WO2022072634A1 - Bicyclic compounds for use in the treatment cancer - Google Patents

Bicyclic compounds for use in the treatment cancer Download PDF

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Publication number
WO2022072634A1
WO2022072634A1 PCT/US2021/052878 US2021052878W WO2022072634A1 WO 2022072634 A1 WO2022072634 A1 WO 2022072634A1 US 2021052878 W US2021052878 W US 2021052878W WO 2022072634 A1 WO2022072634 A1 WO 2022072634A1
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Prior art keywords
compound
group
optionally substituted
ring
independently selected
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PCT/US2021/052878
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French (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 WO2022072634A1 publication Critical patent/WO2022072634A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

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 overexpresmion 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, in which R 1c , R 2a , R 2b , R 3a , R 3b , 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: Ring C is selected from the group consisting of: • 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 ; • 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 1-4 substituents independently selected from the group consisting of oxo and R c ; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • 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 ; • 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 1-4 substituents independently selected from the group consisting of oxo and R c ; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring
  • a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4)
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g),
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),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-a
  • 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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1
  • a method for inhibiting a BUB (budding uninhibited by benzimidazole, BUB1-3) kinase includes 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-
  • 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.
  • 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).
  • 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., -OCH 3 ).
  • 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 or ) or on different ring atoms (e.g., ring carbon and/or nitrogen atoms (e.g., vicinal ring carbon and/or nitrogen atoms)) (e.g., ).
  • 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.
  • heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridone (e.g., , , (e.g., ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., ) herein is a constituent part of the heteroaryl ring).
  • pyridone e.g., , (e.g., )
  • 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., or ), or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • 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 moiety: encompasses the tautomeric form containing the moiety: .
  • 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.
  • a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
  • 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
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • 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 ; • 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 1-4 substituents independently selected from the group consist
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • 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 ; • 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 1-4 substituents independently selected from the group consisting of oxo and R c ; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • 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 ; • 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 1-4 substituents independently selected from the group consisting of oxo and R c ; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring
  • this disclosure features compounds of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • 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 ; • 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 1-4 substituents independently selected from the group consisting of oxo and R c ; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring
  • pyridone e.g., , or
  • pyrimidone e.g., pyridazinone
  • pyrazinone e.g.,
  • Ring C or R g when Ring C or R g is heteroaryl, said heteroaryl is not substituted with –OH.
  • the heteroaryl is selected from the group consisting of: aromatic lactams, aromatic cyclic ureas, and vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g., , , or ), pyrimidone (e.g., or ), pyridazinone (e.g., or ), pyrazinone (e.g., or ), and imidazolone (e.g., ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., herein is a constituent part
  • 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: • 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 • 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 from 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 C is monocyclic heteroaryl including from 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 is , wherein n is 0, 1, or 2.
  • n can be 0.
  • Ring C is , wherein n is 0, 1, or 2.
  • n can be 0.
  • Ring C is , wherein n is 0, 1, or 2.
  • n can be 0.
  • Ring C is , wherein n is 0, 1, or 2.
  • n can be 0.
  • 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 (e.g., 10) ring atoms, wherein from 1-4 (e.g., 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 substituted with X 1 and further optionally substituted with from 1-3 R c .
  • 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 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 is selected from the group consisting of: and , each of which is optionally substituted with from 1-2 R c .
  • Ring C can be .
  • Ring C can be .
  • Ring C can be selected from the group consisting of: and each of which is optionally substituted with from 1-2 R c .
  • Ring C can be .
  • Ring C can be
  • Ring C can be
  • Ring C can be
  • Ring C is bicyclic heteroaryl including 9 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 thieno[3,2-b]pyridyl, which is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C is thieno[3,2-b]pyridyl, which is substituted with X 1 and further optionally substituted with from 1-3 R c .
  • Ring C is .
  • Ring C can be which is optionally substituted with from 1-2 R c .
  • Ring C can be .
  • Ring C is selected from the group consisting of: • 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 • 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 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 .
  • Ring C can be selected from the group consisting of: .
  • Ring C can be As non-limiting examples, Ring C can be selected from the group consisting of: .
  • 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: , , , , , , and
  • Ring C can be selected from the group consisting of: , , , , and
  • Ring C pyridyl or pyrimidyl, each of which is optionally substituted with from 1-2 R c .
  • Ring C can be selected from the group consisting of: , and In certain embodiments, Ring C is selected from the group consisting of: w c herein the R present in Ring C is C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, Ring C is selected from the group consisting of: wherein the R c present in Ring C is selected from the group consisting of: halo and C 1-3 alkyl optionally substituted with from 1-3 R a , optionally wherein the R c is –F, -Cl, or C 1-3 alkyl optionally substituted with from 1-3 independently selected halo.
  • 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 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 to via a 5- membered ring.
  • Ring C can be selected from the group consisting of: , , , , , , , , , , , , , In certain embodiments (when Ring C is bicyclic heteroaryl including 9 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 attached to via a 6-membered ring.
  • Ring C is: , wherein Z 0 is N or CH; and Ring D is an aromatic or partially unsaturated ring including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R d ), O, and S(O) 0-2 , wherein Ring D is optionally substituted with from 1-2 R c .
  • Ring C can be selected from the group consisting of:
  • Ring C can be
  • Ring C can be c (e.g., the R present in Ring C is halo or C 1-3 alkyl which is optionally substituted with from 1-3 R a ).
  • Ring C can be As further non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of: , , , , , , , , and , each further optionally substituted w c ith from 1-2 R .
  • 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), 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: As further non-limiting examples, Ring C can be and (e.g., each R c present in Ring C is independently selected from the group consisting of C 1-4 alkoxy and C 1-4 haloalkoxy).
  • Ring C 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 X 1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • Ring C is 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 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • each R c present on one or more ring atoms of Ring C is independently selected from the group consisting of: halo, cyano, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-6 alkyl, and C 1-6 alkyl optionally substituted with from 1-3 independently selected halo.
  • each of the R c can be independently selected C 1-6 alkyl (e.g., methyl)).
  • each of the R c can be independently selected from the group consisting of C 1-4 alkoxy and C 1-4 haloalkoxy (e.g., -OMe).
  • Variables m, X 2 , L 1 , and R 5 In certain embodiments, m is 1.
  • m is 0.
  • X 2 is –N(R N )S(O) 1-2 -*.
  • X 2 can be – N(H)S(O) 2 -*.
  • L 1 is C 1-10 alkylene optionally substituted with from 1-6 R a .
  • L 1 is C 1-3 alkylene optionally substituted with from 1-6 R a .
  • L 1 is C 1-3 alkylene.
  • L 1 can be –CH 2 -.
  • L 1 can be –CH(Me)- (e.g., or
  • L 1 can be –CH 2 CH 2 -.
  • L 1 is C 3-8 alkylene optionally substituted with from 1-6 R a . In certain of these embodiments, L 1 is branched C 3-6 alkylene optionally substituted with from 1-6 R a . In certain of the foregoing embodiments, 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 . In certain embodiments, 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 is 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 –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 (e.g., 4, 5, 6, 7, or 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 (e.g., 1, 2, or 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 x0 is 0, 1, 2, or 3, provided that x0+x1 ⁇ 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.
  • R 5 when R 5 is x1 is 0.
  • R 5 when R 5 is X a is –O-.
  • R 5 can be ).
  • x1 is 1 or 2.
  • x1 can be 1.
  • x1 can be 2.
  • X a is –O-.
  • R 5 can be selected from the group consisting of: In certain embodiments (when R 5 is a ; and x1 is 1 or 2), X is N(H) or N(R d ).
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X b and X c are each independently selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 .
  • X b and X c are independently selected from the group consisting of O and N(R d ) (e.g., O and N(C 1-3 alkyl)).
  • R 5 can be selected from the group consisting of: optionally wherein R d is C 1-4 alkyl, such as methyl.
  • R 5 is bicyclic heterocyclyl including from 6-10 (e.g., 6-8 or 8-10 (e.g., 6-8)) 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 can be In certain embodiments, R 5 is bicyclic heterocyclyl including from 7-10 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 In certain embodiments (when R 5 is –R g ), 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 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 from 1-4 R c .
  • R 5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, 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 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 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 .
  • R 5 can be selected from the group consisting of:
  • R 5 can be selected from the group consisting of:
  • 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: each optionally substituted with from 1-2 R c .
  • R 5 is bicyclic heteroaryl including from 9-10, such as 9, 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 , such as wherein R 5 is .
  • R 5 is phenyl optionally substituted with from 1-2 R c , such as unsubstituted phenyl.
  • 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 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is C 3-6 cycloalkyl.
  • R 5 can be cyclopropyl.
  • R 5 can be cyclopentyl.
  • R 5 is C 3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C 1-4 alkyl; C 1-4 alkyl substituted with R a , such as C 1-4 alkyl substituted with C 1-4 alkoxy; C 1-4 alkoxy; and C 1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R c .
  • R 5 can be selected from the group consisting of:
  • R 5 can be In certain embodiments, R 5 is H or halo. In certain of these embodiments, R 5 is H.
  • R 5 is R W . In certain embodiments, R 5 is -R g2 -R W or -R g2 -R Y . In certain embodiments, R 5 is –R g2 -R W . In certain embodiments (when R 5 is -R g2 -R W or -R g2 -R Y (e.g., –R g2 -R W )), the –R g2 group present in R 5 is which is optionally substituted with from 1-2 R c , wherein bb is the point of attachment to R W or R Y ; and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0.
  • x2 is 1 or 2. In certain embodiments, x2 is 0.
  • the –R g2 group present in R 5 can be selected from the group consisting of: wherein bb is the point of attachment to R W or R Y .
  • R 5 is -R g2 -R W or -R g2 -R Y (e.g., –R g2 -R W )
  • the –R g2 group present in R 5 is which is optionally substituted with from 1-2 R c ;
  • X b is selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 ; and bb is the point of attachment to R W or R Y .
  • the –R g2 group present in R 5 can be selected from the group consisting of: wherein bb is the point of attachment to R W or R Y ; and optionally wherein R d is C 1-4 alkyl, such as methyl.
  • the R g2 group present in R 5 is bicyclic heterocyclylene including from 6-10 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 (e.g., R g2 is wherein bb is the point of W Y attachment to R or R .
  • W is C 2-6 alkenyl (e.g., C2-4 alkenyl (e.g., C2-3 alkenyl)) optionally substituted with from 1-3 R a .
  • W is C 2-6 alkenyl or C 2-6 alkynyl optionally substituted with from 1-3 R a .
  • R W can be or As further non-limiting examples of the foregoing embodiments, R W can be Non-Limiting Combinations of m, X 2 , L 1 , and R 5 [AA]
  • m is 0 or 1
  • L 1 is C 1-3 alkylene optionally substituted with from 1-3 R a
  • R 5 is selected from the group consisting of: C 1-6 alkoxy or S(O) 2 (C 1-6 alkyl) each optionally substituted with from 1-6 R a ; -OH; and –NR e R f .
  • R 5 is C 1-6 alkoxy optionally substituted with from 1-6 R a . In certain of these embodiments, R 5 is C 1-3 alkoxy, such as methoxy. In certain embodiments of [AA], R 5 is S(O) 2 (C 1-6 alkyl) which is optionally substituted with from 1-6 R a . In certain of these embodiments, R 5 is S(O) 2 (C 1-3 alkyl). For example, R 5 can be S(O) 2 Me. In certain embodiments of [AA], L 1 is CH 2 . In certain embodiments of [AA], L 1 is –CH(Me)-. In certain embodiments of [AA], L 1 is –CH 2 CH 2 -.
  • m is 0 or 1;
  • L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ; and
  • 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 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 x0 is 0, 1, 2, or 3, provided that x0+x1 ⁇ 1.In certain of these embodiments, x1 is 0. In certain embodiments, X a is –O-. In certain embodiments of [BB], 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, x1 is 0. In certain embodiments, X a is –O-.
  • [BB] when R 5 is x1 is 1 or 2.
  • R 5 can be selected from the group consisting of: In certain embodiments of [BB], R 5 is which is optionally substituted with from 1-2 R c , wherein X b and X c are each independently selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 . As non-limiting examples of the foregoing embodiments, R 5 is selected from the group consisting of: , ; , optionally wherein R d is C 1-4 alkyl, such as methyl.
  • R 5 is bicyclic heterocyclyl including from 6-10 (e.g., 6-8) 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 can be In certain embodiments of [BB], R 5 is bicyclic heterocyclyl including from 7-10 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 , such as wherein R 5 is In certain embodiments of [BB], L 1 is CH 2 . In certain embodiments of [BB], L 1 is –CH(Me)-. In certain embodiments of [BB], L 1 is –CH 2 CH 2 -.
  • L 1 is a bond.
  • m is 1.
  • X 2 is —O-.
  • X 2 is -N(R N )- (e.g., –N(H)-).
  • m is 0.
  • m is 0 or 1
  • L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a
  • R 5 is selected from the group consisting of: • 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 ; and • C 6-10 aryl optionally substituted with from 1-4 R c
  • R 5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such
  • 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 ,
  • R 5 can be In certain embodiments of [CC], 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 can be
  • R 5 can be In certain embodiments of [CC], 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: each optionally substituted with fr c om 1-2 R .
  • R 5 is bicyclic heteroaryl including from 9-10, such as 9, 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 , such as wherein R 5 is .
  • R 5 is phenyl optionally substituted with from 1-2 R c , such as unsubstituted phenyl.
  • L 1 is CH 2 .
  • L 1 is –CH(Me)-.
  • m is 0.
  • m is 0 or 1;
  • L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ; and
  • R 5 is C 3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is C 3-6 cycloalkyl.
  • R 5 can be cyclopropyl.
  • R 5 can be cyclopentyl.
  • R 5 is C 3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C 1-4 alkyl; C 1-4 alkyl substituted with R a , such as C 1- 4 alkyl substituted with C 1-4 alkoxy; C 1-4 alkoxy; and C 1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R c .
  • R 5 can be selected from the group consisting of: In certain embodiments of [DD], L 1 is CH 2 . In certain embodiments of [DD], L 1 is –CH(Me)-.
  • m is 0.
  • L 1 is C 1-3 alkylene optionally substituted with from 1-3 R a ; and R 5 is H.
  • L 1 is CH 2 .
  • m is 1;
  • L 1 is branched C 3-6 alkylene optionally substituted with from 1-6 R a ; and
  • R 5 is selected from the group consisting of: C 1-6 alkoxy or S(O) 2 (C 1-6 alkyl) each optionally substituted with from 1-6 R a ; -OH; and –NR e R f .
  • R 5 is C 1-6 alkoxy optionally substituted with from 1-6 R a .
  • R 5 is C 1-3 alkoxy.
  • R 5 is S(O) 2 (C 1-6 alkyl) optionally substituted with from 1-6 R a .
  • X 2 is –O-.
  • X 2 is -N(R N )- (e.g., –N(H)-).
  • X 2 is .
  • L 1 is branched C 3-6 alkylene. In certain of these embodiments, L 1 is selected from the group consisting of: wherein aa is the point of attachment to R 5 .
  • m is 0 or 1;
  • L 1 is a bond or C 1-3 alkylene optionally substituted with from 1-3 R a ;
  • R g2 is which is optionally substituted with from 1-2 R c , wherein bb is the point of attachment to R W ; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0.
  • R g2 is selected from the group consisting of: wherein bb is the p W oint of attachment to R .
  • R g2 is which is optionally substituted with from 1-2 R c ;
  • X b is selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 ; and bb is the point of attachment to R W .
  • R g2 is selected from the group consisting of: such as , wherein bb is the point W of attachment to R ; and optionally wherein R d is C 1-4 alkyl, such as methyl.
  • R g2 is is bicyclic heterocyclylene including from 6-8 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 heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c , wherein bb is the point of attachment to R W .
  • R g2 can be wherein bb is the p W oint of attachment to R .
  • W is C 2-6 alkenyl optionally substituted with from 1-3 R a .
  • R W can be or
  • L 1 is CH 2 .
  • L 1 is —CH(Me)-.
  • L 1 is –CH 2 CH 2 -.
  • L 1 is a bond.
  • m is 1.
  • X 2 is –O-.
  • X 2 is -N(R N )- (e.g., –N(H)-).
  • m is 0.
  • R 1c , R 2a , R 2b , R 3a , and R 3b In some embodiments, R 1c is H. In some embodiments, R 2a and R 2b are H.
  • 1-2, such as 1, of R 2a and R 2b is a substituent other than H.
  • R 2a can be a substituent other than H.
  • one of R 2a and R 2b e.g., R 2a
  • one of R 2a and R 2b is C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl; and the other of R 2a and R 2b is H.
  • one of R 2a and R 2b e.g., R 2a
  • R g the other of R 2a and R 2b is H.
  • one of R 2a and R 2b is heterocyclyl including from 4-6 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 ; and 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; • 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 • 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; • 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 • 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 3a and R 3b are H.
  • from 1-2, such as 1, of R 3a and R 3b is a substituent other than H.
  • R 3a can be a substituent other than H.
  • one of R 3a and R 3b (e.g., R 3a ) is R b ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl optionally substituted with from 1-3 independently selected halo; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is C 1-3 alkyl optionally substituted with from 1-3 R a ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is C 1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., –CH 3 , –CH 2 F, - CH 2 CH 2 F, or –CHF 2 ); and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is C 1-3 alkyl; and the other of R 3a and R 3b is H.
  • R 3a and R 3b can be methyl, ethyl, or isopropyl; and the other of R 3a and R 3b can be H.
  • one of R 3a and R 3b e.g., R 3a
  • one of R 3a and R 3b e.g., R 3a
  • R 3a can be CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 , or -CH 2 CH 2 F; and the other of R 3a and R 3b can be H.
  • one of R 3a and R 3b (e.g., R 3a ) is C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f ; and the other of R 3a and R 3b is H.
  • R 3a and R 3b can be –CH 2 OMe, -CH 2 CH 2 OMe, -CH(Me)CH 2 OMe, - CH 2 CH(Me)OMe, -CH 2 OEt, -CH 2 CH 2 OCHF 2 , -CH 2 NR e R f (e.g., -CH 2 N(CF 3 )Me), or – CH 2 CH 2 NR e R f (e.g., -CH 2 CH 2 NMe 2 ); and the other of R 3a and R 3b can be H.
  • R 3a and R 3b can be H.
  • one of R 3a and R 3b is C 1-3 alkyl substituted with C 1-4 alkoxy; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b e.g., R 3a
  • R 3a and R 3b can be —CH 2 OMe, -CH 2 CH 2 OMe, -CH(Me)CH 2 OMe, -CH 2 CH(Me)OMe, or -CH 2 OEt.
  • one of R 3a and R 3b e.g., R 3a
  • R 3a can be –CH 2 OMe.
  • one of R 3a and R 3b is C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b e.g., R 3a
  • R 3a and R 3b can be —CH 2 OMe, -CH 2 CH 2 OMe, -CH(Me)CH 2 OMe, - CH 2 CH(Me)OMe, or -CH 2 OEt; and the other of R 3a and R 3b can be H.
  • one of R 3a and R 3b (e.g., R 3a ) is R g or –(L g ) g -R g ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b (e.g., R 3a ) is R g ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b (e.g., R 3a ) is C 3-6 cycloalkyl optionally substituted with from 1-4 R c ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is heterocyclyl including from 4-6 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 ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C 1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with R d ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is –(C 1-3 alkylene)-R g or - (C 1-3 alkylene)-O-R g , optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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 ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is –(C 1-3 alkylene)-R g , optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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 ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is –CH 2 -R g , –CH 2 CH 2 R g , or –CH 2 -O-R g , wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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 ; and the other of R 3a and R 3b is H.
  • one of R 3a and R 3b is –CH 2 -R g , – CH 2 CH 2 R g , or –CH 2 -O-R g , wherein the R g group of R 3a or R 3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C 1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with R d ; and the other of R 3a and R 3b is H.
  • R 3a and R 3b can be selected from the group consisting of: ; ; a 3a 3b nd the other of R and R can be H.
  • R 3a and R 3b are each independently selected R b .
  • R 3a and R 3b are each independently selected C 1-3 alkyl which is optionally substituted with from 1-3 R a .
  • R 3a and R 3b can each be independently C 1-3 alkyl (e.g., methyl).
  • R 3a and R 3b together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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 • 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, R c , and R W .
  • R 3a and R 3b together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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 • 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 3a and R 3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; • 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 • 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 3a and R 3b 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 together with the Ring B ring atom to which each is attached can form a fused cyclopropyl or cyclobutyl.
  • R 3a and R 3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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 • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R c .
  • R 3a and R 3b together with the Ring B ring atom to which each is attached, can form , , , As further non-limiting examples, R 3a and R 3b , together with the Ring B ring atom to which each is attached, can form For example, R 3a and R 3b , together with the Ring B ring atom to which each is attached, can form wherein R d is C 1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., R d is C 1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH 2 CF 3 )).
  • R d is C 1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., R d is C 1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH 2 CF 3 )).
  • R 3a and R 3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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 • wherein the fused saturated ring of 4-6 ring atoms is substituted with R W and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R c .
  • R 3a and R 3b together with the Ring B ring atom to which each is attached form:
  • R 3a and R 3b together with the Ring B ring atom to which each is attached form: , , , R W is or
  • R 3a and R 3b together with the Ring B ring atom to which each is attached can form , wherein R W is .
  • R 1c , R 2a , and R 2b are each H.
  • the other of R 2a and R 2b and the other of R 3a and R 3b are each H.
  • R 2a and R 2b e.g., R 2a
  • R 3a and R 3b e.g., R 3a
  • the compound can have formula or .
  • one of R 2a and R 2b (e.g., R 2a ) and one of R 3a and R 3b (e.g., R 3a ) combine to form a double bond between the Ring B ring atoms to which each is attached.
  • the other of R 2a and R 2b and the other of R 3a and R 3b are each H.
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is selected from the group consisting of: R b , R g , and –(L g ) g -R g .
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is selected from the group consisting of: (i) C 1-3 alkyl; (ii) C 1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f ; (iv) C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy; or (v) –R g , –CH 2 -R g , –CH 2 CH 2 R g , or –CH 2 -O-R g , wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are
  • R 2a and R 2b e.g., R 2a
  • R 3a and R 3b e.g., R 3a
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is: (i) C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f ; or (ii) –CH 2 OMe, -CH 2 CH 2 OMe, -CH(Me)CH 2 OMe, -CH 2 CH(Me)OMe, -CH 2 OEt, - CH 2 CH 2 OCHF 2 , -CH 2 NR e R f (e.g., -CH 2 N(CF 3 )Me), or –CH 2 CH 2 NR e R f (e.g., - CH
  • R 2a and R 2b e.g., R 2a
  • R 3a and R 3b e.g., R 3a
  • R 2a , R 2b , R 3a , and R 3b taken together with the Ring B ring atoms to which each is attached form: , wherein: R 3c is C 1-4 alkoxy, C 1-4 haloalkoxy, NR e R f , or R g ; and bb is the point of attachment to N(R 1c ).
  • the compound can have the following formula: (e.g., R 3c can be C 1-4 alkoxy).
  • R 3c can be C 1-4 alkoxy.
  • R 1c is H.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is C 1-3 alkyl optionally substituted with from 1-3 R a ; optionally the other of R 3a and R 3b is H; and optionally each R a substituent present in R 3a or R 3b is independently selected from the group consisting of: halo, C 1-4 alkoxy, and C 1-4 haloalkoxy.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is C 1-3 alkyl (e.g., methyl, ethyl, or isopropyl); and the other of R 3a and R 3b is H.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is C 1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH 2 F, -CHF 2 , CF 3 , or –CH 2 CH 2 F); and the other of R 3a and R 3b is H.
  • R 3a and R 3b is C 1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH 2 F, -CHF 2 , CF 3 , or –CH 2 CH 2 F); and the other of R 3a and R 3b is H.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b is C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy (e.g., –CH 2 OMe, -CH 2 CH 2 OMe, - CH(Me)CH 2 OMe, -CH 2 CH(Me)OMe, or -CH 2 OEt); and the other of R 3a and R 3b (e.g., R 3a ) is H.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is –R g , –(C 1-3 alkylene)-R g , or –(C 1-3 alkylene)-O-R g , optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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 ; and the other of R 3a and R 3b is H.
  • R 3a and R 3b is H
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is –R g or –(C 1-3 alkylene)-R g , optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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 ; and optionally the other of R 3a and R 3b is H.
  • R 1c , R 2a , and R 2b are each H; and R 3a and R 3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 (e.g., 3 or 4) ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R c .
  • R 1c , R 2a , and R 2b are each H; and R 3a and R 3b taken together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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 • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R c .
  • R 3a and R 3b together with the Ring B ring atom to which each is attached, can form Variable Ring A
  • Ring A is w cB herein each R 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 of the foregoing embodiments, m is 1 or 2 (e.g., 2). In certain embodiments, Ring A is ), wherein 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 wher cB1 c cB2 ein R is R ; and R is H or R c , optionally wherein 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 (e.g., –F or –Cl (e.g., –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, –CHF 2 , or –CF 3 .
  • 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 cyano; 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, -CHF 2 , -CF 3 , or -CH 2 CHF 2 .
  • Ring A is selected from the group consisting of: In some embodiments, 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 substituents independently selected from the group consisting of R c and oxo.
  • 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 substituents independently selected from the group consisting of R c and oxo.
  • Ring A can be selected from the group consisting of: each of which is furthe c r optionally substituted with R .
  • the compound of Formula (I) 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. In certain embodiments, the compound of Formula (I) 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. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c):
  • the compound of 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, the compound of Formula (I) is a compound of Formula (I-d): 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, the compound of Formula (I) is a compound of Formula (I-e):
  • n is 0.
  • m, X 2 , L 1 , and R 5 can be as defined for Formula (I) anywhere herein.
  • R 5 is C 1-6 alkoxy optionally substituted with from 1-6 R a . In certain of these embodiments, R 5 is C 1-3 alkoxy, such as methoxy. In certain embodiments of [AA1], R 5 is S(O) 2 (C 1-6 alkyl) which is optionally substituted with from 1-6 R a . In certain of these embodiments, R 5 is S(O) 2 (C 1-3 alkyl). For example, R 5 can be S(O) 2 Me. In certain embodiments of [AA1], L 1 is CH 2 . In certain embodiments of [AA1], L 1 is –CH(Me)-. In certain embodiments of [AA1], L 1 is –CH 2 CH 2 -.
  • 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 x0 is 0, 1, 2, or 3, provided that x0+x1 ⁇ 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.
  • [BB1] when R 5 is x1 is 0.
  • X is –O-.
  • R 5 can be selected from the group consisting of: In certain embodiments of [BB1], R 5 is which is optionally substituted with from 1-2 R c , wherein X b and X c are each independently selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 . As non-limiting examples of the foregoing embodiments, R 5 can be selected from the group consisting of: optionally wherein R d is C 1-4 alkyl, such as methyl.
  • R 5 is bicyclic heterocyclyl including from 6-10 (e.g., 6-8) 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 can be (e.g., In certain embodiments of [BB1], R 5 is bicyclic heterocyclyl including from 7-10 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 , such as wherein R 5 is In certain embodiments of [BB1], L 1 is CH 2 . In certain embodiments of [BB1], L 1 is –CH(Me)-.
  • m is 0.
  • 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 , example, R 5 can be In certain embodiments of [CC1], 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 can be , , , , , ,
  • R 5 can be In certain embodiments of [CC1], 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 each optionall c y substituted with from 1-2 R .
  • R 5 is bicyclic heteroaryl including from 9-10, such as 9, 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 , such as wherein R 5 is or
  • R 5 is phenyl optionally substituted with from 1- 2 R c , such as unsubstituted phenyl.
  • L 1 is CH 2 .
  • L 1 is –CH(Me)-.
  • m is 0.
  • R 5 is C 3-6 cycloalkyl.
  • R 5 can be cyclopropyl.
  • R 5 is C 3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C 1-4 alkyl; C 1-4 alkyl substituted with R a , such as C 1-4 alkyl substituted with C 1-4 alkoxy; C 1-4 alkoxy; and C 1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R c .
  • R 5 can be selected from the group consisting of: such as In certain embodiments of [DD1], L 1 is CH 2 .
  • m is 0.
  • L 1 is –CH 2 CH 2 -.
  • R 5 is C 1-6 alkoxy optionally substituted with from 1-6 R a . In certain of these embodiments, R 5 is C 1-3 alkoxy. In certain embodiments of [FF1], R 5 is S(O) 2 (C 1-6 alkyl) optionally substituted with from 1-6 R a . In certain embodiments of [FF1], X 2 is –O-. In certain embodiments of [FF1], X 2 is -N(R N )- (e.g., –N(H)-). In certain embodiments of [FF1], X 2 is .
  • L 1 is branched C 3-6 alkylene. In certain of these embodiments, L 1 is selected from the group consisting of: w 5 herein aa is the point of attachment to R .
  • R g2 is which is optionally substituted with from 1-2 R c , wherein bb is the point of attachment to R W ; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0.
  • R g2 is selected from the group consisting of:
  • R g2 is which is optionally substituted with from 1-2 R c ;
  • X b is selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 ; and
  • bb is the point of attachment to R W .
  • R g2 is selected from the group consisting of: such as wherein bb is the point of attac W hment to R ; and optionally wherein R d is C 1-4 alkyl, such as methyl.
  • R g2 is is bicyclic heterocyclylene including from 6-8 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 heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c , wherein bb is the point of attachment to R W .
  • R g2 can be wherein bb is the point of attachmen W t to R .
  • W is C 2-6 alkenyl optionally substituted with from 1-3 R a .
  • R W can be or
  • L 1 is CH 2 .
  • L 1 is —CH(Me)-.
  • L 1 is –CH 2 CH 2 -.
  • L 1 is a bond.
  • m is 1.
  • X 2 is –O-.
  • X 2 is -N(R N )- (e.g., –N(H)-).
  • m is 0.
  • the compound of Formula (I) is a compound of Formula (I-a1):
  • Formula (I-a1) or a pharmaceutically acceptable salt thereof wherein: n is 0, 1, or 2; and R 5 is heterocyclyl including from 4-10 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 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 x0 is 0, 1, 2, or 3, provided that x0+x1 ⁇ 1. In certain of these embodiments, x1 is 0. In certain embodiments, x0 is 1, 2, or 3. In certain embodiments, X a is –O-.
  • x1 is 1 or 2.
  • R 5 is selected from the group consisting of: .
  • R 5 is which is optionally substituted with from 1-2 R c , wherein X b and X c are each independently selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 .
  • R 5 is selected from the group consisting of: , , optionally wherein R d is C 1-4 alkyl, such as methyl.
  • R 5 is bicyclic heterocyclyl including from 6-10 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 , such as wherein R 5 is such as In certain embodiments of Formula (I-a1), n is 0.
  • the compound of Formula (I) is a compound of Formula (I-a2): Formula (I-a2) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R 5 is selected from the group consisting of: • 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, and wherein the heteroaryl is optionally substituted with from 1-3 R c ; and • C6 aryl optionally substituted with from 1-4 R c .
