WO2022072645A2 - Méthodes de traitement du cancer - Google Patents

Méthodes de traitement du cancer Download PDF

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Publication number
WO2022072645A2
WO2022072645A2 PCT/US2021/052894 US2021052894W WO2022072645A2 WO 2022072645 A2 WO2022072645 A2 WO 2022072645A2 US 2021052894 W US2021052894 W US 2021052894W WO 2022072645 A2 WO2022072645 A2 WO 2022072645A2
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WIPO (PCT)
Prior art keywords
compound
ring
optionally substituted
group
independently selected
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PCT/US2021/052894
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English (en)
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WO2022072645A3 (fr
Inventor
Benjamin C. MILGRAM
JR. David St. Jean
Ryan D. WHITE
Angel Guzman-Perez
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Scorpion Therapeutics, Inc.
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Publication of WO2022072645A2 publication Critical patent/WO2022072645A2/fr
Publication of WO2022072645A3 publication Critical patent/WO2022072645A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • compositions containing the same as well as methods of using and making the same are members of a family of proteins which regulate cellular processes implicated in tumor growth, including proliferation and differentiation.
  • EGFR overexpression is present in at least 70% of human cancers, such as non-small cell lung carcinoma (NSCLC), breast cancer, glioma, and prostate cancer.
  • NSCLC non-small cell lung carcinoma
  • HER2 overexpression occurs in approximately 30% of all breast cancer.
  • HER2 overexpression has also been correlated with poor prognosis in human cancer, including metastasis, and early relapse.
  • EGFR and HER2 are, therefore, widely recognized as targets for the design and development of therapies that can specifically bind and inhibit tyrosine kinase activity and its signal transduction pathway in cancer cells, and thus can serve as diagnostic or therapeutic agents.
  • EGFR tyrosine kinase inhibitors TKIs
  • NSCLC advanced non-small cell lung cancer
  • BUB1 Budding uninhibited by benzimidazole, BUB1
  • BUB1 is often associated with proliferating cells, including cancer cells, and tissues (Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci.36, 141 , 2010). This protein is an essential part of the complex network of proteins that form the mitotic checkpoint.
  • the major function of an unsatisfied mitotic checkpoint is to keep the anaphase-promoting complex/cyclosome (APC/C) in an inactive state.
  • APC/C anaphase-promoting complex/cyclosome
  • ubiquitin-ligase targets cyclin B and securin for proteolytic degradation leading to separation of the paired chromosomes and exit from mitosis.
  • Incomplete mitotic checkpoint function has been linked with aneuploidy and tumourigenesis (see Weaver BA and Cleveland DW, Cancer Res. 67, 10103, 2007; King RW, Biochim Biophys Acta 1786, 4, 2008).
  • mitotic checkpoint inhibition through inhibition of BUB1 kinase represents an approach for the treatment of proliferative disorders, including solid tumors such as carcinomas, sarcomas, leukemias and lymphoid malignancies or other disorders, associated with uncontrolled cellular proliferation.
  • This disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and/or Human epidermal growth factor receptor 2 (HER2, ERBB2).
  • EGFR epidermal growth factor receptor
  • HER2 ERBB2 Human epidermal growth factor receptor 2
  • These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR and/or HER2 activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human).
  • This disclosure also provides compositions containing the same as well as methods of using and making the same.
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1c , R 2a , R 2b , Y 1 , R 4 , Ring A, and Ring C can be as defined anywhere herein.
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y 1 is selected from the group consisting of: a bond , wherein aa represents the point of attachment to -C(R 2a R 2b )-; Ring C is selected from the group consisting of: x C 3-10 cycloalkyl or C 3-10 cycloalkenyl, each of which is optionally substituted with X 1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c ; x heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X 1 and further optionally substituted with from
  • a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-
  • a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.
  • Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4)
  • a method of treating an EGFR-associated disease or disorder in a subject comprising administering to a subject identified or diagnosed as having an EGFR-associated disease or disorder a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or
  • This disclosure also provides a method of treating an EGFR-associated disease or disorder in a subject, the method comprising: determining that the cancer in the subject is an EGFR-associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-
  • a method of treating an EGFR-associated cancer in a subject comprising administering to a subject identified or diagnosed as having an EGFR- associated cancer a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided here
  • This disclosure also provides a method of treating an EGFR-associated cancer in a subject, the method comprising: determining that the cancer in the subject is an EGFR- associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1)
  • Also provided herein is a method of treating a subject having a cancer comprising: (a) administering one or more doses of a first EGFR inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); and (c) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one
  • a method of treating a subject having a cancer comprises: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers
  • Also provided herein is a method of treating a subject having a cancer comprising: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I
  • a method of treating a subject having a cancer comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor does not have one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering additional doses of the first EGFR inhibitor to the subject.
  • This disclosure also provides a method for inhibiting EGFR in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-b), (I-
  • Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-
  • a method of treating a HER2-associated cancer in a subject comprising administering to a subject identified or diagnosed as having a HER2-associated cancer a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition as
  • This disclosure also provides a method of treating a HER2-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a HER2- associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a method of treating a subject having a cancer comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g
  • Also provided herein is a method of treating a subject having a cancer comprising: (a) administering one or more doses of a first HER2 inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one HER2 inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor of step (a); and (c) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one
  • a method of treating a subject having a cancer comprises: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first HER2 inhibitor has one or more HER2 inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one HER2 inhibitor resistance mutation that confers
  • Also provided herein is a method of treating a subject having a cancer comprising: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first HER2 inhibitor has one or more HER2 inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I
  • a method of treating a subject having a cancer comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first HER2 inhibitor does not have one or more HER2 inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; and (b) administering additional doses of the first HER2 inhibitor to the subject.
  • This disclosure also provides a method for inhibiting HER2 in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-b), (I-
  • a compound of Formula (I) e.g., Formula (I-a), (I-
  • a method of treating an EGFR-associated and HER2- associated cancer in a subject comprising administering to a subject identified or diagnosed as having an EGFR-associated and a HER2-associated cancer a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • This disclosure also provides a method of treating a an EGFR-associated and HER2-associated cancer in a subject, the method comprising: determining that the cancer in the subject is an EGFR-associated and a HER2-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same and a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e
  • This disclosure also provides a method for inhibiting EGFR and HER2 in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • the methods provided herein include methods for inhibiting BUB11.
  • a method for inhibiting BUB1 in a mammalian cell comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • Other embodiments include those described in the Detailed Description and/or in the claims.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • excipient or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
  • pharmaceutical composition refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • oxo refers to a divalent doubly bonded oxygen atom (i.e., As used herein, oxo groups are attached to carbon atoms to form carbonyls.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C 1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • alkylene refers to a divalent alkyl (e.g., -CH 2 -).
  • terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively.
  • cycloalkylene and “heterocyclylene”, the two radicals can be on the same ring carbon atom (e.g., a geminal diradical such as different ring atoms (e.g., ring carbon and/or nitrogen atoms (e.g., vicinal ring carbon and/or nitrogen atoms)) (e.g., , , , .
  • ring carbon atom e.g., ring carbon and/or nitrogen atoms (e.g., vicinal ring carbon and/or nitrogen atoms)
  • alkenyl refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms.
  • C 2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.
  • Alkenyl groups can either be unsubstituted or substituted with one or more substituents.
  • alkynyl refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms.
  • C 2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.
  • Alkynyl groups can either be unsubstituted or substituted with one or more substituents.
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • saturated as used in this context means only single bonds present between constituent carbon atoms.
  • cycloalkenyl as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted.
  • Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall.
  • Cycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.
  • heteroaryl means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazoliny
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent.
  • ring atoms e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system
  • heteroatoms selected from O, N, or S (e.g.
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7- azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2- azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane
  • heterocycloalkenyl as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent.
  • heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.
  • partially unsaturated cyclic groups heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall.
  • Heterocycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings.
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • rings examples include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro- fused ring systems) (e.g., (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., , In addition
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the encompasses the tautomeric form containing the moiety: . m ar y, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • optical isomers e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • optical isomers e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • This disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and/or Human epidermal growth factor receptor 2 (HER2, ERBB2).
  • EGFR epidermal growth factor receptor
  • HER2 ERBB2 Human epidermal growth factor receptor 2
  • These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR and/or HER2 activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human).
  • the chemical entities provided herein can inhibit an EGFR kinase and/or a HER2 kinase that has an exon 20 mutation (e.g., any of the exon 20 mutations described herein).
  • Exon 20 mutations can confer intrinsic resistance to EGFR and/or HER2 inhibitors, and there are currently only limited targeted therapies that have been approved for subjects with these mutations.
  • This disclosure also provides compositions containing the chemical entities provided herein as well as methods of using and making the same.
  • Formula (I) Compounds in one aspect, this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y 1 is selected from the group consisting of: a bond , wherein aa represents the point of attachment to -C(R 2a R 2b )-; Ring C is selected from the group consisting of: x C 3-10 cycloalkyl or C 3-10 cycloalkenyl, each of which is optionally substituted with X 1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c ; x heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X 1
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y 1 is selected from the group consisting of: a bond , wherein aa represents the point of attachment to -C(R 2a R 2b )-; Ring C is selected from the group consisting of: x C 3-10 cycloalkyl or C 3-10 cycloalkenyl, each of which is optionally substituted with X 1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c ; x heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X 1 and further optionally substituted with from
  • pyridone e.g., , (e.g., )
  • Ring C or R g when Ring C or R g is heteroaryl, said heteroaryl is not substituted with –OH.
  • Ring C when Ring C or R g is heteroaryl, said heteroaryl is substituted with –OH.
  • Ring C is selected from the group consisting of: x heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with X 1 and further optionally substituted with from 1-4 R c ; and x C 6-10 aryl optionally substituted with X 1 and further optionally substituted with from 1-4 R c .
  • Ring C is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is substituted with X 1 and further optionally substituted with from 1-4 R c .
  • Ring C is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C can be pyridyl or pyrimidyl, each of which is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring wherein n is 0, 1, or 2 (e.g., n is 0).
  • Ring wherein n is 0, 1, or 2 (e.g., n is 0). In certain embodiments, Ring , wherein n is 0, 1, or 2 (e.g., n is 0; or n is 1).
  • Ring C can be .
  • Ring C can .
  • Ring C is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C can be selected from the group consisting of: quinolinyl; naphthyridinyl (e.g., 1,5-naphthyridin-4-yl); and pyridopyrimidinyl (e.g., pyrido[3,2-d]pyrimidin-4-yl), each of which is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C can be selected from the group consisting of: , , , , , , , each of which is further optionally substituted with from .
  • Ring C can be selected from the group , As another non-limiting example, Ring C can . As another non-limiting, Ring C can . In certain embodiments, Ring C is selected from the group consisting of: , each of which is optionally substituted with from 1-2 .
  • Ring C is selected from the group consisting of: x heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c ; and x C 6-10 aryl optionally substituted with from 1-4 R c .
  • Ring C is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-3 R c .
  • Ring C is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring C can be selected from the group consisting of: , , , , , .
  • Ring C is selected from the group consisting of: , , , , , , .
  • each R c present in Ring C is halo, such as –F or –Cl.
  • each R c present in Ring C is C 1-3 alkyl optionally substituted with from 1-3 R a .
  • Ring C is .
  • the R c present in Ring C is halo, such as –F or –Cl.
  • the R c present in Ring C is C 1-3 alkyl optionally substituted with from 1-3 R a .
  • Ring C is or .
  • the R c present in Ring C is halo, such as –F or –Cl.
  • the R c present in Ring C is C 1-3 alkyl optionally substituted with from 1-3 R a .
  • Ring C is , wherein the R c present in Ring C is halo or C 1-3 alkyl optionally substituted with from 1-3 R a .
  • the R c can be – F.
  • Ring C is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4, such as 2-4, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C is attached t 5-membered ring.
  • Ring C can , each further optionally substituted with R c .
  • Ring C In certain embodiments (when Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4, such as 2-4, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c ), Ring C is attached - membered ring.
  • Ring C can be with from 1-2 R c .
  • Ring C can be selected from the group consisting of: .
  • Ring C is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C is selected from , each further optionally substituted with R c . further optionally substituted with R c .
  • Ring C can be selected from the group ,
  • Ring C is .
  • the R c present in Ring C is C 1-4 alkoxy or C 1-4 haloalkoxy.
  • the R c present in Ring C is C 1-3 alkyl or C 1-3 alkyl substituted with from 1- 3 R a (e.g., C 1-3 alkyl substituted with from 1-3 independently selected halo; or C 1-3 alkyl substituted with C 1-3 alkoxy).
  • the R c present in Ring C can be independently C 1-4 alkoxy; C 1-3 alkyl; or C 1-3 alkyl substituted with from 1-3 independently selected halo.
  • the R c present in Ring C can be OMe or OEt.
  • the R c present in Ring C can be Me or CHF2. In certain embodiments, Ring .
  • each R c present in Ring C is independently C 1-4 alkoxy; C 1-3 alkyl; or C 1-3 alkyl substituted with from 1-3 R a (e.g., C 1-3 alkyl substituted with from 1-3 independently selected halo; or C 1-3 alkyl substituted with C 1-3 alkoxy).
  • each R c present in Ring C can be independently C 1-4 alkoxy; C 1-3 alkyl; or C 1-3 alkyl substituted with from 1-3 independently selected halo.
  • each occurrence of R c present on one or more ring atoms of Ring C can be independently selected from the group consisting of: OMe, OEt, Me, and CHF2.
  • Ring C is selected from the group consisting of: : each occurrence of R c present on one or more ring atoms of Ring C is independently selected from the group consisting of: halo; NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; C 1-3 alkyl substituted with from 1-3 independently selected halo; C 1-3 alkyl substituted with C 1-4 alkoxy; and C 1-4 alkoxy substituted with C 1-4 alkoxy.
  • each R c present in Ring C is independently selected from the group consisting of: C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-3 R a (e.g., C 1-3 alkyl substituted with from 1-3 independently selected halo; or C 1-3 alkyl substituted with C 1-3 alkoxy).
  • each R c present in Ring C can be independently C 1-4 alkoxy; C 1-3 alkyl; or C 1-3 alkyl substituted with from 1- 3 independently selected halo.
