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US-12622909-B2 - Allosteric EGFR inhibitors and methods of use thereof

US12622909B2US 12622909 B2US12622909 B2US 12622909B2US-12622909-B2

Abstract

The disclosure relates to compounds that act as an 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.

Inventors

  • Nathanael S. Gray
  • David A. Scott
  • Thomas Gero
  • Michael Eck
  • DAVID HEPPNER
  • Tyler Beyett
  • CIRIC TO

Assignees

  • DANA-FARBER CANCER INSTITUTE, INC.

Dates

Publication Date
20260512
Application Date
20200619

Claims (20)

  1. 1 . A compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein: A is a 6-10 membered aryl or a 5-10 membered heteroaryl; W and W a are each, independently, CH, CR 6 , or N; X and B are each, independently, N, CH, CF, or C—(C 1 -C 3 alkyl); Y and Z are each independently N, CH, or CR 2 ; provided that at least one of X, Y, Z, or B is CH; R 1 is phenyl or pyridinyl, wherein phenyl or pyridinyl is optionally substituted one or two times, independently, with R 7 ; R 2 is independently, at each occurrence, selected from the group consisting of halo, 6-10 membered aryl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-7 membered heterocycloalkyl, OR 4 , NR 4 R 4 , SO 2 R 4 , SO 2 NHR 4 , NHSO 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, and C 2 -C 6 alkynyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, and 3-6 membered cycloalkyl are optionally substituted with R 3 , and wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl are each optionally substituted one, two, or three times with R 4 ; R 3 is selected from the group consisting of halo, —OH, —SH, —CN, —NO 2 , —NH 2 , OR 4 , NR 4 R 4 , SO 2 R 4 , SO 2 NHR 4 , NHSO 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, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, and 4-7 membered heterocycloalkyl, wherein 4-7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl-OH, halo, and ═O; R 4 is independently, at each occurrence, selected from the group consisting of hydrogen, (CH 2 ) 0-3 -(3-7 membered cycloalkyl), (CH 2 ) 0-3 -(4-7 membered cycloalkenyl), (CH 2 ) 0-3 -(6-10 membered aryl), (CH 2 ) 0-3 -(5- to 6-membered heteroaryl), or (CH 2 ) 0-3 -(4- to 7-membered heterocycloalkyl), wherein 6-10 membered aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl are each optionally substituted one, two, or three times with R 5 ; R 5 is independently, at each occurrence, selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, COOH, C(O)O(C 1 -C 6 alkyl), O(CH 2 ) 1-3 OH, NH 2 , OH, CN, (CH 2 ) 0-3 (6-10 membered aryl), (CH 2 ) 0-3 (5- to 6-membered heteroaryl), and (CH 2 ) 0-3 (4- to 7-membered heterocycloalkyl), wherein 6-10 membered aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 NH 2 , (CH 2 ) 1-2 OH, C(O)(CH 2 ) 1-2 OH, and C(O)O(C 1 -C 6 alkyl); R 6 is independently, at each occurrence, C 1 -C 6 alkyl or halo; and R 7 is independently, at each occurrence, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halo, OH, SH, NO 2 , NH 2 , (CH 2 ) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH 2 , or CN.
  2. 2 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II: or a pharmaceutically acceptable salt thereof; wherein: A is a 6-10 membered aryl or a 5-10 membered heteroaryl; W and W a are each, independently, CH, CR 6 , or N; R 2 is independently, at each occurrence, selected from the group consisting of halo, 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl are optionally substituted with R 3 ; R 3 is selected from the group consisting of halo, —OH, —SH, —CN, —NO 2 , —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, and 4-7 membered heterocycloalkyl, wherein 4-7 membered heterocycloalkyl is optionally substituted with one or more substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl-OH, halo, and ═O; R 7 is selected from the group consisting of halo, —OH, —SH, —CN, —NO 2 , and —NH 2 ; m is 0, 1, or 2; and n is 1 or 2.
  3. 3 . The compound of claim 1 , wherein R 7 is absent or at least one R 7 is halo.
  4. 4 . The compound of claim 3 , wherein at least one R 7 is fluoro.
  5. 5 . The compound of claim 1 , wherein A is 5-6 membered heteroaryl.
  6. 6 . The compound of claim 1 , wherein A is thiazolyl or pyridinyl.
  7. 7 . The compound of claim 1 , wherein R 2 is selected from the group consisting of halo, 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl, wherein 6-10 membered aryl is optionally substituted with R 3 .
  8. 8 . The compound of claim 1 , wherein R 2 is bromo or chloro.
  9. 9 . The compound of claim 1 , wherein R 2 is phenyl further substituted with R 3 .
  10. 10 . The compound of claim 9 , wherein R 3 is a 6-membered heterocycloalkyl optionally substituted with C 1 -C 4 alkyl.
  11. 11 . The compound of claim 10 , wherein R 3 is piperidinyl or piperazinyl, each further substituted with methyl.
  12. 12 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII: or a pharmaceutically acceptable salt thereof, wherein n=1 or 2, and m=0, 1, or 2.
  13. 13 . The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  14. 14 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  15. 15 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , optionally in combination with a therapeutically effective amount of a second active agent.
  16. 16 . The method according to claim 15 , 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.
  17. 17 . The method according to claim 15 , wherein the cancer is non-small cell lung cancer (NSCLC).
  18. 18 . A method of inhibiting EGFR in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
  19. 19 . A method of 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 of claim 1 .
  20. 20 . The method according to claim 19 , wherein the EGFR-mediated disorder is resistant to an EGFR-targeted therapy.