  • R 5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R c .
  • R 5 is In certain embodiments of Formula (I-a2), 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 . In certain of these embodiments, R 5 is . In certain embodiments of Formula (I-a2), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a3):
  • R 5 is C 3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • R 5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R c .
  • R 5 is In certain embodiments of Formula (I-a3), 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 . In certain of these embodiments, R 5 is In certain embodiments of Formula (I-a3), n is 0.
  • R g2 is which is optionally substituted with from 1-2 R c , wherein bb is the point of attachment to R W ; and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments of Formula (I-a4), R g2 is selected from the group consisting wherein W bb is the point of attachment to R .
  • R g2 is which is optionally substituted with from 1-2 R c ;
  • X b is selected from the group consisting of: O, N(H), N(R d ), and S(O) 0-2 ; and bb is the point of attachment to R W .
  • R g2 is selected from the group consisting of: or wherein bb is the point of attachment to R W ; and option d ally wherein R is C 1-4 alkyl, such as methyl.
  • R g2 is is bicyclic heterocyclylene including from 6-8 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 heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c (e.g., R g2 is such as wherein bb is the point of attachment to R W .
  • W is C 2-6 alkenyl (e.g., C 2-4 alkenyl) optionally substituted with from 1-3 R a .
  • R W is or such as .
  • n is 0.
  • the compound is a compound of Formula (I-a5):
  • Formula (I-a5) or a pharmaceutically acceptable salt thereof wherein: n is 0, 1, or 2; L 1 is C 1-6 alkylene optionally substituted with from 1-6 R a ; and R 5 is selected from the group consisting of: H; C 1-6 alkoxy or S(O) 2 (C 1-6 alkyl) each optionally substituted with from 1-6 R a ; -OH; and –NR e R f .
  • L 1 is branched C 3-6 alkylene.
  • L 1 is selected from the group consisting of: , , , and wherein aa is the point of attachment to R 5 .
  • R 5 is H. In certain embodiments of Formula (I-a5), R 5 is C 1-6 alkoxy optionally substituted with from 1-6 R a . In certain embodiments of Formula (I-a5), R 5 is –OH. In certain embodiments of Formula (I-a5), R 5 is –NR e R f . In certain embodiments of Formula (I-a5), n is 0.
  • the compound is a compound of Formula (I-f): Formula (I-f) or a pharmaceutically acceptable salt thereof, wherein: Ring C1 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 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 C1 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 .
  • Ring C1 can be selected from the group consisting of: .
  • Ring C1 can be As non-limiting examples, Ring C1 can be selected from the group consisting of: .
  • 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 consisting of: , , , , , , and As non-limiting examples, Ring C1 can be selected from the group consisting of: .
  • Ring C1 pyridyl or pyrimidyl, each of which is optionally substituted with from 1-2 R c .
  • Ring C can be selected from the group consisting of: .
  • Ring C1 is selected from the group consisting of: wherein the R c present in Ring C is C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl optionally substituted with from 1-3 independently selected halo.
  • Ring C1 is selected from the group consisting of: wherein the R c present in Ring C1 is selected from the group consisting of: halo and C 1-3 alkyl optionally substituted with from 1-3 R a , optionally wherein the R c is –F, -Cl, or C 1-3 alkyl optionally substituted with from 1-3 independently selected halo.
  • the compound is a compound of Formula (I-g): Formula (I-g) 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 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 can be selected from the group consisting of: , , , each further optionally substituted with from 1- 2 R c .
  • Ring C2 can be selected from the group consisting of: As further non-limiting examples, Ring C2 can be selected from the group consisting of: each further optionally substituted with from 1-2 R c .
  • Ring C2 can be selected from the group consisting of: As further non-limiting examples, Ring C2 can be selected from the group consisting of:
  • Ring C2 In certain embodiments of Formula (I-g), 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), and N(R d ), and wherein the heteroaryl is optionally substituted with from 1-4 R c .
  • Ring C2 can be selected from the group consisting of: As further non-limiting examples, Ring C2 can be selected from the group consisting of:
  • the compound is a compound of Formula (I-g1): Formula (I-g1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: N, NH, NR d , CH, CR c , CX 1 , O, and S; and each is independently a single bond or a double bond, provided that the 5-membered ring including Y 1 , Y 2 , and Y 3 is heteroaryl; and from 0-1 of Y 1 , Y 2 , and Y 3 is selected from the group consisting of: O, S, and CR X1 .
  • Y 1 is S.
  • Y 2 is selected from the group consisting of: N, CH, CR c , and CX 1 .
  • Y 2 is CH or CR c .
  • Y 2 is N.
  • Y 3 is selected from the group consisting of CH and CR c .
  • Y 3 is CH.
  • Y 1 is S; and Y 2 and Y 2 are each CH.
  • Y 1 is S; Y 2 is N; and Y 3 is CH.
  • Y 1 is S; Y 2 is CR c ; and Y 3 is CH.
  • the R c group present in Y 2 is selected from the group consisting of: (i) C 1-6 alkyl; (ii) halo; and (iii) C 1-6 alkyl substituted with from 1-6 independently selected R a .
  • the R c group present in Y 2 is selected from the group consisting of: (i) C 1-3 alkyl; (ii) halo; and (iii) C 1-3 alkyl substituted with from 1-3 independently selected halo.
  • the R c group present in Y 2 is selected from the group consisting of: (i) methyl; (ii) -F; and (iii) –CHF 2 .
  • the R c group present in Y 2 is selected from the group consisting of: (i) C 1-3 alkyl (e.g., methyl); (ii) halo (e.g., -F); and (iii) C 1-3 alkyl substituted with from 1-3 independently selected halo (e.g., R c is – CHF 2 ) .
  • the compound is a compound of Formula (I-g1-1): Formula (I-g1-1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1, such as 0; In certain embodiments, the compound is a compound of Formula (I-g1-2): Formula (I-g1-2) or a pharmaceutically acceptable salt thereof.
  • one of Y 1 , Y 2 , Y 3 is CX 1 ; and X 1 can be defined anywhere herein.
  • X 1 can be defined according to [AA1], [BB1], [CC1], [DD1], [EE1], [FF1], or [GG1].
  • n is 0.
  • the compound is a compound of Formula (I-h): Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: Ring C3 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 X 1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c .
  • Ring C3 is 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 , and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R c , such as wherein Ring C is tetrahydropyranyl, such as .
  • each occurrence of R c present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 is independently selected from the group consisting of: C 1-3 alkyl; C 1-3 alkyl substituted with from 1-3 R a ; halo; cyano; NR e R f , such as NH 2 , NH(C 1-3 alkyl), or N(C 1-3 alkyl) 2 ; -OH; C 1-4 alkoxy; and C 1-4 haloalkoxy.
  • each occurrence of R c present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 can be independently selected from the group consisting of: halo; C 1-6 alkyl; C 1-6 alkyl substituted with from 1-6 independently selected halo; C 1-4 alkoxy; and C 1-4 haloalkoxy.
  • R 1c is H.
  • R 2a and R 2b are H.
  • R 2a and R 2b are C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl; and the other of R 2a and R 2b is H.
  • R 2a and R 2b are C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl (e.g., methyl); and the other of R 2a and R 2b is H.
  • R 2a and R 2b are heterocyclyl including from 4-6 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 ; and the other of R 2a and R 2b is H.
  • R 3a and R 3b are C 1-3 alkyl optionally substituted with from 1-3 R a , such as C 1-3 alkyl optionally substituted with from 1-3 independently selected halo; and the other of R 3a and R 3b is H.
  • R 3a and R 3b are C 1-3 alkyl optionally substituted with from 1-3 independently selected halo, such as –CH 3 , –CH 2 F, -CH 2 CH 2 F, or –CHF 2 ; and the other of R 3a and R 3b is H.
  • R 3a and R 3b are C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy or NR e R f (e.g., –CH 2 OMe, -CH 2 CH 2 OMe, -CH(Me)CH 2 OMe, -CH 2 CH(Me)OMe, -CH 2 OEt, -CH 2 NR e R f (e.g., - CH 2 N(CF 3 )Me), or –CH 2 CH 2 NR e R f (e.
  • R 3a and R 3b are C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy; and the other of R 3a and R 3b is H.
  • R 3a and R 3b are heterocyclyl including from 4-6 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 ; and the other of R 3a and R 3b is H.
  • R 3a and R 3b are C 3-6 cycloalkyl optionally substituted with from 1-4 R c ; and the other of R 3a and R 3b is H.
  • R 3a and R 3b e.g., R 3a
  • R 3a is –(C 1-3 alkylene)-R g (e.g., -CH 2 -R g or –CH 2 CH 2 -R g ) or –(C 1-3 alkylene)-O-R g (e.g., -CH 2 O-R g ), wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 ring atoms, wherein from 1-3
  • R 3a and R 3b are –(C 1-3 alkylene)-R g , optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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
  • R 3a and R 3b together with the Ring B ring atom to which each is attached form:
  • R W is or .
  • R 3a and R 3b together with the Ring B ring atom to which each is attached can form wherein R W is .
  • the other of R 2a and R 2b and the other of R 3a and R 3b are each H.
  • the other of R 2a and R 2b and the other of R 3a and R 3b are each H.
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is selected from the group consisting of: (i) C 1-3 alkyl; (ii) C 1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f ; (iv) C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy; or (v) –R g , –CH 2 -R g , –CH 2 CH 2 R g , or –CH 2 -O-R g , wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f .
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is selected from the group consisting of: (i) C 1-3 alkyl; (ii) C 1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f ; (iv) C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy; or (v) –R g , –CH 2 -R g , –CH 2 CH 2 R g , or –CH 2 -O-R g , wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are
  • the other of R 2a and R 2b is H; and the other of R 3a and R 3b is C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f .
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is C 1-3 alkyl optionally substituted with from 1-3 R a ; and the other of R 3a and R 3b is H, optionally each R a substituent present in R 3a or R 3b is independently selected from the group consisting of: halo, C 1-4 alkoxy, and C 1-4 haloalkoxy.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b is C 1-3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy; and the other of R 3a and R 3b is H.
  • R 1c , R 2a , and R 2b are each H; and R 3a and R 3b are independently selected C 1-3 alkyl.
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is –R g , –(C 1-3 alkylene)-R g (e.g., -CH 2 -R g or –CH- 2 CH 2 -R g ), or –(C 1-3 alkylene)-O-R g (e.g., -CH 2 -O-R g ), optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted
  • R 1c , R 2a , and R 2b are each H; one of R 3a and R 3b (e.g., R 3a ) is –R g or –(C 1-3 alkylene)-R g , optionally wherein the R g group of R 3a or R 3b is: C 3-6 cycloalkyl optionally substituted with from 1-4 R c , or heterocyclyl including from 4-6 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
  • R 1c , R 2a , and R 2b are each H; and R 3a and R 3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 (e.g., 3 or 4) ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R c .
  • R 1c , R 2a , and R 2b are each H; and R 3a and R 3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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 • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting
  • R 1c is H; one of R 2a and R 2b (e.g., R 2a ) and one of R 3a and R 3b (e.g., R 3a ) combine to form a double bond between the Ring B ring atoms to which each is attached; and the other of R 2a and R 2b and the other of R 3a and R 3b are each H.
  • R 1c is H; one of R 2a and R 2b and one of R 3a and R 3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R 2a and R 2b is H; and the other of R 3a and R 3b is selected from the group consisting of: (i) C 1-3 alkyl; (ii) C 1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C 1-3 alkyl substituted with C 1-4 alkoxy, C 1-4 haloalkoxy, or NR e R f ; (iv) C
  • R 1c is H; one of R 2a and R 2b and one of R 3a and R 3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R 2a and R 2b is H; and the other of R 3a and R 3b is C 1- 3 alkyl substituted with C 1-4 alkoxy or C 1-4 haloalkoxy.
  • 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 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.
  • Ring A is wherein 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 selected from the group consisting of: .
  • 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 substituents independently selected from the group consisting of R c and oxo.
  • 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 substituents independently selected from the group consisting of R c and oxo.
  • Ring A can be selected from the group consisting of: , each of which is further optio c nally substituted with R .
  • R Optio c nally substituted with R .
  • the moiety is In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the moiety is In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (
  • the moiety is .
  • the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof. Table C1 For certain compounds, the symbol * at a chiral center denotes that this chiral center has been resolved (i.e., is a single epimer) and the absolute stereochemistry at that center has not been determined.”
  • 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 EC50 value.
  • a compound with a lower EC50 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 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 IC 50 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 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 EC50 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 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. Chem.
  • the compounds of Formula (I) can selectively target an EGFR kinase.
  • Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 EC50 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 IC 50 value. A compound with a lower IC 50 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 EC50 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.
  • Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof 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. It can be desireable to selectively target a HER2 kinase over a wild type EGFR kinase due to undesireable side effects (e.g., diarrhea and skin rashes) that can impact quality of life and compliance. See, e.g., Morphy. J. Med. Chem.2010, 53, 4, 1413– 1437 and Peters. J. Med. Chem.2013, 56, 22, 8955–8971.
  • a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I
  • 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 second EGFR inhibitor e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-
  • 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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).
  • the compounds of Formula (I) can selectively target an EGFR and a HER2 kinase.
  • Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.
  • 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.
  • another kinase e.g., wild type EGFR
  • non-kinase target e.g.
  • 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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
  • 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 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 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 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 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 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- a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I- g1-2),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- a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g
  • 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g
  • 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 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 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 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 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).
  • 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.
  • 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.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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),
  • an EGFR inhibitor resistance mutation can result in an EGFR kinase that has one or more of an increased Vmax, a decreased Km, 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 2b.
  • compounds of Formula (I) 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 2b) by either dosing in
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or
  • 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 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1),
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Formula (I-a) e.g., Formula (I-a),
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.
  • 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-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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
  • 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-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (
  • 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 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3),
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h
  • 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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (
  • 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.,
  • 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.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)
  • a pharmaceutically acceptable salt thereof e.g., Formula (I-a), (I-a
  • 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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or
  • 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-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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
  • 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-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.
  • Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h) or a pharmaceutically acceptable salt thereof, for
  • 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 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. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a HER2-associated cancer.
  • 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/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).
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-a1),
  • 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-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I
  • the compounds of Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), including pharmaceutically acceptable salts or solvates thereof, can be administered in the form of pharmaceutical compositions as described herein.
  • Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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.
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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; (ii)
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-a1), (I-a2), (I-a3), (I-a4),
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with the first EGFR inhibitor.
  • methods of treating a subject identified as having a cancer cell that has one or more EGFR inhibitor resistance mutations that include administering to the subject a compound of Formula (I), 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 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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
  • 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-
  • 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-a1), (I-a2), (I-a3), (I- a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof.
  • Formula (I) e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I- a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-
  • 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 N-(4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-3-yl)pivalamide (Compound 101) Int1A is reacted with tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide under basic conditions (e.g., with NaH in DMF) to provide Int1B.
  • Basic conditions e.g., with NaH in DMF
  • Example 2 N-(4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-3-yl)-2-methoxy-2-methylpropanamide
  • Compound 102 Part 1: Synthesis of 2-methoxy-2-methylpropanoyl chloride 2-Methoxy-2-methylpropanoic acid is reacted with 2-chloroacryloyl chloride (e.g., in the presence of DCM and DMF) at 0 °C. The reaction mixture is then warmed to about 40 °C to provide 2-methoxy-2-methylpropanoyl chloride.
  • 2-chloroacryloyl chloride e.g., in the presence of DCM and DMF
  • Int2A is prepared using the method as described in Example 1. Int2A is reacted with 2-methoxy-2-methylpropanoyl chloride under basic conditions (e.g., Et3N in DCM) to provide Int2B. Int2B is brominated e.g., with 1,3-dibromo-5,5-dimethylimidazolidine- 2,4-dione in AcOH at 100 °C to provide Int2C.
  • basic conditions e.g., Et3N in DCM
  • Int2B is brominated e.g., with 1,3-dibromo-5,5-dimethylimidazolidine- 2,4-dione in AcOH at 100 °C to provide Int2C.
  • Int3A is reacted with 1-iodo-2-methoxyethane under basic conditions (e.g., NaH in DMF) to provide Int3B.
  • Basic conditions e.g., NaH in DMF
  • Int3E is brominated with e.g., 1,3-dibromo-5,5- dimethylimidazolidine-2,4-dione in AcOH at 100 °C to provide Int3F.
  • the resulting mixture was concentrated under reduced pressure.
  • the crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3- chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (116.1 mg, 48.50%) as a light yellow solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150mm 5um; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min, 50% B; Wave Length: 254; 220 nm; RT1(min): 6.97) to afford 2- (2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (6.0 mg, 25.0%) as a light yellow solid.
  • the crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 51% B in 7 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.37) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4 mg ⁇ 11.4%) as a white solid.
  • a solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one 500 mg, 2.00 mmol, 1.00 equiv
  • bis(pinacolato)diboron 1013.81 mg, 3.99 mmol, 2.00 equiv
  • KOAc (489.77 mg, 4.99 mmol, 2.50 equiv)
  • Pd(dppf)Cl 2 146.06 mg, 0.200 mmol, 0.1 equiv
  • DME 30.00 mL, 309.92 mmol,
  • the resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS.
  • the resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure.
  • the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave Length: 254;220 nm; RT1(min): 7.7 to afford (7S)-3-[(3-fluoro-2- methoxyphenyl)amino]-7-methyl-2- ⁇ 1H-pyrazolo[4,3-b]pyridin-7-yl ⁇ -5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.6 mg, 18.40%) as a off-white solid.
  • the resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS.
  • the resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure.
  • the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave Length: 254;220 nm; RT1(min): 7.7) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2- ⁇ 1H-pyrazolo[4,3-b]pyridin-7-yl ⁇ -5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.5 mg, 30.48%) as a off-white solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5­m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 57% B in 10 min, 57% B; Wave Length: 254/220 nm; RT1(min): 7.37) to afford 2-[2-(2- aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.5 mg, 33.04%) as a white solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5­m; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 57% B in 8 min, 57% B; Wave Length: 254 ⁇ 220 nm; RT1(min): 7.32) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2- ⁇ 2-[2-(dimethylamino)ethoxy]thieno[3,2-b]pyridin-7-yl ⁇ - 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.1 mg, 38.96%) as a white solid.
  • a solution of tert-butyl N-[2-( ⁇ 7-chlorothieno[3,2-b]pyridin-2-yl ⁇ oxy)ethyl]carbamate 250 mg, 0.760 mmol, 1 equiv) in MeOH was treated with HCHO (45.66 mg, 1.520 mmol, 2 equiv) and a drop of acetic acid for 30 min at RT under nitrogen atmosphere followed by the addition of NaBH3CN (477.80 mg, 7.600 mmol, 10 equiv) added in portions at rt.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 47% B in 8 min, 47% B; Wave Length: 254; 220 nm; RT1(min): 7.02) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2- ⁇ 2-[2- (methylamino)ethoxy]thieno[3,2-b]pyridin-7-yl ⁇ -5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (84.1 mg, 50.49%) as a white solid.
  • the crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(8.1mg 99.4%) as a white solid.
  • Example 21 (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 358)
  • 4-bromo-6-methoxyquinoline 200 mg, 0.840 mmol, 1.00 equiv
  • (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (654.33 mg, 2.100 mmol, 2.5 equiv) in DMF (2 mL) were added K 2 CO 3 (290.25 mg, 2.100 mmol, 2.5 equiv) and Pd(dppf)Cl 2 (61.47 mg, 0.084 mmol, 0.10 equi
  • the crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.82) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(15mg 98.2%) as a as a white solid.
  • Example 23 (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 360)
  • 4-bromo-6,7-dimethoxyquinoline 300 mg, 1.119 mmol, 1 equiv
  • (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (552.28 mg, 2.797 mmol, 2.5 equiv) in DMF (6 mL)
  • K2CO3 386.61 mg, 2.797 mmol, 2.50 equiv
  • Pd(dppf)Cl 2 122.81 mg, 0.168 mmol, 0.15 equiv
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 28% B to 38% B in 8 min, 38% B; Wave Length: 254;220 nm; RT1(min): 6.9) to afford 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(4.1 mg, 8.27%) as a yellow green solid.
  • Example 27 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 317)
  • 6-chloro-1H-1,7-naphthyridin-4-one 300 mg, 1.661 mmol, 1.00equiv
  • benzyl bromide 340.95 mg, 1.993 mmol, 1.2 equiv
  • K 2 CO 3 (459.18 mg, 3.322 mmol, 2 equiv) in portions at rt under N 2 atmosphere.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C 18, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 *H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254;220 nm; RT 1 (min): 7.7) to afford 2-(6-amino-1,7-naphthyridin-4- yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 11.14%) as a yellow green solid.
  • Example 29 N-(4- ⁇ 3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl ⁇ -1,7-naphthyridin-6-yl)prop-2-enamide (compound 321)
  • 6-chloro-1H-1,7-naphthyridin-4-one 300 mg, 1.661 mmol, 1.00 equiv
  • benzyl bromide 340.95 mg, 1.993 mmol, 1.2 equiv
  • K 2 CO 3 (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N 2 atmosphere.
  • Example 30 (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 279)
  • methyl 5-bromo-2H-pyrazole-3-carboxylate (6 g, 29.267 mmol, 1.00 equiv)
  • DIEA 11.35 g, 87.801 mmol, 3 equiv
  • SEM-Cl (6.83 g, 40.974 mmol, 1.4 equiv) dropwise at 0 degrees C under nitrogen atmosphere.
  • Example 34 3-[(3-chloro-2-methoxyphenyl)amino]-2- ⁇ 2-[(2-methoxypyrimidin-4- yl)amino]pyridin-4-yl ⁇ -5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 311)
  • a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (1 g, 5.844 mmol, 1.00 equiv) and PPh 3 (2299.24 mg, 8.766 mmol, 1.5 equiv) in THF (20 mL) was added DIAD (1418.07 mg, 7.013 mmol, 1.2 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere.
  • Desired product could be detected by LCMS.
  • the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10 g, 62.17%) as a grey solid.
  • Example 35 3-[(3-chloro-2-methoxyphenyl)amino]-2- ⁇ 2-[(6-methoxypyrimidin-4- yl)amino]pyridin-4-yl ⁇ -5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 310)
  • Example 36 3-[(3-chloro-2-methoxyphenyl)amino]-2- ⁇ 2-[(4-methoxypyrimidin-2- yl)amino]pyridin-4-yl ⁇ -5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 309)
  • Desired product could be detected by LCMS.
  • the resulting mixture was concentrated under vacuum.
  • the residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid.
  • To a stirred mixture of methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate (11.4 g, 47.609 mmol, 1.00 equiv) in MeOH (100 mL) was added NaOH (20 mL, 500.036 mmol, 10.50 equiv) at room temperature.
  • the reaction was quenched by the addition of Water (300 mL) at room temperature. The aqueous layer was dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (100 mL). To the above mixture was added K 2 CO 3 (5.45 g, 39.417 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 100 degree C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH 2 Cl 2 (3x100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for 2 h at 60 degree C under nitrogen atmosphere. Desired product could be detected by LCMS.
  • the resulting mixture was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product (180 mg) was purified by Prep- HPLC with the following conditions(Column: Xselect CSH C18 OBD Column 30*150mm 5 ⁇ m, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 8 min, 63% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2- ⁇ [1,2]thiazolo[4,5- b]pyridin-7-yl ⁇ -7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid.

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Abstract

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). 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.

Description

BICYCLIC COMPOUNDS FOR USE IN THE TREATMENT CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63/085,686, filed on September 30, 2020; and U.S. Provisional Application Serial No. 63/143,442, filed on January 29, 2021; each of which is incorporated herein by reference in its entirety. TECHNICAL FIELD 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). 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. BACKGROUND Epidermal growth factor receptor (EGFR, ERBB1) and Human epidermal growth factor receptor 2 (HER2, ERBB2) are members of a family of proteins which regulate cellular processes implicated in tumor growth, including proliferation and differentiation. Several investigators have demonstrated the role of EGFR and HER2 in development and cancer (Reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232, Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184). EGFR overexpresmion is present in at least 70% of human cancers, such as non-small cell lung carcinoma (NSCLC), breast cancer, glioma, and prostate cancer. HER2 overexpression occurs in approximately 30% of all breast cancer. It has also been implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. 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. For example, EGFR tyrosine kinase inhibitors (TKIs) are effective clinical therapies for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. However, the vast majority of patients develop disease progression following successful treatment with an EGFR TKI. Common mechanisms of resistance include acquired, secondary mutation T790M, C797S, and EGFR exon 20 insertion mutations. For example, NSCLC tumors can have EGFR exon 20 insertion mutations that are intrinsically resistant to current EGFR TKIs. Overexpression of another protein, BUB1 (Budding uninhibited by benzimidazole, BUB1) kinase, 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. As soon as the checkpoint gets satisfied the APC/C 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). In contrast, complete inhibition of the mitotic checkpoint has been recognized to result in severe chromosome missegregation and induction of apoptosis in tumour cells (see Kops GJ et al., Nature Rev. Cancer 5, 773, 2005; Schmidt M and Medema RH, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007). Thus, 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. SUMMARY 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). 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. In one aspect, this disclosure features compounds of Formula (I):
Figure imgf000004_0001
Formula (I) or a pharmaceutically acceptable salt thereof, in which R1c, R2a, R2b, R3a, R3b, Ring A, and Ring C can be as defined anywhere herein. In one aspect, this disclosure features compounds of Formula (I):
Figure imgf000004_0002
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000005_0001
• -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; and • -L5-Rg2-RW or –L5-Rg2-RY; provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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 Rc; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):
Figure imgf000009_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000010_0001
; • -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; • -L5-Rg2-RW or –L5-Rg2-RY; and • -RW provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 Rc, wherein x is 1 or 2; and y is an integer from 1 to 6; RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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, Rc, and RW; or one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating an EGFR-associated disease or disorder in a subject, the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating an EGFR-associated cancer in a subject, the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),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. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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 increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); or (d) administering additional doses of the first EGFR inhibitor of step (a) to the subject if the subject has not been determined to have a cancer cell that 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). Further provided herein is a method of treating a subject having a cancer, wherein the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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 increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; or (c) administering additional doses of the first EGFR inhibitor to the subject if the subject has not been determined to have a cancer cell that 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 previously administered to the subject. Also provided herein is a method of treating a subject having a cancer, wherein the method 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject. Further provided herein is a method of treating a subject having a cancer, wherein the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a HER2-associated cancer in a subject, the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject having a cancer, the method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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 increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor of step (a); or (d) administering additional doses of the first HER2 inhibitor of step (a) to the subject if the subject has not been determined to have a cancer cell that 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). Further provided herein is a method of treating a subject having a cancer, wherein the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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 increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; or (c) administering additional doses of the first HER2 inhibitor to the subject if the subject has not been determined to have a cancer cell that 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 previously administered to the subject. Also provided herein is a method of treating a subject having a cancer, wherein the method 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject. Further provided herein is a method of treating a subject having a cancer, wherein the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating an EGFR-associated and HER2- associated cancer in a subject, the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),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. 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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In addition to the above, provided herein is a method for inhibiting a BUB (budding uninhibited by benzimidazole, BUB1-3) kinase. In some embodiments, the methods provided herein include methods for inhibiting BUB11. For example, a method for inhibiting BUB1 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-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. “API” refers to an active pharmaceutical ingredient. The terms “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. For example, 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. The term “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. In one embodiment, 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. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, 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. In some instances, 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. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. 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. The term “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. 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. The term “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. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 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. The term “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. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo. The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3). The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two radicals can be on the same ring carbon atom (e.g., a geminal diradical such as or
Figure imgf000024_0001
Figure imgf000024_0003
) or on different ring atoms (e.g., ring carbon and/or nitrogen atoms (e.g., vicinal ring carbon and/or nitrogen atoms)) (e.g.,
Figure imgf000024_0002
Figure imgf000024_0004
). The term "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. For example, C2-6 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. The term "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. For example, C2-6 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. The term "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. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term "cycloalkyl" as used herein 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. Examples of 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). Non-limiting examples of 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. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term "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. As partially unsaturated cyclic hydrocarbon groups, 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. The term “heteroaryl”, as used herein, 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. Examples of heteroaryl 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, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridone (e.g.,
Figure imgf000026_0001
, ,
Figure imgf000026_0002
(e.g.,
Figure imgf000027_0001
), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e.,
Figure imgf000027_0002
) herein is a constituent part of the heteroaryl ring). The term "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. Examples of 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]pentane, 3-oxabicyclo[3.1.0]hexane, 5- oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of 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, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7- dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3- oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. The term "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. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As 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. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. As used herein, 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. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such 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.,
Figure imgf000029_0006
)); (ii) a single ring atom (spiro- fused ring systems) (e.g., or ), or (iii) a contiguous
Figure imgf000029_0004
Figure imgf000029_0005
array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
Figure imgf000029_0001
,
Figure imgf000029_0008
Figure imgf000029_0007
or ). In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:
Figure imgf000029_0002
encompasses the tautomeric form containing the moiety:
Figure imgf000029_0003
. Similarly, 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. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION 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). 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). In some embodiments, 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):
Figure imgf000030_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000031_0001
• -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; and • -L5-Rg2-RW or –L5-Rg2-RY; provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 Rc, wherein x is 1 or 2; and y is an integer from 1 to 6; RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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, Rc, and RW; or one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):
Figure imgf000035_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000036_0001
• -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; and • -L5-Rg2-RW or –L5-Rg2-RY; provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 Rc, wherein x is 1 or 2; and y is an integer from 1 to 6; RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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 Rc; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):
Figure imgf000040_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000040_0002
• -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; and • -L5-Rg2-RW or –L5-Rg2-RY; provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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 Rc; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; - S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):
Figure imgf000044_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000045_0001
• -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; • -L5-Rg2-RW or –L5-Rg2-RY; and • -RW provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 Rc, wherein x is 1 or 2; and y is an integer from 1 to 6; RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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, Rc, and RW; or one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl. In some embodiments, when Ring C or Rg is heteroaryl, the heteroaryl is other than aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridone (e.g.,
Figure imgf000049_0001
Figure imgf000049_0003
, or
Figure imgf000049_0004
), pyrimidone (e.g.,
Figure imgf000049_0002
), pyridazinone (e.g.,
Figure imgf000049_0014
or
Figure imgf000049_0017
), pyrazinone (e.g.,
Figure imgf000049_0016
and imidazolone (e.g.,
Figure imgf000049_0015
), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). In some embodiments, when Ring C or Rg is heteroaryl, said heteroaryl is not substituted with –OH. In some embodiments, when Ring C or Rg is heteroaryl, the heteroaryl is selected from the group consisting of: aromatic lactams, aromatic cyclic ureas, and vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g.,
Figure imgf000049_0007
, , , or
Figure imgf000049_0008
), pyrimidone (e.g.,
Figure imgf000049_0005
or
Figure imgf000049_0013
), pyridazinone (e.g.,
Figure imgf000049_0009
or ), pyrazinone (e.g.,
Figure imgf000049_0006
or
Figure imgf000049_0010
Figure imgf000049_0012
), and imidazolone (e.g.,
Figure imgf000049_0011
), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., herein is a constituent part of the heteroaryl ring). In some embodiments, when Ring C or Rg is heteroaryl, said heteroaryl is substituted with –OH. Variable Ring C In some embodiments, Ring C is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc. In certain embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-4 Rc. In certain of these embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc. In certain of the foregoing embodiments, Ring C is monocyclic heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(Rd), and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc. As non-limiting examples of the foregoing embodiments, Ring C can be pyridyl or pyrimidyl, each of which is substituted with X1 and further optionally substituted with from 1-3 Rc. In certain embodiments (when Ring C is monocyclic heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(Rd), and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc), Ring C is
Figure imgf000051_0001
, wherein n is 0, 1, or 2. For example, n can be 0. In certain embodiments, Ring C is
Figure imgf000051_0002
, wherein n is 0, 1, or 2. For example, n can be 0. In certain embodiments, Ring C is
Figure imgf000051_0003
, wherein n is 0, 1, or 2. For example, n can be 0. In certain embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc. In certain of the foregoing embodiments Ring C is bicyclic heteroaryl including from 9-10 (e.g., 10) ring atoms, wherein from 1-4 (e.g., 2-4) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc. In certain of the foregoing embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc. As non-limiting examples of the foregoing embodiments, 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 X1 and further optionally substituted with from 1-3 Rc. In certain embodiments, Ring C is selected from the group consisting of:
Figure imgf000052_0001
and
Figure imgf000052_0002
, each of which is optionally substituted with from 1-2 Rc. For example, Ring C can be
Figure imgf000052_0003
. As another non-limiting example, Ring C can be
Figure imgf000052_0004
. As further non-limiting examples, Ring C can be selected from the group consisting of:
Figure imgf000052_0005
and
Figure imgf000052_0006
each of which is optionally substituted with from 1-2 Rc. For example, Ring C can be
Figure imgf000053_0003
. For example, Ring C can be
Figure imgf000053_0005
For example, Ring C can be
Figure imgf000053_0004
. As another non- limiting example, Ring C can be
Figure imgf000053_0002
In certain embodiments, Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc. In certain of these embodiments, Ring C is thieno[3,2-b]pyridyl, which is substituted with X1 and further optionally substituted with from 1-3 Rc. In certain of these embodiments, Ring C is thieno[3,2-b]pyridyl, which is substituted with X1 and further optionally substituted with from 1-3 Rc. For example, Ring C is
Figure imgf000053_0001
.