  • each occurrence of R c present on one or more ring atoms of Ring C can be independently selected from the group consisting of: OMe, OEt, Me, and CHF2.
  • Variable X 1 In some embodiments, X 1 is –O-L 1 -R 5 . In some embodiments, X 1 is –L 1 -R 5 .
  • L 1 is C 1-10 alkylene optionally substituted with from 1-6 R a . In certain of these embodiments, L 1 is C 1-3 alkylene optionally substituted with from 1-6 R a . In certain of the foregoing embodiments, L 1 is C 1-3 alkylene.
  • L 1 can be –CH2-.
  • L 1 can be —CH(Me)- (e.g., As another non-limiting example, L 1 can be –CH2CH2-.
  • L 1 is C 3-8 alkylene optionally substituted with from 1-6 R a .
  • L 1 is branched C3-6 alkylene optionally substituted with from 1-6 R a .
  • L 1 is branched C3-6 alkylene.
  • L 1 can be selected from the group consisting of: , wherein aa is the point of attachment to R 5 .
  • L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CHF-, -CF 2 -, -CH 2 CHF-, or –CH 2 CF 2 -.
  • L 1 is a bond.
  • R 5 is selected from the group consisting of: -OH; -NR e R f ; and C 1-6 alkoxy or -S(O) 0-2 (C 1-6 alkyl) each optionally substituted with from 1-6 R a .
  • R 5 is C 1-6 alkoxy optionally substituted with from 1-6 R a .
  • R 5 can be C 1-3 alkoxy (e.g., methoxy).
  • R 5 is -S(O) 0-2 (C 1-6 alkyl) which is optionally substituted with from 1-6 R a .
  • R 5 is –S(O)2(C 1-6 alkyl) which is optionally substituted with from 1-6 R a .
  • R 5 can be –S(O) 2 (C 1-3 alkyl) (e.g., -S(O) 2 Me).
  • R 5 is –H or –halo.
  • R 5 can be –H or –F.
  • R 5 is –R g .
  • R 5 is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is heterocyclyl including from 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl is optionally substituted with from 1-3 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); x1 is 0, 1, or 2; and x2 is 0, 1, 2, or 3, provided that x1+x2 ⁇ 1.
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); and x1 and x2 are each independently 0, 1, or 2. In certain embodiments (when R 5 is In certain embodiments (when R 5 is . In certain embodiments (when R 5 is As non-limiting examples of the foregoing embodiments, R 5 can be selected from the group consisting of: ); and (e.g., or ).
  • R 5 is C 3-10 cycloalkyl or C 3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is C 3-10 cycloalkyl which is optionally substituted with from 1-2 R c .
  • R 5 is C 3-6 cycloalkyl which is optionally substituted with from 1-2 R c .
  • R 5 can be cyclopropyl or cyclobutyl.
  • R 5 is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-3 R c .
  • R 5 is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-3 R c .
  • R 5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R c , and wherein a ring nitrogen atom is optionally substituted with R d .
  • R 5 can be selected from .
  • R 5 is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 can be selected from the group consisting of: , , , , and , each of which is optionally substituted with R c .
  • R 5 is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 is -R g2 -R W or -R g2 -R Y . In certain of these embodiments, R 5 is -R g2 -R W .
  • the –R g2 present in –R 5 is heterocyclylene or heterocycloalkenylene including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • the –R g2 present in –R 5 is heterocyclylene including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • –R 5 is , wherein Ring D is heterocyclylene including from 3-10 ring atoms, wherein from 0-2 ring atoms (in addition to the ring nitrogen atom bonded to R W ) are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene is optionally substituted with from 1-3 substituents each independently selected from the group consisting of: oxo and –R c .
  • optionally substituted with from 1-2 R c wherein x1 and x2 are each independently 0, 1, or 2.
  • W is C 2-4 alkenyl optionally substituted with from 1-3 R a and further optionally substituted with R g , wherein W is attached to L W via an sp 2 hybridized carbon atom.
  • L 2 is a bond.
  • L 2 is C 1-10 alkylene optionally substituted with from 1-6 R a .
  • L 2 is C 1-6 alkylene optionally substituted with from 1-6 R a .
  • L 2 is branched C3-6 alkylene.
  • L 2 is .
  • R 6 is -C 1-6 alkoxy or -S(O) 0-2 (C 1-6 alkyl), each optionally substituted with from 1-6 R a .
  • R 6 is -C 1-6 alkoxy.
  • R 6 can be –C 1-3 alkoxy (e.g., methoxy).
  • R 6 is R g .
  • R 6 is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 6 is heterocyclyl including from 3-10, such as 4-8, ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 6 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); and x1 and x2 are each independently 0, 1, or 2.
  • x1 is 0.
  • X a is –O-.
  • R 6 can be .
  • R 1 , R 1c , R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b In some embodiments, Y 1 is a bond. In some embodiments, wherein aa represents the point of attachment to -C(R 2a R 2b )-. In some embodiments, R 1c is H.
  • R 2a and R 2b is an independently selected substituent that is other than H.
  • one of R 2a and R 2b , such as R 2a is –R b .
  • one of R 2a and R 2b , such as R 2a is C 1-6 alkyl, which is optionally substituted with from 1-6 R a .
  • one of R 2a and R 2b , such as R 2a is C 1-6 alkyl, such as C 1-3 alkyl.
  • one of R 2a and R 2b can be methyl, ethyl, or n-propyl (e.g., methyl).
  • one of R 2a and R 2b such as R 2a
  • one of R 2a and R 2b such as R 2a
  • one of R 2a and R 2b can be selected from the group consisting of: -CF3, -CHF2, -CH2F, -CH2CH2F,
  • one of R 2a and R 2b is C 1-6 alky which is substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f and further optionally substituted with from 1-3 independently selected halo.
  • one of R 2a and R 2b , such as R 2a is C 1-6 alky which is substituted with C 1-4 alkoxy or C 1-4 haloalkoxy.
  • one of R 2a and R 2b , such as R 2a is C 1-3 alkyl substituted with C 1-4 alkoxy.
  • one of R 2a and R 2b , such as R 2a can be – CH2CH2OMe.
  • one of R 2a and R 2b , such as R 2a is –R g .
  • one of R 2a and R 2b , such as R 2a is C 3-10 cycloalkyl or C 3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • one of R 2a and R 2b is C 3-10 cycloalkyl (such as C3-6 cycloalkyl) which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • one of R 2a and R 2b can be C3-6 cycloalkyl (e.g., cyclopropyl), which is optionally substituted with from 1-2 R c .
  • R 2a and R 2b are as defined supra
  • the other of R 2a and R 2b is H.
  • R 2a and R 2b together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 ; and x wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 2a and R 2b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 ; and x wherein the fused saturated ring of 3-6 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 2a and R 2b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R c .
  • R 2a and R 2b are both H.
  • R 3a and R 3b are both H.
  • from 1-2 of R 3a and R 3b is an independently selected substituent that is other than H.
  • one of R 3a and R 3b is –R b .
  • one of R 3a and R 3b is C 1-6 alkyl optionally substituted with from 1-6 R a .
  • one of R 3a and R 3b can be C 1-3 alkyl (e.g., methyl, ethyl, or propyl).
  • the other of R 3a and R 3b is H.
  • the other of R 3a and R 3b is C 1-3 alkyl.
  • the other of R 3a and R 3b can be methyl.
  • R 4a and R 4b are both H. In some embodiments, from 1-2 of R 4a and R 4b is an independently selected substituent that is other than H. In certain embodiments, one of R 4a and R 4b is C 1-6 alkyl optionally substituted with from 1-6 R a . For example, one of R 4a and R 4b can be C 1-3 alkyl; and the other of R 4a and R 4b can be H. In certain embodiments, one of R 4a and R 4b , such as R 4a , is C 1-6 alky which is substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f and further optionally substituted with from 1-3 independently selected halo.
  • one of R 4a and R 4b is C 1-6 alky which is substituted with C 1-4 alkoxy or C 1-4 haloalkoxy.
  • one of R 4a and R 4b is C 1-3 alkyl substituted with C 1-4 alkoxy.
  • one of R 4a and R 4b can be – CH2CH2OMe.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each indepenendently selected from the group consisting of H, R b , R g , -CH2R g , halo, cyano, C 1-4 alkoxy, and C1- 4 haloalkoxy.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each indepenendently selected from the group consisting of H, R b , R g , -CH2R g , halo, cyano, C1- 4 alkoxy, and C 1-4 haloalkoxy.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each indepenendently selected from the group consisting of H and C 1-3 alkyl optionally substituted with from 1- 3 independently selected R a .
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are H.
  • from 1-2 of R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a ; and each of the remaining 4-5 R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is H.
  • one of R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); and each of the remaining five R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is H.
  • two of R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are independently selected C 1-3 alkyl, each optionally substituted with from 1-3 independently selected R a (e.g., methyl); and each of the remaining four R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is H.
  • one of R 3a and R 3b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); the other of R 3a and R 3b is H; and each of R 2a , R 2b , R 4a , and R 4b is H.
  • one of R 4a and R 4b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); the other of R 4a and R 4b is H; and each of R 2a , R 2b , R 3a , and R 3b is H.
  • one of R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is C3-6 cycloalkyl or –CH 2 (C 3-6 cycloalkyl); each of the remaining five R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is H; and the C3-6 cycloalkyl is optionally substituted with from 1-2 R c .
  • one of R 3a and R 3b is R g or –CH2R g ; the other of R 3a and R 3b is –H; and each of R 2a , R 2b , R 4a , and R 4b is H.
  • two of the variables R 3a , R 3b , R 4a , and R 4b (e.g., R 3a and R 4a ) on adjacent ring atoms, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 ; and x wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • two of the variables R 3a , R 3b , R 4a , and R 4b (e.g., R 3a and R 4a ) on adjacent ring atoms, together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R d ), O, and S(O) 0-2 ; and x wherein the fused saturated ring of 3-6 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • two of the variables R 3a , R 3b , R 4a , and R 4b (e.g., R 3a and R 4a ) on adjacent ring atoms, together with the Ring B ring atom to which each is attached, form a fused cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R c .
  • one of R 2a and R 2b (e.g., R 2a ) and one of R 4a and R 4b (e.g., R 4a ) taken together with the Ring B ring atoms to which each is attached form a fused cyclobutyl.
  • R 2a and R 2b e.g., R 2a
  • R 4a and R 4b e.g., R 4a
  • the other of R 2a and R 2b and the other of R 4a and R 4b are each H.
  • R 3a and R 3b are independently selected from the group consisting of H and R b .
  • R 3a and R 3b are independently selected from the group consisting of H and C 1-3 alkyl.
  • R 3a and R 3b can each be H.
  • R 3a and R 3b can each be independently selected C 1-3 alkyl (e.g., methyl).
  • R 2a and R 2b e.g., R 2a
  • R 4a and R 4b taken together with the Ring B ring atoms to which each is attached, form a fused C 3- 6 cycloalkyl which is optionally substituted with from 1-2 R c ; and the other of R 2a and R 2b and the other of R 4a and R 4b are each H.
  • R 3a and R 3b are independently selected from the group consisting of H and C 1-3 alkyl.
  • R 3a and R 3b can each be H.
  • R 3a and R 3b can each be independently selected C 1-3 alkyl (e.g., methyl).
  • the other of R 3a and R 3b and the other of R 4a and R 4b are each H.
  • the other of R 3a and R 3b and the other of R 4a and R 4b are each H.
  • R 3a and R 3b e.g., R 3a
  • R 4a and R 4b e.g., R 4a
  • the other of R 3a and R 3b and the other of R 4a and R 4b are each H.
  • Y 1 is a bond, , , , , or another non-limiting example, Y 1 can .
  • Y 1 can be .
  • Y 1 can .
  • Y 1 is a bond, .
  • Y 1 can .
  • Y 1 can be .
  • Y 1 can .
  • Variable Ring A In some embodiments, Ring A is , wherein each R cB is an independently selected R c ; and m is 0, 1, 2, 3, or 4. In certain of these embodiments, m is 1, 2, or 3. In certain embodiments, m is 1 or 2. For example, m can be 2.
  • each R cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo. ), wherein each R cB is an independently selected R c . In certain embodiments, each R cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo.
  • Ring A is .
  • R cB1 and R cB2 are each independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo.
  • R cB1 is halo, such as –F or –Cl, such as – F.
  • R cB1 is C 1-3 alkyl or C 1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R cB1 is methyl, –CHF2, or –CF3.
  • R cB2 is selected from the group consisting of: halo; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo.
  • R cB2 is C 1-4 alkoxy or C 1-4 haloalkoxy.
  • R cB2 is selected from the group consisting of -CN; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R cB2 is cyano, methyl, ethyl, -CHF2, -CF3, or -CH2CHF2.
  • Ring A is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring A is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N , O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring A can be selected .
  • Ring A is C8-10 bicyclic aryl, optionally substituted with from 1-2 R c .
  • Ring A is naphthyl which is optionally substituted with from 1-2 R c .
  • Ring A can be .
  • R 4 is H.
  • the compound is a compound of Formula (I-a): Formula (I-a) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0.
  • the compound is a compound of Formula (I-b): Formula (I-b) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0.
  • the compound is a compound of Formula (I-c): Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, n is 1.
  • the compound is a compound of Formula (I-d): or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, the compound is a compound of Formula (I-e): Formula (I-e) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; and Ring D is an aromatic ring including from 5-6 ring atoms, wherein from 0-2 of the ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R d ), O, and S, wherein Ring D is optionally substituted with from 1-2 R c .
  • Ring D is an aromatic ring including 6 ring atoms wherein from 0-2 of the ring atoms are ring nitrogen atoms, wherein Ring D is optionally substituted with from 1-2 R c .
  • the compound is a compound of Formula (I-e1): Formula (I-e1) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0.
  • the compound is a compound of Formula (I-e2): Formula (I-e2) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0.
  • the compound is a compound of Formula (I-e3): Formula (I-e3) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, the compound is a compound of Formula (I-f): Formula (I-f) or a pharmaceutically acceptable salt thereof.
