillin, and 100 units / mL streptomycin. The I941R mutation of EGFR 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 confirmed by DNA sequencing. The Cre recombination system (Agilent Technologies, Santa Clara, CA) was used to shuttle the constructs into the retroviral vector JP1540. Then, Ba / F3 cells were infected with the retrovirus according to a standard protocol as described previously (Zhou et al., Nature 2009). Stable clones were obtained by selection in puromycin (2 μg / ml).

[0646] Proliferation and growth inhibition were evaluated by the Cell Titer Glo assay (Promega, Madison, WI) and performed according to the manufacturer's instructions. The Cell Titer Glo assay is a luminescence-based method used for determining viable cell numbers based on the quantification of ATP present, which is directly proportional to the amount of metabolically active cells present. Ba / F3 cells with different EGFR genotypes were exposed to the compound as a single agent or the compound in combination with 1 μg / ml of cetuximab for 72 hours, and the number of cells used per experiment was empirically determined as previously established (Zhou et al., Nature 2009). All experimental points were arranged in triplicate within a 384-well plate, and all experiments were repeated at least three times. The luminescence signal was detected using a spectrometer, and the data were graphed using GraphPad Prism version 5.0 for Windows (GraphPad Software; www.graphpad.com). The curves were fitted using a non-linear regression model with a sigmoid dose response. The results of this assay for the compounds disclosed herein are shown in Table 8 (Table 32).

[0647]

Table 32A

[0648]

Table 32B

[0649]

Table 32C

[0650]

Table 32D

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

[0652] All references cited herein (e.g., published documents or patents or patent applications) are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., published document or patent or patent application) were 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 III: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, 【Chemistry 2】 is a single bond or a double bond, B and D are each independently C or N; W and Z are each independently N, CH, C-halo, C-(C 1 ~C 3 alkyl) or C-(C 1 ~C 3 alkoxy), X and Y are each independently N, CH or CR 3 and with the proviso 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 assigned to each occurrence: halogen, OR 4 , N.R. 4 R 4 , S.O. 2 R 4 , S.O. 2 NHR 4 , N.H.S.O. 2 R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, 3-7 membered cycloalkyl, C 4 ~C 7 Cycloalkenyl, C 6 ~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 aryl, heteroaryl or heterocyclyl are each optionally substituted once, twice or three times with 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 formula III is represented by formula IIIa: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

3. When the compound of formula III is a compound of formula IIIb: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

4. R 1 4. The compound according to claim 1, wherein is selected from the group consisting of benzimidazole, imidazopyrazine, purine, imidazole, pyrazole, triazole and imidazopyridine.

5. R 1 but 【Chemistry 5】 all of which optionally contain one, two or three R 8 4. The compound according to claim 1 , 2 or 3, substituted with:

6. Y is CR 3 and R 3 One or two R 5 6-10 membered aryl substituted with

7. The compound of formula III 【Table 1】 or a pharma- ceutically acceptable salt thereof.

8. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

9. 10. The pharmaceutical composition of claim 8, further comprising a second active agent.

10. 10. The pharmaceutical composition of claim 9, wherein the second active agent is selected from the group consisting of a MEK inhibitor, a PI3K inhibitor, and an mTor inhibitor.

11. The pharmaceutical composition of claim 9, wherein the second active agent prevents EGFR dimerization in the subject.

12. 10. The pharmaceutical composition of claim 9, wherein the second active agent is selected from the group consisting of cetuximab, trastuzumab and panitumumab.

13. 10. The pharmaceutical composition of claim 9, wherein the second active agent is an ATP-competitive EGFR inhibitor.

14. 15. The pharmaceutical composition of claim 14, wherein the ATP-competitive EGFR inhibitor is osimertinib, gefitinib or erlotinib.

15. 17. A method of inhibiting EGFR in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7 or a composition of any one of claims 8 to 14.

16. A method for treating or preventing an EGFR-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 7 or a composition described in any one of claims 8 to 14.

17. 17. The method of claim 16, wherein the EGFR-mediated disorder is cancer.

18. 18. The method of claim 17, 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.

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

20. 17. The method of claim 16, wherein the EGFR-mediated disorder is resistant to an EGFR-targeted therapy, and the EGFR-targeted therapy comprises gefitinib, erlotinib, osimertinib, CO-1686, and WZ4002.

Images