As non-limiting examples of the foregoing embodiments, Ring C can be
Figure imgf000054_0001
which is optionally substituted with from 1-2 Rc. For example, Ring C can be
Figure imgf000054_0002
. In certain embodiments, Ring C is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc. In certain of these embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc. In certain of the foregoing embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-3 Rc. In certain embodiments, Ring C is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd. As non-limiting examples, Ring C can be selected from the group consisting of:
Figure imgf000055_0001
. For example, Ring C can be
Figure imgf000055_0002
As non-limiting examples, Ring C can be selected from the group consisting of:
Figure imgf000055_0003
. In certain embodiments, 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:
Figure imgf000055_0004
, , , , , and
Figure imgf000055_0005
As non-limiting examples, Ring C can be selected from the group consisting of:
Figure imgf000055_0006
, , , , and
Figure imgf000055_0007
In certain embodiments, Ring C pyridyl or pyrimidyl, each of which is optionally substituted with from 1-2 Rc. For example, Ring C can be selected from the group consisting of: , and
Figure imgf000055_0008
Figure imgf000055_0009
In certain embodiments, Ring C is selected from the group consisting of: w c
Figure imgf000056_0002
herein the R present in Ring C is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, Ring C is selected from the group consisting of:
Figure imgf000056_0003
wherein the Rc present in Ring C is selected from the group consisting of: halo and C1-3 alkyl optionally substituted with from 1-3 Ra, optionally wherein the Rc is –F, -Cl, or C1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc. In certain embodiments, Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc. In certain of these embodiments, Ring C is attached to
Figure imgf000056_0001
via a 5- membered ring. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:
Figure imgf000057_0002
, , , ,
Figure imgf000057_0003
, , , , , ,
Figure imgf000057_0001
In certain embodiments (when Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc), Ring C is attached to
Figure imgf000057_0004
via a 6-membered ring. In certain of these embodiments, Ring C is:
Figure imgf000057_0005
, wherein Z0 is N or CH; and Ring D is an aromatic or partially unsaturated ring including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(Rd), O, and S(O)0-2, wherein Ring D is optionally substituted with from 1-2 Rc. As non-limiting examples, Ring C can be selected from the group consisting of:
Figure imgf000058_0004
For example, Ring C can be
Figure imgf000058_0005
As another non-limiting example, Ring C can be c
Figure imgf000058_0006
(e.g., the R present in Ring C is halo or C1-3 alkyl which is optionally substituted with from 1-3 Ra). As another non-limiting example, Ring C can be
Figure imgf000058_0007
As further non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:
Figure imgf000058_0001
, , ,
Figure imgf000058_0002
, , , , , , , and , each further optionally substituted w c
Figure imgf000058_0003
ith from 1-2 R . In certain embodiments, 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), and N(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:
Figure imgf000059_0001
Figure imgf000059_0002
As further non-limiting examples, Ring C can be
Figure imgf000059_0003
and
Figure imgf000059_0004
(e.g., each Rc present in Ring C is independently selected from the group consisting of C1-4 alkoxy and C1-4 haloalkoxy). In certain embodiments, Ring C 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of these embodiments, Ring C is 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(Rd), 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 Rc. As a non-limiting example of the foregoing embodiments, Ring C can be tetrahydropyranyl (e.g.,
Figure imgf000059_0005
In certain embodiments, each occurrence of Rc present on one or more ring atoms of Ring C is independently selected from the group consisting of: C1-3 alkyl; C1-3 alkyl substituted with from 1-3 Ra; halo; cyano; NReRf, such as NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, or NHC(=O)C1-3 alkyl; -OH; C1-4 alkoxy; and C1-4 haloalkoxy. In certain embodiments, each Rc present on one or more ring atoms of Ring C is independently selected from the group consisting of: halo, cyano, C1-4 alkoxy, C1-4 haloalkoxy, C1-6 alkyl, and C1-6 alkyl optionally substituted with from 1-3 independently selected halo. For example, each of the Rc can be independently selected C1-6 alkyl (e.g., methyl)). As another non-limiting example, each of the Rc can be independently selected from the group consisting of C1-4 alkoxy and C1-4 haloalkoxy (e.g., -OMe). Variables m, X2, L1, and R5 In certain embodiments, m is 1. In other embodiments, m is 0. In certain embodiments, X2 is -O-, -N(RN)-, or –S(O)0-2. In certain of these embodiments, X2 is –O-. In certain embodiments, X2 is –N(RN)-. As a non-limiting example of the foregoing embodiments, X2 can be –N(H)-. In certain embodiments, X2 is
Figure imgf000060_0001
In certain embodiments, X2 is selected from the group consisting of: -OC(=O)-*, - N(RN)C(=O)-*, and –N(RN)S(O)1-2-*. In certain of these embodiments, X2 is - N(RN)C(=O)-*. As a non-limiting example of the foregoing embodiments, X2 can be – N(H)C(=O)-*. In certain embodiments, X2 is –N(RN)S(O)1-2-*. For example, X2 can be – N(H)S(O)2-*. In certain embodiments, X2 is selected from the group consisting of: - OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, and –N(RN)S(O)1-2N(RN)-. In certain of these embodiments, X2 is -N(RN)C(=O)O-*, such as –N(H)C(=O)O-*. In certain of the foregoing embodiments, X2 is –N(H)C(=O)N(RN)-*. For example, X2 can be – N(H)C(=O)N(C1-3 alkyl)-* (e.g., -N(H)C(=O)N(Me)). In certain embodiments, L1 is C1-10 alkylene optionally substituted with from 1-6 Ra. In certain of these embodiments, L1 is C1-3 alkylene optionally substituted with from 1-6 Ra. In certain of the foregoing embodiments, L1 is C1-3 alkylene. For example, L1 can be –CH2-. As another non-limiting example, L1 can be –CH(Me)- (e.g.,
Figure imgf000061_0001
or
Figure imgf000061_0003
As another non-limiting example, L1 can be –CH2CH2-. In certain embodiments, L1 is C3-8 alkylene optionally substituted with from 1-6 Ra. In certain of these embodiments, L1 is branched C3-6 alkylene optionally substituted with from 1-6 Ra. In certain of the foregoing embodiments, L1 is branched C3-6 alkylene. As non-limiting examples of the foregoing embodiments, L1 can be selected from the group consisting of:
Figure imgf000061_0002
wherein aa is the point of attachment to R5. In certain embodiments, L1 is a bond. In certain embodiments, R5 is selected from the group consisting of: -OH; -NReRf; and C1-6 alkoxy or -S(O)0-2(C1-6 alkyl) each optionally substituted with from 1-6 Ra. In certain of the foregoing embodiments, R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is C1-3 alkoxy (e.g., methoxy). In certain embodiments, R5 is -S(O)0-2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is –S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra. As a non-limiting example of the foregoing embodiments, R5 can be –S(O)2(C1-3 alkyl) (e.g., -S(O)2Me). In certain embodiments, R5 is –Rg. In certain of the foregoing embodiments, R5 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(Rd), 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 Rc. In certain of these embodiments, R5 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(Rd), 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 Rc. In certain of these embodiments, R5 is heterocyclyl including from 4-8 (e.g., 4, 5, 6, 7, or 8) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl is optionally substituted with from 1-3 (e.g., 1, 2, or 3) substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, R5 is
Figure imgf000062_0001
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1. In certain of the foregoing embodiments, R5 is
Figure imgf000062_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); and x1 and x2 are each independently 0, 1, or 2. In certain embodiments (when R5 is
Figure imgf000062_0003
x1 is 0. In certain embodiments (when R5 is
Figure imgf000063_0004
Xa is –O-. As a non- limiting example of the foregoing embodiments, R5 can be
Figure imgf000063_0005
). As further non-limiting examples, R5 can be
Figure imgf000063_0006
In certain embodiments (when R5 is Xa is N( d
Figure imgf000063_0003
H) or N(R ). In certain of these embodiments, Xa is N(H). In certain embodiments, Xa is N(Rd). In certain embodiments, Xa is N(Rd), wherein the Rd present in Xa is C1-4 alkyl. In certain embodiments, Xa is N(Rd), wherein the Rd present in Xa is C(=O)(C1-4 alkyl) or S(O)2(C1- 4 alkyl). As non-limitng examples, R5 can be selected from the group consisting of:
Figure imgf000063_0001
optionally wherein Rd
Figure imgf000063_0002
is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). For exampleR5 can be selected from the group consisting of:
Figure imgf000064_0001
such as
Figure imgf000064_0007
, optionally wherein Rd is C alk d
Figure imgf000064_0008
1-4 yl or wherein R is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). In certain embodiments (when R5 is
Figure imgf000064_0002
), x1 is 1 or 2. For example x1 can be 1. As another non-limiting example, x1 can be 2. In certain embodiments (when R5 is and x1 is 1 or 2), Xa
Figure imgf000064_0003
is –O-. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000064_0004
In certain embodiments (when R5 is a
Figure imgf000064_0005
; and x1 is 1 or 2), X is N(H) or N(Rd). For example, Xa can be N(Rd). In certain of these embodiment, Xa is N(Rd); and Rd is C1-4 alkyl. In certain embodiments, Xa is N(Rd); and Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). As a non-limiting example, R5 can be d
Figure imgf000064_0006
wherein R is C1- 4 alkyl; or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). In certain embodiments, R5 is
Figure imgf000065_0003
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2. In certain of these embodiments, Xb and Xc are independently selected from the group consisting of O and N(Rd) (e.g., O and N(C1-3 alkyl)). As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000065_0004
Figure imgf000065_0005
optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments, R5 is bicyclic heterocyclyl including from 6-10 (e.g., 6-8 or 8-10 (e.g., 6-8)) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. As a non-limiting example, R5 can be
Figure imgf000065_0001
Figure imgf000065_0002
In certain embodiments, R5 is bicyclic heterocyclyl including from 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc.For example, R5 is
Figure imgf000066_0001
In certain embodiments (when R5 is –Rg), R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of these embodiments, R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of the foregoing embodiments, R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-3 Rc. In certain of these embodiments, R5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd. As non-limiting examples, R5 can be selected from the group consisting of:
Figure imgf000066_0002
Figure imgf000066_0003
For example, R5 can be selected from the group consisting of:
Figure imgf000067_0006
Figure imgf000067_0005
In certain embodiments, R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000067_0001
Figure imgf000067_0002
For example, R5 can be selected from the group consisting of:
Figure imgf000067_0003
Figure imgf000067_0004
In certain embodiments (when R5 is –Rg), R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of these embodiments, R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000068_0001
each optionally substituted with from 1-2 Rc. In certain embodiments, R5 is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is .
Figure imgf000068_0002
In certain embodiments, R5 is phenyl optionally substituted with from 1-2 Rc, such as unsubstituted phenyl. In certain embodiments, R5 is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of these embodiments, R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of the foregoing embodiments, R5 is C3-6 cycloalkyl. For example, R5 can be cyclopropyl. As another non-limiting example, R5 can be cyclopentyl. In certain embodiments, R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1-4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000069_0004
Figure imgf000069_0005
As a non-limiting example of the foregoing embodiments, R5 can be
Figure imgf000069_0003
Figure imgf000069_0002
In certain embodiments, R5 is H or halo. In certain of these embodiments, R5 is H. In some embodiments, R5 is RW. In certain embodiments, R5 is -Rg2-RW or -Rg2-RY. In certain embodiments, R5 is –Rg2-RW. In certain embodiments (when R5 is -Rg2-RW or -Rg2-RY (e.g., –Rg2-RW)), the –Rg2 group present in R5 is
Figure imgf000069_0001
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW or RY; and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments, x2 is 1 or 2. In certain embodiments, x2 is 0. As non-limiting examples of the foregoing embodiments, the –Rg2 group present in R5 can be selected from the group consisting of:
Figure imgf000070_0004
Figure imgf000070_0005
Figure imgf000070_0006
wherein bb is the point of attachment to RW or RY. In certain embodiments (when R5 is -Rg2-RW or -Rg2-RY (e.g., –Rg2-RW)), the –Rg2 group present in R5 is
Figure imgf000070_0003
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW or RY. As non-limiting examples of the foregoing embodiments, the –Rg2 group present in R5 can be selected from the group consisting of:
Figure imgf000070_0001
Figure imgf000070_0002
wherein bb is the point of attachment to RW or RY; and optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments (when R5 is -Rg2-RW or -Rg2-RY (e.g., –Rg2-RW)), the Rg2 group present in R5 is bicyclic heterocyclylene including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc (e.g., Rg2 is
Figure imgf000071_0004
wherein bb is the point of W Y
Figure imgf000071_0005
attachment to R or R . In certain embodiments (when R5 is -Rg2-RW), the RW present in R5 is –C(=O)-W or –S(O)2-W, such as wherein RW is –C(=O)-W. In certain embodiments (when R5 is -Rg2-RW or -RW), the RW present in R5 is – C(=O)-W, –S(O)2-W, or –NH-C(=O)-W, such as wherein RW is –C(=O)-W or –NH- C(=O)-W. In certain embodiments (when R5 is -Rg2-RW), W is C2-6 alkenyl (e.g., C2-4 alkenyl (e.g., C2-3 alkenyl)) optionally substituted with from 1-3 Ra. In certain embodiments (when R5 is -Rg2-RW or -RW), W is C2-6 alkenyl or C2-6 alkynyl optionally substituted with from 1-3 Ra. As non-limiting examples of the foregoing embodiments, RW can be
Figure imgf000071_0001
or
Figure imgf000071_0002
As further non-limiting examples of the foregoing embodiments, RW can be
Figure imgf000071_0003
Non-Limiting Combinations of m, X2, L1, and R5 [AA] In certain embodiments, m is 0 or 1; X2 is –O-, -N(RN)-, N
Figure imgf000072_0002
–N(R )C(=O)- *, or -N(RN)S(O)2-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf. In certain embodiments of [AA], R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is C1-3 alkoxy, such as methoxy. In certain embodiments of [AA], R5 is S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is S(O)2(C1-3 alkyl). For example, R5 can be S(O)2Me. In certain embodiments of [AA], L1 is CH2. In certain embodiments of [AA], L1 is –CH(Me)-. In certain embodiments of [AA], L1 is –CH2CH2-. In certain embodiments of [AA], m is 1. In certain embodiments of [AA], X2 is –O-. In certain embodiments of [AA], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [AA], X2 is
Figure imgf000072_0001
In certain embodiments of [AA], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [AA], m is 0. [BB] In certain embodiments, m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000073_0001
, – N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 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(Rd), 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 Rc. In certain embodiments of [BB], R5 is
Figure imgf000073_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.In certain of these embodiments, x1 is 0. In certain embodiments, Xa is –O-. In certain embodiments of [BB], R5 is
Figure imgf000073_0003
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments, Xa is –O-. As a non-limiting example of the foregoing embodiments, R5 can be
Figure imgf000073_0004
As further non-limiting examples, R5 can be
Figure imgf000073_0006
(e.g.,
Figure imgf000073_0007
or
Figure imgf000073_0008
Figure imgf000073_0005
). In certain embodiments of [BB] (when R5 is Xa is N(Rd),
Figure imgf000073_0009
optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000074_0001
, ; ( g,
Figure imgf000074_0002
, optionally wherein Rd is C d
Figure imgf000074_0003
1-4 alkyl or wherein R is C(=O)(C1-4 alkyl) or S(O)2(C1- 4 alkyl). As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000074_0004
, op d
Figure imgf000074_0005
tionally wherein R is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). In certain embodiments of [BB] (when R5 is
Figure imgf000074_0006
x1 is 1 or 2. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000074_0007
In certain embodiments of [BB], R5 is
Figure imgf000075_0003
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2. As non-limiting examples of the foregoing embodiments, R5 is selected from the group consisting of:
Figure imgf000075_0005
, ; ,
Figure imgf000075_0004
optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments of [BB], R5 is bicyclic heterocyclyl including from 6-10 (e.g., 6-8) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. For example, R5 can be
Figure imgf000075_0002
Figure imgf000075_0001
In certain embodiments of [BB], R5 is bicyclic heterocyclyl including from 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein R5 is
Figure imgf000076_0001
In certain embodiments of [BB], L1 is CH2. In certain embodiments of [BB], L1 is –CH(Me)-. In certain embodiments of [BB], L1 is –CH2CH2-. In certain embodiments of [BB], L1 is a bond. In certain embodiments of [BB], m is 1. In certain embodiments of [BB], X2 is –O-. In certain embodiments of [BB], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [BB], X2 is
Figure imgf000076_0002
In certain embodiments of [BB], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [BB], m is 0. [CC] In certain embodiments, m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000076_0003
, – N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc In certain embodiments of [CC], R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-3 Rc. In certain of these embodiments, R5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd. As non-limiting examples of the foregoing embodiments, R5 can be
Figure imgf000077_0001
,
Figure imgf000077_0002
For example, R5 can be
Figure imgf000077_0003
In certain embodiments of [CC], R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, R5 can be
Figure imgf000077_0004
Figure imgf000077_0005
For example, R5 can be
Figure imgf000077_0006
In certain embodiments of [CC], R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of these embodiments, R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. For example, R5 can be selected from the group consisting of: each optionally substituted with fr c
Figure imgf000078_0002
om 1-2 R . In certain embodiments of [CC], R5 is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is .
Figure imgf000078_0001
In certain embodiments of [CC], R5 is phenyl optionally substituted with from 1-2 Rc, such as unsubstituted phenyl. In certain embodiments of [CC], L1 is CH2. In certain embodiments of [CC], L1 is –CH(Me)-. In certain embodiments of [CC], L1 is –CH2CH2-. In certain embodiments of [CC], L1 is a bond. In certain embodiments of [CC], m is 1. In certain embodiments of [CC], X2 is –O-. In certain embodiments of [CC], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [CC], X2 is
Figure imgf000079_0004
In certain embodiments of [CC], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [CC], m is 0. [DD] In certain embodiments, m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000079_0003
– N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments of [DD], R5 is C3-6 cycloalkyl. For example, R5 can be cyclopropyl. As another non-limiting example, R5 can be cyclopentyl. In certain embodiments of [DD], R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1- 4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000079_0001
Figure imgf000079_0002
In certain embodiments of [DD], L1 is CH2. In certain embodiments of [DD], L1 is –CH(Me)-. In certain embodiments of [DD], L1 is –CH2CH2-. In certain embodiments of [DD], L1 is a bond. In certain embodiments of [DD], m is 1. In certain embodiments of [DD], X2 is –O-. In certain embodiments of [DD], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [DD], X2 is
Figure imgf000080_0002
In certain embodiments of [DD], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [DD], m is 0. [EE] In certain embodiments, m is 1; X2 is –N(RN)C(=O)-*, -N(RN)C(=O)O-* or - N(RN)C(=O)N(RN)-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is H. In certain embodiments of [EE], L1 is CH2. In certain embodiments of [EE], L1 is –CH(Me)-. In certain embodiments of [EE], L1 is –CH2CH2-. In certain embodiments of [EE], X2 is -N(RN)C(=O)-* (e.g., –N(H)C(=O)-*). In certain embodiments of [EE], X2 is selected from the group consisting of - N(RN)C(=O)N(RN)-* (e.g., –N(H)C(=O)N(RN)-* (e.g., -N(H)C(=O)N(C1-3 alkyl)); and - N(RN)C(=O)O-* (e.g., –N(H)C(=O)O-*). [FF] In certain embodiments, m is 1; X2 is –O-, -N(RN)-,
Figure imgf000080_0001
–N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is branched C3-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf. In certain embodiments of [FF], R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is C1-3 alkoxy. In certain embodiments of [FF], R5 is S(O)2(C1-6 alkyl) optionally substituted with from 1-6 Ra. In certain embodiments of [FF], X2 is –O-. In certain embodiments of [FF], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [FF], X2 is
Figure imgf000081_0001
. In certain embodiments of [FF], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-* (e.g., – N(H)C(=O)-* or –N(H)S(O)2-*). For example, X2 can be –N(H)C(=O)-*. In certain embodiments of [FF], L1 is branched C3-6 alkylene. In certain of these embodiments, L1 is selected from the group consisting of:
Figure imgf000081_0002
wherein aa is the point of attachment to R5. [GG] In certain embodiments, m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000081_0003
– N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is –Rg2-RW, wherein: the -Rg2 of R5 is heterocyclylene 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(Rd), 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 Rc; and -RW is –C(=O)-W or –S(O)2-W. In certain embodiments of [GG], Rg2 is
Figure imgf000082_0006
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0. As non-limiting examples of the foregoing embodiments, Rg2 is selected from the group consisting of:
Figure imgf000082_0003
Figure imgf000082_0004
wherein bb is the p W
Figure imgf000082_0005
oint of attachment to R . In certain embodiments of [GG], Rg2 is
Figure imgf000082_0002
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW. As non-limiting examples of the foregoing embodiments, Rg2 is selected from the group consisting of:
Figure imgf000082_0001
such as , wherein bb is the point W
Figure imgf000083_0001
of attachment to R ; and optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments of [GG], Rg2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, wherein bb is the point of attachment to RW. For example, Rg2 can be
Figure imgf000083_0002
wherein bb is the p W
Figure imgf000083_0003
oint of attachment to R . In certain embodiments of [GG], RW is –C(=O)-W. In certain embodiments of [GG], W is C2-6 alkenyl optionally substituted with from 1-3 Ra. As non-limiting examples of the foregoing embodiments, RW can be
Figure imgf000083_0004
or
Figure imgf000083_0005
In certain embodiments of [GG], L1 is CH2. In certain embodiments of [GG], L1 is –CH(Me)-. In certain embodiments of [GG], L1 is –CH2CH2-. In certain embodiments of [GG], L1 is a bond. In certain embodiments of [GG], m is 1. In certain embodiments of [GG], X2 is –O-. In certain embodiments of [GG], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [GG], X2 is
Figure imgf000084_0001
In certain embodiments of [GG], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [GG], m is 0. Variables R1c, R2a, R2b, R3a, and R3b In some embodiments, R1c is H. In some embodiments, R2a and R2b are H. In some embodiments, 1-2, such as 1, of R2a and R2b is a substituent other than H. For example, R2a can be a substituent other than H. In certain of these embodiments, one of R2a and R2b (e.g., R2a) is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl; and the other of R2a and R2b is H. In certain embodiments, one of R2a and R2b (e.g., R2a) is Rg; and the other of R2a and R2b is H. In certain of these embodiments, one of R2a and R2b (e.g., R2a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R2a and R2b is H. In some embodiments, R2a and R2b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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 Rc. In certain embodiments, R2a and R2b, together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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 Rc. In certain embodiments, R2a and R2b 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 Rc. In some embodiments, R3a and R3b are H. In some embodiments, from 1-2, such as 1, of R3a and R3b is a substituent other than H. For example, R3a can be a substituent other than H. In certain embodiments, one of R3a and R3b (e.g., R3a) is Rb; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl optionally substituted with from 1-3 independently selected halo; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 Ra; and the other of R3a and R3b is H. In certain of the foregoing embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., –CH3, –CH2F, - CH2CH2F, or –CHF2); and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl; and the other of R3a and R3b is H. For example, one of R3a and R3b (e.g., R3a) can be methyl, ethyl, or isopropyl; and the other of R3a and R3b can be H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with from 1-3 independently selected halo; and the other of R3a and R3b is H. For example, one of R3a and R3b (e.g., R3a) can be CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CH2F; and the other of R3a and R3b can be H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; and the other of R3a and R3b is H. For example, one of R3a and R3b (e.g., R3a) can be –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, - CH2CH(Me)OMe, -CH2OEt, -CH2CH2OCHF2, -CH2NReRf (e.g., -CH2N(CF3)Me), or – CH2CH2NReRf (e.g., -CH2CH2NMe2); and the other of R3a and R3b can be H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with C1-4 alkoxy; and the other of R3a and R3b is H. For example, one of R3a and R3b (e.g., R3a) can be –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, or -CH2OEt. For example, one of R3a and R3b (e.g., R3a) can be –CH2OMe. In certain embodiments, one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; and the other of R3a and R3b is H. For example, one of R3a and R3b (e.g., R3a) can be –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, - CH2CH(Me)OMe, or -CH2OEt; and the other of R3a and R3b can be H. In certain embodiments, one of R3a and R3b (e.g., R3a) is Rg or –(Lg)g-Rg; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is Rg; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is C3-6 cycloalkyl optionally substituted with from 1-4 Rc; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with Rd; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is –(C1-3 alkylene)-Rg or - (C1-3 alkylene)-O-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is –(C1-3 alkylene)-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments, one of R3a and R3b (e.g., R3a) is –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain of these embodiments, one of R3a and R3b (e.g., R3a) is –CH2-Rg, – CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with Rd; and the other of R3a and R3b is H. As non-limiting examples of the foregoing embodiments, one of R3a and R3b can be selected from the group consisting of:
Figure imgf000088_0001
Figure imgf000088_0002
; ; a 3a 3b
Figure imgf000088_0003
nd the other of R and R can be H. In certain embodiments, R3a and R3b are each independently selected Rb. In certain of these embodiments, R3a and R3b are each independently selected C1-3 alkyl which is optionally substituted with from 1-3 Ra. For example, R3a and R3b can each be independently C1-3 alkyl (e.g., methyl). In certain embodiments, R3a and R3b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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, Rc, and RW. In certain embodiments, R3a and R3b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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 Rc. In certain embodiments, R3a and R3b, together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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 Rc. In certain embodiments, R3a and R3b 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 Rc. For example, R3a and R3b together with the Ring B ring atom to which each is attached can form a fused cyclopropyl or cyclobutyl. In certain embodiments, R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc. For example, R3a and R3b, together with the Ring B ring atom to which each is attached, can form
Figure imgf000090_0001
, , As further non-limiting examples, R3a and R3b, together with the Ring B ring atom to which each is attached, can form
Figure imgf000090_0002
For example, R3a and R3b, together with the Ring B ring atom to which each is attached, can form
Figure imgf000090_0003
wherein Rd is C1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., Rd is C1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH2CF3)). In certain embodiments, R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with RW and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments, one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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 Rc. In certain embodiments, one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused saturated ring of 3-8 ring atoms; • 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 3-8 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain of these embodiments, R3a and R3b together with the Ring B ring atom to which each is attached, form:
Figure imgf000091_0001
In certain embodiments, R3a and R3b together with the Ring B ring atom to which each is attached, form: , , , wherei W W W
Figure imgf000092_0001
n R is –L -W, wherein L is C(=O) or S(O)2; and RW is C2-6 alkenyl which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 hybridized carbon atom. In certain embodiments, R3a and R3b together with the Ring B ring atom to which each is attached, form:
Figure imgf000092_0002
, , , RW is
Figure imgf000092_0003
or
Figure imgf000092_0004
For example, R3a and R3b together with the Ring B ring atom to which each is attached, can form
Figure imgf000092_0006
, wherein RW is
Figure imgf000092_0005
. In certain embodiments (when R3a and R3b together with the Ring B ring atom to which each is attached form a fused ring as described anywhere supra), R1c, R2a, and R2b are each H. In certain of the foregoing embodiments, one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 cycloalkyl which is optionally substituted with from 1-2 Rc. In certain of these embodiments, the other of R2a and R2b and the other of R3a and R3b are each H. For example, one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused cyclopropyl or cyclobutyl. For example, the compound can have formula
Figure imgf000093_0002
or
Figure imgf000093_0001
. In certain embodiments, wherein one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached. In certain of these embodiments, the other of R2a and R2b and the other of R3a and R3b are each H. In certain embodiments (when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached), the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: Rb, Rg, and –(Lg)g-Rg. In certain of these embodiments, the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. In certain embodiments (when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached), the other of R2a and R2b is H; and the other of R3a and R3b is: (i) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; or (ii) –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, -CH2OEt, - CH2CH2OCHF2, -CH2NReRf (e.g., -CH2N(CF3)Me), or –CH2CH2NReRf (e.g., - CH2CH2NMe2) In certain of these embodiments, the other of R2a and R2b is H; and the other of R3a and R3b is: (i) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (ii) –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, -CH2OEt, or -CH2CH2OCHF2; or (iii) –CH2OMe or –CH2CH2OMe. In certain embodiments (when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached), R2a, R2b, R3a, and R3b taken together with the Ring B ring atoms to which each is attached form:
Figure imgf000094_0001
, wherein: R3c is C1-4 alkoxy, C1-4 haloalkoxy, NReRf, or Rg; and bb is the point of attachment to N(R1c). For example, the compound can have the following formula:
Figure imgf000094_0002