  • X 1 is as defined in [AA1]: [AA1]: x X 1 is –O-L 1 -R 5 ; x -L 1 is C 1-10 alkylene optionally substituted with from 1-6 R a ; and x R 5 is selected from the group consisting of: H; halo; -OH; -NR e R f ; and -C 1- 6 alkoxy or -S(O) 0-2 (C 1-6 alkyl), each optionally substituted with from 1-6 R a .
  • R 5 is -C 1-6 alkoxy or -S(O) 0-2 (C 1-6 alkyl), each optionally substituted with from 1-6 R a .
  • R 5 is –C 1-6 alkoxy optionally substituted with from 1-6 R a .
  • R 5 is –C 1-6 alkoxy.
  • R 5 can be C 1-3 alkoxy (e.g., methoxy).
  • R 5 is –H.
  • R 5 is –F.
  • L 1 is C 1-3 alkylene.
  • L 1 is –CH2-. In certain embodiments, L 1 is –CH(Me)-. In certain embodiments, L 1 is –CH 2 CH 2 -. In certain embodiments of [AA1], L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF2-, -CH2CH(F)-, or –CH2CF2-. In certain embodiments of [AA1], L 1 is branched C 3-6 alkylene. As non-limiting examples of the foregoing embodiments, L 1 can be selected from the group consisting of: , , , wherein aa is the point of attachment to R 5 .
  • X 1 is as defined in [BB1]: [BB1]: x X 1 is –O-L 1 -R 5 ; x -L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ; and x -R 5 is heterocyclyl including from 3-10, such as 4-8, ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); x1 is 0, 1, or 2; and x2 is 0, 1, 2, or 3, provided that x1+x2 ⁇ 1.
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments (when R 5 is . In certain of these embodiments(when R 5 is , x1 is 1.
  • L 1 is –CH2-. In certain embodiments, L 1 is –CH(Me)-. In certain embodiments, L 1 is –CH2CH2-. In certain embodiments of [BB2], L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF 2 -, -CH 2 CH(F)-, or –CH 2 CF 2 -. In certain embodiments of [BB1], L 1 is a bond.
  • Formula (I-a), (I-b), (I-c), (I-d), (I-e) e.g., Formula (I- e1) defined in [BB2]: [BB2]: x X 1 is –O-L 1 -R 5 ; x -L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ; and x -R 5 is C 3-10 cycloalkyl which is optionally substituted with from 1-2 R c .
  • R 5 is C3-6 cycloalkyl which is optionally substituted with from 1-2 R c .
  • R 5 can be cyclopropyl or cyclobutyl.
  • L 1 is C 1-3 alkylene. In certain of these embodiments, L 1 is –CH2-. In certain embodiments, L 1 is –CH(Me)-. In certain embodiments, L 1 is –CH2CH2-. In certain embodiments of [BB2], L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF2-, -CH2CH(F)-, or –CH2CF2-. In certain embodiments of [BB2], L 1 is a bond.
  • X 1 is as defined in [CC1]: [CC1]: x X 1 is –O-L 1 -R 5 ; x -L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ; and x -R 5 is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-3 R c .
  • R 5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R c , and wherein a ring nitrogen atom is optionally substituted with R d .
  • R 5 can be selected from the group consisting of: .
  • R 5 is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted with from 1-4 R c , such as wherein .
  • R 5 is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • R 5 can be selected from .
  • R 5 is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • L 1 is C 1-3 alkylene. In certain of these embodiments, L 1 is –CH2-. In certain embodiments, L 1 is –CH(Me)-. In certain embodiments, L 1 is –CH 2 CH 2 -.
  • L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF2-, -CH2CH(F)-, or –CH2CF2-. In certain embodiments of [CC1], L 1 is a bond.
  • X 1 is as defined in [DD1]: [DD1]: x X 1 is –O-L 1 -R 5 ; x -L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ; and x -R 5 is -R g2 -R W or -R g2 -R Y .
  • Ring D is heterocyclylene including from 3-10 ring atoms, wherein from 0-2 ring atoms (in addition to the ring nitrogen atom bonded to R Z ) are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene is optionally substituted with from 1-3 substituents each independently selected from the group consisting of: oxo and –R c ; and R Z is R W or R Y . In certain embodiments optionally substituted with from 1-2 R c , wherein x1 and x2 are each independently 0, 1, or 2.
  • L 1 is –CH(Me)-. In certain embodiments, L 1 is –CH2CH2-. In certain embodiments of [DD1], L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF 2 -, -CH 2 CH(F)-, or –CH 2 CF 2 -. In certain embodiments of [DD1], L 1 is a bond.
  • X 1 is as defined in [EE1]: [EE1]: x X 1 is –L 1 -R 5 ; and x R 5 is R g .
  • R 5 is heterocyclyl including from 3-10, such as 4-8, ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); x1 is 0, 1, or 2; and x2 is 0, 1, 2, or 3, provided that x1+x2 ⁇ 1.
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); and x1 and x2 are each independently 0, 1, or 2.
  • [EE1] when , 1.
  • R 5 can be selected from In certain embodiments of [EE1], R 5 is C 3-10 cycloalkyl which is optionally substituted with from 1-2 R c . In certain embodiments of [EE1], R 5 is C 3-10 cycloalkyl which is optionally substituted with from 1-2 R c . As non-limiting examples of the forgoing embodiments, R 5 can be cyclopropyl or cyclobutyl. In certain embodiments of [EE1], L 1 is C 1-3 alkylene. In certain of these embodiments, L 1 is –CH 2 -. In certain embodiments, L 1 is –CH(Me)-.
  • L 1 is –CH2CH2-.
  • L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF 2 -, -CH 2 CH(F)-, or –CH 2 CF 2 -.
  • L 1 is a bond.
  • X 1 is as defined in [EE2]: [EE2]: x X 1 is –L 1 -R 5 ; x L 1 is C 1-10 alkylene optionally substituted with from 1-3 R a ; and x R 5 is selected from the group consisting of: H; halo; -OH; -NR e R f ; and -C 1-6 alkoxy or -S(O) 0-2 (C 1-6 alkyl), each optionally substituted with from 1-6 R a .
  • R 5 is H. In certain embodiments of [EE2], R 5 is -F.
  • L 1 is C 1-3 alkylene optionally substituted with from 1-3 R a .
  • L 1 can be C 1-3 alkylene optionally substituted with from 1-3 independently selected halo.
  • L 1 is C 1-3 alkylene. In certain of these embodiments, L 1 is –CH2-. In certain embodiments, L 1 is –CH(Me)-. In certain embodiments, L 1 is –CH 2 CH 2 -.
  • L 1 is C 1-3 alkylene substituted with from 1-3 independently selected halo, such as –CH(F)-, -CF2-, -CH2CH(F)-, or –CH2CF2-.
  • halo such as –CH(F)-, -CF2-, -CH2CH(F)-, or –CH2CF2-.
  • X 1 is as defined in [FF1]: [FF1]: x x L 2 is C 1-6 alkylene optionally substituted with from 1-3 R a ; and x R 6 is selected from the group consisting of: H; halo; -OH; NR e R f ; and -C1- 6 alkoxy or -S(O) 0-2 (C 1-6 alkyl), each optionally substituted with from 1-6 R a .
  • R 6 is C 1-6 alkoxy or -S(O) 0-2 (C 1-6 alkyl), each optionally substituted with from 1-6 R a .
  • R 6 is C 1-6 alkoxy optionally substituted with from 1-6 R a , such as C 1-3 alkoxy, such as methoxy.
  • R 6 is –S(O)2(C 1-6 alkyl) optionally substituted with from 1-6 R a .
  • R 6 is –NR e R f .
  • L 2 is C 1-3 alkylene.
  • L 2 is –CH 2 - or –CH(Me)-. In certain embodiments of [FF1], L 2 is –CH 2 CH 2 -. In certain embodiments of [FF1], L 2 is C3-6 branched alkylene. In certain embodiments of [FF1], L 2 is –C(Me) 2 -.
  • X 1 is as defined in [GG1]: [GG1]: x x L 2 is a bond; and x R 6 is R g .
  • R 6 is heterocyclyl including from 3-10, such as 4-8, ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 6 is which is optionally substituted with from 1-2 R c , wherein X a is O, N(H), or N(R d ); and x1 and x2 are each independently 0, 1, or 2.
  • x1 is 0.
  • X a is –O-.
  • R 6 can be ,
  • the compound is a compound of Formula (I-g): Formula (I-g) or a pharmaceutically acceptable salt thereof, wherein: Ring C1 is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1- 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C1 is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring C1 can be selected from the group In certain embodiments of Formula (I-g), Ring C1 .
  • each R c present in Ring C1 is halo (e.g., –F or –Cl).
  • each R c present in Ring C1 is C 1-3 alkyl optionally substituted with from 1-3 R a ; or in certain embodiments of Formula (I-g), Ring , wherein the R c present in Ring C1 is halo or C 1-3 alkyl optionally substituted with from 1-3 R a .
  • the R c can be –F.
  • the compound is a compound of Formula (I-h): Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: Ring C2 is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C2 is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4, such as 2-4, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c .
  • Ring C2 is attached t a 5-membered ring.
  • Ring C2 can be selected from the group consisting of: , , , , , In certain embodiments (when Ring C2 is bicyclic heteroaryl including 9 ring atoms as defined supra), Ring C2 is attached via a 6-membered ring. As non-limiting examples of the foregoing embodiments, Ring C2 can be selected with from 1-2 R c .
  • Ring C2 can be selected from the group consisting of: In certain embodiments of Formula (I-h), Ring C2 is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N , O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with 1-4 R c . In certain of these embodiments, Ring C2 is selected from the group consisting of: , For example, Ring C2 can or . As further non-limiting examples, Ring C2 can .
  • Ring C2 is selected from the group consisting of: , wherein: each occurrence of R c present on one or more ring atoms of Ring C2 is independently selected from the group consisting of: halo; NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; C 1-3 alkyl substituted with from 1-3 independently selected halo; C 1-3 alkyl substituted with C 1-4 alkoxy; and C 1-4 alkoxy substituted with C 1-4 alkoxy.
  • each occurrence of R c present on one or more ring atoms of Ring C2 is independently selected from the group consisting of C 1-4 alkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-3 independently selected halo.
  • each occurrence of R c present on one or more ring atoms of Ring C2 can be independently selected from the group consisting of: OMe, OEt, methyl, and CHF2.
  • each occurrence of R c present on one or more ring atoms of Ring C, Ring C1, or Ring C2 is independently selected from the group consisting of: halo; NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; C 1-3 alkyl substituted with from 1-3 independently selected halo; C 1-3 alkyl substituted with C 1-4 alkoxy; and C 1- 4 alkoxy substituted with C 1-4 alkoxy.
  • R 1c is H.
  • Y 1 is a bond.
  • Y 1 is In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), (I-e) (e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), Y 1 is In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), (I-e) (e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), R 2a is C 1-6 alkyl, which is optionally substituted with from 1-6 R a .
  • R 2a is C 1-6 alkyl, such as C 1-3 alkyl, such as wherein R 2a is methyl, ethyl, or n-propyl, such as methyl.
  • R 2a is C 1-6 alkyl which is substituted with from 1-6 independently selected halo, such as C 1-3 alkyl substituted with from 1-3 –F, such as: wherein R 2a is selected from the group consisting of: -CF3, -CHF2, -CH2F, -CH2CH2F, In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), (I-e) (e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), R 2a is C 3-10 , such as C 3-6 , cycloalkyl which is optional
  • R 2a is C 3-6 cycloalkyl, such as cyclopropyl, which is optionally substituted with from 1-2 R c .
  • R 2a is H.
  • R 2b is H.
  • R 2a and R 2b are both H.
  • R 2a and R 2b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R c .
  • R 3a and R 3b are both H.
  • one of R 3a and R 3b is C 1-6 alkyl optionally substituted with from 1-6 R a , such as wherein one of R 3a and R 3b is C 1-3 alkyl, such as methyl, ethyl, or propyl. In certain of these embodiments, the other of R 3a and R 3b is H.
  • R 4a and R 4b are both H.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each indepenendently selected from the group consisting of H, R b , R g , -CH2R g , halo, cyano, C1- 4 alkoxy, and C 1-4 haloalkoxy.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of H and C 1-3 alkyl optionally substituted with from 1-3 independently selected R a .
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each H.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); and each of the remaining five R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is H.
  • R 3a and R 3b are C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); the other of R 3a and R 3b is H; and each of R 2a , R 2b , R 4a , and R 4b is H.
  • R 4a and R 4b are C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); the other of R 4a and R 4b is H; and each of R 2a , R 2b , R 3a , and R 3b is H.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is C 3-6 cycloalkyl or –CH 2 (C 3-6 cycloalkyl); each of the remaining five R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b is H; and the C3-6 cycloalkyl is optionally substituted with from 1-2 R c .
  • R 3a and R 3b are C 3-6 cycloalkyl or –CH 2 (C 3- 6 cycloalkyl); the other of R 3a and R 3b is –H; and each of R 2a , R 2b , R 4a , and R 4b is H; and the C3-6 cycloalkyl is optionally substituted with from 1-2 R c .
  • R 2a and R 2b and the other of R 4a and R 4b are each H; and R 3a and R 3b are independently selected from the group consisting of H and C 1-3 alkyl.
  • Formula (I-a), (I-b), (I-c), (I-d), (I-e) e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), wherein the other of R 3a and R 3b and the other of R 4a and R 4b are each H.
  • Formula (I-a), (I-b), (I-c), (I-d), (I-e) e.g., Formula (I- , wherein each R cB is an independently selected R c ; and m is 0, 1, 2, 3, or 4. In certain of these embodiments, m is 1 or 2, such as 2.
  • each R cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo.
  • -halo such as -Cl and -F
  • -CN C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo.
  • Ring each R cB is an independently selected R c .
  • each R cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo.
  • Ring A is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring A is bicyclic heteroaryl including from 9- 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring A can be selected , In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), (I-e) (e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), Ring A is C 8-10 bicyclic aryl, optionally substituted with from 1-2 R c .
  • Ring A can be naphthyl optionally substituted with from 1-2 R c (e.g., In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), (I-e) (e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), R 4 is H.