Description

RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62/864,914, filed on Jun. 21, 2019, 62/877,093, filed on Jul. 22, 2019, and 63/027,734, filed on May 20, 2020, the contents of which are hereby incorporated by reference in their entirety. FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R01 CA201049 awarded by the National Institute of Health (NIH). The government has certain rights in the invention. BACKGROUND The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a family of receptor tyrosine kinases that mediate the proliferation, differentiation, and survival of normal and malignant cells (Arteaga, C. L., J. Clin. Oncol. 19, 2001, 32-40). Deregulation of EGFR has been implicated in many types of human cancer, with overexpression of the receptor present in at least 70% of human cancers (Seymour, L. K., Curr. Drug Targets 2, 2001, 117-133), including non-small lung cell carcinomas, breast cancers, gliomas, squamous cell carcinomas of the head and neck, and prostate cancer (Raymond, E., et al., Drugs 60 (Suppl. 1), 2000, 15-23, discussion 41-2; Salomon, D. S., et al., Crit. Rev. Oncol. Hematol. 19, 1995, 183-232; Voldborg B. R., et al., Ann. Oncol. 8, 1997, 1197-1206). EGFR has, therefore, emerged as an attractive target for the design and development of diagnostic and therapeutic agents that can specifically bind and inhibit the receptor's tyrosine kinase activity and signal transduction pathway in cancer cells. For example, the EGFR tyrosine kinase (EGFR-TK) reversible inhibitor TARCEVA® is approved by the FDA for treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR targeted molecules have also been approved, including Lapatinib and IRESSA®. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective clinical therapies for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients (Mok, T. S., et al., N. Engl. J. Med. 361, 2009, 947-57; Paez, J. G., et al., Science 304, 2004, 1497-500; Lynch, T. J., et al., N. Engl. J. Med. 350, 2004, 2129-39; Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46). Several randomized clinical trials have demonstrated that EGFR TKIs are more effective, as measured by response rate (RR) and progression free survival (PFS), than chemotherapy when used as initial systemic treatment for advanced EGFR mutant NSCLC (Mok, T. S., et al., N. Engl. J. Med. 361, 2009, 947-57: Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46; Sequest, L. V. et al., J. Clin. Oncol. 31, 2013, 3327-34; Wu, Y. L, et al., Lancet Oncol. 15, 2014, 213-22; Maemondo, M., et al., N. Engl. J. Med. 362, 2010, 2380-8; Zhou, C., et al., Lancet Oncol. 12, 2011, 735-42; Mitsudomi, T., et al., Lancet Oncol. 11, 2010, 121-8). However, the vast majority of patients will develop disease progression following successful treatment with an EGFR TKI. The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation in EGFR at position T790 (T790M) (Yu, H. A., et al., Clin. Cancer Res. 19, 2013, 2240-7). This mutation leads to an increase in ATP affinity, thus making it more difficult for reversible EGFR TKIs gefitinib and erlotinib to bind the EGFR TKI domain (Yun C. H., et al., Proc. Natl. Acad. Sci. USA 105, 2008, 2070-5). Covalent EGFR inhibitors have emerged for inhibiting EGFR T790M-containing cancers. However, in lung cancer patients, afatinib is only effective in EGFR TKI naïve EGFR mutant cancers and has a RR of less than 10% in patients with NSCLC that have developed resistance to gefitinib or erlotinib (Miller, V. A., et al., Lancet Oncol. 13, 2012, 528-38). Afatinib is a potent inhibitor of both mutant and wild type (WT) EGFR. Inhibition of WT EGFR leads to toxicities, including skin rash and diarrhea, which limits the ability to escalate afatinib doses in patients to those necessary to inhibit EGFR T790M. Irreversible pyrimidine EGFR inhibitors including the tool compound WZ4002 and clinical compounds CO-1686 and AZD9291, overcome many of the limitations of afatinib (Zhou, W., et al., Nature 462, 2009, 1070-4; Walter, A. O., et al., Cancer Discov. 3, 2013, 1404-15; Cross, D. A. E., et al., Cancer Discov. 4, 2014, 1046-61). They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (Zhou, W., et al; Walter A. O., et al, Cross, D. A. E., et al.). However, all current EGFR TKIs target the ATP site, and while third generation irreversible inhibitors can overcome T790M, they are all rendered impotent by the C797S mutation, which is already arising in treated patients. Cetuximab, an anti-EGFR antibody that blocks receptor dimerization, is not effective in EGFR-mutant NSCLC because mutational activation of the kinase is effectively “downstream” of receptor dimerization. Hence, alternative strategies to in