(e.g., R3c can be C1-4 alkoxy). In certain embodiments (when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused ring as described anywhere supra; or when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached), R1c is H. In certain embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 Ra; optionally the other of R3a and R3b is H; and optionally each Ra substituent present in R3a or R3b is independently selected from the group consisting of: halo, C1-4 alkoxy, and C1-4 haloalkoxy. In certain embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is C1-3 alkyl (e.g., methyl, ethyl, or isopropyl); and the other of R3a and R3b is H. In certain embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH2F, -CHF2, CF3, or –CH2CH2F); and the other of R3a and R3b is H. In certain embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy (e.g., –CH2OMe, -CH2CH2OMe, - CH(Me)CH2OMe, -CH2CH(Me)OMe, or -CH2OEt); and the other of R3a and R3b (e.g., R3a) is H. In certain embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is –Rg, –(C1-3 alkylene)-Rg, or –(C1-3 alkylene)-O-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is –Rg or –(C1-3 alkylene)-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and optionally the other of R3a and R3b is H. In certain embodiments, R1c, R2a, and R2b are each H; and R3a and R3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 (e.g., 3 or 4) ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 Rc. In certain embodiments, R1c, R2a, and R2b are each H; and R3a and R3b taken together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc. For example, R3a and R3b, together with the Ring B ring atom to which each is attached, can form
Figure imgf000096_0001
Variable Ring A In some embodiments, Ring A is w cB
Figure imgf000097_0001
herein each R is an independently selected Rc; and m is 0, 1, 2, 3, or 4. In certain of these embodiments, m is 1, 2, or 3. In certain of the foregoing embodiments, m is 1 or 2 (e.g., 2). In certain embodiments, Ring A is
Figure imgf000097_0002
), wherein each RcB is an independently selected Rc. In certain embodiments, each RcB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments, Ring A is wher cB1 c cB2
Figure imgf000097_0003
ein R is R ; and R is H or Rc, optionally wherein RcB1 and RcB2 are each independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo. In certain of these embodiments, RcB1 is halo (e.g., –F or –Cl (e.g., –F)). In certain embodiments, RcB1 is C1-3 alkyl or C1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein RcB1 is methyl, –CHF2, or –CF3. In certain embodiments, RcB2 is selected from the group consisting of: halo; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments, RcB2 is C1-4 alkoxy or C1-4 haloalkoxy. In certain embodiments, RcB2 is selected from the group consisting of cyano; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein RcB2 is cyano, methyl, ethyl, -CHF2, -CF3, or -CH2CHF2. In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000098_0001
In some embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo. In certain of these embodiments, 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo. As non-limiting examples of the foregoing embodiments, Ring A can be selected from the group consisting of:
Figure imgf000098_0002
each of which is furthe c
Figure imgf000098_0003
r optionally substituted with R . Non-Limiting Combinations In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a):
Figure imgf000099_0001
Formula (I-a) 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 of Formula (I) is a compound of Formula (I-b):
Figure imgf000099_0002
Formula (I-b) 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 of Formula (I) is a compound of Formula (I-c):
Figure imgf000100_0001
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, the compound of Formula (I) is a compound of Formula (I-d):
Figure imgf000100_0002
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, the compound of Formula (I) is a compound of Formula (I-e):
Figure imgf000101_0001
Formula (I-e) or a pharmaceutically acceptable salt thereof. In certain of these embodiments, n is 0. In Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 can be as defined for Formula (I) anywhere herein. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [AA1]: [AA1]: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000101_0002
, –N(RN)C(=O)-*, or - N(RN)S(O)2-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf. In certain embodiments of [AA1], R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is C1-3 alkoxy, such as methoxy. In certain embodiments of [AA1], R5 is S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is S(O)2(C1-3 alkyl). For example, R5 can be S(O)2Me. In certain embodiments of [AA1], L1 is CH2. In certain embodiments of [AA1], L1 is –CH(Me)-. In certain embodiments of [AA1], L1 is –CH2CH2-. In certain embodiments of [AA1], m is 1. In certain embodiments of [AA1], X2 is –O-. In certain embodiments of [AA1], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [AA1], X2 is
Figure imgf000102_0005
In certain embodiments of [AA1], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [AA1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [BB1]: [BB1]: m is 0 or 1; X2 is –O-, -N(RN)-, N
Figure imgf000102_0004
–N(R )C(=O)*, or - N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 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(Rd), 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 Rc. In certain embodiments of [BB1], R5 is
Figure imgf000102_0001
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1. In certain embodiments of [BB1], R5 is
Figure imgf000102_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); and x1 and x2 are each independently 0, 1, or 2. In certain embodiments of [BB1] (when R5 is
Figure imgf000102_0003
x1 is 0. In certain embodiments of [BB1] (when R5 is a
Figure imgf000103_0001
), X is –O-. As a non-limiting example of the foregoing embodiments, R5 can be
Figure imgf000103_0002
(e.g., As a further non- 5
Figure imgf000103_0003
limiting example, R can be
Figure imgf000103_0005
(e.g.,
Figure imgf000103_0006
or
Figure imgf000103_0004
In certain embodiments, Xa is N(Rd), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). As non-limiting examples, R5 can be selected from the group consisting of:
Figure imgf000103_0007
optionally wherein Rd
Figure imgf000103_0008
is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000103_0009
optionally w d
Figure imgf000104_0001
herein R is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). In certain embodiments of [BB1] (when R5 is
Figure imgf000104_0002
x1 is 1 or 2. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000104_0006
In certain embodiments of [BB1], R5 is
Figure imgf000104_0003
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2. As non-limiting examples of the foregoing embodiments, R5 can be selected from the group consisting of:
Figure imgf000104_0004
Figure imgf000104_0005
optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments of [BB1], R5 is bicyclic heterocyclyl including from 6-10 (e.g., 6-8) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. For example, R5 can be
Figure imgf000105_0001
(e.g.,
Figure imgf000105_0002
In certain embodiments of [BB1], R5 is bicyclic heterocyclyl including from 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein R5 is
Figure imgf000105_0003
In certain embodiments of [BB1], L1 is CH2. In certain embodiments of [BB1], L1 is –CH(Me)-. In certain embodiments of [BB1], L1 is –CH2CH2-. In certain embodiments of [BB1], L1 is a bond. In certain embodiments of [BB1], m is 1. In certain embodiments of [BB1], X2 is –O-. In certain embodiments of [BB1], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [BB1], X2 is
Figure imgf000105_0004
In certain embodiments of [BB1], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be – N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [BB1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [CC1]: [CC1]: m is 0 or 1; X2 is –O-, -N(RN)-, N
Figure imgf000105_0005
–N(R )C(=O)*, or - N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc In certain embodiments of [CC1], R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-3 Rc. In certain of these embodiments, R5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd. As non-limiting examples, R5 can be
Figure imgf000106_0001
,
Figure imgf000106_0002
example, R5 can be
Figure imgf000106_0003
In certain embodiments of [CC1], R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples, R5 can be
Figure imgf000106_0004
Figure imgf000107_0005
, , , , For example, R5 can be
Figure imgf000107_0006
In certain embodiments of [CC1], R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of these embodiments, R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc. For example, R5 can be selected from the group consisting
Figure imgf000107_0003
each optionall c
Figure imgf000107_0004
y substituted with from 1-2 R . In certain embodiments of [CC1], R5 is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is
Figure imgf000107_0001
or
Figure imgf000107_0002
In certain embodiments of [CC1], R5 is phenyl optionally substituted with from 1- 2 Rc, such as unsubstituted phenyl. In certain embodiments of [CC1], L1 is CH2. In certain embodiments of [CC1], L1 is –CH(Me)-. In certain embodiments of [CC1], L1 is –CH2CH2-. In certain embodiments of [CC1], L1 is a bond. In certain embodiments of [CC1], m is 1. In certain embodiments of [CC1], X2 is –O-. In certain embodiments of [CC1], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [CC1], X2 is
Figure imgf000108_0001
In certain embodiments of [CC1], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [CC1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [DD1]: [DD1]: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000108_0002
, –N(RN)C(=O)*, or - N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments of [DD1], R5 is C3-6 cycloalkyl. For example, R5 can be cyclopropyl. In certain embodiments of [DD1], R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1-4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc. As non-limiting examples, R5 can be selected from the group consisting of:
Figure imgf000109_0004
such as
Figure imgf000109_0001
Figure imgf000109_0002
In certain embodiments of [DD1], L1 is CH2. In certain embodiments of [DD1], L1 is –CH(Me)-. In certain embodiments of [DD1], L1 is –CH2CH2-. In certain embodiments of [DD1], L1 is a bond. In certain embodiments of [DD1], m is 1. In certain embodiments of [DD1], X2 is –O-. In certain embodiments of [DD1], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [DD1], X2 is
Figure imgf000109_0003
In certain embodiments of [DD1], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [DD1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [EE1]: [EE1]: m is 1; X2 is –N(RN)C(=O)-*, -N(RN)C(=O)O-* or -N(RN)C(=O)N(RN)-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is H. In certain embodiments of [EE1], L1 is CH2. In certain embodiments of [EE1], L1 is –CH(Me)-. In certain embodiments of [EE1], L1 is –CH2CH2-. In certain embodiments of [EE1], X2 is -N(RN)C(=O)-* (e.g., –N(H)C(=O)-*). In certain embodiments of [EE1], X2 is selected from the group consisting of - N(RN)C(=O)N(RN)-* (e.g., –N(H)C(=O)N(RN)-* (e.g., -N(H)C(=O)N(C1-3 alkyl)); and - N(RN)C(=O)O-* (e.g., –N(H)C(=O)O-*). In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [FF1]: [FF1]: m is 1; X2 is –O-, -N(RN)-, –N( N N
Figure imgf000110_0001
R )C(=O)*, or -N(R )S(O)2-*; L1 is branched C3-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: H; C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf; or [FF1]: m is 1; X2 is –O-, -N(RN)-, N N
Figure imgf000110_0002
, –N(R )C(=O)*, or -N(R )S(O)2-*; L1 is branched C3-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf. In certain embodiments of [FF1], R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra. In certain of these embodiments, R5 is C1-3 alkoxy. In certain embodiments of [FF1], R5 is S(O)2(C1-6 alkyl) optionally substituted with from 1-6 Ra. In certain embodiments of [FF1], X2 is –O-. In certain embodiments of [FF1], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [FF1], X2 is
Figure imgf000110_0003
. In certain embodiments of [FF1], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-* (e.g., –N(H)C(=O)-* or – N(H)S(O)2-*). For example, X2 can be –N(H)C(=O)-*. In certain embodiments of [FF1], L1 is branched C3-6 alkylene. In certain of these embodiments, L1 is selected from the group consisting of:
Figure imgf000111_0001
w 5
Figure imgf000111_0005
herein aa is the point of attachment to R . In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X2, L1, and R5 are as defined in [GG1]: [GG1]: m is 0 or 1; X2 is –O-, -N(RN)-, N
Figure imgf000111_0004
, –N(R )C(=O)*, or - N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is –Rg2-RW, wherein: the -Rg2 of R5 is heterocyclylene 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(Rd), 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 Rc; and -RW is –C(=O)-W or –S(O)2-W. In certain embodiments of [GG1], Rg2 is
Figure imgf000111_0002
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0. As non-limiting examples of the foregoing embodiments, Rg2 is selected from the group consisting of:
Figure imgf000111_0003
Figure imgf000112_0004
wherein bb is the point of W
Figure imgf000112_0005
attachment to R . In certain embodiments of [GG1], Rg2 is
Figure imgf000112_0001
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW. As non-limiting examples of the foregoing embodiments, Rg2 is selected from the group consisting of:
Figure imgf000112_0002
such as wherein bb is the point of attac W
Figure imgf000112_0003
hment to R ; and optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments of [GG1], Rg2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, wherein bb is the point of attachment to RW. For example, Rg2 can be
Figure imgf000113_0002
wherein bb is the point of attachmen W
Figure imgf000113_0003
t to R . In certain embodiments of [GG1], RW is –C(=O)-W. In certain embodiments of [GG1], W is C2-6 alkenyl optionally substituted with from 1-3 Ra. As non-limiting examples of the foregoing embodiments, RW can be
Figure imgf000113_0001
or
Figure imgf000113_0004
In certain embodiments of [GG1], L1 is CH2. In certain embodiments of [GG1], L1 is –CH(Me)-. In certain embodiments of [GG1], L1 is –CH2CH2-. In certain embodiments of [GG1], L1 is a bond. In certain embodiments of [GG1], m is 1. In certain embodiments of [GG1], X2 is –O-. In certain embodiments of [GG1], X2 is -N(RN)- (e.g., –N(H)-). In certain embodiments of [GG1], X2 is
Figure imgf000113_0005
In certain embodiments of [GG1], X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*. For example, X2 can be –N(H)C(=O)* or –N(H)S(O)2-* (e.g., –N(H)C(=O)*). In certain embodiments of [GG1], m is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a1):
Figure imgf000114_0001
Formula (I-a1) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is heterocyclyl including from 4-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. In certain embodiments of Formula (I-a1), R5 is
Figure imgf000114_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1. In certain of these embodiments, x1 is 0. In certain embodiments, x0 is 1, 2, or 3. In certain embodiments, Xa is –O-. In certain embodiments of Formula (I-a1), R5 is
Figure imgf000114_0004
In certain embodiments of Formula (I-a1), R5 is
Figure imgf000114_0005
In certain embodiments of Formula (I-a1) (when R5 is a d
Figure imgf000114_0003
X is N(R ), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). In ccertain of these embodiments, x1 is 0. In certain embodiments of Formula (I-a1), R5 is selected from the group consisting of:
Figure imgf000115_0006
Figure imgf000115_0007
; , , optionally wherein Rd
Figure imgf000115_0008
is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl). In certain embodiments of Formula (I-a1) (when R5 is
Figure imgf000115_0005
), x1 is 1 or 2. In certain of these embodiments, R5 is selected from the group consisting of:
Figure imgf000115_0001
Figure imgf000115_0002
. In certain embodiments of Formula (I-a1), R5 is
Figure imgf000115_0003
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2. In certain of these embodiments, R5 is selected from the group consisting of:
Figure imgf000115_0004
, ,
Figure imgf000116_0001
optionally wherein Rd is C1-4 alkyl, such as methyl. In certain embodiments of Formula (I-a1), R5 is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein R5 is
Figure imgf000116_0003
such as
Figure imgf000116_0004
In certain embodiments of Formula (I-a1), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a2):
Figure imgf000116_0002
Formula (I-a2) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is selected from the group consisting of: • 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(Rd), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 Rc; and • C6 aryl optionally substituted with from 1-4 Rc. In certain embodiments of Formula (I-a2), R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 Rc. In certain of these embodiments, R5 is
Figure imgf000117_0003
Figure imgf000117_0004
In certain embodiments of Formula (I-a2), R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of these embodiments, R5 is
Figure imgf000117_0002
Figure imgf000117_0001
. In certain embodiments of Formula (I-a2), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a3):
Figure imgf000118_0001
Formula (I-a3) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments of Formula (I-a3), R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 Rc. In certain of these embodiments, R5 is
Figure imgf000118_0002
Figure imgf000118_0003
In certain embodiments of Formula (I-a3), R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. In certain of these embodiments, R5 is
Figure imgf000119_0003
Figure imgf000119_0001
In certain embodiments of Formula (I-a3), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a4):
Figure imgf000119_0002
Formula (I-a4) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is –Rg2-RW, wherein: the -Rg2 of R5 is heterocyclylene 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(Rd), 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 Rc; and -RW is –C(=O)-W or –S(O)2-W. In certain embodiments of Formula (I-a4), Rg2 is
Figure imgf000120_0005
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW; and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments of Formula (I-a4), Rg2 is selected from the group consisting
Figure imgf000120_0002
wherein W
Figure imgf000120_0003
bb is the point of attachment to R . In certain embodiments of Formula (I-a4), Rg2 is
Figure imgf000120_0004
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW. In certain of these embodiments, Rg2 is selected from the group consisting of:
Figure imgf000120_0001
or wherein bb is the point of attachment to RW; and option d
Figure imgf000121_0006
ally wherein R is C1-4 alkyl, such as methyl. In certain embodiments of Formula (I-a4), Rg2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc (e.g., Rg2 is
Figure imgf000121_0002
such as
Figure imgf000121_0003
wherein bb is the point of attachment to RW. In certain embodiments of Formula (I-a4), RW is –C(=O)-W. In certain embodiments of Formula (I-a4), W is C2-6 alkenyl (e.g., C2-4 alkenyl) optionally substituted with from 1-3 Ra. In certain embodiments of Formula (I-a4), RW is
Figure imgf000121_0004
or
Figure imgf000121_0005
such as
Figure imgf000121_0001
. In certain embodiments of Formula (I-a4), n is 0. In certain embodiments, the compound is a compound of Formula (I-a5):
Figure imgf000122_0001
Formula (I-a5) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; L1 is C1-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: H; C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf. In certain embodiments of Formula (I-a5), L1 is branched C3-6 alkylene. In certain embodiments of Formula (I-a5), L1 is selected from the group consisting of:
Figure imgf000122_0002
, , , and
Figure imgf000122_0003
wherein aa is the point of attachment to R5. In certain embodiments of Formula (I-a5), R5 is H. In certain embodiments of Formula (I-a5), R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra. In certain embodiments of Formula (I-a5), R5 is –OH. In certain embodiments of Formula (I-a5), R5 is –NReRf. In certain embodiments of Formula (I-a5), n is 0. In certain embodiments, the compound is a compound of Formula (I-f):
Figure imgf000123_0001
Formula (I-f) or a pharmaceutically acceptable salt thereof, wherein: Ring C1 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc. In certain embodiments of Formula (I-f), Ring C1 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-3 Rc. In certain embodiments of Formula (I-f), Ring C1 is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd. As non-limiting examples of the foregoing embodiments, Ring C1 can be selected from the group consisting of:
Figure imgf000123_0003
. For example, Ring C1 can be
Figure imgf000123_0004
As non-limiting examples, Ring C1 can be selected from the group consisting of:
Figure imgf000123_0002
. In certain embodiments of Formula (I-f), 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, Ring C1 can be selected from the group consisting of:
Figure imgf000124_0001
, , , , , and
Figure imgf000124_0006
As non-limiting examples, Ring C1 can be selected from the group consisting of:
Figure imgf000124_0002
. In certain embodiments, Ring C1 pyridyl or pyrimidyl, each of which is optionally substituted with from 1-2 Rc. For example, Ring C can be selected from the group consisting of:
Figure imgf000124_0003
. In certain embodiments, Ring C1 is selected from the group consisting of:
Figure imgf000124_0004
wherein the Rc present in Ring C is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, Ring C1 is selected from the group consisting of:
Figure imgf000124_0005
wherein the Rc present in Ring C1 is selected from the group consisting of: halo and C1-3 alkyl optionally substituted with from 1-3 Ra, optionally wherein the Rc is –F, -Cl, or C1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, the compound is a compound of Formula (I-g):
Figure imgf000125_0001
Formula (I-g) 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc. In certain embodiments of Formula (I-g), Ring C2 is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc. As non-limiting examples of the foregoing embodiments, Ring C2 can be selected from the group consisting of:
Figure imgf000125_0002
Figure imgf000125_0003
Figure imgf000126_0001
, , , each further optionally substituted with from 1- 2 Rc. For example, Ring C2 can be selected from the group consisting of:
Figure imgf000126_0002
Figure imgf000126_0003
As further non-limiting examples, Ring C2 can be selected from the group consisting of:
Figure imgf000126_0004
Figure imgf000126_0005
each further optionally substituted with from 1-2 Rc. For example, Ring C2 can be selected from the group consisting of:
Figure imgf000126_0006
Figure imgf000126_0007
As further non-limiting examples, Ring C2 can be selected from the group consisting of:
Figure imgf000127_0005
In certain embodiments of Formula (I-g), 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), and N(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc. As non-limiting examples of the foregoing embodiments, Ring C2 can be selected from the group consisting of:
Figure imgf000127_0002
Figure imgf000127_0003
As further non-limiting examples, Ring C2 can be selected from the group consisting of:
Figure imgf000127_0004
In certain embodiments, the compound is a compound of Formula (I-g1):
Figure imgf000127_0001
Formula (I-g1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Y1, Y2, and Y3 are each independently selected from the group consisting of: N, NH, NRd, CH, CRc, CX1, O, and S; and each
Figure imgf000128_0001
is independently a single bond or a double bond, provided that the 5-membered ring including Y1, Y2, and Y3 is heteroaryl; and from 0-1 of Y1, Y2, and Y3 is selected from the group consisting of: O, S, and CRX1. In certain embodiments of Formula (I-g1), Y1 is S. In certain embodiments of Formula (I-g1), Y2 is selected from the group consisting of: N, CH, CRc, and CX1. In certain of these embodiments, Y2 is CH or CRc. In certain embodiments, Y2 is N. In certain embodiments of Formula (I-g1), Y3 is selected from the group consisting of CH and CRc. In certain of these embodiments, Y3 is CH. In certain embodiments of Formula (I-g1), Y1 is S; and Y2 and Y2 are each CH. In certain embodiments of Formula (I-g1), Y1 is S; Y2 is N; and Y3 is CH. In certain embodiments of Formula (I-g1), Y1 is S; Y2 is CRc; and Y3 is CH. In certain embodiments of Formula (I-g1) (when Y2 is CRc), the Rc group present in Y2 is selected from the group consisting of: (i) C1-6 alkyl; (ii) halo; and (iii) C1-6 alkyl substituted with from 1-6 independently selected Ra. In certain embodiments of Formula (I-g1) (when Y2 is CRc), the Rc group present in Y2 is selected from the group consisting of: (i) C1-3 alkyl; (ii) halo; and (iii) C1-3 alkyl substituted with from 1-3 independently selected halo. In certain embodiments of Formula (I-g1) (when Y2 is CRc), the Rc group present in Y2 is selected from the group consisting of: (i) methyl; (ii) -F; and (iii) –CHF2. In certain embodiments of Formula (I-g1) (when Y2 is CRc), the Rc group present in Y2 is selected from the group consisting of: (i) C1-3 alkyl (e.g., methyl); (ii) halo (e.g., -F); and (iii) C1-3 alkyl substituted with from 1-3 independently selected halo (e.g., Rc is – CHF2 ) . In certain embodiments, the compound is a compound of Formula (I-g1-1):
Figure imgf000129_0001
Formula (I-g1-1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1, such as 0; In certain embodiments, the compound is a compound of Formula (I-g1-2):
Figure imgf000129_0002
Formula (I-g1-2) or a pharmaceutically acceptable salt thereof. In certain embodiments of Formula (I-g1), (I-g1-1) and (I-g1-2), one of Y1, Y2, Y3 (e.g., Y2) is CX1; and X1 can be defined anywhere herein. For example, X1 can be defined according to [AA1], [BB1], [CC1], [DD1], [EE1], [FF1], or [GG1]. In certain embodiments of Formula (I-g1) or (I-g1-1), n is 0. In certain embodiments, the compound is a compound of Formula (I-h):
Figure imgf000130_0001
Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: Ring C3 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments of Formula (I-h), Ring C3 is 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(Rd), 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 Rc, such as wherein Ring C is tetrahydropyranyl, such as
Figure imgf000130_0002
. In certain embodiments of Formula (I-f), (I-g), or (I-h), each occurrence of Rc present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 is independently selected from the group consisting of: C1-3 alkyl; C1-3 alkyl substituted with from 1-3 Ra; halo; cyano; NReRf, such as NH2, NH(C1-3 alkyl), or N(C1-3 alkyl)2; -OH; C1-4 alkoxy; and C1-4 haloalkoxy. For example, each occurrence of Rc present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 can be independently selected from the group consisting of: halo; C1-6 alkyl; C1-6 alkyl substituted with from 1-6 independently selected halo; C1-4 alkoxy; and C1-4 haloalkoxy. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), R1c is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), R2a and R2b are H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), from 1-2, such as 1, of R2a and R2b a substituent other than H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), one of R2a and R2b (e.g., R2a) is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl; and the other of R2a and R2b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), one of R2a and R2b (e.g., R2a) is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl (e.g., methyl); and the other of R2a and R2b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), one of R2a and R2b (e.g., R2a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R2a and R2b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R2a and R2b 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 Rc. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R3a and R3b are H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), from 1-2, such as 1, of R3a and R3b is a substituent other than H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl optionally substituted with from 1-3 independently selected halo; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 independently selected halo, such as –CH3, –CH2F, -CH2CH2F, or –CHF2; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy or NReRf (e.g., –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, -CH2OEt, -CH2NReRf (e.g., - CH2N(CF3)Me), or –CH2CH2NReRf (e.g., -CH2CH2NMe2)); and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is C3-6 cycloalkyl optionally substituted with from 1-4 Rc; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is –(C1-3 alkylene)-Rg (e.g., -CH2-Rg or –CH2CH2-Rg) or –(C1-3 alkylene)-O-Rg (e.g., -CH2O-Rg), wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R3a and R3b (e.g., R3a) is –(C1-3 alkylene)-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R3a and R3b 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 Rc. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with RW and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc. In certain of these embodiments, R3a and R3b together with the Ring B ring atom to which each is attached, form:
Figure imgf000135_0001
In certain of these embodiments, RW is –LW-W, wherein LW is C(=O) or S(O)2; and RW is C2-6 alkenyl which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 hybridized carbon atom. In certain of the foregoing embodiments, RW is
Figure imgf000135_0004
or
Figure imgf000135_0005
. For example, R3a and R3b together with the Ring B ring atom to which each is attached, can form wherein RW is
Figure imgf000135_0003
.
Figure imgf000135_0002
In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 (e.g., C3 or C4) cycloalkyl which is optionally substituted with from 1-2 Rc. In certain of these embodiments, the other of R2a and R2b and the other of R3a and R3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h) (when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 (e.g., C3 or C4) cycloalkyl which is optionally substituted with from 1-2 Rc), the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: Rb, Rg, and –(Lg)g-Rg. In certain of these embodiments, the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. In certain of the foregoing embodiments, the other of R2a and R2b is H; and the other of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached. In certain of these embodiments, the other of R2a and R2b and the other of R3a and R3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h) (when one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached), the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: Rb, Rg, and –(Lg)g-Rg. In certain of these embodiments, the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. In certain of the foregoing embodiments, the other of R2a and R2b is H; and the other of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is C1-3 alkyl optionally substituted with from 1-3 Ra; and the other of R3a and R3b is H, optionally each Ra substituent present in R3a or R3b is independently selected from the group consisting of: halo, C1-4 alkoxy, and C1-4 haloalkoxy. In certain of these embodiments, R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; and R3a and R3b are independently selected C1-3 alkyl. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is –Rg, –(C1-3 alkylene)-Rg (e.g., -CH2-Rg or –CH- 2CH2-Rg), or –(C1-3 alkylene)-O-Rg (e.g., -CH2-O-Rg), optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; one of R3a and R3b (e.g., R3a) is –Rg or –(C1-3 alkylene)-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; and R3a and R3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 (e.g., 3 or 4) ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 Rc. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; and R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c, R2a, and R2b are each H; and R3a and R3b together with the Ring B ring atom to which each is attached, form:
Figure imgf000139_0001
(ii) any group of (i), wherein RW is –LW-W, wherein LW is C(=O) or S(O)2; and RW is C2-6 alkenyl which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 hybridized carbon atom; or (iii) any group of (i), wherein RW is
Figure imgf000139_0002
In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c is H; one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 (e.g., C3 or C4) cycloalkyl which is optionally substituted with from 1-2 Rc; and the other of R2a and R2b and the other of R3a and R3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c is H; one of R2a and R2b (e.g., R2a) and one of R3a and R3b (e.g., R3a) combine to form a double bond between the Ring B ring atoms to which each is attached; and the other of R2a and R2b and the other of R3a and R3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c is H; one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R1c is H; one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R2a and R2b is H; and the other of R3a and R3b is C1- 3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is
Figure imgf000141_0002
wherein each RcB is an independently selected Rc; and m is 0, 1, 2, 3, or 4. In certain of these embodiments, m is 1 or 2, such as 2. In certain of the foregoing embodiments, each RcB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is
Figure imgf000141_0001
wherein each RcB is an independently selected Rc. In
Figure imgf000141_0005
certain of these embodiments, each RcB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is selected from the group consisting of:
Figure imgf000141_0003
.
Figure imgf000141_0004
In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo. As non-limiting examples of the foregoing embodiments, Ring A can be selected from the group consisting of:
Figure imgf000142_0004
, each of which is further optio c
Figure imgf000142_0001
nally substituted with R . In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the
Figure imgf000142_0002
moiety is
Figure imgf000142_0003
In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the
Figure imgf000143_0001
moiety is
Figure imgf000143_0002
. In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the
Figure imgf000143_0006
moiety is
Figure imgf000143_0005
. In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the
Figure imgf000143_0004
moiety is
Figure imgf000143_0003
. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof. Table C1 For certain compounds, the symbol * at a chiral center denotes that this chiral center has been resolved (i.e., is a single epimer) and the absolute stereochemistry at that center has not been determined.”