  • R c e.g., In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), (I-e) (e.g., Formula (I- e1), (I-e2), or (I-e3)), (I-f), (I-g), or (I-h), R 4 is H.
  • the compound is a compound of Formula (I-e4): Formula (I-e4) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Z 1 , Z 2 , and Z 3 are each independently selected from the group consisting of CH, CR c , and N; X 1 is –O-L 1 -R 5 or –L 1 -R 5 , wherein: L 1 is a
  • Z 1 is N; and Z 2 is N. In certain embodiments of Formula (I-e4), Z 1 is N; and Z 2 is CR c . As non-limiting examples, Z 2 can be C-O-C 1-3 alkyl or CH. In certain embodiments of Formula (I-e4), Z 1 is CH; and Z 2 is N or CR c . As non- limiting examples, Z 2 can be N or C-O-C 1-3 alkyl. In certain embodiments of Formula (I-e4), Z 3 is CH; and n is 0. In certtain embodiments of Formula (I-e4), m is 2.
  • X 1 is –O-L 1 -R 5 or –L 1 -R 5 ; and R 5 is selected from the group consisting of: x C3-6 cycloalkyl optionally substituted with from 1-2 R c ; and x heterocyclyl including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , wherein the heterocyclyl is optionally substituted with from 1-2 R c .
  • R 5 is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and tetrahydrofuranyl, each optionally substituted with from 1-2 R c .
  • X 1 is –O-L 1 -R 5 or –L 1 -R 5 ; and R 5 is selected from the group consisting of: H and F.
  • L 1 is a bond.
  • L 1 is C 1-3 alkylene optionally substituted with from 1-3 R a .
  • L 1 is C 1-3 alkylene optionally substituted with from 1-3 independently selected halo.
  • L 1 can be selected from the group consisting of: -CH2-, -CH2CH2-, -CH(Me)-, and –CH(F)-.
  • X 1 is selected from the group consisting of: , , .
  • X 1 is selected from the group consisting of: Me, CHF2, cyclopropyl.
  • X 1 is selected from the group consisting
  • the compound is a compound of Formula (I-g1): Formula (I-g1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Z 1 , Z 2 , and Z 3 are each independently selected from the group consisting of CH, CR cC2 , and N, provided that at least one of Z 1 , Z 2 , and Z 3 is CH; each R cC2 independently is selected from the group consisting of: -halo; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with from 1-6 independently selected halo; m is 1, 2, or 3; each R cB is independently selected from the group consisting of: -halo; -CN; C 1-4 alkoxy; C 1-4 haloalkoxy; C 1-3 alkyl; and C 1-3 alkyl substituted with
  • Z 1 is N; and Z 2 is N. In certain embodiments of Formula (I-g1), Z 1 is N; and Z 2 is CR cC2 . As non- limiting examples, Z 2 can be C-O-C 1-3 alkyl or CH. In certain embodiments of Formula (I-g1), Z 1 is CH; and Z 2 is N or CR cC2 . As non- limiting examples, Z 2 can be N or C-O-C 1-3 alkyl. In certain embodiments of Formula (I-g1), Z 3 is CH; and n is 0. In certtain embodiments of Formula (I-g1), m is 2.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are defined according to (AA).
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of H and C 1-3 alkyl optionally substituted with from 1-3 independently selected R a .
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each H.
  • one of R 3a and R 3b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); the other of R 3a and R 3b is H; and each of R 2a , R 2b , R 4a , and R 4b is H.
  • one of R 4a and R 4b is C 1-3 alkyl optionally substituted with from 1-3 independently selected R a (e.g., methyl); the other of R 4a and R 4b is H; and each of R 2a , R 2b , R 3a , and R 3b is H.
  • R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are defined according to (BB).
  • the other of R 2a and R 2b and the other of R 4a and R 4b are each H; and R 3a and R 3b are independently selected from the group consisting of H and C 1-3 alkyl.
  • one of R 2a and R 2b and one of R 4a and R 4b taken together with the Ring B ring atoms to which each is attached can form a fused cyclobutyl; and optionally the other of R 2a and R 2b and the other of R 4a and R 4b can each be H.
  • one of R 3a and R 3b and one of R 4a and R 4b taken together with the Ring B ring atoms to which each is attached form a fused C 3-6 cycloalkyl which is optionally substituted with from 1-2 R c .
  • the other of R 3a and R 3b and the other of R 4a and R 4b are each H.
  • Non-Limiting Exemplary Compounds the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof. Table C1
  • a chemical entity e.g., a compound that inhibits EGFR and/or HER2, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof
  • a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.
  • the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-
  • Cyclodextrins such as ⁇ -, E, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared.
  • the contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.
  • Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, sub
  • compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes.
  • parenteral administration e.g., intratumoral
  • Such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
  • injectables either as liquid solutions or suspensions
  • solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
  • the preparation of such formulations will be known to those of skill in the art in light of the present disclosure.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788–795.
  • Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylo
  • suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.
  • compositions for rectal administration are in the form of an enema.
  • the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule).
  • Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
  • physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms.
  • Various preservatives are well known and include, for example, phenol and ascorbic acid.
  • the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.
  • solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel.
  • Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques.
  • enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat).
  • hydroxypropyl methylcellulose phthalate series Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat).
  • Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).
  • viscogens e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol
  • Stabilizers e.g., Pluronic (triblock copolymers), Cyclodextrins
  • Preservatives e.g., Benzalkonium chloride, ETDA, SofZ
  • Topical compositions can include ointments and creams.
  • Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
  • Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil.
  • Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.
  • the dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts.
  • the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.
  • the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg
  • the foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).
  • a daily basis e.g., as a single dose or as two or more divided doses
  • non-daily basis e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month.
  • the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a therapeutic compound is administered to an individual for a period of time followed by a separate period of time.
  • a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped.
  • the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time.
  • a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • Methods of Treatment Indications Provided herein are methods for inhibiting epidermal growth factor receptor tyrosine kinase (EGFR) and/or human epidermal growth factor receptor 2 (HER2).
  • inhibitors of EGFR useful for treating or preventing diseases or disorders associated with dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same (i.e., an EGFR-associated disease or disorder), such as a central nervous system diseases, a pulmonary disorder, cardiovascular disease, ischemia, liver disease, a gastrointestinal disorder, a viral or bacterial infection, an inflammatory and/or autoimmune disease, or cancer (e.g., EGFR-associated cancer).
  • an EGFR-associated disease or disorder such as a central nervous system diseases, a pulmonary disorder, cardiovascular disease, ischemia, liver disease, a gastrointestinal disorder, a viral or bacterial infection, an inflammatory and/or autoimmune disease, or cancer (e.g., EGFR-associated cancer).
  • inhibitors of HER2 useful for treating or preventing diseases or disorders associated with dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, such as cancer (e.g., HER2- associated cancer).
  • cancer e.g., HER2- associated cancer
  • An “EGFR inhibitor” as used herein includes any compound exhibiting EGFR inactivation activity (e.g., inhibiting or decreasing).
  • an EGFR inhibitor can be selective for an EGFR kinase having one or more mutations.
  • an EGFR inhibitor can bind to the adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain.
  • an EGFR inhibitor is an allosteric inhibitor.
  • the compounds provided herein can inhibit EGFR.
  • the compounds can bind to the EGFR adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain.
  • the ability of test compounds to act as inhibitors of EGFR may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as EGFR inhibitors can be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of the kinase and/or ATPase activity. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labelling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radioligands. In some cases, an EGFR inhibitor can be evaluated by its effect on the initial velocity of EGFR tyrosine kinase catalyzed peptide phosphorylation (e.g., Yun et al.
  • the binding constant of an EGFR inhibitor can be determined using fluorescence kinetics (e.g., Yun et al. Cancer Cell. 2007;11(3):217–227).
  • fluorescence kinetics e.g., Yun et al. Cancer Cell. 2007;11(3):217–227).
  • SPR surface plasmon resonance
  • Additional EGFR inhibitor assays can be found, for example, in WO 2019/246541 and WO 2019/165358 both of which are incorporated by reference in their entireties).
  • Assays can include, for example, proliferation inhibition assays such as those that measure cell growth inhibition, such as an MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®).
  • proliferation inhibition assays such as those that measure cell growth inhibition, such as an MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®).
  • MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®).
  • MTS assay assay for Luminescent Cell viability assay
  • Promega® Cell Titer Glo Luminescent Cell viability assay
  • Such assays use a luminescent oxygen-channeling chemistry to detect molecules of interest in, for example, buffer, cell culture media, serum, and plasma.
  • a biotinylated EGF is bound to streptavidin-coated Alpha donor beads, and EGFR-Fc is captured by anti- human IgG Fc-specific AlphaLISA acceptor beads.
  • donor beads and acceptor beads come into close proximity, and the excitation of the donor beads provokes the release of singlet oxygen molecules that triggers a cascade of energy transfers in the acceptor beads. This results in a sharp peak of light emission at 615 nm.
  • Such assays can be used, for example, in competitive binding experiments.
  • assays can include assays based on Sox technology (e.g., see the PHOSPHOSENS® Sox-based Homogeneous, Kinetic or Endpoint/Red Fluorescence- based Assays from ASSAYQUANT®).
  • Sox chelation-enhanced fluorescence
  • Sox sulfonamido-oxine
  • Potency of an EGFR inhibitor as provided herein can be determined by EC 50 value.
  • a compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 value.
  • the substantially similar conditions comprise determining an EGFR- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, A431 cells, Ba/F3 cells, or 3T3 cells cells expressing a wild type EGFR, a mutant EGFR, or a fragment of any thereof). Potency of an EGFR inhibitor as provided herein can also be determined by IC 50 value.
  • a compound with a lower IC50 value, as determined under substantially similar conditions is a more potent inhibitor relative to a compound with a higher IC50 value.
  • the substantially similar conditions comprise determining an EGFR- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, A431 cells, Ba/F3 cells, or 3T3 cells expressing a wild type EGFR, a mutant EGFR, or a fragment of any thereof).
  • the selectivity between wild type EGFR and EGFR containing one or more mutations as described herein can also be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity.
  • murine Ba/F3 cells transfected with a suitable version of wild type EGFR such as VIII; containing a wild type EGFR kinase domain
  • Ba/F3 cells transfected with L858R/T790M, Del/T790M/L718Q, L858R/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R, exon 19 deletion/T790M, or an exon 20 insertion such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, or H773_V774insX (e.g., A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNP
  • Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 ⁇ M, 3 ⁇ M, 1.1 ⁇ M, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC 50 is calculated.
  • An alternative method to measure effects on EGFR activity is to assay EGFR phosphorylation.
  • EGFR can be transfected into cells which do not normally express endogenous EGFR and the ability of the inhibitor (e.g., using concentrations as above) to inhibit EGFR phosphorylation can be assayed. Cells are exposed to increasing concentrations of inhibitor and stimulated with EGF.
  • the compounds provided herein can exhibit potent and selective inhibition of EGFR.
  • the compounds provided herein can bind to the EGFR adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain.
  • ATP adenosine triphosphate
  • the compounds provided herein can exhibit nanomolar potency against an EGFR kinase including an activating mutation or an EGFR inhibitor resistance mutation, including, for example, the resistance mutations in Table 2a and Table 2b (e.g., L747S, D761Y, T790M, and T854A), with minimal activity against related kinases (e.g., wild type EGFR).
  • Inhibition of wild type EGFR can cause undesireable side effects (e.g., diarrhea and skin rashes) that can impact quality of life and compliance.
  • the inhibititon of wild type EGFR can lead to dose limiting toxicities. See, e.g., Morphy. J. Med.
  • the compounds of Formula (I) can selectively target an EGFR kinase.
  • Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof can selectively target an EGFR kinase.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target an EGFR kinase over another kinase or non-kinase target.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of EGFR containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1a and Table 1b) relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of EGFR having a combination of mutations described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000- fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit greater inhibition of EGFR containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1a and Table 1b) relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit at least 2-fold, 3-fold, 5- fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit up to 10000-fold greater inhibition of EGFR having a combination of mutations described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR.
  • Compounds of Formula (I) are useful for treating diseases and disorders which can be treated with an EGFR inhibitor, such as EGFR-associated diseases and disorders, e.g., central nervous system diseases (e.g., neurodegenerative diseases), pulmonary disorders, cardiovascular disease, ischemia, liver disease, gastrointestinal disorders, viral or bacterial infections, inflammatory and/or autoimmune diseases (e.g., psoriasis and atopic dermatitis), and proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors).
  • EGFR-associated diseases and disorders e.g., central nervous system diseases (e.g., neurodegenerative diseases), pulmonary disorders, cardiovascular disease, ischemia, liver disease, gastrointestinal disorders, viral or bacterial infections, inflammatory and/or autoimmune diseases (e.g., psoriasis and atopic dermatitis), and proliferative disorders such as cancers, including hematological cancers and solid tumors (e
  • a “HER2 inhibitor” as used herein includes any compound exhibiting HER2 inactivation activity (e.g., inhibiting or decreasing).
  • a HER2 inhibitor can be selective for a HER2 kinase having one or more mutations.
  • a HER2 inhibitor can bind to the HER2 adenosine triphosphate (ATP)- binding site in the tyrosine kinase domain.
  • the compounds provided herein can inhibit HER2.
  • the compounds can bind to the HER2 adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain.
  • the compounds provided herein can inhibit wild type HER2.
  • the compounds provided herein can inhibit HER2 having one or more mutations as described herein.
  • the ability of test compounds to act as inhibitors of HER2 may be demonstrated by assays known in the art.
  • the activity of the compounds or compositions provided herein as HER2 inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase and/or ATPase activity.
  • HER2 inhibitor can be evaluated by its effect on the initial velocity of HER2 tyrosine kinase catalyzed peptide phosphorylation (e.g., Yun et al. Cancer Cell. 2007;11(3):217–227).
  • an assay that indirectly measures ADP formed from the HER2 kinase reaction can be used (see, e.g., ATP/NADH coupled assay systems and luminescent kinase assays such as ADP-GLO TM Kinase Assay from Promega). See, e.g., Hanker et al. Cancer Discov.2017 Jun;7(6):575-585; Robichaux et al. Nat Med. 2018 May; 24(5): 638–646; and Yun et al. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5.