Figure imgf000144_0001
143
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
175
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
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Figure imgf000189_0001
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Figure imgf000200_0001
Figure imgf000201_0001
Pharmaceutical Compositions and Administration General In some embodiments, 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) is administered as 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. In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-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-block polymers, and wool fat. Cyclodextrins such as α-, E, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl-β-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%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK.2012). Routes of Administration and Composition Components In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. 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, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, 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. 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. In all cases 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. In many cases, it will be preferable to include 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. Generally, 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. In the case of 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 caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate. In certain embodiments, 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. In other embodiments, compositions for rectal administration are in the form of an enema. In other embodiments, 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. In such solid dosage forms, 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 i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, 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. In one embodiment, 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. In another solid dosage form, 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. Other 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. In certain embodiments 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. In certain embodiments, 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. For targeting various regions in the intestinal tract, several 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). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap. 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.)). 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. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non- sensitizing. In any of the foregoing embodiments, pharmaceutical 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. Dosages 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. In some embodiments, 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/Kg to about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1 mg/Kg to about 0.5 mg/Kg). Regimens 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). In some embodiments, 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. In a further embodiment, 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. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, 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. In an aspect of this embodiment, 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. In a further embodiment, 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. In a further embodiment, 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). For example, provided herein are 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). In some embodiments, provided herein are 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). In some embodiments, provided herein are inhibitors of EGFR and HER2. An “EGFR inhibitor” as used herein includes any compound exhibiting EGFR inactivation activity (e.g., inhibiting or decreasing). In some embodiments, an EGFR inhibitor can be selective for an EGFR kinase having one or more mutations. For example, an EGFR inhibitor can bind to the adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, an EGFR inhibitor is an allosteric inhibitor. The compounds provided herein can inhibit EGFR. In some embodiments, 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. Cancer Cell.2007;11(3):217–227). In some embodiments, 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). Examples of surface plasmon resonance (SPR) binding assays include those disclosed in Li, Shiqing, et al. Cancer cell 7.4 (2005): 301-311. 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®). 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. As another example, 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-EGFR(Tyrl 068)(3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204)(4370), total ERK (9102), and HSP90 (SC-7947)). Additional assays can include, for example, assays based on ALPHALISA TECHNOLOGY® (e.g., see the ALPHALISA® EGF/EGFR binding kit from Promega). Such assays use a luminescent oxygen-channeling chemistry to detect molecules of interest in, for example, buffer, cell culture media, serum, and plasma. For example, 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. When EGF is bound to EGFR, 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. Further examples of 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®). Such assays utilize chelation-enhanced fluorescence (CHEF) using a sulfonamido-oxine (Sox) chromophore in peptide or protein substrates to create real-time sensors of phosphorylation. See, e.g., U.S. Patent Nos. 8,586,570 and 6,906,194. Potency of an EGFR inhibitor as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 value. In some embodiments, 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 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 IC50 value. In some embodiments, 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. For example, murine Ba/F3 cells transfected with a suitable version of wild type EGFR (such as VIII; containing a wild type EGFR kinase domain), or Ba/F3 cells transfected with L858R/T790M, Del/T790M/L718Q, L858R/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R, 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_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, or P772_H773insPNP) can be used. Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC50 is calculated. An alternative method to measure effects on EGFR activity is to assay EGFR phosphorylation. Wildtype or mutant (L858R/T790M, Del/T790M, Del/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R, or L858R/T790M/L718Q) EGFR can be transfected into 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 effects on EGFR phosphorylation are assayed by Western Blotting using phospho-specific EGFR antibodies. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of EGFR. For example, the compounds provided herein can bind to the EGFR adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, 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 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. In some cases, the inhibititon of wild type EGFR can lead to dose limiting toxicities. See, e.g., Morphy. J. Med. Chem. 2010, 53, 4, 1413–1437 and Peters. J. Med. Chem.2013, 56, 22, 8955–8971. In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR kinase. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR kinase over another kinase or non-kinase target. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 1b) relative to inhibition of wild type EGFR. In some embodiments, 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. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 1b) 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 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, 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. In some embodiments, 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. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. 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 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. 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 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) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, 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). A “HER2 inhibitor” as used herein includes any compound exhibiting HER2 inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a HER2 inhibitor can be selective for a HER2 kinase having one or more mutations. In some embodiments, 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. For example, the compounds can bind to the HER2 adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, the compounds provided herein can inhibit wild type HER2. In some embodiments, 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. 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, a 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). For example, 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-GLOTM 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. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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 EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 value. In some embodiments, 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 IC50 value. In some embodiments, 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. As another example, 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. For example, 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_Y781insGSP can be used. Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC50 is calculated. An alternative method to measure effects on HER2 activity is to assay HER2 phosphorylation. Wildtype or mutant (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_Y781insGSP) 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) to inhibit HER2 phosphorylation can be assayed. Cells are exposed to increasing concentrations of inhibitor and stimulated with EGF. The effects on HER2 phosphorylation are assayed by Western Blotting using phospho-specific HER2 antibodies. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of HER2. For example, the compounds provided herein can bind to the HER2 adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, 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). In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can selectively target a HER2 kinase. For example, 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. It can be desireable to selectively target a HER2 kinase over a wild type EGFR kinase due to undesireable side effects (e.g., diarrhea and skin rashes) that can impact quality of life and compliance. See, e.g., Morphy. J. Med. Chem.2010, 53, 4, 1413– 1437 and Peters. J. Med. Chem.2013, 56, 22, 8955–8971. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. 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 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. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, 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). In some embodiments, 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). In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR and a HER2 kinase. For example, 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. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. 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 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. In some embodiments, 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. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. 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 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. 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 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. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. Also provided herein are methods for inhibiting a BUB (budding uninhibited by benzimidazole, BUB1-3) kinase. For example, provided herein are 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. See, for example, WO 2013/050438, WO 2013/092512, WO 2013/167698, WO 2014/147203, WO 2014/147204, WO 2014/202590, WO 2014/202588, WO 2014/202584, WO 2014/202583, WO 2015/063003, WO2015/193339, WO 2016/202755, and WO 2017/021348. In some embodiments, the disease or disorder is cancer. A “BUB1 inhibitor” as used herein includes any compound exhibiting BUB1 inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a BUB1 inhibitor can be selective for BUB1 over other kinases (e.g., wildtype EGFR). The compounds provided herein can inhibit a Bub kinase. In some embodiments, 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. For example, 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. See, for example, WO 2017/021348. In addition, 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. In some embodiments, the compounds provided herein exhibit central nervous system (CNS) penetrance. For example, 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. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e.g., an EGFR-associated cancer or a HER2-associated cancer such as an EGFR- or HER2-associated brain or CNS cancer or an EGFR-associated or a HER2-associated cancer that has metastasized to the brain or CNS) can include administration (e.g., oral administration) of the compound to the patient. The ability of the compounds described herein, to cross the BBB can be demonstrated by 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. Nat Commun.2017; 8: 15623; Bagchi et al. Drug Des Devel Ther.2019; 13: 3591–3605; Gastfriend et al. Curr Opin Biomed Eng.2018 Mar; 5: 6–12; and Wang et al. Biotechnol Bioeng.2017 Jan; 114(1): 184–194. In some embodiments, the compounds described herein, are fluorescently labeled, and the fluorescent label can be detected using microscopy (e.g., confocal microscopy). In some such embodiments, 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. In some assays, such as a calcein- AM-based assay, 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. Non-limiting examples of 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). In some embodiments, 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). In some embodiments, 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. In some embodiments, 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). In some embodiments, binding of the compounds described herein to brain tissue is quantified. For example, 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) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, 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. Accordingly, provided herein is a method for treating a disease or disorder as provided herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease or disorder is cancer. As used herein, 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. As used herein, 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. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, 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). In some embodiments, 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). For example, the subject has a tumor that is positive for a mutation as described in Table 1a and 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). In some embodiments, the subject is suspected of having an EGFR-associated cancer. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). For example, 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). In some embodiments, the subject is suspected of having a HER2-associated cancer. In some embodiments, 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). In some embodiments, 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. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, 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). In some embodiments, 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. In certain embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, 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). The term "preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof. The term "EGFR-associated disease or disorder" as used herein 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). In some embodiments of any of the methods or uses described herein, 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. See, e.g., Wang et al. Am J Transl Res.2019; 11(2): 520–528; Starosyla et al. World J Pharmacol. Dec 9, 2014; 3(4): 162-173; Choi et al. Biomed Res Int.2018 May 15;2018:9439182; and Wang et al. Sci Rep.2017; 7: 45917. In some embodiments of any of the methods or uses described herein, the central nervous system disease is a neurodegenerative disease. In some embodiments, 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. 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 cell), an alternative spliced version of an EGFR mRNA that results in an EGFR protein having a deletion of at least one amino acid in the EGFR protein as compared to the wild type EGFR protein), or increased expression (e.g., increased levels) of a wild type EGFR kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, 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 1b. Additional examples of EGFR kinase protein mutations (e.g., point mutations) are EGFR inhibitor resistance mutations (e.g., EGFR inhibitor mutations). Non-limiting examples of EGFR inhibitor resistance mutations are described in Table 2a and 2b. For example, 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). In some embodiments, 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. In some embodiments, 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 2b). In some embodiments, 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 2b). 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). In some embodiments, the individual has two or more EGFR inhibitor resistance mutations that increase resistance of the cancer to a first EGFR inhibitor. For example, the individual can have two EGFR inhibitor resistance mutations. In some embodiments, the two mutations occur in the same EGFR protein. In some embodiments, the two mutations occur in separate EGFR proteins. In some embodiments, 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. For example, 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. The term “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. For example, 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. In another example, 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. In another example, 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. The term "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. The term "wild type EGFR" or "wild-type EGFR" describes an EGFR nucleic acid (e.g., an EGFR gene or an EGFR mRNA) or protein (e.g., an EGFR protein) that is found in a subject that does not have an EGFR-associated disease, e.g., an EGFR-associated cancer (and optionally also does not have an increased risk of developing an EGFR- associated disease and/or is not suspected of having an EGFR-associated disease), or is found in a cell or tissue from a subject that does not have an EGFR-associated disease, e.g., an EGFR-associated cancer (and optionally also does not have an increased risk of developing an EGFR-associated disease and/or is not suspected of having an EGFR- associated disease). Provided herein is a method of treating cancer (e.g., an EGFR-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I- a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I- g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating an EGFR- associated cancer in a subject in need of such treatment, the method 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. In some embodiments, 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 1b. In some embodiments, 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). In some embodiments, 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. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion. In some embodiments, 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. For example, 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; or any combination thereof; e.g., any two or more independently selected exon 20 insertions; e.g., any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD). In some embodiments of any of the methods or uses described herein, the cancer (e.g., EGFR-associated cancer) is selected from 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)), 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 pleura, cancer of the nose, nasal cavity, or middle ear, oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, cancer of the vulva, colon cancer, esophageal cancer, tracheal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, ovarian cancer, pancreatic cancer including pancreatic islet cell cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, ureter cancer, biliary cancer, and urinary bladder cancer. In some embodiments, 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. In some embodiments, 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. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, 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. Cancer Res.2003 Mar 1;63(5):1106-13). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, 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. In some embodiments, the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer). In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. In some embodiments, 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. In some embodiments, the cancer is a cancer of B cell origin. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, 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. In some embodiments, the cancer is an EGFR-associated cancer. Accordingly, also provided herein is a method for treating a subject diagnosed with or identified as having an EGFR-associated cancer, e.g., any of the exemplary EGFR-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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein. In some embodiments, 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. In some embodiments, 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 1b. In some embodiments, 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. In some embodiments, 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 1b).In some embodiments, 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 1b. In some embodiments, 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 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. In some embodiments, 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. For example, 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; or any combination thereof; e.g., any two 10 or more independently selected exon 20 insertions; e.g., any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD)..
Table 1a. EGFR Protein Amino Acid Substitutions/Insertions/DeletionsA
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
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. doi:10.1186/s13000-019-0789-1. 3 Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06. 4 Pines, Gur, Wolfgang J. Köstler, and Yosef Yarden. FEBS letters 584.12 (2010): 2699- 2706. 5 Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. 6 Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235. 7Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). 8 Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. 9 Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015. 10 Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004. 11 Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. 12 Vyse and Huang et al. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038/s41392-019-0038-9. 13 PCT Patent Application Publication No. WO2019/046775. 14 PCT Patent Application Publication No. WO 2018/094225. Table 1b. EGFR Protein Amino Acid Substitutions/Insertions/DeletionsA
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
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. doi:10.1186/s13000-019-0789-1. 3 Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06. 4 Pines, Gur, Wolfgang J. Köstler, and Yosef Yarden. FEBS letters 584.12 (2010): 2699- 2706. 5 Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. 6 Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235. 7Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). 8 Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. 9 Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015. 10 Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004. 11 Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. 12 Vyse and Huang et al. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038/s41392-019-0038-9. 13 PCT Patent Application Publication No. WO2019/046775. 14 PCT Patent Application Publication No. WO 2018/094225. 15Mondal, Gourish, et al. Acta Neuropathol.2020; 139(6): 1071-1088 16Udager, Aaron M., et al. Cancer Res, 2015; 75(13): 2600-2606 In some embodiments, 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. In some embodiments, 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. In some cases, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),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). In other embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In such embodiments, an EGFR inhibitor resistance mutation can result in an EGFR kinase that has one or more of an increased Vmax, a decreased Km, 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. Exemplary Sequence of Mature Human EGFR Protein (UniProtKB entry P00533) (SEQ ID NO: 1)
Figure imgf000253_0001
In some embodiments, 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 2b. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I- g1-2),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 2b) 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 EGFR; e.g., first and/or second EGFR inhibitors).
Table 2a. EGFR Protein Amino Acid Resistance Mutations
Figure imgf000255_0001
1 PCT Patent Application Publication No. WO2019/246541 2 Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06 3 Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. 4 Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235 5Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). 6 Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. 7 Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015 8 Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004 Table 2b. EGFR Protein Amino Acid Resistance Mutations
Figure imgf000256_0001
Figure imgf000257_0001
1 PCT Patent Application Publication No. WO2019/246541 2 Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06 3 Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. 4 Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235 5Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). 6 Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. 7 Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015 8 Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004 9Papadimitrakopoulou, V.A., et al. Annals of Oncology 2018; 29 Supplement 8 VIII741 In some embodiments, 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; D770_N771insSV; N771delinsNPH; N771_H773dup; L858R/C797S (or C797G); or Del_19 and C797S (or C797G), or any combination thereof. As used herein, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein. As used 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. When both a first and a second inhibitor of EGFR are present in a method provided herein, the first and second inhibitors of EGFR are different. In some embodiments, the first and/or second inhibitor of EGFR bind in a different location than a compound of Formula (I). For example, in some embodiments, a first and/or second inhibitor of EGFR can inhibit dimerization of EGFR, while a compound of Formula (I) can inhibit the active site. In some embodiments, 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. In some embodiments, 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. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts and solvates thereof, 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 2b including substitutions at amino acid position 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A)). In some embodiments, 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 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). It is frequently mutated and/or overexpressed in different types of human cancers and is the target of multiple cancer therapies currently adopted in the clinical practice (Yarden Y and Pines G (2012) Nat Rev Cancer 12, 553–563). Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, 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. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an EGFR-associated cancer. For example, the EGFR-associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations. The term "regulatory agency" refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA). Also provided are methods for treating cancer in a subject in need thereof, the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an EGFR-associated cancer. For example, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. 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). In some embodiments of these methods, 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. In some embodiments, 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. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, 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. In some embodiments, 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. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. Also provided is the use of 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. Some embodiments of 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. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, 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. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. Also provided is the use of 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. In some embodiments, the cancer is an EGFR-associated cancer, for example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, 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. As provided herein, an EGFR-associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an EGFR-associated cancer (e.g., a cancer having one or more EGFR inhibitor resistance mutations). In some embodiments, provided herein are methods for treating an EGFR-associated cancer in a subject in need of such treatment, the method 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, 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. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and 1b. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. Non-limiting examples of EGFR inhibitor resistance mutations are described in Table 2a and 2b. In some embodiments, 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). In some embodiments, 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 . In some embodiments, the EGFR exon 20 mutation is an exon 20 insertion such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments of any of the methods or uses described herein, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some such embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of any of the methods or uses described herein, 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). As is well-known in the art, 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). In some embodiments, 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. In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin- embedded biopsy sample) from the subject. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or 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. The term "HER2-associated disease or disorder" as used herein 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. The term “HER2-associated cancer” as used herein 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. Non-limiting examples of a HER2-associated cancer are described herein. In some embodiments, the EGFR-associated cancer is also a HER2-associated cancer. For example, 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 HER2 mRNA that results in a HER2 protein having a deletion of at least one amino acid in the HER2 protein as compared to the wild-type HER2 protein), or increased expression (e.g., increased levels) of a wild type HER2 kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, 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) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, 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). In some embodiments, 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. The term “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. For example, 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. In another example, 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. In another example, 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. The term "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). Provided herein is a method of treating a HER2-associated cancer (in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating a HER2-associated cancer in a subject in need of such treatment, the method 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. In some embodiments, 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. Non-limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5. In some embodiments, 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. In some embodiments, 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_Y781insGSP. In some embodiments, 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. In some embodiments of any of the methods or uses described herein, the cancer (e.g., HER2-associated cancer) is selected from 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 pleura, cancer of the nose, nasal cavity, or middle ear, tracheal cancer, oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, cancer of the vulva, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer including pancreatic islet cell cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, ureter cancer, biliary cancer, and urinary bladder cancer. In some embodiments, 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. In some embodiments, 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. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, 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. Cancer Res.2003 Mar 1;63(5):1106-13). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, 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. In some embodiments, the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer). In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. In some embodiments, 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. In some embodiments, the cancer is a cancer of B cell origin. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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 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). In some embodiments, 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/DeletionsA
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
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. 1 Li et al. J Thorac Oncol.2016 Mar;11(3):414-9. 2 Arcila et al. Clin Cancer Res. 2012 Sep 15; 18(18): 10.1158/1078-0432.CCR-12- 0912. 3 Bose et al. Cancer Discov.2013 Feb;3(2):224-37. 4 Hanker et al. Cancer Discov.2017 Jun;7(6):575-585. 5 Christgen et al. Virchows Arch.2018 Nov;473(5):577-582. 6 Si et al. Cancer Biomark.2018;23(2):165-171. 7 Kavuri et al. Cancer Discov.2015 Aug; 5(8): 832–841. 8 Robichaux et al. Nat Med.2018 May; 24(5): 638–646. 9 Kosaka et al. Cancer Res.2017 May 15; 77(10): 2712–2721. 10 Pahuja et al. Cancer Cell.2018 Nov 12; 34(5): 792–806.e5. 11 Ross et al. Cancer.2018 Apr 1;124(7):1358-1373. 12 Gharib et al. J Cell Physiol.2019 Aug;234(8):13137-13144. 13 Krawczyk et al. Oncol Lett.2013 Oct; 6(4): 1063–1067. 14 Lai et al. Eur J Cancer.2019 Mar; 109: 28–35. 15 Sun et al. J Cell Mol Med.2015 Dec; 19(12): 2691–2701. 16 Xu et al. Thorac Cancer.2020 Mar;11(3):679-685. In some embodiments, 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. In some embodiments, the splice variant of HER2 is Δ16HER-3 or p95HER‐2. See, e.g., Sun et al. J Cell Mol Med. 2015 Dec; 19(12): 2691–2701. In some embodiments, 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). See, e.g., Rexer and Arteaga. Crit Rev Oncog.2012; 17(1): 1– 16. In some embodiments, 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. In some embodiments, 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
Figure imgf000280_0001
1 Yu et al. J Transl Med.2015; 13: 116. In some embodiments, 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. In other embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. Exemplary Sequence of Mature Human HER2 Protein (UniProtKB entry P04626) (SEQ ID NO: 2)
Figure imgf000280_0002
Figure imgf000281_0001
In some embodiments, 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. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)) and pharmaceutically acceptable salts and solvates thereof, 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/or second HER2 inhibitors). Table 5. HER2 Protein Amino Acid Resistance Mutations
Figure imgf000282_0001
1 Hanker et al. Cancer Discov.2017 Jun;7(6):575-585. 2 Sun et al. J Cell Mol Med.2015 Dec; 19(12): 2691–2701. As used herein, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein. As used 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. When both a first and a second inhibitor of HER2 are present in a method provided herein, the first and second inhibitors of HER2 are different. In some embodiments, the first and/or second inhibitor of HER2 bind in a different location than a compound of Formula (I). For example, in some embodiments, a first and/or second inhibitor of HER2 can inhibit dimerization of HER2, while a compound of Formula (I) can inhibit the active site. In some embodiments, 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. In some embodiments, a first or second inhibitor of HER2 can be selected from the group consisting of: trastuzumab (e.g., TRAZIMERA™, 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., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17- AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts and solvates thereof, 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)). In some embodiments, 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. Like EGFR, the epidermal growth factor receptor 2 (HER2) 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; and Moasser. Oncogene. 2007 Oct 4; 26(45): 6469–6487). It is frequently mutated and/or overexpressed in different types of human cancers and is the target of multiple cancer therapies currently adopted in the clinical practice (Moasser. Oncogene. 2007 Oct 4; 26(45): 6469–6487). Accordingly, provided herein are methods for treating a subject identified or diagnosed as having a HER2-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, 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. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a HER2-associated cancer. Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a HER2-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, the test or assay is provided as a kit. In some embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. 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). In some embodiments of these methods, 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. In some embodiments, 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. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, 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. As used herein, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein. As used 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. When both a first and a second HER2 inhibitor are present in a method provided herein, the first and second HER2 inhibitors are different. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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-associated cancer. Also provided is the use of 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. Some embodiments of 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. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency- approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. Also provided is the use of 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 (. In some embodiments, 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. As provided herein, a HER2- associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, 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. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a HER2-associated cancer. In some embodiments, provided herein are methods for treating a HER2-associated cancer in a subject in need of such treatment, the method 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. In some embodiments, 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. Non- limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5. In some embodiments, 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). In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is an exon 20 point mutation/insertion/deletion. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments of any of the methods or uses described herein, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. In some such embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In some embodiments of any of the methods or uses described herein, 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). As is well-known in the art, 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 a HER2 gene, a HER2 kinase, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, 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. In some embodiments, 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). 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) 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-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided is 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. Further provided herein is 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. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, 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. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is an EGFR-associated cancer cell. In some embodiments, the cancer cell is a HER2-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. 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. The phrase "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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),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. When employed as pharmaceuticals, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),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, wherein the method 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 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject. Further provided herein is a method of treating a subject having a cancer, wherein the method 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. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, 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. For example, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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)). In some embodiments, 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)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is EGFR inhibitor naïve. For example, the subject is naïve to treatment with a selective EGFR inhibitor. In some embodiments, a subject is not EGFR inhibitor naïve. In some embodiments, a subject is HER2 inhibitor naïve. For example, the subject is naïve to treatment with a selective HER2 inhibitor. In some embodiments, a subject is not HER2 inhibitor naïve. In some embodiments, a subject has undergone prior therapy. For example, treatment with a multi-kinase inhibitor (MKI), an EGFR tyrosine kinase inhibitor (TKI), osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD- 9291, CL-387785, CO-1686, or WZ4002. In some embodiments of any the methods described herein, the compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. 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. In some embodiments, the other EGFR-targeted therapeutic is a multi-kinase inhibitor exhibiting EGFR inhibition activity. In some embodiments, the other EGFR- targeted therapeutic inhibitor is selective for an EGFR kinase. Non-limiting examples of EGFR-targeted therapeutic agents (e.g., a first EGFR inhibitor or a second EGFR inhibitor) include an EGFR-selective inhibitor, a panHER inhibitor, and an anti-EGFR antibody. In some embodiments, the EGFR inhibitor is a covalent inhibitor. In some embodiments, 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), nazartinib (EGF816, NVS- 816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ- 61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, 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) 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. In some embodiments, 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. Non-limiting examples of HER2-targeted therapeutic agents (e.g., a first HER2 inhibitor or a second HER2 inhibitor) include a HER2-selective inhibitor, a panHER inhibitor, and an anti-HER2 antibody. Exemplary HER2-targeted therapeutic agents include trastuzumab (e.g., TRAZIMERA™, 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., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. Additional HER2-targeted therapeutic agents (e.g., a first HER2 inhibitor or a second HER2 inhibitor) 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. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, 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. In some embodiments, 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). In some embodiments, a KRAS modulator is a covalent inhibitor. Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849. Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI- 402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN- 193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof. In some embodiments, 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-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin- 3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof. In some embodiments, 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. Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277. In some embodiments, a chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVENTM), or combinations thereof. Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof. In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof Non-limiting examples of 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. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo, et al., J Hematol Oncol.11: 39 (2018). In some embodiments, the additional therapy or therapeutic agent is a combination of atezolizumab and nab-paclitaxel. Accordingly, also provided herein is 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. 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 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. These additional therapeutic agents may be administered with one or more doses of the compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. Also provided herein is (i) 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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 of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a subject in need thereof. In some embodiments, the cancer is an EGFR-associated cancer. For example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-associated cancer. For example, 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. The term "fixed combination" means that a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. The term "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. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients Accordingly, also provided herein is 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, 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. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is an EGFR-associated cancer. For example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-associated cancer. For example, a HER2-associated cancer having one or more HER2 inhibitor resistance mutations. In some embodiments, 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. For example, provided herein are 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with the first EGFR inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more EGFR inhibitor resistance mutations that include administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with the first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations include one or more EGFR inhibitor resistance mutations listed in Table 2a and 2b. For example, 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). For example, provided herein are methods for treating an EGFR-associated cancer in a subject in need of such treatment, the method 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. In some embodiments, 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),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. Methods useful when a HER2 activating mutation is present in a tumor are described herein. For example, provided herein are 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-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided are methods of treating a subject identified as having a cancer that has one or more HER2 activating mutations that include administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, 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. For example, provided herein are 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-a1), (I-a2), (I-a3), (I- a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Compound Preparation 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. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. 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: N-(4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-3-yl)pivalamide (Compound 101)
Figure imgf000305_0001
Int1A is reacted with tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide under basic conditions (e.g., with NaH in DMF) to provide Int1B. Removal of the Boc protecting group from Int1B under acidic conditions (e.g., HCl in dioxane and DCM) followed by lactamization of the resulting amine under basic conditions (e.g., MeONa in MeOH) provides Int1D. Sequential Miyaura borylation of Int1D and Suzuki-Miyaura coupling of the resulting boronic acid (Int 1E) with 4-chloropyridin-3-amine provides Int1F. Int1F is reacted with pivaloyl chloride under basic conditions (e.g., Et3N in DCM) followed by treatment with NaOH and H2O in THF to provide Int1G. Bromination of Int1G e.g., with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione in AcOH at 100 °C provides Int1H. Finally, Buchwald-Hartwig amination of Int1H with 3-fluoro-2- methoxyaniline affords Compound 101. Example 2: N-(4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-3-yl)-2-methoxy-2-methylpropanamide (Compound 102)
Figure imgf000306_0001
Part 1: Synthesis of 2-methoxy-2-methylpropanoyl chloride 2-Methoxy-2-methylpropanoic acid is reacted with 2-chloroacryloyl chloride (e.g., in the presence of DCM and DMF) at 0 °C. The reaction mixture is then warmed to about 40 °C to provide 2-methoxy-2-methylpropanoyl chloride.
Figure imgf000306_0002
Part 2: Synthesis of Compound 102 Int2A is prepared using the method as described in Example 1. Int2A is reacted with 2-methoxy-2-methylpropanoyl chloride under basic conditions (e.g., Et3N in DCM) to provide Int2B. Int2B is brominated e.g., with 1,3-dibromo-5,5-dimethylimidazolidine- 2,4-dione in AcOH at 100 °C to provide Int2C. Finally, Buchwald-Hartwig amination of Int2C (e.g., in the presence of Ephos Pd G4, Ephos, Cs2CO3 in dioxane) with 3-fluoro-2- methoxyaniline affords Compound 102. Example 3: 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((2- methoxyethyl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 103)
Figure imgf000307_0001
Int3D is prepared using the method as described for Example 1. Int3A is reacted with 1-iodo-2-methoxyethane under basic conditions (e.g., NaH in DMF) to provide Int3B. Removal of the Boc protecting group from Int3B followed by Suzuki-Miyaura coupling with Int3D provides Int3E. Int3E is brominated with e.g., 1,3-dibromo-5,5- dimethylimidazolidine-2,4-dione in AcOH at 100 °C to provide Int3F. Buchwald-Hartwig amination of Int3F (e.g., in the presence of Ephos Pd G4, Ephos, Cs2CO3 in dioxane) with 3-fluoro-2-methoxyaniline affords Int3G. Acidic treatment of Int3G (e.g., with TFA) affords Compound 103. Example 4. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 347)
Figure imgf000308_0001
3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane(5 mL) and H2O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs2CO3(438 mg),PCy3(37.7 mg) and Pd2(dba)3 (123.1 mg) was added, the reaction was stirred for 12 hours, the reaction was stirred for 12 hours under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3- chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (116.1 mg, 48.50%) as a light yellow solid. LC-MS: M+H found: 300.
Figure imgf000308_0002
3-chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(100 mg) was dissolved in DMF(5 mL), 3-chloro-2-methoxyaniline (105 mg), Cs2CO3(326 mg), EPhos Pd G4(306 mg) and EPhos (89 mg) was added, the reaction was stirred for 4 hours under N2 atmosphere.The resulting mixture was concentrated under reduced pressure.The crude p roduct (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (24.7 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 421. 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.08 (d, J = 4.6 Hz, 1H), 8.73 (d, J = 5.8 Hz, 1H), 8.37 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 7.46 (s, 1H), 6.57 (dt, J = 15.8, 7.7 Hz, 2H), 6.17 (d, J = 7.8 Hz, 1H), 4.52 (s, 2H), 3.75 (s, 2H), 3.68 (s, 3H). Example 5. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 344)
Figure imgf000309_0001
A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (500.00 mg, 1.996 mmol, 1.00 equiv), pyridin-4-ylboronic acid (368.05 mg, 2.994 mmol, 1.50 equiv), Pd(dppf)Cl2 (146.06 mg, 0.200 mmol, 0.10 equiv) and K2CO3 (827.64 mg, 5.988 mmol, 3.00 equiv) in 1,4-dioxane (10.00 mL) and water (1.00 mL) was stirred for overnight at 70 degrees C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (40:1) to afford 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (200 mg, 40.29%) as a yellow solid. LC-MS: M+H found: 249.
Figure imgf000310_0001
A mixture of 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.402 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (95.07 mg, 0.603 mmol, 1.50 equiv), EPhos Pd G4 (36.94 mg, 0.040 mmol, 0.10 equiv), EPhos (21.51 mg, 0.040 mmol, 0.10 equiv) and K2CO3 (166.73 mg, 1.206 mmol, 3.00 equiv) in 1,4-dioxane (1.00 mL) and Toluene (1.00 mL) was stirred for overnight at 60 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.58) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (35.6 mg, 23.87%) as a white solid. LC-MS: (M+H)+ found: 370. 1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.69 (d, J = 5.1 Hz, 2H), 7.08 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.73 – 6.50 (m, 2H), 6.19 (dd, J = 8.1, 1.5 Hz, 1H), 4.46 (dd, J = 7.1, 5.0 Hz, 2H), 4.05 (s, 3H), 3.94 – 3.75 (m, 2H). Example 6. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 348)
Figure imgf000311_0001
3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane(5 mL) and H2O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs2CO3(438 mg), PCy3(37.7 mg) and Pd2(dba)3 (123.1 mg) was added, the reaction was stirred for 12 hours, the reaction was stirred for 12 hours under N2 atmosphere. The resulting mixture was concentrated under reduced pressure.The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-chloro-2-(7-methoxy-1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (102.1 mg, 45.50%) as a light yellow solid. LC-MS: M+H found: 330.
Figure imgf000311_0002
3-chloro-2-(7-methoxy-1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(100 mg) was dissolved in DMF (10 mL), 3-chloro-2-methoxyaniline(96 mg), Cs2CO3(296 mg), EPhos Pd G4(139 mg) and EPhos (81 mg) was added, the reaction was stirred for 12 hours under N2 atmosphere. The resulting mixture was concentrated under reduced pressure.The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7- methoxy-1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (46.1 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 451. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.37 (s, 1H), 7.54 – 7.42 (m, 2H), 7.22 (s, 1H), 6.67 – 6.50 (m, 2H), 6.16 (dd, J = 7.9, 1.7 Hz, 1H), 4.50 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.78 (s, 3H), 3.99 (s, 2H). Example 7. 3-[(3-chloro-2-methoxyphenyl) amino]-2-{1H-pyrrolo[3,2-b] pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 346)
Figure imgf000312_0001
A mixture of 7-bromo-1H-pyrrolo[3,2-b] pyridine (500 mg, 2.538 mmol, 1.00 equiv), Boc2O (664.59 mg, 3.046 mmol, 1.2 equiv) and DMAP (31.00 mg, 0.254 mmol, 0.1 equiv) in THF (10 mL, 123.430 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 7-bromopyrrolo[3,2-b] pyridine-1-carboxylate (700 mg, 92.83%) as a brown oil. LC-MS: M+H found: 297.