  • an assay that detects substrate phosphorylation using a labeled anti-phospho-tyrosine antibody can be used (see, e.g., Rabindran et al. Cancer Res.2004 Jun 1;64(11):3958-65).
  • the binding constant of a HER2 inhibitor can be determined using fluorescence kinetics (e.g., Yun et al. Cancer Cell. 2007;11(3):217–227). Examples of SPR binding assays include those disclosed in Li, Shiqing, et al. Cancer cell 7.4 (2005): 301-311.
  • covalent binding of a HER2 inhibitor to HER2 can be detected using mass spectrometry, see, e.g., Irie et al. Mol Cancer Ther. 2019 Apr;18(4):733-742. Additional HER2 inhibitor assays can be found, for example, in U.S. Patent No.9,920,060, WO 2019/241715, and U.S. Publication No.2017/0166598, each of which are incorporated by reference in their entireties. Potency of a HER2 inhibitor as provided herein can be determined by EC50 value. A compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC 50 value.
  • the substantially similar conditions comprise determining an HER2- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells or Ba/F3 cells expressing a wild type HER2, a mutant HER2, or a fragment of any thereof). Potency of an HER2 inhibitor as provided herein can also be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC 50 value.
  • the substantially similar conditions comprise determining an HER2- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells or Ba/F3 cells expressing a wild type HER2, a mutant HER2, or a fragment of any thereof).
  • Assays can include, for example, proliferation inhibition assays such as those that measure cell growth inhibition, such as an MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®). To perform such an assay, cells are seeded and grown in cell culture plates before being exposed to a test compound for varying durations. Assessment of the viability of the cells following this exposure is then performed. Data are normalized with respect to untreated cells and can be displayed graphically.
  • Growth curves can be fitted using a nonlinear regression model with sigmoidal dose response.
  • a Western Blot analysis can be used. In such assays cells are seeded and grown in culture plates and then treated with a test compound the following day for varying durations. Cells are washed with PBS and lysed.
  • SDS-PAGE gels are used to separate the lysates which are transferred to nitrocellulose membranes, and probed with appropriate antibodies (e.g., phospho-HER2(Tyr1248)(2247), phospho-EGFR-Tyr1173 phospho- HER2-Tyr877, phospho-HER2-Tyr1221, total HER2, phospho-AKT-Thr308, phospho- AKT-Ser374, total AKT, phospho-p44/42 MAPK-Thr202/Tyr204, and p44/42 MAPK).
  • the selectivity between wild type HER2 and HER2 containing one or more mutations as described herein can also be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity.
  • murine Ba/F3 cells transfected with a suitable version of wild type HER2, or Ba/F3 cells transfected with HER2 having one or more mutations such as S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, V842I, M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, or P780_Y781insG
  • Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 ⁇ M, 3 ⁇ M, 1.1 ⁇ M, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC 50 is calculated.
  • An alternative method to measure effects on HER2 activity is to assay HER2 phosphorylation.
  • HER2 can be transfected into cells which do not normally express endogenous HER2 and the ability of the inhibitor (e.g., using concentrations as above
  • the compounds provided herein can exhibit potent and selective inhibition of HER2.
  • the compounds provided herein can bind to the HER2 adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain.
  • ATP adenosine triphosphate
  • the compounds provided herein can exhibit nanomolar potency against a HER2 kinase including an activating mutation or a HER2 inhibitor resistance mutation, including, for example, exon 20 insertions and/or the resistance mutations in Table 5 (e.g., L755S, L755P, T798I, and T798M), with minimal activity against related kinases (e.g., wild type EGFR).
  • a HER2 kinase including an activating mutation or a HER2 inhibitor resistance mutation including, for example, exon 20 insertions and/or the resistance mutations in Table 5 (e.g., L755S, L755P, T798I, and T798M), with minimal activity against related kinases (e.g., wild type EGFR).
  • the compounds of Formula (I) can selectively target a HER2 kinase.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target a HER2 kinase over another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Table 3) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 10000-fold greater inhibition of wild type HER2 or HER2 having a combination of mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 10-fold to about 100-fold greater inhibition of wild type HER2 or containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 1000-fold to about 10000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Table 3) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100- fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • non- kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit up to 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit up to 10000-fold greater inhibition of wild type HER2 or HER2 having a combination of mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 2-fold to about 10-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 10-fold to about 100-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 100-fold to about 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 1000-fold to about 10000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • Compounds of Formula (I) are useful for treating diseases and disorders which can be treated with a HER2 inhibitor, such as HER2-associated diseases and disorders, e.g., proliferative disorders such as cancers (e.g., a HER2-associated cancer), including hematological cancers and solid tumors (e.g., advanced solid tumors).
  • a HER2 inhibitor such as HER2-associated diseases and disorders, e.g., proliferative disorders such as cancers (e.g., a HER2-associated cancer), including hematological cancers and solid tumors (e.g., advanced solid tumors).
  • the compounds provided herein can also inhibit EGFR and HER2 as described herein. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of EGFR and HER2. In some embodiments, the compounds provided herein can exhibit nanomolar potency against an EGFR kinase having one or more mutations, including, for example, one or more of the mutations in Tables 1a, 1b and 2a, 2b, and a HER2 kinase having one or more mutations, including, for example, the mutations in Table 3, with minimal activity against related kinases (e.g., wild type EGFR).
  • related kinases e.g., wild type EGFR
  • the compounds of Formula (I) can selectively target an EGFR and a HER2 kinase.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target an EGFR kinase and a HER2 kinase over another kinase or non-kinase target.
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Tables 3-5) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • non-kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • non-kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 having one or more mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 100-fold to about 1000- fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Table 3) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2)
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25- fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • non- kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or HER2 inhibitor can exhibit up to 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 having a combination of mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • non- kinase target e.g., wild type EGFR
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein and HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • non- kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein and HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target.
  • another kinase e.g., wild type EGFR
  • non- kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein and second HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • non-kinase target e.g., wild type EGFR
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target.
  • another kinase e.g., wild type EGFR
  • methods for inhibiting a BUB budding uninhibited by benzimidazole, BUB1-3
  • inhibitors of BUB1 kinase useful for treating or preventing diseases or disorders associated with enhanced uncontrolled proliferative cellular processes such as, for example, cancer, inflammation, arthritis, viral diseases, cardiovascular diseases, or fungal diseases.
  • diseases or disorders associated with enhanced uncontrolled proliferative cellular processes such as, for example, cancer, inflammation, arthritis, viral diseases, cardiovascular diseases, or fungal diseases.
  • the disease or disorder is cancer.
  • a “BUB1 inhibitor” as used herein includes any compound exhibiting BUB1 inactivation activity (e.g., inhibiting or decreasing).
  • a BUB1 inhibitor can be selective for BUB1 over other kinases (e.g., wildtype EGFR).
  • the compounds provided herein can inhibit a Bub kinase.
  • the compounds provided herein can inhibit BUB1 kinase.
  • the ability of test compounds to act as inhibitors of BUB1 may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as BUB1 inhibitors can be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of the kinase.
  • BUB1 inhibition of a compound provided herein can be determined using a time-resolved fluorescence energy transfer (TR-FRET) assay which measures phosphorylation of a synthetic peptide (e.g., Biotin-AHX-VLLPKKSFAEPG (C-terminus in amide form) by the (recombinant) catalytic domain of human BUB1 (amino acids 704-1085), expressed in Hi5 insect cells with an N-terminal His6-tag and purified by affinity- (Ni-NTA) and size exclusion chromatography.
  • TR-FRET time-resolved fluorescence energy transfer
  • BUB1 activity can be determined at a high ATP concentration using a BUB1 TR-FRET high ATP kinase assay using similar methods as those described above. See, e.g. WO 2019/081486.
  • the compounds provided herein exhibit central nervous system (CNS) penetrance.
  • CNS central nervous system
  • such compounds can be capable of crossing the blood brain barrier (BBB) and inhibiting an EGFR and/or HER2 kinase in the brain and/or other CNS structures.
  • the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount.
  • treatment of a patient with cancer can include administration (e.g., oral administration) of the compound to the patient.
  • administration e.g., oral administration
  • assays known in the art.
  • Such assays include BBB models such as the transwell system, the hollow fiber (dynamic in vitro BBB) model, other microfluidic BBB systems, the BBB spheroid platform, and other cell aggregate-based BBB models. See, e.g., Cho et al.
  • the compounds described herein are fluorescently labeled, and the fluorescent label can be detected using microscopy (e.g., confocal microscopy).
  • microscopy e.g., confocal microscopy
  • the ability of the compound to penetrate the surface barrier of the model can be represented by the fluorescence intensity at a given depth below the surface.
  • the fluorescent label is non-fluorescent until it permeates live cells and is hydrolyzed by intracellular esterases to produce a fluorescent compound that is retained in the cell and can be quantified with a spectrophotometer.
  • fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared IRDye® CW-800 (LICOR #929-71012), far-red IRDye® 650 (LICOR #929- 70020), sodium fluorescein (Na-F), lucifer yellow (LY), 5’carboxyfluorescein, and calcein-acetoxymethylester (calcein-AM).
  • the BBB model (e.g., the tissue or cell aggregate) can be sectioned, and a compound described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analyses).
  • mass spectrometry e.g., MALDI-MSI analyses.
  • the ability of a compound described herein to cross the BBB through a transcellular transport system such as receptor-mediated transport (RMT), carrier- mediated transport (CMT), or active efflux transport (AET), can be demonstrated by assays known in the art. See, e.g., Wang et al. Drug Deliv. 2019; 26(1): 551–565.
  • assays to determine if compounds can be effluxed by the P-glycoprotein (Pgp) include monolayer efflux assays in which movement of compounds through Pgp is quantified by measuring movement of digoxin, a model Pgp substrate (see, e.g., Doan et al.2002. J Pharmacol Exp Ther.303(3):1029-1037).
  • Alternative in vivo assays to identify compounds that pass through the blood-brain barriers include phage-based systems (see, e.g., Peng et al. 2019. ChemRxiv. Preprint doi.org/10.26434/chemrxiv.8242871.v1).
  • binding of the compounds described herein to brain tissue is quantified.
  • a brain tissue binding assay can be performed using equilibrium dialysis, and the fraction of a compound described herein unbound to brain tissue can be detected using LC-MS/MS (Cyprotex: Brain Tissue Binding Assay www.cyprotex.com/admepk/protein_binding/brain-tissue-binding/).
  • Compounds of Formula (I) are useful for treating diseases and disorders which can be treated with an EGFR inhibitor, a HER2 inhibitor, a dual EGFR and HER2 inhibitor, and/or a BUB1 inhibitor, such as those described herein, e.g., cancer.
  • a method for treating a disease or disorder as provided herein in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the disease or disorder is cancer.
  • terms “treat” or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the terms “subject,” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the subject is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (an EGFR-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject has a tumor that is positive for a mutation as described in Table 1a and Table 1b.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having an EGFR-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (a HER2-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency- approved assay or kit).
  • the subject has a tumor that is positive for a mutation as described in Table 3.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA- approved, assay or kit).
  • the subject can be a subject whose tumors have a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a HER2-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the subject is a pediatric subject.
  • the term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment.
  • the term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed.
  • a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday).
  • a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.
  • compounds of Formula (I) are useful for preventing diseases and disorders as defined herein (for example, autoimmune diseases, inflammatory diseases, pulmonary disorders, cardiovascular disease, ischemia, liver disease, gastrointestinal disorders, viral or bacterial infections, central nervous system diseases (e.g., neurodegenerative diseases), and cancer).
  • diseases and disorders for example, autoimmune diseases, inflammatory diseases, pulmonary disorders, cardiovascular disease, ischemia, liver disease, gastrointestinal disorders, viral or bacterial infections, central nervous system diseases (e.g., neurodegenerative diseases), and cancer).
  • EGFR-associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of an EGFR gene, an EGFR kinase (also called herein an EGFR kinase protein), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of an EGFR gene, an EGFR kinase, an EGFR kinase domain, or the expression or activity or level of any of the same described herein).
  • Non-limiting examples of an EGFR-associated disease or disorder include, for example, cancer, a central nervous system disease, a pulmonary disorder, cardiovascular disease, ischemia, liver disease, a gastrointestinal disorder, a viral or bacterial infection, and an inflammatory and/or autoimmune disease (e.g., psoriasis, eczema, atopic dermatitis, and atherosclerosis).
  • an inflammatory and/or autoimmune disease e.g., psoriasis, eczema, atopic dermatitis, and atherosclerosis.
  • the inflammatory and/or autoimmune disease is selected from arthritis, systemic lupus erythematosus, atherosclerosis, and skin related disorders such as psoriasis, eczema, and atopic dermatitis.
  • the central nervous system disease is a neurodegenerative disease.
  • the central nervous system disease is selected from Alzheimer's disease, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, brain ischemia, and a psychiatric disorder such as schizophrenia.
  • a psychiatric disorder such as schizophrenia. See, e.g., Iwakura and Nawa. Front Cell Neurosci..2013 Feb 13;7:4; and Chen et al. Sci Rep.2019 Feb 21;9(1):2516.
  • the term “EGFR-associated cancer” as used herein refers to cancers associated with or having a dysregulation of an EGFR gene, an EGFR kinase (also called herein an EGFR kinase protein), or expression or activity, or level of any of the same.
  • Non-limiting examples of an EGFR-associated cancer are described herein.
  • the phrase “dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in an EGFR gene that results in the expression of an EGFR protein that includes a deletion of at least one amino acid as compared to a wild type EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with one or more point mutations as compared to a wild type EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with at least one inserted amino acid as compared to a wild type EGFR protein, a gene duplication that results in an increased level of EGFR protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of EGFR protein in a
  • a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same can be a mutation in an EGFR gene that encodes an EGFR protein that is constitutively active or has increased activity as compared to a protein encoded by an EGFR gene that does not include the mutation.
  • Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and Table 1b. Additional examples of EGFR kinase protein mutations (e.g., point mutations) are EGFR inhibitor resistance mutations (e.g., EGFR inhibitor mutations).
  • EGFR inhibitor resistance mutations are described in Table 2a and Table 2b.