Figure imgf000312_0002
A mixture of tert-butyl 7-bromopyrrolo[3,2-b]pyridine-1-carboxylate (700 mg, 2.356 mmol, 1.00 equiv), 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (841.13 mg, 2.827 mmol, 1.2 equiv), Pd(DtBPF)Cl2 (153.53 mg, 0.236 mmol, 0.1 equiv) and K2CO3 (976.71 mg, 7.068 mmol, 3 equiv) in 1,4- dioxane (15 mL, 170.251 mmol) was stirred for 4 h at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl}pyrrolo[3,2-b]pyridine-1-carboxylate (500 mg, 54.73%) as a white solid. LC-MS: (M+H)+ found: 388.
Figure imgf000313_0001
A mixture of tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2- yl}pyrrolo [3,2-b]pyridine-1-carboxylate (200 mg, 0.516 mmol, 1.00 equiv) , EPhos Pd G4 (47.37 mg, 0.052 mmol, 0.1 equiv)and Cs2CO3 (504.08 mg, 1.548 mmol, 3 equiv) in 1,4-dioxane (4 mL) was stirred for overnight at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (50:1) to afford tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1-carboxylate (35 mg, 13.33%) as a white solid. LC-MS: (M+H)+ found: 509.
Figure imgf000314_0001
A mixture of tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1-carboxylate (50 mg, 0.098 mmol, 1.00 equiv) and TFA (56.01 mg, 0.490 mmol, 5 equiv) in DCM (1 mL, 15.730 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro-2-methoxyphenyl) amino]- 2-{1H-pyrrolo[3,2-b] pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (37 mg, 92.12%) as a yellow solid. LC-MS: (M+H)+ found: 409. 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.26 (d, J = 5.1 Hz, 1H), 7.70 (t, J = 3.1 Hz, 1H), 7.42 – 7.33 (m, 2H), 6.77 – 6.65 (m, 2H), 6.65 – 6.58 (m, 1H), 6.16 (dd, J = 6.8, 2.9 Hz, 1H), 4.51 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.72 (s, 2H). Example 8.2-(2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 335)
Figure imgf000314_0002
To a solution of 2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.00 g, 4.629 mmol, 1.00 equiv) and tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl]carbamate (1.78 g, 5.555 mmol, 1.20 equiv) in dioxane (10.00 mL) and H2O (2.00 mL)were added K2CO3 (1.28 g, 9.258 mmol, 2.00 equiv) and Pd(dppf)Cl2*CH2Cl2 (0.75 g, 0.926 mmol, 0.20 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (20 mL). The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4- [4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (1.05 g, 68.87%) as a white solid. LC-MS: M+H found: 330.
Figure imgf000315_0001
To a stirred solution of tert-butyl N-(4-[4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (1.00 g, 3.036 mmol, 1.00 equiv) in DMF (20.00 mL) was added NBS (0.54 g, 3.036 mmol, 1.00 equiv) in portions at 0 degrees C . The resulting mixture was stirred for 2 h at 80 degrees C. The resulting mixture was filtered, and the filter cake was washed with H2O and EA. The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (700 mg, 56.47%) as a white solid. LC-MS: M+H found: 408.
Figure imgf000315_0002
To a solution tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (200.00 mg, 0.490 mmol, 1.00 equiv) of and 3-chloro-2- methoxyaniline (154.41 mg, 0.980 mmol, 2.00 equiv) in THF (4.00 mL)were added t- BuONa (70.62 mg, 0.735 mmol, 1.50 equiv) and Pd PEPPSI IPentCl (42.16 mg, 0.049 mmol, 0.10 equiv). After stirring for 4 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EA (3 x 20mL). The combined organic layers were washed with brine (1x10mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl]pyridin-2-yl)carbamate (30 mg, 12.63%) as a pink solid. LC-MS: M+H found: 485.
Figure imgf000316_0001
To a stirred solution of tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (30.00 mg) in DCM (6.00 mL) was added TFA (2.00 mL) dropwise at rt . The resulting mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150mm 5um; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min, 50% B; Wave Length: 254; 220 nm; RT1(min): 6.97) to afford 2- (2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (6.0 mg, 25.0%) as a light yellow solid. LC-MS: M+H found: 385. 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.02 (s, 2H), 6.79 (t, J = 8.1 Hz, 1H), 6.65 (dd, J = 8.0, 1.5 Hz, 1H), 6.31 (dd, J = 8.2, 1.5 Hz, 1H), 5.94 (s, 2H), 4.35 (dd, J = 7.1, 5.1 Hz, 2H), 3.84 (s, 3H), 3.61 (ddd, J = 7.7, 4.7, 2.6 Hz, 2H). Example 9. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 351)
Figure imgf000317_0001
To a solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.399 mmol, 1.00 equiv) and 1H-pyrazolo[3,4-b]pyridin-4-ylboronic acid (78.06 mg, 0.000 mmol, 1.20 equiv) in dioxane (2.00 mL) and H2O (0.40 mL) were added K2CO3 (110.35 mg, 0.798 mmol, 2.00 equiv) and Pd(dppf)Cl2*CH2Cl2 (32.52 mg, 0.040 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (400 mg, 69.41%) as a yellow solid. LC-MS: M+H found: 289.
Figure imgf000317_0002
To a solution of 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (400.00 mg, 1.386 mmol, 1.00 equiv) in DMF (8.00 mL)was added NaH (66.50 mg, 1.663 mmol, 1.20 equiv, 60%) at 0 degrees C. The mixture was stirred for 15 min. [2-(chloromethoxy)ethyl]trimethylsilane (277.19 mg, 1.663 mmol, 1.20 equiv) was added, and the mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with H2O (50 ml) at 0 degrees C. The resulting mixture was filtered, the filter cake was washed with H2O (30 mL). The filterate was concentrated under reduced pressure to afford 3-chloro-5-[[2-(trimethylsilyl)ethoxy]methyl]-2-(1-[[2- (trimethylsilyl)ethoxy]methyl]pyrazolo [3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 40.61%) as a yellow solid. LC-MS: M+H found: 549.
Figure imgf000318_0001
To a solution of 3-chloro-5-{[2-(trimethylsilyl)ethoxy]methyl}-2-(1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 0.910 mmol, 1 equiv) and 3-chloro-2-methoxyaniline (286.95 mg, 1.820 mmol, 2 equiv) in DMF (12.50 mL, 161.452 mmol, 177.42 equiv) were added Cs2CO3 (593.24 mg, 1.820 mmol, 2 equiv) and EPhos Pd G4 (418.12 mg, 0.455 mmol, 0.5 equiv), EPhos (486.87 mg, 0.910 mmol, 1 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-5-{[2- (trimethylsilyl)ethoxy]methyl}-2-(1-{[2-(trimethylsilyl)ethoxy] methyl}pyrazolo[3,4- b]pyridin-4-yl)-6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 14.98%) as a brown solid. LC-MS: M+H found: 670.
Figure imgf000318_0002
3-[(3-chloro-2-methoxyphenyl)amino]-5-[[2-(trimethylsilyl)ethoxy]methyl]-2-(1-[[2- (trimethylsilyl)ethoxy]methyl]pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200.00 mg) was dissolved in 1,4-dioxane (5.00 mL) containing HCl(g). The resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL), EDA (1 mL) was added at 0 degrees C, then the mixture was stirred for 2 h at rt. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3 x 30mL). The combined organic layers were washed with brine (1x20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford crude product. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 51% B in 7 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.37) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4 mgˈ11.4%) as a white solid. LC-MS: M+H found: 410. 1H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 6.72 – 6.64 (m, 2H), 6.21 – 6.12 (m, 1H), 4.41 (t, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H). Example 10.3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 352)
Figure imgf000319_0001
To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (380.95 mg, 1.768 mmol, 2.00 equiv) and 4-chlorothieno[2,3-b]pyridine (150.00 mg, 0.884 mmol, 1.00 equiv) in dioxane (5.00 mL, 59.020 mmol, 66.74 equiv) and H2O (1.00 mL, 0.056 mmol, 0.06 equiv) were added Pd(dppf)Cl2 (64.70 mg, 0.088 mmol, 0.10 equiv) and K2CO3 (244.42 mg, 1.768 mmol, 2.00 equiv) at rt under N2 atmosphere. Then, the solution was stirred at 80 degrees C for 2 h. The mixture was diluted with 300 ml water and filtrate the solid to afford 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (109 mg, 40.45%) as a black solid. LC-MS: M+1 found: 304.95.
Figure imgf000320_0001
To a stirred solution of 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (130.00 mg, 0.427 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (134.46 mg, 0.853 mmol, 2 equiv) in DMF (7.00 mL, 0.008 mmol, 0.25 equiv) were added Cs2CO3 (277.98 mg, 0.853 mmol, 2.00 equiv), EPhos (228.13 mg, 0.427 mmol, 1.00 equiv) and EPhos Pd G4 (195.92 mg, 0.213 mmol, 0.50 equiv) at rt under N2 atmosphere. Then, the solution was stirred at 50 degrees C for 2h. The resulting mixture was diluted with water (50 mL) and washed with 3×40 mL of EA. The filtrate was concentrated under reduced pressure.The residue was purified by reverse flash chromatography with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.62) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3- b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.9 mg, 3.25%) as a yellow solid. LC-MS: M+1 found: 425.9. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.44 (s, 1H), 6.67 (dd, J = 8.1, 1.8 Hz, 1H), 6.63 (t, J = 7.9 Hz, 1H), 6.12 (dd, J = 7.8, 1.8 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.85 (s, 3H), 3.70 (s, 2H). Example 11.3-[(3-chloro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7- yl}-5H,6H,7H-pyrazolo [1,5-a]pyrazin-4-one (compound 353)
Figure imgf000321_0001
A solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 2.00 mmol, 1.00 equiv) and bis(pinacolato)diboron (1013.81 mg, 3.99 mmol, 2.00 equiv), KOAc (489.77 mg, 4.99 mmol, 2.50 equiv) and Pd(dppf)Cl2 (146.06 mg, 0.200 mmol, 0.1 equiv) in DME (30.00 mL, 309.92 mmol,) was stirred 2h at 100°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was filtered; the filter cake was washed with DCM (2x210 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EA (5ml). The resulting mixture was filtered; the filter cake was washed with EA (2x210ml). The filtrate was concentrated under reduced pressure to afford crude product 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-ylboronic acid (800 mg) as a black oil. LC-MS: (M+H)+ found: 216.3.
Figure imgf000321_0002
To a solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol, 1.00 equiv) in DMF (5 mL, 64.61 mmol, 25.59 equiv) was added sodium hydride (60% in oil, 90.98 mg) at 0 degrees C. The mixture was stirred for 15 min, then [2- (chloromethoxy)ethyl]trimethylsilane (547.25 mg, 3.28 mmol, 1.30 equiv) was added, and the mixture was allowed to warm to RT where it was stirred for 3 h. The reaction mixture was quenched with water and extracted with DCM (3*25 mL). The residue was purified by prep-TLC (DCM:MeOH =15:1) to afford 7-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine(400 mg, 48.26%) as a brown solid. LC-MS: (M+H)+ found: 328.1.
Figure imgf000322_0001
To a solution of 7-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine (400 mg, 1.22 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-ylboronic acid (787.36 mg, 3.65 mmol, 3 equiv) in dioxane (20.00 mL) and H2O (4.00 mL) were added K2CO3 (420.99 mg, 3.045 mmol, 2.5 equiv) and Pd(dppf)Cl2 (89.15 mg, 0.122 mmol, 0.10 equiv) . After stirring for 5h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro-2- (1-{[2-(trimethylsilyl) ethoxy] methyl}pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (250 mg, 48.97%) as a brown solid. LC-MS: (M+H)+ found: 419.3.
Figure imgf000322_0002
To a solution of 3-chloro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3- b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.477 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (112.85 mg, 0.716 mmol, 1.5 equiv) in DMF (10.00 mL) and EPhos (127.65 mg, 0.238 mmol, 0.5 equiv) were added Cs2CO3 (388.84 mg, 1.192 mmol, 2.50 equiv) and EPhos Pd G4 (219.25 mg, 0.239 mmol, 0.50 equiv). After stirring for 3 h at 50°C under a nitrogen atmosphere, the resulting mixture was extracted with EA (3x50 mL). The combined organic layers were washed with brine(3x20ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified three times by prep-TLC (DCM:MeOH 20:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[(2Z)-3-[(E)-(2- iminoethylidene) amino]prop-2-en-1-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20 mg, purity:50%) as off-white solid. LC-MS: (M+H)+ found: 540.4.
Figure imgf000323_0001
3-[(3-chloro-2-methoxyphenyl) amino]-2-(1-{[2-(trimethylsilyl) ethoxy] methyl} pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg) was dissolved in dioxane (250 mL) containing HCl (g). The solution was stirred at RT under N2 atmosphere for 2 h. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3x15ml), dried over anhydrous Na2SO4. After extraction, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 10 min, 45% B; Wave Length: 254/220 nm; RT1(min): 9.42) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo [1,5- a]pyrazin-4-one (7.1 mg, 1.9 %) as a white solid. LC-MS: (M+H)+ found: 410.2. 1H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 3.6 Hz, 2H), 7.47 (d, J = 4.7 Hz, 1H), 6.80 – 6.67 (m, 2H), 6.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.54 (dd, J = 7.0, 5.1 Hz, 2H), 3.92 (s, 3H), 3.73 (s, 2H). Example 12. (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 302)
Figure imgf000324_0001
Into a 40 mL vial were added (7S)-3-amino-2-bromo-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg, 0.816 mmol, 1 equiv) and 3-fluoro-2-methoxyphenylboronic acid (208.03 mg, 1.224 mmol, 1.5 equiv) and Cu(OAc)2 (29.64 mg, 0.163 mmol, 0.2 equiv) and Pyridine (32.28 mg, 0.408 mmol, 0.5 equiv) in MeOH (15mL) at room temperature. The resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH 15:1) to afford (7S)-2- bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (170 mg) as a pink solid. LC-MS: M+H found: 370.80.
Figure imgf000324_0002
Into a 8-mL vial, was placed (7S)-2-bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-7- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.271 mmol, 1 equiv), 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-b]pyridine (212.43 mg, 0.867 mmol, 3.2 equiv), K2CO3 (93.59 mg, 0.677 mmol, 2.5 equiv), Pd(dppf)Cl2*CH2Cl2 (22.06 mg, 0.027 mmol, 0.1 equiv) in 1,4-Dioxane (10 mL) and H2O (0.4 mL). The resulting solution was stirred for 3 h at 80 degrees C under a nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM/MeOH (12:1) to afford (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow crude solid. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave Length: 254;220 nm; RT1(min): 7.7 to afford (7S)-3-[(3-fluoro-2- methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.6 mg, 18.40%) as a off-white solid. LC-MS: (M+H)+ found: 408.05. 1H NMR (400 MHz, DMSO-d6) δ 13.17 – 13.12 (m, 1H), 8.44 (d, J = 4.7 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.34 (s, 1H), 7.48 (d, J = 4.7 Hz, 1H), 7.39 (s, 1H), 6.72 – 6.62 (m, 1H), 6.59 – 6.50 (m, 1H), 6.00 (d, J = 8.2 Hz, 1H), 4.76 – 4.67 (m, 1H), 3.96 – 3.91 (m, 3H), 3.83 – 3.75 (m, 1H), 3.49 – 3.41 (m, 1H), 1.65 (d, J = 6.5 Hz, 3H). Example 13. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 301)
Figure imgf000325_0001
Into a 40 mL vial were added (7S)-3-amino-2-bromo-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg, 0.816 mmol, 1 equiv) and 3-chloro-2-methoxyphenylboronic acid (228.17 mg, 1.224 mmol, 1.5 equiv) and Cu(OAc)2 (29.64 mg, 0.163 mmol, 0.2 equiv) and Pyridine (32.28 mg, 0.408 mmol, 0.5 equiv) in MeOH (15mL) at room temperature. The resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CHCl3/MeOH 15:1) to afford (7S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 47.66%) as a pink solid. LC-MS: M+H found: 385.00.
Figure imgf000326_0001
Into a vial was placed (7S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.259 mmol, 1 equiv), 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-b]pyridine (203.37 mg, 0.829 mmol, 3.2 equiv), K2CO3 (89.59 mg, 0.647 mmol, 2.5 equiv), Pd(dppf)Cl2*CH2Cl2 (21.12 mg, 0.026 mmol, 0.1 equiv), 1,4-Dioxane (20 mL), and H2O (1 mL). The resulting solution was stirred for 3 h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM/MeOH (12:1) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.5 mg, 30.48%) as a yellow crude solid. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave Length: 254;220 nm; RT1(min): 7.7) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.5 mg, 30.48%) as a off-white solid. LC-MS: (M+H)+ found: 424.00. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.38 – 8.32 (m, 2H), 7.51 – 7.42 (m, 2H), 6.77 – 6.67 (m, 2H), 6.15 (dd, J = 7.3, 2.4 Hz, 1H), 4.76 – 4.67 (m, 1H), 3.91 (s, 3H), 3.83 – 3.75 (m, 1H), 3.44 (ddd, J = 13.0, 6.8, 2.9 Hz, 1H), 1.66 (d, J = 6.5 Hz, 3H). Example 14. 2-[2-(2-aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 314)
Figure imgf000327_0001
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (5 g, 29.476 mmol, 1.00 equiv) in THF (12 mL) was added LDA (3.79 g, 35.371 mmol, 1.20 equiv) dropwise at -78 °C under argon atmosphere. The resulting mixture was stirred for 1 h at -78 °C under argon atmosphere. To the above mixture was added a solution of Iodine (9.35 g, 36.845 mmol, 1.25 equiv) in THF (5.2 mL) dropwise, and the solution was stirred for 2 h at -78 °C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 7- chloro-2-iodothieno[3,2-b]pyridine (5.6 g, 64.29%) as a yellow solid. LC-MS: M+H found: 296.
Figure imgf000327_0002
To a stirred solution of 7-chloro-2-iodothieno[3,2-b]pyridine (1 g, 3.384 mmol, 1 equiv) and tert-butyl N-(2-hydroxyethyl)carbamate (545.48 mg, 3.384 mmol, 1 equiv) in Toluene, were added RockPhos Pd G3 (170.23 mg, 0.203 mmol, 0.06 equiv) and Cs2CO3 (2205.06 mg, 6.768 mmol, 2 equiv). The reaction mixture was stirred at room temperature under nitrogen atmosphere then heated for 2 h at 90 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 1:1) to afford tert-butyl N-[2-({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]carbamate (450 mg, 40.44%) as a red solid. LC-MS: M+H found: 329.
Figure imgf000328_0001
A mixture of bis(pinacolato)diboron (154.46 mg, 0.608 mmol, 2 equiv), tert-butyl N-[2- ({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]carbamate (100 mg, 0.304 mmol, 1.00 equiv) and Pd(dppf)Cl2*CH2Cl2 (24.77 mg, 0.030 mmol, 0.1 equiv) in dioxane was stirred for 16 h at 120°C under N2 atmosphere. LCMS indicated the reaction was complete. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with DCM (10 mL). The resulting mixture was filtered, then the filter cake was washed with DCM (3x3mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with EA (10 mL). The resulting mixture was filtered, the filter cake was washed with EA (3X3mL). The filtrate was concentrated under reduced pressure. The crude product got 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}thieno[3,2-b]pyridin-7- ylboronic acid (300 mg, 291.68%). LC-MS: M+H found: 421.
Figure imgf000329_0001
A solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}thieno[3,2-b]pyridin-7- ylboronic acid (136.51 mg, 0.404 mmol, 1.5 equiv), 2-bromo-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.269 mmol, 1.00 equiv), Pd(dppf)Cl2*CH2Cl2 (21.92 mg, 0.027 mmol, 0.1 equiv) and K2CO3 (74.38 mg, 0.538 mmol, 2 equiv) in dioxone/H2O (0.5mL, 5:1) was stirred for 16 h at 100°C under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MEOH (10:1) to afford tert-butyl N-{2-[(7-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2-b]pyridin-2-yl)oxy]ethyl}carbamate (80 mg, 50.81%) as an off-white solid LC-MS: M+H found: 585.
Figure imgf000329_0002
To a stirred solution/mixture of tert-butyl N-{2-[(7-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2- b]pyridin-2-yl)oxy]ethyl}carbamate (100 mg, 0.171 mmol, 1 equiv) in DCM (1 mL) was added 1,4-dioxane) containing HCl (g) (1 mL). The resulting mixture was stirred for 2 h at room temperature, then concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5­m; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 57% B in 10 min, 57% B; Wave Length: 254/220 nm; RT1(min): 7.37) to afford 2-[2-(2- aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.5 mg, 33.04%) as a white solid. LC-MS: M+H found: 485. 1H NMR (300 MHz, DMSO-d6) δ 8.43 – 8.32 (m, 2H), 7.50 – 7.39 (m, 2H), 6.79 – 6.67 (m, 3H), 6.13 (dd, J = 6.3, 3.3 Hz, 1H), 4.47 (dd, J = 7.1, 5.0 Hz, 2H), 4.21 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.69 (s, 2H), 2.95 (t, J = 5.6 Hz, 2H). Example 15. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[2- (dimethylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 312)
Figure imgf000330_0001
To a stirred solution of 2-[2-(2-aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.165 mmol, 1 equiv) in MeOH were added HCHO (9.91 mg, 0.330 mmol, 2 equiv) and a drop of AcOH. The resulting mixture was stirred for 20 min at room temperature. NaBH3CN (103.67 mg, 1.650 mmol, 10 equiv) was added, anf the resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5­m; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 57% B in 8 min, 57% B; Wave Length: 254 ˗ 220 nm; RT1(min): 7.32) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[2-(dimethylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.1 mg, 38.96%) as a white solid. LC-MS: M+H found: 513. 1H NMR (300 MHz, DMSO-d6) δ 8.43 – 8.29 (m, 2H), 7.50 – 7.39 (m, 2H), 6.73 (t, J = 3.2 Hz, 3H), 6.13 (dd, J = 6.4, 3.2 Hz, 1H), 4.47 (t, J = 6.1 Hz, 2H), 4.34 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.69 (s, 2H), 2.71 (t, J = 5.4 Hz, 2H), 2.24 (s, 6H). Example 16.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[2- (methylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 313)
Figure imgf000331_0001
A solution of tert-butyl N-[2-({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]carbamate (250 mg, 0.760 mmol, 1 equiv) in MeOH was treated with HCHO (45.66 mg, 1.520 mmol, 2 equiv) and a drop of acetic acid for 30 min at RT under nitrogen atmosphere followed by the addition of NaBH3CN (477.80 mg, 7.600 mmol, 10 equiv) added in portions at rt. The reaction was quenched with H2O, and extracted extracted with EA (3x35 mL). The combined organic phase was concentrated to afford tert-butyl N-[2-({7-chlorothieno[3,2- b]pyridin-2-yl}oxy)ethyl]-N-methylcarbamate (230 mg, 88.24%) as a brown solid. LC-MS: M+H found: 343.
Figure imgf000331_0002
A solution of bis(pinacolato)diboron (148.14 mg, 0.584 mmol, 2 equiv), tert-butyl N-[2- ({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]-N-methylcarbamate (100 mg, 0.292 mmol, 1.00 equiv), AcOK (57.25 mg, 0.584 mmol, 2 equiv), and Pd(dppf)Cl2 (21.34 mg, 0.029 mmol, 0.1 equiv) in dioxane was stirred for 16 h at 120°C under N2 atmosphere. The resulting mixture was concentrated under vacuum then redissolved in DCM (10 mL). The resulting mixture was filtered, the filter cake was washed with DCM (3x3mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with EA (10mL). The resulting mixture was filtered, then the filter cake was washed with EA (3X3 mL). The filtrate was concentrated under reduced pressure to afford 2-{2-[(tert- butoxycarbonyl)(methyl)amino]ethoxy}thieno[3,2-b]pyridin-7-ylboronic acid (300 mg, 292.02%) LC-MS: M+H found: 353.
Figure imgf000332_0001
A solution of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.269 mmol, 1 equiv), 2-{2-[(tert- butoxycarbonyl)(methyl)amino]ethoxy}thieno[3,2-b]pyridin-7-ylboronic acid (189.55 mg, 0.538 mmol, 2 equiv) , Pd(dppf)Cl2 (19.69 mg, 0.027 mmol, 0.1 equiv), and K2CO3 (74.38 mg, 0.538 mmol, 2 equiv) in dioxane/H2O (0.5 mL, 5:1) was stirred for 16 h at 100°C under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MEOH (10:1) to afford tert-butyl N-{2-[(7-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2- b]pyridin-2-yl)oxy]ethyl}-N-methylcarbamate (40 mg, 24.81%) as an off-white solid LC-MS: M+H found: 599.
Figure imgf000333_0001
To a stirred solution/mixture of tert-butyl N-{2-[(7-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2- b]pyridin-2-yl)oxy]ethyl}-N-methylcarbamate (200 mg, 0.334 mmol, 1 equiv) in DCM (2.00 mL) was added 2 mL HCl/dioxane . The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 47% B in 8 min, 47% B; Wave Length: 254; 220 nm; RT1(min): 7.02) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[2- (methylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (84.1 mg, 50.49%) as a white solid. LC-MS: M+H found: 499. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J = 16.4, 4.3 Hz, 2H), 7.49 – 7.40 (m, 2H), 6.78 – 6.68 (m, 3H), 6.13 (dd, J = 6.8, 2.8 Hz, 1H), 4.39 (dt, J = 56.5, 5.8 Hz, 4H), 3.91 (s, 3H), 3.69 (s, 2H), 2.95 (t, J = 5.4 Hz, 2H), 2.38 (s, 3H). Example 17. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H-imidazo[4,5- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 336)
Figure imgf000334_0001
To a stirred solution of methyl 4-nitro-2H-pyrazole-3-carboxylate (5.00 g, 29.221 mmol, 1.00 equiv) and tert-butyl N-(2-bromoethyl)carbamate (9.82 g, 43.831 mmol, 1.5 equiv) in DMF (50.00 mL) were added K2CO3 (8.08 g, 58.441 mmol, 2 equiv) and NaI (2.19 g, 14.610 mmol, 0.5 equiv) at rt. The solution was stirred at rt about 16 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (4x50mL). The combined organic phase was concentrated under reduced pressure to afford methyl 2-[2-[(tert- butoxycarbonyl)amino]ethyl]-4-nitropyrazole-3-carboxylate (11.8 g) as a white solid. LC-MS: M+Na found: 337.10.
Figure imgf000334_0002
A solution of methyl 2-[2-[(tert-butoxycarbonyl)amino]ethyl]-4-nitropyrazole-3- carboxylate (6.00 g) 1,4-dioxane/HCl (20.00 mL) and DCM (40.00 mL) was stirred at rt about 2 h. The resulting mixture was extracted with DCM, the combined organic layers were washed with saturation NaHCO3, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the methyl 2-(2- aminoethyl)-4-nitropyrazole-3-carboxylate about 4.2 g as a yellow solid. LC-MS: M+H found: 215.20.
Figure imgf000334_0003
A solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (4.20 g, 19.610 mmol, 1.00 equiv) and K2CO3 (9.49 g, 68.635 mmol, 3.50 equiv) in EtOH (40.00 mL, 688.541 mmol, 35.11 equiv) was stirred at 50 degrees C for about 16 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (4x50mL). The combined organic layers were washed with saturated salt solution (3x30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and get the 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 650 mg as a white solid. LC-MS: M+H found: 183.10.
Figure imgf000335_0001
Into a 100 mL Stand-up flask were added 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (0.6 g) , Pd/C (0.26 g) and EtOH (35.00 mL) at rt. The flask was sealed, purged/evacuated, and then attached to the hydrogen packet. The solution was stirred at rt for 16 h.The resulting mixture was filtered, the filter cake was washed with MeOH.The filtrate was concentrated under reduced pressure to afford 3-amino-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one about 520mg as a white solid. LC-MS: M+H found: 153.10.
Figure imgf000335_0002
To a stirred solution of 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500.00 mg, 3.286 mmol, 1.00 equiv) in MeCN (5.00 mL) were added NBS (643.36 mg, 3.615 mmol, 1.10 equiv) dropwise at 0 degrees C. The solution was stirred at rt about 30 min. The resulting mixture was diluted with water (50 mL) and extracted with EA(4x50mL). The combined organic layers was concentrated under reduced pressure to afford 3-amino-2- bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 370 mg (yield = 49%) as a yellow solid. LC-MS: M+H found: 231.
Figure imgf000336_0001
A mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.00 mg, 0.043 mmol, 1.00 equiv) and 3-chloro-2-methoxyphenylboronic acid (9.68 mg, 0.052 mmol, 1.20 equiv), Cu(OAc)2 (8.65 mg, 0.048 mmol, 1.1 equiv), Et3N (13.14 mg, 0.130 mmol, 3 equiv) in DCE (0.50 mL) was stirred for 12 h at 25 °C under oxygen atmosphere. The residue was dissolved in water (10 mL).The resulting mixture was extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH=15/1) to afford 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5 mg, 29.53%) as a white solid. LC-MS: M+H found: 371.05.
Figure imgf000336_0002
To a stirred solution of 7-bromo-1H,3H-imidazo[4,5-b]pyridin-2-one (325.00 mg, 1.519 mmol, 1.00 equiv) and bis(pinacolato)diboron (771.23 mg, 3.037 mmol, 2.00 equiv) in DMF (4.00 mL, 51.687 mmol, 44.25 equiv) were added KOAc (298.07 mg, 3.037 mmol, 2.00 equiv) and Pd(dppf)Cl2 (222.22 mg, 0.304 mmol, 0.20 equiv) at RT under N2 atmosphere. The solution was stirred at 150 degrees C in a microwave reactor. The resulting mixture was diluted with 5 mL of DMF and filtrated. The residue was purified by reverse flash chromatography with the following conditions: (column, C18 silica gel; mobile phase, ACN in water, 1% to 100% gradient in 10 min; detector, UV 254 nm) to afford 2-oxo-1H,3H-imidazo[4,5-b]pyridin-7-ylboronic acid (138 mg, 66.02%) as a brown solid. LC-MS: M+H found: 180.05.