  • the one or more EGFR inhibitor resistance mutations can include a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, or T854A).
  • Such mutation and overexpression is associated with the development of a variety of cancers (Shan et al., Cell 2012, 149(4) 860-870).
  • dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in an EGFR gene.
  • dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be caused by a genetic mutation that results in the expression of an EGFR kinase that has increased resistance to an EGFR inhibitor, a tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR kinase (see, e.g., the amino acid substitutions in Table 2a and Table 2b).
  • TKI tyrosine kinase inhibitor
  • MKI multi-kinase inhibitor
  • dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be caused by a mutation in a nucleic acid encoding an altered EGFR protein (e.g., an EGFR protein having a mutation (e.g., a primary mutation)) that results in the expression of an altered EGFR protein that has increased resistance to inhibition by an EGFR inhibitor, a tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR kinase (see, e.g., the amino acid substitutions in Table 2a and Table 2b).
  • an altered EGFR protein e.g., an EGFR protein having a mutation (e.g., a primary mutation)
  • TKI tyrosine kinase inhibitor
  • MKI multi-kinase inhibitor
  • the exemplary EGFR kinase point mutations, insertions, and deletions shown in Tables 1a, 1b and 2a, 2b can be caused by an activating mutation and/or can result in the expression of an EGFR kinase that has increased resistance to an EGFR inhibitor), tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI).
  • the individual has two or more EGFR inhibitor resistance mutations that increase resistance of the cancer to a first EGFR inhibitor.
  • the individual can have two EGFR inhibitor resistance mutations.
  • the two mutations occur in the same EGFR protein.
  • the two mutations occur in separate EGFR proteins.
  • the individual can have three EGFR inhibitor resistance mutations. In some embodiments, the three mutations occur in the same EGFR protein. In some embodiments, the three mutations occur in separate EGFR proteins.
  • the individual has two or more EGFR inhibitor resistance mutations selected from Del 19/L718Q, Del 19/T790M, Del 19/L844V, Del 19/T790M/L718Q, Del/T790M/C797S, Del 19/T790M/L844V, L858R/L718Q, L858R/L844V, L858R/T790M, L858R/T790M/L718Q, L858R/T790M/C797S, and L858R/T790M/I941R, or any combination thereof; e.g., any two of the aforementioned EGFR inhibitor resistance mutations.
  • activating mutation in reference to EGFR describes a mutation in an EGFR gene that results in the expression of an EGFR kinase that has an increased kinase activity, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in an EGFR gene that results in the expression of an EGFR kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions.
  • one or more e.g., two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in an EGFR gene that results in the expression of an EGFR kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in an EGFR gene that results in the expression of an EGFR kinase that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wild type EGFR kinase, e.g., the exemplary wild type EGFR kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art.
  • wild type or wild-type describes a nucleic acid (e.g., an EGFR gene or an EGFR mRNA) or protein (e.g., an EGFR protein) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein.
  • nucleic acid e.g., an EGFR gene or an EGFR mRNA
  • protein e.g., an EGFR protein
  • wild type EGFR or wild-type EGFR
  • an EGFR nucleic acid e.g., an EGFR gene or an EGFR mRNA
  • protein e.g., an EGFR protein
  • wild type EGFR or wild-type EGFR
  • an EGFR-associated disease e.g., an EGFR-associated cancer
  • protein e.g., an EGFR protein
  • an EGFR-associated disease e.g., an EGFR-associated cancer
  • a method of treating cancer e.g., an EGFR-associated cancer
  • the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I- b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I- b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutical composition thereof.
  • kits for treating an EGFR-associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR kinase protein point mutations/insertions.
  • Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and Table 1b.
  • the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20 (e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, or H773_V774insX).
  • the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A.
  • the EGFR kinase protein insertion is an exon 20 insertion.
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; e.g., any two or more independently selected exon 20 insertion
  • the cancer e.g., EGFR-associated cancer
  • a hematological cancer e.g., acute lymphocytic cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia such as acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute- promyelocytic leukemia, and acute lymphocytic leukemia (ALL)
  • AML acute-myelogenous leukemia
  • CML chronic-myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • central or peripheral nervous system tissue cancer an endocrine or neuroendocrine cancer including multiple neuroendocrine type I and type II tumors, Li-Fraumeni tumors, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile
  • the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and oesophageal cancers, pancreatic, gastrointestinal cancer, gastric, breast, endometrial and colorectal cancers, hepatocellular carcinoma, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma.
  • the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, lung cancer, or breast cancer. In some cases, the cancer is melanoma, colon cancer, renal cancer, leukemia, or breast cancer.
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, Liu et al. J Exp Clin Cancer Res.2019 May 23;38(1):219); and Ding et al.
  • gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogli
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a metastatic brain tumor, e.g., a metastatic brain tumor from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, kidney cancer, bladder cancer, or undifferentiated carcinoma.
  • the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer).
  • the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance.
  • CNS central nervous system
  • the patient has previously been treated with another anticancer agent, e.g., another EGFR and/or HER2 inhibitor (e.g., a compound that is not a compound of Formula I) or a multi-kinase inhibitor.
  • the cancer is a cancer of B cell origin.
  • the cancer is a lineage dependent cancer.
  • the cancer is a lineage dependent cancer where EGFR or the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, plays a role in the initiation and/or development of the cancer.
  • the cancer is an EGFR-associated cancer.
  • a method for treating a subject diagnosed with or identified as having an EGFR-associated cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, as defined herein.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more deletions (e.g., deletion of an amino acid at position 4), insertions, or point mutation(s) in an EGFR kinase.
  • dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes at least one deletion, insertion, or point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions in Table 1a and Table 1b.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes a deletion of one or more residues from the EGFR kinase, resulting in constitutive activity of the EGFR kinase domain.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions, insertions, or deletions as compared to the wild type EGFR kinase (see, for example, the point mutations listed in Table 1a and Table 1b).
  • dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions in Table 1a and Table 1b.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes an insertion of one or more residues in exon 20 of the EGFR gene (e.g., any of the exon 20 insertions described in Table 1a and Table 1b).
  • Exon 20 of EGFR has two major regions, the c -helix (residues 762-766) and the loop following the c-helix (residues 767-774). Studies suggest that for some exon 20 insertions (e.g., insertions after residue 764), a stabilized and ridged active conformation induces resistance to first generation EGFR inhibitors.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes an insertion of one or more residues in exon 20 selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; e.g., any two 10 or more independently selected exon 20
  • EGFR Protein Amino Acid Substitutions/Insertions/Deletions A The EGFR mutations shown may be activating mutations and/or confer increased resistance of EGFR to an EGFR inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR B Potentially oncogenic variant. See, e.g., Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. 1 PCT Patent Application Publication No. WO2019/246541. 2 Grosse A, Grosse C, Rechsteiner M, Soltermann A. Diagn Pathol. 2019;14(1):18. Published 2019 Feb 11.
  • EGFR Protein Amino Acid Substitutions/Insertions/Deletions A The EGFR mutations shown may be activating mutations and/or confer increased resistance of EGFR to an EGFR inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR B Potentially oncogenic variant. See, e.g., Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. 1 PCT Patent Application Publication No. WO2019/246541. 2 Grosse A, Grosse C, Rechsteiner M, Soltermann A. Diagn Pathol. 2019;14(1):18. Published 2019 Feb 11.
  • MKI multi-kinase inhibitor
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes a splice variation in an EGFR mRNA which results in an expressed protein that is an alternatively spliced variant of EGFR having at least one residue deleted (as compared to the wild type EGFR kinase) resulting in a constitutive activity of an EGFR kinase domain.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions or insertions or deletions in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acids inserted or removed, as compared to the wild type EGFR kinase.
  • the resulting EGFR kinase is more resistant to inhibition (e.g., inhibition of its signaling activity) by one or more first EGFR inhibitors, as compared to a wild type EGFR kinase or an EGFR kinase not including the same mutation.
  • Such mutations optionally, do not decrease the sensitivity of the cancer cell or tumor having the EGFR kinase to treatment with a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, (e.g., as compared to a cancer cell or a tumor that does not include the particular EGFR inhibitor resistance mutation).
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions as compared to the wild type EGFR kinase, and which has increased resistance to a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I- e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as compared to a wild type EGFR kinase or an EGFR kinase not including the same mutation.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-
  • an EGFR inhibitor resistance mutation can result in an EGFR kinase that has one or more of an increased V max , a decreased K m , and a decreased KD in the presence of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to a wild type EGFR kinase or an EGFR kinase not having the same mutation in the presence of the same compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes at least one EGFR inhibitor resistance mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions as described in Table 2a and Table 2b.
  • compounds of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)) and pharmaceutically acceptable salts and solvates thereof, are useful in treating subjects that develop cancers with EGFR inhibitor resistance mutations (e.g., that result in an increased resistance to a first EGFR inhibitor, e.g., a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A), and/or one or more EGFR inhibitor resistance mutations listed in Table 2a and Table 2b) by either dosing in combination or as a subsequent or additional (e.g., follow-up) therapy
  • the EGFR Protein Amino Acid Substitutions/Insertions/Deletions include any one or more, or any two or more (e.g., any two), of the EGFR Protein Amino Acid Substitutions/Insertions/Deletions delineated in Table 1a, 1b and/or Table 2a, 2b; e.g., any one or more, or any two or more (e.g., any two), of the following and independently selected EGFR Protein Amino Acid Substitutions/Insertions/Deletions: V769L; V769M; M766delinsMASVx2; A767_V769dupASV; A767delinsASVDx3; A767delinsASVG; S768_V769insX; V769_D770insX; V769_D770insASV; D770delinsDN; D770delinsDNPH
  • a “first inhibitor of EGFR” or “first EGFR inhibitor” is an EGFR inhibitor as defined herein, but which does not include a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof as defined herein.
  • a “second inhibitor of EGFR” or a “second EGFR inhibitor” is an EGFR inhibitor as defined herein, but which does not include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • the first and second inhibitors of EGFR are different.
  • the first and/or second inhibitor of EGFR bind in a different location than a compound of Formula (I).
  • a first and/or second inhibitor of EGFR can inhibit dimerization of EGFR, while a compound of Formula (I) can inhibit the active site.
  • a first and/or second EGFR inhibitor can be an allosteric inhibitor of EGFR, while a compound of Formula (I) can inhibit the EGFR active site.
  • exemplary first and second inhibitors of EGFR are described herein.
  • a first or second inhibitor of EGFR can be selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.
  • compounds of Formula (I) are useful for treating a cancer that has been identified as having one or more EGFR inhibitor resistance mutations (that result in an increased resistance to a first or second inhibitor of EGFR, e.g., a substitution described in Table 2a and Table 2b including substitutions at amino acid position 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A)).
  • the one or more EGFR inhibitor resistance mutations occurs in a nucleic acid sequence encoding a mutant EGFR protein (e.g., a mutant EGFR protein having any of the mutations described in Table 2a and Table 2b) resulting in a mutant EGFR protein that exhibits EGFR inhibitor resistance.
  • the epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and provides critical functions in epithelial cell physiology (Schlessinger J (2014) Cold Spring Harb Perspect Biol 6, a008912).
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I
  • Also provided herein are methods for treating a subject identified or diagnosed as having an EGFR-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the subject that has been identified or diagnosed as having an EGFR- associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is an EGFR-associated cancer.
  • the EGFR-associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations.
  • regulatory agency refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • methods for treating cancer in a subject in need thereof comprising: (a) detecting an EGFR-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e),
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or an immunotherapy).
  • another anticancer agent e.g., a second EGFR inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or an immunotherapy.
  • the subject was previously treated with a first EGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is an EGFR-associated cancer.
  • the EGFR-associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations.
  • Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy).
  • another anticancer agent e.g., a second EGFR inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy.
  • the subject was previously treated with a first EGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy.
  • the subject is a subject suspected of having an EGFR-associated cancer, a subject presenting with one or more symptoms of an EGFR-associated cancer, or a subject having an elevated risk of developing an EGFR-associated cancer.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy. Additional, non- limiting assays that may be used in these methods are described herein. Additional assays are also known in the art.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations.
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an EGFR-associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, where the presence of a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, identifies that the subject has an EGFR-associated cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an EGFR-associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same where the presence of dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, identifies that the subject has an EGFR- associated cancer.
  • any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency- approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy.
  • the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having an EGFR-associated cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having an EGFR-associated cancer.
  • the cancer is an EGFR- associated cancer, for example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations.
  • a subject is identified or diagnosed as having an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject.
  • an EGFR-associated cancer includes those described herein and known in the art.
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • the subject has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • the subject can be a subject whose tumors have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • the subject is suspected of having an EGFR-associated cancer (e.g., a cancer having one or more EGFR inhibitor resistance mutations).
  • kits for treating an EGFR-associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I
  • the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR kinase protein point mutations/insertions/deletions.
  • EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and Table 1b.
  • the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20.
  • the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A.
  • the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations.
  • EGFR inhibitor resistance mutations are described in Table 2a and Table 2b.
  • the EGFR inhibitor resistance mutation is a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A).
  • the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more point mutations/insertions/deletions in exon 20.
  • Non-limiting examples of EGFR exon 20 mutations are described in Tables 1a, 1b and 2a, 2b.
  • the EGFR exon 20 mutation is an exon 20 insertion such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP.
  • the cancer with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the tumor that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is a tumor positive for one or more EGFR inhibitor resistance mutations.
  • the tumor with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same (e.g., a tumor having one or more EGFR inhibitor resistance mutations).
  • Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same.
  • the method also includes administering to a subject determined to have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3),
  • the method includes determining that a subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more point mutation in the EGFR gene (e.g., any of the one or more of the EGFR point mutations described herein).
  • the one or more point mutations in an EGFR gene can result, e.g., in the translation of an EGFR protein having one or more of the following amino acid substitutions, deletions, and insertions: G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20 (e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX).
  • the one or more mutations in an EGFR gene can result, e.g., in the translation of an EGFR protein having one or more of the following amino acid substitutions or deletions: L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A.
  • the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more EGFR inhibitor resistance mutations (e.g., any combination of the one or more EGFR inhibitor resistance mutations described herein).
  • the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more EGFR exon 20 insertions (e.g., any of the exon 20 insertions described herein).
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
  • the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or immunotherapy).
  • another anticancer agent e.g., a second EGFR inhibitor, a second compound of Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • another anticancer agent e.g
  • an assay used to determine whether the subject has a dysregulation of an EGFR gene, or an EGFR kinase, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen- binding fragment thereof.
  • Assays can utilize other detection methods known in the art for detecting dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or levels of any of the same (see, e.g., the references cited herein).
  • the dysregulation of the EGFR gene, the EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations.
  • the sample is a biological sample or a biopsy sample (e.g., a paraffin- embedded biopsy sample) from the subject.
  • the subject is a subject suspected of having an EGFR-associated cancer, a subject having one or more symptoms of an EGFR-associated cancer, and/or a subject that has an increased risk of developing an EGFR-associated cancer).
  • dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016.
  • Liquid biopsy methods can be used to detect total tumor burden and/or the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same.
  • Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and/or dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same.
  • liquid biopsies can be used to detect the presence of dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same at an earlier stage than traditional methods.
  • the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof.
  • a liquid biopsy can be used to detect circulating tumor cells (CTCs).
  • CTCs circulating tumor cells
  • a liquid biopsy can be used to detect cell-free DNA.
  • cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells.
  • Analysis of ctDNA can be used to identify dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same.
  • NGS next-generation sequencing
  • PCR digital PCR
  • microarray analysis can be used to identify dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same.
  • HER2-associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a HER2 gene, a HER2 kinase, a HER2 kinase domain, or the expression or activity or level of any of the same described herein).
  • Non-limiting examples of a HER2-associated disease or disorder include, for example, cancer.
  • HER2-associated cancer refers to cancers associated with or having a dysregulation of a HER2 gene, a HER2 kinase (also called herein a HER2 protein), or expression or activity, or level of any of the same.
  • a HER2-associated cancer are described herein.
  • the EGFR-associated cancer is also a HER2-associated cancer.
  • an EGFR-associated cancer can also have a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same.
  • the phrase “dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a HER2 gene that results in the expression of a HER2 protein that includes a deletion of at least one amino acid as compared to a wild type HER2 protein, a mutation in a HER2 gene that results in the expression of a HER2 protein with one or more point mutations as compared to a wild type HER2 protein, a mutation in a HER2 gene that results in the expression of a HER2 protein with at least one inserted amino acid as compared to a wild type HER2 protein, a gene duplication that results in an increased level of HER2 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of HER2 protein in a cell), an alternative spliced version of
  • a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same can be a mutation in a HER2 gene that encodes a HER2 protein that is constitutively active or has increased activity as compared to a protein encoded by a HER2 gene that does not include the mutation.
  • Non- limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5. Such mutation and overexpression is associated with the development of a variety of cancers (Moasser. Oncogene.2007 Oct 4; 26(45): 6469–6487).
  • Compounds of Formula (I) are useful for treating diseases and disorders such as HER2-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors).
  • diseases and disorders such as HER2-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors).
  • dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in a HER2 gene.
  • the exemplary HER2 kinase fusions or point mutations, insertions, and deletions shown in Tables 3-5 can be caused by an activating mutation.
  • activating mutation in reference to HER2 describes a mutation in a HER2 gene that results in the expression of a HER2 kinase that has an increased kinase activity, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in a HER2 gene (that results in the expression of a HER2 kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions.
  • one or more e.g., two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in a HER2 gene that results in the expression of a HER2 kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in a HER2 gene that results in the expression of a HER2 kinase that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wild type HER2 kinase, e.g., the exemplary wild type HER2 kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art.
  • wild type HER2 or "wild-type HER2 kinase” describes a HER2nucleic acid (e.g., a HER2 gene or a HER2 mRNA) or protein (e.g., a HER2 protein) that is found in a subject that does not have a HER2-associated disease, e.g., a HER2-associated cancer (and optionally also does not have an increased risk of developing a HER2-associated disease and/or is not suspected of having a HER2-associated disease), or is found in a cell or tissue from a subject that does not have a HER2-associated disease, e.g., a HER2- associated cancer (and optionally also does not have an increased risk of developing a HER2-associated disease and/or is not suspected of having a HER2-associated disease).
  • a HER2-associated disease e.g., a HER2-associated cancer
  • a method of treating a HER2-associated cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-b), (I-c), (I-d), (
  • a method for treating a HER2-associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same includes one or more HER2 kinase protein point mutations/insertions.
  • HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5.
  • the HER2 kinase protein point mutations/insertions/deletions are selected from the group consisting of S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, V842I, Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP.
  • the HER2 kinase protein point mutations/insertions/deletions are exon 20 point mutations/insertions/deletions selected from the group consisting of V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L, S783P, M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781in
  • the HER2 kinase protein point mutations/insertions/deletions are exon 20 point mutations/insertions/deletions selected from the group consisting of Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP.
  • the cancer e.g., HER2-associated cancer
  • a hematological cancer e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia such as acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL)
  • alveolar rhabdomyosarcoma central or peripheral nervous system tissue cancer
  • an endocrine or neuroendocrine cancer including multiple neuroendocrine type I and type II tumors, Li-Fraumeni tumors, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or
  • the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and oesophageal cancers, pancreatic, gastrointestinal cancer, gastric, breast, endometrial and colorectal cancers, hepatocellular carcinoma, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma.
  • the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, lung cancer, or breast cancer. In some cases, the cancer is melanoma, colon cancer, renal cancer, leukemia, or breast cancer.
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, Liu et al. J Exp Clin Cancer Res.2019 May 23;38(1):219); and Ding et al.
  • gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogli
  • the brain tumor is a primary brain tumor.
  • the brain tumor is a metastatic brain tumor, e.g., a metastatic brain tumor from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, kidney cancer, bladder cancer, or undifferentiated carcinoma.
  • the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer).
  • the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance.
  • CNS central nervous system
  • the patient has previously been treated with another anticancer agent, e.g., another EGFR and/or HER2 inhibitor (e.g., a compound that is not a compound of Formula I) or a multi-kinase inhibitor.
  • another anticancer agent e.g., another EGFR and/or HER2 inhibitor (e.g., a compound that is not a compound of Formula I) or a multi-kinase inhibitor.
  • the cancer is a cancer of B cell origin.
  • the cancer is a lineage dependent cancer.
  • the cancer is a lineage dependent cancer where HER2 or the dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same, plays a role in the initiation and/or development of the cancer.
  • Also provided herein is a method for treating a subject diagnosed with or identified as having a HER2-associated cancer, e.g., any of the exemplary HER2-associated cancers disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes one or more deletions (e.g., deletion of an amino acid at position 12), insertions, or point mutation(s) in a HER2 kinase.
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes a deletion of one or more residues from the HER2 kinase, resulting in increased signaling activity of HER2.
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acid substitutions, insertions, or deletions as compared to the wild-type HER2 kinase (see, for example, the point mutations listed in Table 3).
  • dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more of the amino acid substitutions, insertions, or deletions in Table 3.
  • the dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same includes an insertion of one or more residues in exon 20 of the HER2 gene (e.g., any of the exon 20 insertions described in Table 1a and Table 1b).
  • Exon 20 of HER2 has two major regions, the c-helix (residues 770-774) and the loop following the c-helix (residues 775-783).
  • the dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same includes an insertion of one or more residues in exon 20 selected from the group consisting of: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP. Table 3.
  • HER2 Protein Amino Acid Substitutions/Insertions/Deletions A The HER2 mutations shown may be activating mutations and/or confer increased resistance of HER2 to a HER2 inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype HER2.
  • MKI multi-kinase inhibitor
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes a splice variation in a HER2 mRNA which results in an expressed protein that is an alternatively spliced variant of HER2 having at least one residue deleted (as compared to the wild-type HER2 kinase) resulting in a constitutive activity of a HER2 kinase domain.
  • the splice variant of HER2 is ⁇ 16HER-3 or p95HER ⁇ 2. See, e.g., Sun et al. J Cell Mol Med. 2015 Dec; 19(12): 2691–2701.
  • dysregulation of an HER2 gene, an HER2 kinase, or the expression or activity or level of any of the same can be caused by a splice variation in a HER2 mRNA that results in the expression of an altered HER2 protein that has increased resistance to inhibition by an HER2 inhibitor, a tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type HER2 kinase (e.g., the HER2 variants described herein).
  • TKI tyrosine kinase inhibitor
  • MKI multi-kinase inhibitor
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes one or more chromosome translocations or inversions resulting in HER2 gene fusions, respectively.
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from a non-HER2 partner protein and HER2, and include a minimum of a functional HER2 kinase domain, respectively.
  • Table 4 Exemplary HER2 Fusion Proteins and Cancers 1 Yu et al.
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acid substitutions or insertions or deletions in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acids inserted or removed, as compared to the wild-type HER2 kinase.
  • the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acid substitutions as compared to the wild-type HER2 kinase, and which has increased resistance to a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I- e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as compared to a wild type HER2 kinase or a HER2 kinase not including the same mutation.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I
  • dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same includes at least one HER2 inhibitor resistance mutation in an HER2 gene that results in the production of an HER2 kinase that has one or more of the amino acid substitutions, insertions, or deletions as described in Table 5.
  • compounds of Formula (I) are useful in treating subjects that develop cancers with HER2 inhibitor resistance mutations (e.g., that result in an increased resistance to a first HER2 inhibitor, e.g., a substitution at amino acid position 755 or 798 (e.g., L755S, L755P, T798I, and T798M), and/or one or more HER2 inhibitor resistance mutations listed in Table 5) by either dosing in combination or as a subsequent or additional (e.g., follow-up) therapy to existing drug treatments (e.g., other inhibitors of HER2; e.g., first and
  • a “first inhibitor of HER2” or “first HER2 inhibitor” is a HER2 inhibitor as defined herein, but which does not include a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof as defined herein.
  • a “second inhibitor of HER2” or a “second HER2 inhibitor” is a HER2 inhibitor as defined herein, but which does not include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • the first and second inhibitors of HER2 are different.
  • the first and/or second inhibitor of HER2 bind in a different location than a compound of Formula (I).
  • a first and/or second inhibitor of HER2 can inhibit dimerization of HER2, while a compound of Formula (I) can inhibit the active site.
  • a first and/or second inhibitor of HER2 can be an allosteric inhibitor of HER2, while a compound of Formula (I) can inhibit the HER2 active site.
  • exemplary first and second inhibitors of HER2 are described herein.
  • a first or second inhibitor of HER2 can be selected from the group consisting of: trastuzumab (e.g., TRAZIMERATM, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKY
  • compounds of Formula (I) are useful for treating a cancer that has been identified as having one or more HER2 inhibitor resistance mutations (that result in an increased resistance to a first or second inhibitor of HER2, e.g., a substitution described in Table 5 including substitutions at amino acid position 755 or 798 (e.g., L755S, L755P, T798I, and T798M)).
  • the one or more HER2 inhibitor resistance mutations occurs in a nucleic acid sequence encoding a mutant HER2 protein (e.g., a mutant HER2 protein having any of the mutations described in Table 3) resulting in a mutant HER2 protein that exhibits HER2 inhibitor resistance.
  • HER2 epidermal growth factor receptor 2
  • RTKs receptor tyrosine kinases
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e
  • the subject that has been identified or diagnosed as having a HER2- associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is a HER2-associated cancer.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or an immunotherapy).
  • the subject was previously treated with a first HER2 inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have a HER2- associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is a HER2-associated cancer.
  • Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy).
  • another anticancer agent e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy.
  • the subject was previously treated with a first HER2 inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy.
  • the subject is a subject suspected of having a HER2-associated cancer, a subject presenting with one or more symptoms of a HER2-associated cancer, or a subject having an elevated risk of developing a HER2-associated cancer.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art.
  • a “first inhibitor of HER2” or “first HER2 inhibitor” is a HER2 inhibitor as defined herein, which does not include a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof as defined herein.
  • a “second inhibitor of HER2” or a “second HER2 inhibitor” is an inhibitor of HER2 as defined herein, which does not include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • a first and a second HER2 inhibitor are present in a method provided herein, the first and second HER2 inhibitors are different.
  • a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a HER2- associated cancer in a subject identified or diagnosed as having a HER2-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, where the presence of a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, identifies that the subject has a HER2-
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a HER2-associated cancer in a subject identified or diagnosed as having a HER2-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same where the presence of dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, identifies that the subject has a HER2-associated cancer.
  • any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a HER2-associated cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a HER2-associated cancer (.
  • a subject is identified or diagnosed as having a HER2-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved, kit for identifying dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject.
  • a HER2-associated cancer includes those described herein and known in the art.
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • the subject has a tumor that is positive for a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • the subject can be a subject whose tumors have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • the subject is suspected of having a HER2-associated cancer.
  • methods for treating a HER2-associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same includes one or more HER2 kinase protein point mutations/insertions/deletions.
  • HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5.
  • the HER2 kinase protein point mutations/insertions/deletions are selected from the group consisting of a point mutation at amino acid position 310, 678, 755, 767, 773, 777, or 842 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I) and/or an insertion or deletion at amino acid positions 772, 775, 776, 777, and 780 (e.g., Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP).
  • a point mutation at amino acid position 310, 678, 755, 767, 773, 777, or 842 e.g., S310F, S310Y, R678Q, R67
  • the HER2 kinase protein point mutation/insertion/deletion is an exon 20 point mutation/insertion/deletion.
  • the HER2 exon 20 point mutation/insertion/deletion is a point mutation at amino acid position 773, 776, 777, 779, 780, and 783 (e.g., V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L, and S783P) and/or an exon 20 insertion/deletion such as an insertion/deletion at amino acid positions 774, 775, 776, 777, 778, and 780.
  • the HER2 kinase protein insertion is an exon 20 insertion selected from the group consisting of: A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781insGSP.
  • the HER2 kinase protein mutation/insertion/deletion is an exon 20 insertion/deletion selected from the group consisting of: is Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, or P780_Y781insGSP.
  • the cancer with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit.
  • the tumor that is positive for a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is a tumor positive for one or more HER2 inhibitor resistance mutations.