Figure imgf000337_0001
To a stirred mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.00 mg, 0.108 mmol, 1.00 equiv) and 2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-ylboronic acid (38.52 mg, 0.215 mmol, 2 equiv) in THF (0.40 mL) and H2O (0.10 mL) were added K2CO3 (29.75 mg, 0.216 mmol, 2.00 equiv) and XPhos Pd G3 (18.22 mg, 0.022 mmol, 0.2 equiv) in portions at RT under N2 atmosphere. The resulting mixture was stirred for 16 hours at 80 degrees C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (1x110 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA and MeOH 50:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.8 mg, 8.17%) as a off-white solid. LC-MS: M+H found: 426.2. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 10.46 (s, 1H), 8.30 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J = 5.6 Hz, 1H), 6.74 – 6.68 (m, 2H), 6.13 (p, J = 4.1 Hz, 1H), 4.46 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.68 (q, J = 6.6, 4.8 Hz, 2H). Example 18. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxy-1,7-naphthyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 350)
Figure imgf000337_0002
To a stirred mixture of 6-methoxy-1H-1,7-naphthyridin-4-one (300 mg, 1.703 mmol, 1.00 equiv) and phosphorus oxychloride (3 mL, 19.567 mmol, 11.49 equiv) for 2 hours at 100 degrees C under N2 atmosphere. The reaction was quenched with H2O at 0 degrees C. The aqueous layer was extracted with EA and H2O 3x1150 mL). The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 4-chloro-6-methoxy-1,7-naphthyridine (120 mg, 36.21%) as a light yellow oil. LC-MS: M+H found: 194.95.
Figure imgf000338_0001
To a stirred mixture of 4-chloro-6-methoxy-1,7-naphthyridine (360 mg, 1.850 mmol, 1.00 equiv) and 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (1100.79 mg, 3.700 mmol, 2 equiv) in dioxane (4 mL, 47.216 mmol, 25.53 equiv) and H2O (1 mL, 55.508 mmol, 30.01 equiv) were added Pd(dppf)Cl2*CH2Cl2 (150.69 mg, 0.185 mmol, 0.1 equiv) and K2CO3 (511.29 mg, 3.700 mmol, 2 equiv) in portions at RT. The resulting mixture was stirred for 2 hours at 80 degrees C under N2 atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH= 10:1) to afford 3-chloro-2-(6- methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (320 mg, 52.46%) as a light yellow solid. LC-MS: M+H found: 330.2.
Figure imgf000338_0002
To a stirred mixture of 3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.607 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (114.71 mg, 0.728 mmol, 1.2 equiv) in dioxane (5.00 mL) were added Cs2CO3 (592.87 mg, 1.821 mmol, 3.00 equiv) and EPhos (32.44 mg, 0.061 mmol, 0.10 equiv) and EPhos Pd G4 (55.71 mg, 0.061 mmol, 0.10 equiv) in portions at RT under N2 atmosphere. The resulting mixture was stirred for 16 hours at 50 degrees C under N2 atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (1x1 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]- 2-(6-methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (37.0 mg, 13.57%) as a light yellow solid. LC-MS: M+H found: 451.0. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.9 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.44 (s, 1H), 6.61 (dd, J = 8.1, 1.5 Hz, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.49 (dd, J = 7.1, 5.0 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 3.77 – 3.69 (m, 2H). Example 19. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 359)
Figure imgf000339_0001
To a solution of (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazine-4-one (651.62 mg, 2.092 mmol, 2.5 equiv) and 4-bromo-6-methoxy-1,7-naphthyridine (200 mg, 0.837 mmol, 1.00 equiv) in DMF (10 mL) were added K2CO3 (289.05 mg, 2.092 mmol, 2.5 equiv) and Pd(dppf)Cl2 (61.21 mg, 0.084 mmol, 0.1 equiv). After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (15:1) to afford the (7R)-3-chloro-2-(6-methoxy- 1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg 73.2%) as a brown solid. LC-MS: M+H found: 344.0.
Figure imgf000340_0001
To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs2CO3 (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50ml). The combined organic layers were washed with brine (2x1 20ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=15:1) to afford the crude product (50mg, 78%). The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(8.1mg 99.4%) as a white solid. LC-MS: M+H found: 464.95. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 7.77 – 7.70 (m, 2H), 7.48 (s, 1H), 6.65 – 6.58 (m, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.1 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.96 (s, 3H), 3.77 (t, J = 3.8 Hz, 1H), 3.53 ̢ 3.43 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H). Example 20. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 357)
Figure imgf000341_0001
To a solution of 4-chloro-6-methoxyquinoline (150.00 mg, 0.775 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (965.46 mg, 3.10 mmol, 4.00 equiv) in dioxane (5.00 mL) and H2O (1.00 mL) were added K2CO3 (214.13 mg, 1.550 mmol, 2.00 equiv) and Pd(dppf)Cl2*CH2Cl2 (63.11 mg, 0.078 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)- 3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 43.55%) as a brown solid. LC-MS: M+H found: 343.
Figure imgf000342_0001
To a solution of (7S)-3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.438 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (285.16 mg, 0.876 mmol, 2.00 equiv), E Phos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, developed with DCM:MeOH (15:1) followed by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.85) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (44.4 mg, 21.70%)as a light yellow solid. LC-MS: M+H found: 464. 1H NMR (400 MHz, DMSO-d6):δ 8.70 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.0, 1.5 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.13 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.60 (m, 1H), 3.83 (s, 3H), 3.80 (dd, J = 8.0, 3.9 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.1, 8.5, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 21. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 358)
Figure imgf000343_0001
To a solution of 4-bromo-6-methoxyquinoline (200 mg, 0.840 mmol, 1.00 equiv) and (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (654.33 mg, 2.100 mmol, 2.5 equiv) in DMF (2 mL) were added K2CO3 (290.25 mg, 2.100 mmol, 2.5 equiv) and Pd(dppf)Cl2 (61.47 mg, 0.084 mmol, 0.10 equiv) . After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM: MeOH (15:1) to afford (7R)-3-chloro-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo [1,5-a]pyrazine-4-one(150mg 66.9%) a brown solid. LC-MS: M+H found: 343.0.
Figure imgf000343_0002
To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs2CO3 (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH 15:1) to afford the crude product. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.82) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(15mg 98.2%) as a as a white solid. LC-MS: M+H found: 464.0. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 2.9 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.62 (m, 1H), 3.82 (s, 3H), 3.79 (dd, J = 8.1, 4.1 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.2, 8.4, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 22. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 361)
Figure imgf000344_0001
To a solution of 4-bromo-6,7-dimethoxyquinoline (150.00 mg, 0.559 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (697.26 mg, 2.236 mmol, 4.00 equiv) in dioxane (5.00 mL) and H2O (1.00 mL) were added K2CO3 (154.64 mg, 1.118 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (45.58 mg, 0.056 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)- 3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (150 mg, 68.61%) as a brown solid. LC-MS: M+H found: 373.
Figure imgf000345_0001
To a solution of (7S)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.402 mmol, 1.00 equiv)and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (285.16 mg, 0.876 mmol, 2.00 equiv), EPhos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) and Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 6.60) to afford (7S)- 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (42.8 mg, 21.43%)as a light yellow solid. LC-MS: M+H found: 494. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 4.7 Hz, 1H), 8.37 – 8.32 (m, 1H), 7.86 (s, 1H), 7.47 (d, J = 4.9 Hz, 2H), 7.39 (s, 1H), 6.61 (dd, J = 8.0, 1.5 Hz, 1H), 6.53 (t, J = 8.1 Hz, 1H), 6.11 (dd, J = 8.1, 1.6 Hz, 1H), 4.66 (ddd, J = 8.6, 6.4, 4.4 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.78-3.72 (m, 4H), 3.48 (ddd, J = 13.0, 8.6, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 23. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 360)
Figure imgf000346_0001
To a solution of 4-bromo-6,7-dimethoxyquinoline (300 mg, 1.119 mmol, 1 equiv) and (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (552.28 mg, 2.797 mmol, 2.5 equiv) in DMF (6 mL)were added K2CO3 (386.61 mg, 2.797 mmol, 2.50 equiv) and Pd(dppf)Cl2 (122.81 mg, 0.168 mmol, 0.15 equiv) . After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (20:1) to afford (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (300 mg, 90.8%) as a brown solid. LC-MS: M+H found: 373.00.
Figure imgf000346_0002
To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.805 mmol, 1 equiv),Cs2CO3 (655.47 mg, 2.013 mmol, 2.5 equiv) and 3-chloro-2-methoxyaniline (380.46 mg, 2.414 mmol, 3.00 equiv) in DMF (5 mL) was added EPhos Pd G4 (369.58 mg, 0.403 mmol, 0.5 equiv) and EPhos (215.17 mg, 0.403 mmol, 0.5 equiv) at 50°C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 59% B in 7 min, 59% B; Wave Length: 254/220 nm; RT1(min): 6.42) to afford(7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.3 mg, 98.4%) as a white solid. LC-MS: M+H found: 494.00. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.7 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.49 – 7.41 (m, 2H), 7.37 (s, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.2 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.77 (m, 4H), 3.50 (d, J = 10.5 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 24. (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 368)
Figure imgf000347_0001
Into a 20 mL sealed tube was placed (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv) , EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv) and Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum, and the residue was purified by Prep-TLC with DCM/MeOH (25:1). The semi-pure product was purified further by Prep-HPLC with following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 6.60).This resulted in 67mg of (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (67.8 mg, 33.10%) as a white solid LC-MS: M+H found: 425. 1H NMR (300 MHz, DMSO-d6) δ 9.31 (d, J = 1.4 Hz, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H), 6.78 – 6.68 (m, 1H), 6.66 – 6.57 (m, 1H), 6.05 (d, J = 8.1 Hz, 1H), 4.97 – 4.51 (m, 1H), 3.98 (s, 3H), 3.81 – 3.67 (m, 1H), 3.56 – 3.40 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 25. 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 369)
Figure imgf000348_0001
Into a 20 mL sealed tube was placed (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv), EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) and Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum, and the residue was purified by Prep-TLC with DCM/MeOH (30:1). The semi-pure product was further purified by Prep- -HPLC with following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.95). This resulted in (7R)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (53.6 mg, 26.81%) as a white solid. LC-MS: M+H found: 425. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.42 (s, 1H), 7.68 (d, J = 4.9 Hz, 1H), 7.49 (s, 1H), 6.74 (q, J = 7.8 Hz, 1H), 6.62 (t, J = 9.8 Hz, 1H), 6.05 (d, J = 8.3 Hz, 1H), 4.69 (d, J = 10.2 Hz, 1H), 3.98 (s, 3H), 3.75 (d, J = 13.2 Hz, 1H), 3.54 – 3.43 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 26. 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 298)
Figure imgf000349_0001
To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00 equiv) and benzyl bromide (340.95mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K2CO3 (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 2 h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: (M+H) found: 271.
Figure imgf000349_0002
To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (761.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs2CO3 (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd2(dba)3*CHCl3 (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N2 atmosphere. The resulting mixture was stirred for 16 h at 100°C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H) found: 352.
Figure imgf000350_0001
To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH (200 mL) was added Pd/C (200 mg, 60%) in portions rt under H2 atmosphere. The resulting mixture was stirred for 16h at rt under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x300 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate)( 765.7 mg, 83.72%) as a orange yellow solid. LC-MS: (M+H) found: 262.
Figure imgf000350_0002
To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf2Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040 mmol, 8 equiv) dropwise at rt under N2 atmosphere. The resulting mixture was stirred for 16 h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322 mg, 71.14%) as a light yellow solid. LC-MS: (M+H) found: 394.
Figure imgf000351_0001
To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H2O (1.5 mL) were added Pd2(dba)3*CHCl3 (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy3 (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs2CO3 (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 2 h at 60°C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(130mg, 42.81%) as a light yellow solid. LC-MS: (M+H) found: 415.
Figure imgf000352_0001
To a stirred solution tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl}-1,7-naphthyridin-6-yl)carbamate (62 mg, 0.149 mmol, 1 equiv) and 3-chloro-2- methoxyaniline (42.40 mg, 0.268mmol, 1.8 equiv) in DMF (3 mL) were added EPhos Pd G4 (96.10 mg, 0.104 mmol, 0.7 equiv) and EPhos (55.95 mg, 0.104 mmol, 0.7 equiv) and Cs2CO3(194.78 mg, 0.596 mmol, 4 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 8 h at 60°C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=25:1 ) to afford tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(62.4 mg, 36.85%) as a brown yellow solid. LC-MS: (M+H) found: 536.
Figure imgf000352_0002
A mixture of tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (60 mg, 0.112 mmol, 1 equiv) and TFA (1 mL) in DCM (3 mL) was stirred for 20 min at rt under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 19*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 28% B to 38% B in 8 min, 38% B; Wave Length: 254;220 nm; RT1(min): 6.9) to afford 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(4.1 mg, 8.27%) as a yellow green solid. LC-MS: (M+H)+ found: 436.1. 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 0.9 Hz, 1H), 8.49 (d, J = 4.3 Hz, 1H), 8.45 – 8.31 (m, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J = 0.9 Hz, 1H), 6.68 – 6.48 (m, 2H), 6.15 (s, 2H), 6.08 (dd, J = 7.8, 1.8 Hz, 1H), 4.45 (dd, J = 7.1, 4.9 Hz, 2H), 3.76 (s, 5H). Example 27.2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 317)
Figure imgf000353_0001
To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00equiv) and benzyl bromide (340.95 mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K2CO3 (459.18 mg, 3.322 mmol, 2 equiv) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 2 h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: M+H found: 271.
Figure imgf000353_0002
To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (761.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs2CO3 (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd2(dba)3CHCl3 (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N2 atmosphere. The resulting mixture was stirred for 16 h at 100 °C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 400 ml). The combined organic layers were washed with brine(3x200mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H)+ found: 352.
Figure imgf000354_0001
To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH(200 mL) was added Pd/C (200 mg, 60%) in portions rt under H2 atmosphere. The resulting mixture was stirred for 16 h at rt under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 300 mL), and the filtrate was concentrated under reduced pressure to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate)( 765.7 mg, 83.72%) as a orange yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 262.
Figure imgf000354_0002
To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf2Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040 mmol, 8 equiv) dropwise at rt under N2 atmosphere. The resulting mixture was stirred for 16 h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322mg, 71.14%) as a light yellow solid. LC-MS: (M+H)+ found: 394.
Figure imgf000355_0001
To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H2O (1.5 mL) were added Pd2(dba)3CHCl3 (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy3 (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs2CO3 (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 2 h at 60°C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x200ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (130mg, 42.81%) as a light yellow solid. LC-MS: (M+H)+ found: 415.
Figure imgf000356_0001
To a stirred solution of tert-butyl 2-{6-[(tert-butoxycarbonyl)amino]-1,7-naphthyridin-4- yl}-3-chloro-4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (125 mg, 0.243 mmol, 1 equiv) and 3-fluoro-2-methoxyaniline (102.78 mg, 0.729 mmol, 3 equiv) in DMF (5 mL) were added EPhos Pd G4 (44.59 mg, 0.049 mmol, 0.2 equiv) and EPhos (25.96 mg, 0.049 mmol, 0.2 equiv) and Cs2CO3 (158.17 mg, 0.486 mmol, 2 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 3 h at 60°C under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with DCM (3x100ml). The residue was purified by Prep-TLC (DCM:MeOH 25:1) to afford tert-butyl 2-{6-[(tert- butoxycarbonyl)amino]-1,7-naphthyridin-4-yl}-3-[(3-fluoro-2-methoxyphenyl)amino]- 4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (44 mg, 26.33%) as a light yellow solid. LC-MS: (M+H)+ found: 520.
Figure imgf000356_0002
A mixture of tert-butyl N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (50 mg, 0.096 mmol, 1 equiv) and TFA (2 mL) in DCM (6 mL) was stirred for 20min at rt under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254;220 nm; RT1(min): 7.7) to afford 2-(6-amino-1,7-naphthyridin-4- yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 11.14%) as a yellow green solid. 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 0.9 Hz, 1H), 8.48 (d, J = 4.3 Hz, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 4.3 Hz, 1H), 7.27 (s, 1H), 7.09 (d, J = 1.0 Hz, 1H), 6.53 – 6.35 (m, 2H), 6.16 (s, 2H), 5.93 (dt, J = 8.1, 1.4 Hz, 1H), 4.44 (dd, J = 7.1, 4.9 Hz, 2H), 3.84 – 3.77 (m, 3H), 3.73 (d, J = 7.1 Hz, 2H). Example 28. N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (compound 322)
Figure imgf000357_0001
To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00equiv) and benzyl bromide (340.95 mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K2CO3 (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 2h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: M+H found: 271.
Figure imgf000357_0002
To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (761.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs2CO3 (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd2(dba)3CHCl3 (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N2 atmosphere. The resulting mixture was stirred for 16h at 100 °C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H)+ found: 352.
Figure imgf000358_0001
To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH (200 mL) was added Pd/C (200 mg, 60%)2 in portions rt under H2 atmosphere. The resulting mixture was stirred for 16h at rt under N2 atmosphere .The resulting mixture was filtered, the filter cake was washed with MeOH (3x300 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate) (765.7 mg, 83.72%) as a orange yellow solid. LC-MS: (M+H) found: 262.
Figure imgf000358_0002
To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf2Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040 mmol, 8 equiv) dropwise at rt under N2 atmosphere. The resulting mixture was stirred for 16h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322mg, 71.14%) as a light yellow solid. LC-MS: (M+H)+ found: 394.
Figure imgf000359_0001
To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H2O (1.5 mL) were added Pd2(dba)3CHCl3 (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy3 (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs2CO3 (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 2 h at 60°C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(130 mg, 42.81%) as a light yellow solid. LC-MS: (M+H)+ found: 415.
Figure imgf000360_0001
To a stirred solution of tert-butyl 2-{6-[(tert-butoxycarbonyl)amino]-1,7-naphthyridin-4- yl}-3-chloro-4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (125 mg, 0.243 mmol, 1 equiv) and 3-fluoro-2-methoxyaniline (102.78 mg, 0.729 mmol, 3 equiv) in DMF (5 mL) were added EPhos Pd G4 (44.59 mg, 0.049 mmol, 0.2 equiv) and EPhos (25.96 mg, 0.049 mmol, 0.2 equiv) and Cs2CO3 (158.17 mg, 0.486 mmol, 2 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 3 h at 60°C under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with DCM (3 x 100 mL). The residue was purified by Prep-TLC (DCM:MeOH 25:1) to afford tert-butyl 2-{6-[(tert- butoxycarbonyl)amino]-1,7-naphthyridin-4-yl}-3-[(3-fluoro-2-methoxyphenyl)amino]- 4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (44 mg, 26.33%) as a light yellow solid. LC-MS: (M+H)+ found: 520.
Figure imgf000360_0002
A mixture of tert-butyl N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (44 mg, 0.085 mmol, 1 equiv) and TFA (2 mL) in DCM (6 mL) was stirred for 30 min at rt under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford 2-(6- amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (56 mg, 152.92%) as a light yellow solid. LC-MS: (M+H)+ found: 420.
Figure imgf000361_0001
To a stirred solution of 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (46 mg, 0.110 mmol, 1 equiv) and acryloyl chloride (5.96 mg, 0.066 mmol, 0.6 equiv) in THF (2 mL) were added NaHCO3 (2 mL, 23.808 mmol) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 2 h at 60°C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 51% B in 10 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.5/9.07) to afford N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (9.9 mg, 19.01%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.20 (s, 1H), 9.11 (s, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.28 (s, 1H), 6.66 (dd, J = 17.0, 10.2 Hz, 1H), 6.45 – 6.34 (m, 3H), 5.91 (d, J = 8.0 Hz, 1H), 5.81 (dd, J = 10.1, 2.0 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.74 (d, J = 6.2 Hz, 5H). Example 29. N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (compound 321)
Figure imgf000362_0001
To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00 equiv) and benzyl bromide (340.95 mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K2CO3 (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 2 h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: M+H found: 271.
Figure imgf000362_0002
To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (261.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs2CO3 (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd2(dba)3CHCl3 (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N2 atmosphere. The resulting mixture was stirred for 16 h at 100 °C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H) found: 352.
Figure imgf000363_0001
To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH (200 mL) was added Pd/C (200 mg, 60%) in portions rt under H2 atmosphere. The resulting mixture was stirred for 16h at rt under N2 atmosphere .The resulting mixture was filtered, the filter cake was washed with MeOH (3x300ml). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate)( 765.7 mg, 83.72%) as a orange yellow solid. LC-MS: (M+H)+ found: 262.
Figure imgf000363_0002
To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf2Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040mmol, 8 equiv) dropwise at rt under N2 atmosphere. The resulting mixture was stirred for 16h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 300ml). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322 mg, 71.14%) as a light yellow solid. LC-MS: (M+H)+ found: 394.
Figure imgf000364_0001
To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H2O (1.5 mL) were added Pd2(dba)3CHCl3 (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy3 (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs2CO3 (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 2 h at 60°C under N2 atmosphere. The resulting mixture was 7iltered, the filter cake was washed with DCM (3 x 200mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(130mg, 42.81%) as a light yellow solid. LC-MS: (M+H)+ found: 415.
Figure imgf000364_0002
To a stirred solution tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl}-1,7-naphthyridin-6-yl)carbamate (62 mg, 0.149 mmol, 1 equiv) and 3-chloro-2- methoxyaniline (42.40 mg, 0.268mmol, 1.8 equiv) in DMF (3 mL) were added EPhos Pd G4 (96.10 mg, 0.104 mmol, 0.7 equiv) and EPhos (55.95 mg, 0.104 mmol, 0.7equiv) and Cs2CO3 (194.78 mg, 0.596 mmol, 4 equiv) in portions at 60°C under N2 atmosphere. The resulting mixture was stirred for 8 h at 60°C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x20). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=25:1 ) to afford tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(62.4 mg, 36.85%) as a brown yellow solid. LC-MS: (M+H)+ found: 536.
Figure imgf000365_0001
To a stirred mixture of tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (57 mg, 0.106 mmol, 1 equiv) in DCM (3 mL) were added TFA (1 mL) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 20min at rt under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford 2-(6-amino-1,7- naphthyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (14 mg, 21.93%) as a yellow green solid.. LC-MS: (M+H) found: 436.
Figure imgf000365_0002
To a stirred solution of 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (65 mg, 0.149mmol, 1equiv) and acryloyl chloride (9.45 mg, 0.104 mmol, 0.7 equiv) in THF (2 mL) were added NaHCO3 (2 mL, 23.808 mmol) in portions at rt under N2 atmosphere. The resulting mixture was stirred for 2 h at rt under N2 atmosphere. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 90 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 54% B in 10 min, 54% B; Wave Length: 254/220 nm; RT1(min): 8.65) to afford N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (3 mg, 4.08%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.21 (d, J = 0.9 Hz, 1H), 9.12 (d, J = 0.9 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.40 (s, 1H), 7.79 (d, J = 4.4 Hz, 1H), 7.33 (s, 1H), 6.70 – 6.56 (m, 2H), 6.50 (t, J = 8.1 Hz, 1H), 6.34 (dd, J = 17.0, 2.0 Hz, 1H), 6.08 (dd, J = 8.1, 1.6 Hz, 1H), 5.81 (dd, J = 10.1, 2.0 Hz, 1H), 4.49 (t, J = 6.1 Hz, 2H), 3.78 (d, J = 18.9 Hz, 2H), 3.70 (s, 3H). Example 30. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 279)
Figure imgf000366_0001
To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (6 g, 29.267 mmol, 1.00 equiv) and DIEA (11.35 g, 87.801 mmol, 3 equiv) in DCM (60.00 mL, 943.861 mmol, 32.25 equiv) was added SEM-Cl (6.83 g, 40.974 mmol, 1.4 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (50:1) to afford methyl 5-bromo-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (5.68 g, 57.89%) as a white oil. LCMS: [M+H]+ found: 335.
Figure imgf000367_0001
To a mixture of methyl 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.73 g, 8.143 mmol, 1.00 equiv) and pyridin-4-ylboronic acid (3.00 g, 24.429 mmol, 3 equiv) in dioxane (83 mL, 979.739 mmol, 120.32 equiv) and H2O (8.3 mL, 460.719 mmol, 56.58 equiv) were added K3PO4 (3.46 g, 16.286 mmol, 2 equiv) and Pd(dppf)Cl2*CH2Cl2 (1.33 g, 1.629 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2:1) to afford methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.23 g, 82.13%) as a brown solid. LCMS: [M+H]+ found: 334.
Figure imgf000367_0002
To a stirred mixture of methyl 5-(pyridin-4-yl)-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.2 g, 6.597 mmol, 1.00 equiv)methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.2 g, 6.597 mmol, 1.00 equiv) were added TFA (20 mL, 269.261 mmol, 40.81 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). This resulted in methyl 5-(pyridin-4-yl)-2H-pyrazole-3- carboxylate (1.83 g, 136.51%) as a light yellow solid. The crude product/ resulting mixture was used in the next step directly without further purification. LCMS: [M+H]+ found: 204.
Figure imgf000368_0001
To a stirred mixture of methyl 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.38 g, 6.791 mmol, 1.00 equiv) in CH2Cl2 (15.50 mL, 243.865 mmol, 35.91 equiv) were added NBS (1.21 g, 6.791 mmol, 1.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL). This resulted in methyl 4-bromo- 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 73.08%) as a white solid.The crude product/ resulting mixture was used in the next step directly without further purification. LC-MS: [M+H]+ found: 282.
Figure imgf000368_0002
To a stirred mixture of methyl 4-bromo-5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 4.963 mmol, 1.00 equiv) and 2-bromoacetonitrile (0.71 g, 5.956 mmol, 1.2 equiv) in MeCN (30 mL) were added K2CO3 (1.37 g, 9.926 mmol, 2.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-bromo-2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate as a white solid. LCMS: [M+H]+ found: 321.
Figure imgf000368_0003
A mixture of (HCHO)n (2.10 g, 46.70 mmol, 6 equiv) in dimethylamine (23.35 mL, 2M in THF, 6 equiv) was stirred for 2 h and added to a mixture of methyl 4-bromo-2- (cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (2.5 g, 7.785 mmol, 1.00 equiv) in DMF (25 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min at 100 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL).The residue was purified by silica gel column chromatography, eluted with EtOAc to afford methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4- yl)pyrazole-3-carboxylate (460 mg, 15.62%) as a yellow solid. LCMS: [M+H]+ found: 378.
Figure imgf000369_0001
To a mixture of Methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4- yl)pyrazole-3-carboxylate (200 mg, 0.529 mmol, 1.00 equiv) and CoCl2 (205.97 mg, 1.587 mmol, 3 equiv) in MeOH (10.00 mL, 247.091 mmol, 467.09 equiv) was added NaBH4 (60.02 mg, 1.587 mmol, 3 equiv) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by reverse phase flash with the following conditions to afford 3- bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (90 mg, 48.60%) as a yellow solid. LCMS: [M+H]+ found: 350.
Figure imgf000369_0002
To a mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs2CO3 (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The crude product was purified by Pre-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.0 mg, 6.10%) as a white solid. LCMS: [M+H]+ found: 427. 1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.68 (d, J = 5.2 Hz, 2H), 7.14 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.64 (t, J = 8.1 Hz, 1H), 6.17 (dd, J = 8.1, 1.4 Hz, 1H), 5.86 (s, 1H), 4.64 (s, 1H), 4.05 (s, 3H), 3.98 (s, 2H), 2.94 (dd, J = 35.1, 22.1 Hz, 2H), 2.49 (s, 6H). Example 31. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 280)
Figure imgf000370_0001
To a stirred mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs2CO3 (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The residue/crude product was purified by reverse phase flash with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7- [(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.6 mg) as a white solid. LCMS: [M+H]+ found: 427. 1H NMR (300 MHz, Chloroform-d) δ 8.65 – 8.48 (m, 2H), 7.66 (d, J = 5.8 Hz, 2H), 7.15 (s, 1H), 6.79 (dd, J = 8.1, 1.4 Hz, 1H), 6.61 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.4 Hz, 1H), 6.06 (s, 1H), 4.76 – 4.53 (m, 1H), 4.02 (s, 5H), 3.31 (s, 2H), 2.82 (s, 6H). Example 32. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 283)
Figure imgf000371_0001
A mixture of methyl 2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (2 g, 8.256 mmol, 1 equiv) and tert-butyl 2-bromoacetate (2.42 g, 12.384 mmol, 1.5 equiv) in THF (50 mL) was stirred 0.5 h at 0°C under nitrogen atmosphere, NaH (0.20 g, 8.256 mmol, 1 equiv) was added, The mixture was stirred 2 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (2:1) to afford methyl 2-[3-(tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole-3- carboxylate (1.1 g, 37.38%) as a yellow solid. LC-MS: M+H found: 357.1.
Figure imgf000372_0001
To a mixture of methyl 2-[3-(tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole- 3-carboxylate (1.1 g, 3.087 mmol, 1 equiv) in MeOH (20 mL) was added CoCl2 (1.20 g, 9.261 mmol, 3 equiv) at 0°C . The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere, and NaBH4 (1.17 g, 30.870 mmol, 10 equiv) was added. The reaction mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, the resulting mixture was diluted with NH4Cl (50 mL). The aqueous layer was extracted with EtOAc 50 mL three times. The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /EtOAc (1:1) to afford tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-7-yl]acetate (400 mg, 39.47%) as a yellow solid. LC-MS: (M+H)+ found: 329.0.
Figure imgf000372_0002
To a mixture of tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7- yl]acetate (500 mg, 1.523 mmol, 1 equiv) and KOAc (224.16 mg, 2.284 mmol, 1.5 equiv) in HOAc (10 mL) was added Br2 (267.67 mg, 1.675 mmol, 1.1 equiv) at room temperature. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with H2O (40 mL), and extracted with EtOAc 50 mL three times. The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether /EtOAc (2:1) to afford tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 7-yl]acetate (420 mg, 67.73%) as a yellow solid. LC-MS: (M+H)+ found: 406.9.
Figure imgf000373_0001
A mixture of tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl]acetate (420 mg, 1.031 mmol, 1 equiv), 3-chloro-2-methoxyaniline (243.79 mg, 1.546 mmol, 1.5 equiv), EPhos Pd G4 (94.73 mg, 0.103 mmol, 0.1 equiv), EPhos (55.15 mg, 0.103 mmol, 0.1 equiv) and Cs2CO3 (672.01 mg, 2.062 mmol, 2 equiv) in 1,4-dioxane (10 mL) at room temperature, The mixture was stirred 3 h at 80°C under nitrogen atmosphere. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc 50 mL three times. The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether /EtOAc (1:1) to afford tert-butyl 2-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7- yl}acetate (200 mg, 40.07%) as a yellow solid. LC-MS: (M+H)+ found: 484.0.
Figure imgf000373_0002
To a mixture of tert-butyl 2-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7-yl}acetate (200 mg, 0.413 mmol, 1 equiv) in THF (10 mL) was added CH3MgBr(in 3M Et2O) (1.239 mL, 1.239 mmol, 3 equiv) at 0°C, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. After the reaction was complete, the resulting mixture was concentrated to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-oxopropyl)-2-(pyridin- 4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 68.18%) as a yellow solid. LC-MS: (M+H)+ found: 426.0.