  • the tumor with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-
  • the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or level of any of the same.
  • the method also includes administering to a subject determined to have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1),
  • the method includes determining that a subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation in a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is one or more point mutation in the HER2 gene (e.g., any of the one or more of the HER2 point mutations described herein).
  • the one or more point mutations in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following amino acid substitutions: S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I.
  • the one or more point mutations in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following exon 20 amino acid substitutions: V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L, and S783P.
  • the dysregulation in a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is one or more insertions in the HER2 gene (e.g., any of the one or more of the HER2 insertions described herein).
  • the one or more insertions in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following exon 20 insertions: M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781insGSP.
  • the one or more insertions in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following exon 20 insertions: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy).
  • another anticancer agent e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy.
  • an assay used to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen- binding fragment thereof.
  • the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject.
  • the subject is a subject suspected of having a HER2- associated cancer, a subject having one or more symptoms of a HER2-associated cancer, and/or a subject that has an increased risk of developing a HER2-associated cancer.
  • dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy).
  • a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016.
  • Liquid biopsy methods can be used to detect total tumor burden and/or the dysregulation of a HER2 gene, a HER2 kinasev, or the expression or activity or level of any of the same.
  • Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and/or dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same.
  • liquid biopsies can be used to detect the presence of dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same at an earlier stage than traditional methods.
  • the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof.
  • a liquid biopsy can be used to detect circulating tumor cells (CTCs).
  • CTCs circulating tumor cells
  • a liquid biopsy can be used to detect cell-free DNA.
  • cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells.
  • Analysis of ctDNA can be used to identify dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same.
  • Also provided is a method for inhibiting EGFR activity in a cell comprising contacting the cell with a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting HER2 activity in a cell comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting EGFR and HER2 activity in a cell comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant EGFR activity and/or HER2 activity.
  • the cell is a cancer cell.
  • the cancer cell is any cancer as described herein.
  • the cancer cell is an EGFR-associated cancer cell.
  • the cancer cell is a HER2-associated cancer cell.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" an EGFR kinase with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having an EGFR kinase, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the EGFR kinase.
  • Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein.
  • a method of increase cell death, in vitro or in vivo comprising contacting a cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increasing tumor cell death in a subject e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein.
  • the method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
  • therapeutically effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat an EGFR kinase-associated disease or disorder or a HER2 kinase-associated disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof that will
  • the compounds of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), including pharmaceutically acceptable salts or solvates thereof, can be administered in the form of pharmaceutical compositions as described herein.
  • Also provided herein is a method of treating a subject having a cancer comprising: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I
  • a method of treating a subject having a cancer comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor does not have one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering additional doses of the first EGFR inhibitor to the subject.
  • Combinations In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer.
  • compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies.
  • a surgery may be open surgery or minimally invasive surgery.
  • Compounds of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or pharmaceutically acceptable salts or solvates thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.
  • additional therapies or therapeutic agents for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)).
  • a cancer e.g., a locally advanced or metastatic tumor
  • standard therapy e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)
  • chemotherapeutic agent such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi- kinase inhibitor
  • immunotherapy e.g., radioactive iodine
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)).
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy.
  • a subject is EGFR inhibitor na ⁇ ve.
  • the subject is na ⁇ ve to treatment with a selective EGFR inhibitor.
  • a subject is not EGFR inhibitor na ⁇ ve.
  • a subject is HER2 inhibitor na ⁇ ve.
  • the subject is na ⁇ ve to treatment with a selective HER2 inhibitor.
  • a subject is not HER2 inhibitor na ⁇ ve.
  • a subject has undergone prior therapy.
  • MKI multi-kinase inhibitor
  • TKI EGFR tyrosine kinase inhibitor
  • osimertinib gefitinib
  • erlotinib afatinib
  • lapatinib lapatinib
  • neratinib AZD- 9291
  • CL-387785 CO-1686
  • WZ4002 WZ4002
  • the compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.
  • additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.
  • Non-limiting examples of additional therapeutic agents include: other EGFR- targeted therapeutic agents (i.e., a first or second EGFR inhibitor), other HER2-targeted therapeutic agents (i.e., a first or second HER2 inhibitor), RAS pathway targeted therapeutic agents, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase- targeted therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)), farnesyl transferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.
  • other EGFR- targeted therapeutic agents i.e., a first or second EGFR inhibitor
  • other HER2-targeted therapeutic agents i.e., a first or second HER2 inhibitor
  • the other EGFR-targeted therapeutic is a multi-kinase inhibitor exhibiting EGFR inhibition activity.
  • the other EGFR- targeted therapeutic inhibitor is selective for an EGFR kinase.
  • Non-limiting examples of EGFR-targeted therapeutic agents include an EGFR-selective inhibitor, a panHER inhibitor, and an anti-EGFR antibody.
  • the EGFR inhibitor is a covalent inhibitor.
  • the EGFR-targeted therapeutic agent is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), creartinib (EGF816, NVS- 816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992,
  • the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.
  • Additional EGFR-targeted therapeutic agents e.g., a first EGFR inhibitor or a second EGFR inhibitor
  • the other HER2-targeted therapeutic is a multi-kinase inhibitor exhibiting HER2 inhibition activity. In some embodiments, the other HER2- targeted therapeutic inhibitor is selective for a HER2 kinase.
  • HER2-targeted therapeutic agents e.g., a first HER2 inhibitor or a second HER2 inhibitor
  • HER2-targeted therapeutic agents include trastuzumab (e.g., TRAZIMERATM, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSATM), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504,
  • Additional HER2-targeted therapeutic agents include those disclosed in WO 2019/246541; WO 2019/165385; WO 2014/176475; and US 9,029,502, each of which is incorporated by reference in its entirety.
  • a “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation).
  • Non- limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR.
  • RAS e.g., KRAS, HRAS, and NRAS
  • RAF e.g., KRAS, HRAS, and NRAS
  • RAF e.g., KRAS, HRAS, and NRAS
  • RAF RAF
  • BRAF MEK
  • ERK ERK
  • PI3K PI3K
  • AKT mTOR
  • mTOR e.g., RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR.
  • a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g.,
  • a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.”
  • a KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation).
  • Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR.
  • a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator).
  • a KRAS modulator is a covalent inhibitor.
  • KRAS-targeted therapeutic agents include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.
  • RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
  • the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVITM), BMS-908662 (XL281), sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC- 0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.
  • the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.
  • the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25- OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK- 8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG- 7482), ASN007, FR148083, 5-7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof.
  • PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC- 907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC- 0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-
  • the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-ace
  • the mTOR inhibitor is selected from MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), or a combination thereof.
  • farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.
  • a chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVEN TM ), or combinations thereof.
  • a taxane include paclitaxel, docetaxel, abraxane, and taxotere.
  • the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.
  • the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof
  • PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.
  • Non-limiting examples of immunotherapy include immune checkpoint therapies, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel.
  • Non-limiting examples of immune checkpoint therapies include inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof.
  • the CTLA-4 inhibitor is ipilimumab (YERVOY®).
  • the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof.
  • the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof.
  • the LAG-3 inhibitor is IMP701 (LAG525).
  • the A2AR inhibitor is CPI-444.
  • the TIM-3 inhibitor is MBG453.
  • the B7-H3 inhibitor is enoblituzumab.
  • the VISTA inhibitor is JNJ-61610588.
  • the IDO inhibitor is indoximod.
  • the additional therapy or therapeutic agent is a combination of atezolizumab and nab-paclitaxel.
  • a method of treating cancer comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3)
  • the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same. In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity, or level of any of the same.
  • Additional therapeutic agents may be administered with one or more doses of the compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and/or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof
  • a pharmaceutical combination for treating a cancer in a subject in need thereof which comprises (a) a compound of Formula (I) (e.g., Formula (I- a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment
  • a pharmaceutical composition comprising
  • the cancer is an EGFR-associated cancer.
  • an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations In some embodiments, the cancer is a HER2-associated cancer.
  • a HER2-associated cancer having one or more HER2 inhibitor resistance mutations In some embodiments, the cancer is a HER2-associated cancer.
  • a HER2-associated cancer having one or more HER2 inhibitor resistance mutations The term "pharmaceutical combination", as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I- d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), are both administered to a subject simultaneously in the form of a single composition or dosage.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I- d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • at least one additional therapeutic agent e.g., a chemotherapeutic agent
  • non-fixed combination means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.
  • additional therapeutic agent e.g., chemotherapeutic agent
  • a method of treating a cancer comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of Formula (I) and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-e1), (I-e2), (I-e3), (I-
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittently dosages.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.
  • the cancer is an EGFR-associated cancer.
  • the cancer is a HER2-associated cancer.
  • a HER2-associated cancer having one or more HER2 inhibitor resistance mutations.
  • the presence of one or more EGFR inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first EGFR inhibitor.
  • Methods useful when an EGFR inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first EGFR inhibitor are described below.
  • methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more EGFR inhibitor resistance mutations; and administering to the identified subject a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with the first EGFR inhibitor.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with the first EGFR inhibitor.
  • the one or more EGFR inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor.
  • the one or more EGFR inhibitor resistance mutations include one or more EGFR inhibitor resistance mutations listed in Table 2a and Table 2b.
  • the one or more EGFR inhibitor resistance mutations can include a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A).
  • a method for treating an EGFR-associated cancer in a subject in need of such treatment comprising (a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first EGFR inhibitor, wherein the first EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD- 9291, CL-387785, CO-1686, or WZ4002.
  • the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one EGFR inhibitor resistance mutation; and (d) administering a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I- e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation; or (e) administering additional doses of the first EGFR inhibitor of step (b) to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation.
  • a compound of Formula (I) e.g., Formula (I-
  • Methods useful when a HER2 activating mutation is present in a tumor are described herein.
  • methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more HER2 activating mutations; and administering to the identified subject a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I- g1), or (I-h)
  • the one or more HER2 activating mutations include one or more HER2 activating mutations listed in Tables 3-5. Methods useful when an activating mutation (e.g., HER2 activating mutation) is present in a tumor in a subject are described herein.
  • methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more HER2 activating mutations; and administering to the identified subject a compound of Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-e1), (I-e2), (I-e3), (I-e4), (I-f), (I-g), (I-g1), or (I-h)
  • the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.
  • the synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.
  • Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M.
  • the synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used.
  • the processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.
  • Example 1 Synthesis of (R)-3-((3-chloro-2-methoxyphenyl)amino)-2-(3-(2- methoxy-2-methylpropoxy)pyridin-4-yl)-7-methyl-5,6,7,8-tetrahydropyrrolo[3,2- c]azepin-4(1H)-one (Compound 101b) and (S)-3-((3-chloro-2-methoxyphenyl)amino)-2- (3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)-7-methyl-5,6,7,8-tetrahydropyrrolo[3,2- c]azepin-4(1H)-one (Compound 101a)
  • Bioactivity EXAMPLE A Inhibitor activity on EGFR-dependent cell growth Cell lines are generated by transducing Ba/F3 cells with retroviruses containing vectors with EGFR WT, EGFR L858R, EGFR exon 19del, EGFR L858R/C797S, EGFR exon 20 NPG Ins D770_N771, EGFR exon 20 ASV Ins V769_D770, EGFR exon 20 SVD Ins D770_N771, or EGFR exon 20 FQEA Ins A763_V764 genes and a puromycin selection marker. Transduced cells are selected with puromycin for 7 days and are then be transferred into culture media without Interleukin 3 (IL3).
  • IL3 Interleukin 3
  • EGFR WT cells are maintained with supplemental EGF. Surviving cells are confirmed to express EGFR by Western blot and maintained as a pool.
  • Study Design 1 Cell seeding 1.1 Cells are harvested from flask into cell culture medium and the cell number counted. 1.2 Cells are diluted with culture medium to the desired density and 40 ⁇ L of cell suspension is added into each well of 384-well cell culture plate and the seeding density is 800 (FQEA, exon 19del), 600 (WT, NPG, L858R/C797S), or 400 (ASV, SVD, L858R) cells/well. 2 Compound preparation and treatment 2.1 Test compounds are dissolved to 10 mM in a DMSO stock solution.
  • EGFR mutant Ba/F3 cells were generated by transduction with retrovirus containing vectors expressing EGFR L858R, EGFR exon 19del, EGFR L858R/C797S, EGFR exon 20 NPG Ins D770_N771, EGFR exon 20 ASV Ins V769_D770, or EGFR exon 20 SVD Ins D770_N771 genes along with a puromycin selection marker.
  • Transduced cells are selected with puromycin for 7 days and are then be transferred into culture media without Interleukin 3 (IL3). Surviving cells are confirmed to express EGFR by Western blot and maintained as a pool.
  • IL3 Interleukin 3
  • CUTO14 cells were obtained from Dr. Robert C. Doebele at the University of Colorado. Study Design 1 Cell seeding 1.1 Cells are harvested from flask into cell culture medium and the cell number counted. 1.2 Cells are diluted with culture medium to the desired density and 40 ⁇ L of cell suspension is added into each well of 384-well cell culture plate and the seeding density is 50K cells/well (Ba/F3) or 12.5K cells/well (CUTO14). 2 Compound preparation and treatment 2.1 Test compounds are dissolved to 10 mM in a DMSO stock solution. 45 ⁇ L of stock solution is transferred to a 384 polypropylene plate (pp-plate).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente divulgation concerne des entités chimiques (par ex., un composé ou un sel, et/ou un hydrate, et/ou un co-cristal, et/ou une combinaison de médicament pharmaceutiquement acceptables du composé) qui inhibent le récepteur du facteur de croissance épidermique (EGFR, ERBB1) et/ou le récepteur 2 du facteur de croissance épidermique humain (HER2, ERBB2). Ces entités chimiques sont utiles, par ex., pour traiter un état, une maladie ou un trouble où l'activation accrue (par ex., excessive) de l'EGFR et/ou de HER2 contribue à la pathologie et/ou aux symptômes et/ou à l'évolution de l'état, de la maladie ou du trouble (par ex., un cancer) chez un sujet (par ex., un être humain). La divulgation concerne également des compositions contenant lesdites entités ainsi que les méthodes d'utilisation et de fabrication correspondants.
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