Figure imgf000374_0001
To a mixture of d3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-oxopropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.282 mmol, 1 equiv) in THF (10 mL) was added CH3Li (0.846 mL, 0.846 mmol, 3 equiv) at 0°C. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. After the reaction, the resulting mixture was diluted with NH4Cl (30 mL).The aqueous layer was extracted with EtOAc 40 mL for three times, and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:2) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40 mg, 32.12%) as a yellow solid. LC-MS: (M+H)+ found: 442.3.
Figure imgf000374_0002
3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81) resulted in (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 14.93%) as a white solid. LC-MS: (M+H)+ found: 442.3. 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 2H), 7.82 (s, 2H), 7.24 (s, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 5.95 (s, 1H), 4.76 (s, 1H), 4.37 – 3.39 (m, 5H), 2.95 (s, 1H), 2.46 (d, J = 15.0 Hz, 1H), 2.03 (s, 1H), 1.42 (s, 6H). Example 33. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 284)
Figure imgf000375_0001
3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81) resulted in (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (peak 2, 4.7 mg, 14.99%) as a white solid. LC-MS: (M+H)+ found: 442.3. 1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.79 (s, 2H), 7.24 (s, 1H), 6.83 (dd, J = 8.1, 1.4 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.15 (dd, J = 8.1, 1.4 Hz, 1H), 5.96 (s, 1H), 4.75 (p, J = 6.0 Hz, 1H), 4.06 (s, 3H), 4.02 – 3.89 (m, 1H), 3.79 (ddd, J = 13.0, 7.7, 2.6 Hz, 1H), 3.00 (s, 1H), 2.51 – 2.42 (m, 1H), 2.03 (dd, J = 14.9, 6.3 Hz, 1H), 1.42 (d, J = 1.4 Hz, 6H). Example 34. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(2-methoxypyrimidin-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 311)
Figure imgf000376_0001
To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (1 g, 5.844 mmol, 1.00 equiv) and PPh3 (2299.24 mg, 8.766 mmol, 1.5 equiv) in THF (20 mL) was added DIAD (1418.07 mg, 7.013 mmol, 1.2 equiv) dropwise at 0 degrees C under nitrogen atmosphere.The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was concentrated under vacuum, and methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3-carboxylate (2 g, crude) as a yellow solid was obtained. LC-MS: (M+H)+ found: 315.
Figure imgf000376_0002
A mixture of methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3- carboxylate (1 g, 3.182 mmol, 1 equiv) and HCl(gas)in 1,4-dioxane (5 mL, 164.564 mmol, 51.72 equiv) in DCM (10 mL) stirred 1 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. After the reaction, the resulting mixture was concentrated under vacuum, and methyl 2-(2-aminoethyl)-4- nitropyrazole-3-carboxylate (700 mg, 102.72%) as a yellow solid was obtained. LC-MS: (M+H)+ found: 215.
Figure imgf000377_0001
A mixture of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (1 g, 4.669 mmol, 1.00 equiv) and Et3N (708.68 mg, 7.003 mmol, 1.50 equiv) in Toluene (10 mL) was stirred for 1h at 100 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL). The solid was concentrated under reduced pressure to afford 3-nitro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (240 mg, 28.22%) as a brown solid. LC-MS: (M+H)+ found: 183.
Figure imgf000377_0002
To a solution of 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1 g, 5.490 mmol, 1.00 equiv) in EtOH (20 mL) was added Pd/C (116.86 mg, 1.098 mmol, 0.2 equiv) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 3h, filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was filtered, the filter cake was washed with EtOH (2 x 20 mL). The filtrate was concentrated under reduced pressure to afford 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (650 mg, 77.81%) as a off-white solid. LC-MS: (M+H)+ found: 153.
Figure imgf000377_0003
To a stirred solution of 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 3.286 mmol, 1.00 equiv) in DMF (10 mL) was added NBS (701.84 mg, 3.943 mmol, 1.20 equiv) in portions at -35°C under nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford 3-amino-2-bromo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (320 mg, 42.15%) as a white solid. LC-MS: (M+H)+ found: 231.
Figure imgf000378_0001
To a stirred mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10 g, 43.280 mmol, 1 equiv.) and 1-chloro-3-iodo-2-methoxybenzene (17.43 g, 64.920 mmol, 1.5 equiv.) in toluene (100 mL) were added Xantphos (5.01 g, 8.656 mmol, 0.2 equiv.) and tert-butoxysodium (4.16 g, 43.280 mmol, 1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10 g, 62.17%) as a grey solid. LC-MS: M+H found: 373.0.
Figure imgf000379_0001
To a stirred mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.6 g, 9.687 mmol, 1 equiv.) and hexamethyldistannane (12.70 g, 38.748 mmol, 4 equiv.) in toluene (50 mL) was added Pd(PPh3)4 (2.24 g, 1.937 mmol, 0.2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 140°C. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro- 2-methoxyphenyl)amino]-2-(trimethylstannyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.5 g, 33.99%) as a white solid. LC-MS: M+H found: 457.25.
Figure imgf000379_0002
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv) and N-(4- bromopyridin-2-yl)-2-methoxypyrimidin-4-amine (135.76 mg, 0.483 mmol, 1.1 equiv) in DMF (5 mL) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv), XPhos (20.93 mg, 0.044 mmol, 0.1 equiv) and ZnCl2 (119.70 mg, 0.878 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 9 min, 50% B; Wave Length: 254/220 nm; RT1(min): 7.17) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(2-methoxypyrimidin-4-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.8 mg, 1.74%) as a white solid. LC-MS: (M+H)+ found: 493. 1H NMR (400 MHz, Chloroform-d) δ 8.24 – 8.18 (m, 2H), 8.08 (s, 1H), 7.35 (dd, J = 5.4, 1.5 Hz, 1H), 7.13 (s, 1H), 7.03 (d, J = 5.5 Hz, 1H), 6.78 (dd, J = 8.1, 1.4 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.22 (dd, J = 8.1, 1.5 Hz, 1H), 6.00 (s, 1H), 4.46 (t, J = 6.0 Hz, 2H), 4.02 (d, J = 2.5 Hz, 6H), 3.89 – 3.81 (m, 2H). Example 35. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6-methoxypyrimidin-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 310)
Figure imgf000380_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv) and N-(4- bromopyridin-2-yl)-6-methoxypyrimidin-4-amine (135.76 mg, 0.483 mmol, 1.1 equiv) in DMF (5 mL) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv), XPhos (20.93 mg, 0.044 mmol, 0.1 equiv) and ZnCl2 (119.70 mg, 0.878 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 72% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(6-methoxypyrimidin-4-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (39.1 mg, 17.92%) as a white solid. LC-MS: (M+H)+ found: 493. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.29 (dd, J = 4.0, 1.8 Hz, 2H), 8.23 (dd, J = 5.4, 0.7 Hz, 1H), 8.03 (t, J = 1.1 Hz, 1H), 7.33 – 7.26 (m, 2H), 7.21 (d, J = 1.0 Hz, 1H), 6.79 – 6.68 (m, 2H), 6.17 (dd, J = 7.3, 2.3 Hz, 1H), 4.41 (dd, J = 7.1, 5.0 Hz, 2H), 3.87 (d, J = 9.6 Hz, 6H), 3.66 (dq, J = 7.8, 4.6, 3.6 Hz, 2H). Example 36. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(4-methoxypyrimidin-2- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 309)
Figure imgf000381_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv) and N-(4- bromopyridin-2-yl)-4-methoxypyrimidin-2-amine (135.76 mg, 0.483 mmol, 1.1 equiv) in DMF (5 mL, 68.404 mmol) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv), XPhos (20.93 mg, 0.044 mmol, 0.1 equiv) and ZnCl2 (119.70 mg, 0.878 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by filtration to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(4-methoxypyrimidin-2-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (58.6 mg, 24.56%) as a white solid. LC-MS: (M+H)+ found: 493. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.91 – 8.85 (m, 1H), 8.29 (t, J = 2.8 Hz, 1H), 8.22 (dd, J = 5.2, 0.8 Hz, 1H), 8.20 – 8.10 (m, 1H), 7.33 – 7.25 (m, 2H), 6.79 – 6.66 (m, 2H), 6.37 (d, J = 5.7 Hz, 1H), 6.17 (dd, J = 7.6, 2.0 Hz, 1H), 4.39 (dd, J = 7.1, 5.0 Hz, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.66 (dq, J = 7.7, 4.3, 3.5 Hz, 2H). Example 37. (R)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 288)
Figure imgf000382_0001
To a stirred mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv) in MeCN (100 mL) was added NCS (6.51 g, 48.778 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid. LC-MS: (M+H)+ found: 239.00.
Figure imgf000382_0002
To a stirred mixture of methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate (11.4 g, 47.609 mmol, 1.00 equiv) in MeOH (100 mL) was added NaOH (20 mL, 500.036 mmol, 10.50 equiv) at room temperature. The resulting mixture was stirred for overnight at 60 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid as an off-white solid. LC-MS: M+H found: 225.00.
Figure imgf000383_0002
To a stirred mixture of 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid (10 g, 44.360 mmol, 1.00 equiv) and oxalyl chloride (11.26 g, 88.720 mmol, 2 equiv) in DCM (100 mL) was added DMF (2 mL, 25.844 mmol, 0.58 equiv) dropwise at room temperature. The resulting mixture was stirred for 0.6 h at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under vacuum. To the above mixture was added Et3N (13.47 g, 133.080 mmol, 3 equiv) and 1,1,1-trifluoro-3-{[(4- methoxyphenyl)methyl]amino}propan-2-ol (11.06 g, 44.360 mmol, 1 equiv) in DCM (100 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3-trifluoro-2- hydroxypropyl)-2H-pyrazole-3-carboxamide as a yellow solid. LC-MS: M+H found: 456.00.
Figure imgf000383_0001
To a stirred mixture of 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3- trifluoro-2-hydroxypropyl)-2H-pyrazole-3-carboxamide (6 g, 13.139 mmol, 1.00 equiv) and Et3N (3.99 g, 39.417 mmol, 3 equiv) in DCM (100 mL) was added TsCl (5.01 g, 26.278 mmol, 2 equiv) in DCM (20 mL) dropwise at 0 degree C .The resulting mixture was stirred for 0.5 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (300 mL) at room temperature. The aqueous layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (100 mL). To the above mixture was added K2CO3 (5.45 g, 39.417 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 100 degree C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 2-bromo-3-chloro- 5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 438.00.
Figure imgf000384_0001
The 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.5 g) was dissolved in trifluoroacetaldehyde (20 mL).The resulting mixture was stirred for 3 h at 60°C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified/basified/neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc to afford 2-bromo-3-chloro-7- (trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one) as a yellow solid. LC-MS: M+H found: 318.00.
Figure imgf000385_0001
To a stirred mixture of 2-bromo-3-chloro-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (1.7 g, 5.338 mmol, 1.00 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isothiazolo[4,5-b]pyridine (1.44 g, 10.676 mmol, 2 equiv) in dioxane (10 mL) and H2O (2 mL) were added Na2CO3 (1.13 g, 10.676 mmol, 2 equiv) and XPhos Pd G3 (0.90 g, 1.068 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120°C under nitrogen atmosphere.The resulting mixture was extracted with CH2Cl2 (3 x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:3) to afford 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 374.00.
Figure imgf000385_0002
To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (490 mg, 1.311 mmol, 1.00 equiv) and 3-fluoro- 2-methoxyaniline (222.06 mg, 1.573 mmol, 1.2 equiv) in dioxane (10 mL) were added Cs2CO3 (854.35 mg, 2.622 mmol, 2 equiv) and EPhos Pd G4 (120.43 mg, 0.131 mmol, 0.1 equiv) and EPhos (70.12 mg, 0.131 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 60 degree C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 mg) was purified by Prep- HPLC with the following conditions(Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 8 min, 63% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 479.00.
Figure imgf000386_0001
The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38) to give 8.0 mg of (R)-3-((3-fluoro-2- methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (peak 1) as a white solid. LC-MS: M+H found: 479.00. 1H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 5.1 Hz, 1H), 7.28 (s, 1H), 6.69 – 6.60 (m, 2H), 6.01 (t, J = 4.6 Hz, 1H), 5.89 (d, J = 4.6 Hz, 1H), 5.24 – 5.16 (m, 1H), 4.32 – 4.23 (m, 1H), 4.13 (m, J = 1.7 Hz, 4H). Example 38. (S)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 289)
Figure imgf000387_0001
The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38) to afford 10.6 mg of (S)-3-((3-fluoro-2- methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one(peak 2) as a white solid. LC-MS: M+H found: 479.00. 1H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.23 (s, 1H), 6.66 – 6.57 (m, 2H), 6.09 – 5.98 (m, 2H), 5.18 (m, J = 6.0 Hz, 1H), 4.25 (m, J = 14.2, 5.1 Hz, 1H), 4.17 – 4.03 (m, 4H). Example 39. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 292)
Figure imgf000387_0002
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.198 mmol, 1.00 equiv.) and 4-bromo- N-(1-methyl-1,2,3-triazol-4-yl)pyridin-2-amine (55.22 mg, 0.218 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (16.72 mg, 0.020 mmol, 0.1 equiv.), XPhos (9.42 mg, 0.020 mmol, 0.1 equiv.) and ZnCl2 (53.86 mg, 0.396 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 7 min, 47% B; Wave Length: 254 nm; RT1(min): 6.98) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.4 mg, 36.18%) as a white solid. LC-MS: (M+H)+ found: 465.90. 1H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.28 (s, 1H), 8.08 (d, J = 4.5 Hz, 2H), 7.30 (d, J = 14.3 Hz, 2H), 7.06 (d, J = 5.9 Hz, 1H), 6.73 (q, J = 5.3, 4.8 Hz, 2H), 6.15 (dd, J = 6.7, 2.9 Hz, 1H), 4.39 (t, J = 5.9 Hz, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.66 (d, J = 6.8 Hz, 2H). Example 40.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-thiazol-5- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 307)
Figure imgf000388_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.198 mmol, 1 equiv.) and 4-bromo-N- (3-methyl-1,2-thiazol-5-yl)pyridin-2-amine (58.71 mg, 0.218 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (16.72 mg, 0.020 mmol, 0.1 equiv.) XPhos (9.42 mg, 0.020 mmol, 0.1 equiv.) and ZnCl2 (53.86 mg, 0.396 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 47% B in 10 min, 47% B; Wave Length: 254 nm; RT1(min): 9.72) to afford 3- [(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-thiazol-5-yl)amino]pyridin-4- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (25.1 mg, 26.31%) as a yellow solid. LC-MS: (M+H)+ found: 481.90. 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.35 – 8.16 (m, 2H), 7.34 (d, J = 9.5 Hz, 2H), 7.23 (d, J = 5.6 Hz, 1H), 6.74 (q, J = 5.2, 4.6 Hz, 2H), 6.54 (s, 1H), 6.17 (dd, J = 6.6, 3.0 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.67 (d, J = 7.1 Hz, 2H), 2.26 (s, 3H). Example 41.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylimidazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 293)
Figure imgf000389_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.198 mmol, 1.00 equiv.) and 4-bromo- N-(1-methylimidazol-4-yl)pyridin-2-amine (55.01 mg, 0.218 mmol, 1.1 equiv.) in DMF (2 mL) were added Xphos Pd G3 (16.72 mg, 0.020 mmol, 0.1 equiv.) and ZnCl2 (53.86 mg, 0.396 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: Xcelect CSH F-pheny OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.05%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 30% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylimidazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.5 mg, 3.80%) as a yellow solid. LC-MS: (M+H)+ found: 465.25 1H NMR (300 MHz, Chloroform-d) δ 8.91 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.16 (d, J = 5.8 Hz, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 6.67 (t, J = 8.1 Hz, 1H), 6.20 (dd, J = 8.1, 1.5 Hz, 1H), 5.98 (s, 1H), 4.44 (t, J = 6.0 Hz, 2H), 4.03 (s, 3H), 3.82 (s, 2H), 3.65 (s, 3H). Example 42.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-oxazol-5- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 306)
Figure imgf000390_0001
To a mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.220 mmol, 1 equiv.) and 4-bromo-N-(3-methyl- 1,2-oxazol-5-yl)pyridin-2-amine (61.36 mg, 0.242 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (18.58 mg, 0.022 mmol, 0.1 equiv.) and ZnCl2 (59.85 mg, 0.440 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 10 min, 65% B; Wave Length: 220/254 nm; RT1(min): 10.13) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-oxazol-5- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (9.9 mg, 9.41%) as a yellow solid. LC-MS: (M+H)+ found: 466.25. 1H NMR (300 MHz, Chloroform-d) δ 8.32 (d, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.20 – 7.13 (m, 2H), 7.02 (t, J = 8.1 Hz, 1H), 6.94 – 6.86 (m, 2H), 5.98 (s, 1H), 4.51 (dd, J = 7.0, 4.6 Hz, 2H), 4.26 (dd, J = 7.0, 4.6 Hz, 2H), 3.92 (s, 3H), 2.28 (s, 3H). Example 43. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylpyrazol-3- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 305)
Figure imgf000391_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.220 mmol, 1 equiv.) and 4-bromo- N-(1-methylpyrazol-3-yl)pyridin-2-amine (61.12 mg, 0.242 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (18.58 mg, 0.022 mmol, 0.1 equiv.) and ZnCl2 (59.85 mg, 0.440 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.05%TEA), Mobile Phase B: MeOH--HPLC; Flow rate: 25 mL/min; Gradient: 36% B to 56% B in 7 min, 56% B; Wave Length: 254/220 nm; RT1(min): 10.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylpyrazol-3- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (24.3 mg, 23.69%) as a white solid. LC-MS: (M+H)+ found: 465.25. 1H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.50 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.05 (s, 1H), 6.78 (dd, J = 8.1, 1.5 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.22 (dd, J = 8.1, 1.5 Hz, 1H), 5.91 (s, 1H), 5.74 (s, 1H), 4.48 – 4.40 (m, 2H), 3.99 (s, 3H), 3.85 – 3.79 (m, 2H), 3.77 (s, 3H). Example 44.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(2-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 294)
Figure imgf000392_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.329 mmol, 1 equiv.) and 4-bromo- N-(2-methyl-1,2,3-triazol-4-yl)pyridin-2-amine (100.40 mg, 0.395 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (27.87 mg, 0.033 mmol, 0.1 equiv.), XPhos (15.70 mg, 0.033 mmol, 0.1 equiv.) and ZnCl2 (89.77 mg, 0.658 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14% B to 38% B in 8 min, 38% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(2-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (16.1 mg, 10.46%) as a light yellow solid. LC-MS: (M+H)+ found: 465.95. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.96 – 7.87 (m, 2H), 7.42 (dd, J = 6.1, 1.5 Hz, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 6.78 (dd, J = 8.1, 1.5 Hz, 1H), 6.68 (t, J = 8.1 Hz, 1H), 6.16 (s, 1H), 6.15 (dd, J = 8.1, 1.5 Hz, 1H), 4.52 – 4.44 (m, 2H), 4.05 (d, J = 14.0 Hz, 6H), 3.86 (dd, J = 12.0, 2.8 Hz, 2H). Example 45.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(4-methoxy-1-methylpyrazol- 3-yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 300)
Figure imgf000393_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv.) and 4-bromo-N- (4-methoxy-1-methylpyrazol-3-yl)pyridin-2-amine (149.17 mg, 0.527 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv.) and ZnCl2 (119.70 mg, 0.878 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 49% B in 10 min, 49% B; Wave Length: 254/220 nm; RT1(min): 9.25) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(4-methoxy-1-methylpyrazol-3-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (44 mg, 19.72%) as a off-white solid. LC-MS: (M+H)+ found: 494.95. 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.33 (s, 1H), 7.14 (dd, J = 8.1, 1.5 Hz, 1H), 7.00 (t, J = 8.1 Hz, 1H), 6.91 – 6.82 (m, 2H), 6.60 (s, 1H), 6.37 (d, J = 1.9 Hz, 1H), 4.48 – 4.40 (m, 2H), 4.17 – 4.09 (m, 2H), 3.90 (s, 3H), 3.76 (d, J = 15.9 Hz, 6H). Example 46.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6-methylpyridin-2- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 308)
Figure imgf000394_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.329 mmol, 1 equiv.) and 4-bromo-N- (6-methylpyridin-2-yl)pyridin-2-amine (104.37 mg, 0.395 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (27.87 mg, 0.033 mmol, 0.1 equiv.) and ZnCl2 (89.77 mg, 0.658 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6- methylpyridin-2-yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.0 mg, 16.92%) as a white solid. LC-MS: (M+H)+ found: 468.90. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.45 (d, J = 5.8 Hz, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.36 – 7.29 (m, 2H), 7.18 (dd, J = 5.9, 1.9 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 6.92 (dd, J = 8.1, 1.3 Hz, 1H), 4.52 (dd, J = 7.1, 4.5 Hz, 2H), 4.33 (dd, J = 7.0, 4.7 Hz, 2H), 3.82 (s, 3H). Example 47. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6-methylpyridin-2- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 304)
Figure imgf000395_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.329 mmol, 1 equiv.) and 4-bromo-N- (6-methylpyridin-2-yl)pyridin-2-amine (104.37 mg, 0.395 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (27.87 mg, 0.033 mmol, 0.1 equiv.) and ZnCl2 (89.77 mg, 0.658 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6- methylpyridin-2-yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.0 mg, 16.92%) as a white solid. LC-MS: (M+H)+ found: 476.00 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.28 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J = 5.3 Hz, 1H), 6.73 (q, J = 7.8 Hz, 3H), 6.17 (dd, J = 7.3, 2.4 Hz, 1H), 4.40 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 2H), 2.34 (s, 3H). Example 48. (6S)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 278)
Figure imgf000396_0001
To a stirred solution of (6S)-3-amino-2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (800 mg, 3.264 mmol, 1 equiv) 1-chloro-3-iodo-2-methoxybenzene (1.31 g, 4.896 mmol, 1.5 equiv) and t-BuONa (627.41 mg, 6.528 mmol, 2 equiv) in Toluene (30 mL) were added XantPhos (377.75 mg, 0.653 mmol, 0.2 equiv) and Pd2(dba)3 (597.83 mg, 0.653 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (6S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-6- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.2 g, 95.32%) as a light yellow solid. LC-MS: (M+H)+ found: 384.90.
Figure imgf000396_0002
To a stirred solution of (6S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.778 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2]thiazolo[4,5-b]pyridine (305.87 mg, 1.167 mmol, 1.5 equiv) in dioxane (10 mL) and H2O (2 mL) were added Cs2CO3 (506.92 mg, 1.556 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst (61.21 mg, 0.078 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (132 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 39% B to 57% B in 8 min, 57% B; Wave Length: 254/220 nm; RT1(min): 8) to afford (6S)-3-[(3-chloro-2-methoxyphenyl)amino]-6- methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (68.3 mg, 19.91%) as a yellow solid. LC-MS: (M+H)+ found: 440.90. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.54 (s, 1H), 6.84 – 6.71 (m, 2H), 6.20 (dd, J = 7.4, 2.2 Hz, 1H), 4.65 (dd, J = 12.8, 4.3 Hz, 1H), 4.28 – 4.20 (m, 1H), 4.14 – 4.06 (m, 1H), 3.94 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H). Example 49. (6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 277)
Figure imgf000397_0001
To a stirred solution of (6R)-3-amino-2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (480 mg, 1.959 mmol, 1.00 equiv) 1-chloro-3-iodo-2-methoxybenzene (788.74 mg, 2.939 mmol, 1.5 equiv) and t-BuONa (376.45 mg, 3.918 mmol, 2 equiv) in Toluene (15 mL) were added XantPhos (226.65 mg, 0.392 mmol, 0.2 equiv) and Pd2(dba)3 (358.70 mg, 0.392 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (6R)-2-bromo-3-[(3-chloro-2- methoxyphenyl)amino]-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (720 mg, 95.32%) as a light yellow solid. LC-MS: (M+H)+ found: 384.90.
Figure imgf000398_0001
To a stirred solution of (6R)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.778 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2]thiazolo[4,5-b]pyridine (305.87 mg, 1.167 mmol, 1.5 equiv) in dioxane (10 mL) and H2O (2 mL) were added Cs2CO3 (506.92 mg, 1.556 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst/ (122.41 mg, 0.156 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (225mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 71% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford (6R)-3-[(3-chloro-2- methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (91.9 mg, 26.79%) as a yellow solid. LC-MS: (M+H)+ found: 440.95. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.54 (s, 1H), 6.80 – 6.74 (m, 2H), 6.20 (dd, J = 7.4, 2.2 Hz, 1H), 4.65 (dd, J = 12.8, 4.3 Hz, 1H), 4.24 (dd, J = 12.9, 9.4 Hz, 1H), 4.11 (d, J = 9.4 Hz, 1H), 3.94 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H). Example 50.3-((3-chloro-2-methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 291)
Figure imgf000399_0001
A mixture of (3-chloro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)boronic acid (1.80 g, 8.37 mmol, 1.00 equiv), 4-bromo-2-fluoropyridine (1.46 g, 8.37 mmol, 1.00 equiv), K3PO4 (5.37 g, 25.1 mmol, 3.00 equiv), Pd(dppf)Cl2 (0.67 g, 0.83 mmol, 0.1 equiv) and water (1 mL) in 1,4-dioxane (10 mL) was stirred for 12 h at 100 degrees C. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (4:1) to afford 3-chloro-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.9 g, 36%) as yellow oil. LC-MS: M+H found: 267.0.
Figure imgf000400_0001
To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (900.00 mg, 3.36 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (689 mg, 4.36 mmol, 1.3 equiv), and Cs2CO3 (2.18 g, 6.72 mmol, 2.00 equiv) in 1,4- dioxane(10.00 mL) were added EPhos (387 mg, 0.67 mmol, 0.20 equiv) and EPhos Pd G4 (300 mg, 0.33 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc /Petroleum ether 1:3) to afford 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (400 mg, 31%) as a yellow solid. LC-MS: (M+H)+ found: 388.
Figure imgf000400_0002
To a stirred solution of 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100.00 mg, 0.26 mmol, 1.00 equiv), 1- methyl-1H-pyrazol-4-amine (38 mg, 0.39 mmol, 1.5 equiv) in 1,4-dioxane(1.00 mL) was added 3N HCl (0.1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 110 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-((3-chloro-2- methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (20.7 mg, 17%) as a white solid. LC-MS: (M+H)+ found: 465. 1H NMR (400 MHz, DMSO-d6) δ 8.79 – 8.66 (m, 1H), 8.34 – 8.21 (m, 1H), 8.11 – 7.98 (m, 1H), 7.82 – 7.73 (m, 1H), 7.33 – 7.24 (m, 2H), 7.11 – 7.04 (m, 1H), 7.01 – 6.97 (m, 1H), 6.83 – 6.71 (m, 2H), 6.22 – 6.11 (m, 1H), 4.45 – 4.34 (m, 2H), 3.93 – 3.85 (m, 3H), 3.81 – 3.73 (m, 3H), 3.71 – 3.62 (m, 2H). Example 51. N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (compound 337)
Figure imgf000401_0001
To a stirring solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazine-4-on (60 mg, 0.16 mmol, 1.00 equiv) in pyridine were added Ac2O (33 mg, 0.33 mmol, 2.00 equiv) in 0.5 ml DCM dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen. The crude product (70 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13% B to 43% B in 7 min, 43% B; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (13.2 mg, 18.38%) as white solid. LC-MS: (M+H)+ found: 411.05. 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.14 (s, 1H), 8.36 (t, 1H), 8.24 (d, 1H), 7.55 (d, 1H), 7.33 (s, 1H), 6.64-6.47 (m, 2H), 6.07 (d, 1H), 4.44 (t, 2H), 3.89 (s, 3H), 3.69 (t, 2H), 2.34 (s, 3H). Example 52.3-((3-chloro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one-6,6,7,7-d4 (compound 276)
Figure imgf000402_0001
To a stirred solution of glycine-2,2-d2 (2.0 g, 25.95 mmol, 1.00 equiv) in MeOH (100.00 mL) was added acetyl chloride (3.46 g, 44.11 mmol, 1.70 equiv) dropwise at 0 °C. The mixture was stirred for 1 h at 68°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 91.95.
Figure imgf000402_0002
To a stirred solution of methyl glycinate-2,2-d2 (2.30 g, 25.24 mmol, 1.00 equiv) in THF (80.00 mL) was added LiAlD4 (2.12 g, 50.49 mmol, 2.00 equiv) dropwise at 0°C. The mixture was stirred for overnight from 0°C to room temperature under argon atmosphere. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (20 mL) at 0°C and stirred for 10 min at room temperature. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 66.25.
Figure imgf000403_0001
To a stirred solution of 2-aminoethan-1,1,2,2-d4-1-ol (1.9 g, 29.18 mmol, 1.00 equiv) in THF (100 mL) was added di-tert-butyl dicarbonate (6.37 g, 29.18 mmol, 1.00 equiv) at room temperature and stirred for 10min. Na2CO3 (sat.) was added to adjust PH to 10. The mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS and TLC. The aqueous layer was extracted with CH2Cl2 (3x20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0:100) to afford tert-butyl (2- hydroxyethyl-1,1,2,2-d4)carbamate (2.7 g, 56.00%) as a colorless oil. LC-MS: (M+H+Na)+ found: 188.05. 1H NMR (400 MHz, CDCl3): δ 5.05 (s, 1H), 2.72 (s, 1H), 1.46 (d, 1H).
Figure imgf000403_0002
To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (1.0 g, 4.88 mmol, 1.00 equiv) in THF (50.00 mL) was added PPh3 (1.92 g, 7.32 mmol, 1.50 equiv) and tert- butyl (2-hydroxyethyl-1,1,2,2-d4)carbamate (0.81 g, 4.88 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 30min at 0°C under argon atmosphere. DIAD (1.48 g, 7.32 mmol, 1.50 equiv) was added in portions at 0°C. The mixture was stirred for overnight from 0°C to room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford methyl 5-bromo- 2-{2-[(tert-butoxycarbonyl)amino](1,1,2,2-d4)ethyl}pyrazole-3-carboxylate (1.9 g, 95.11%) as a colorless oil. LC-MS: (M+H-56)+ found: 298.1.
Figure imgf000404_0001
To a stirred solution of methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino](1,1,2,2- 2H4)ethyl}pyrazole-3-carboxylate (1.8 g, 5.11 mmol, 1.00 equiv) in DCM (5.00 mL) was added HCl(gas) (4M in 1,4-dioxane, 15.00 mL) in portions at 0°C. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 252.1.
Figure imgf000404_0002
To a stirred solution of MeONa (1.37 g, 25.38 mmol, 5.00 equiv) in MeOH (20.00 mL) was added methyl 2-[2-amino(1,1,2,2-2H4)ethyl]-5-bromopyrazole-3-carboxylate (1.28 g, 5.08mmol, 1.00 equiv) dropwise at 0°C. The mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (98:2) to afford 2- bromo(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 89.50%) as a white solid. LC-MS: (M+H)+ found: 220.1.
Figure imgf000405_0001
To a stirred solution of 2-bromo(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 4.54 mmol, 1.00 equiv) in DMF (20.00 mL) was added NCS (607 mg, 4.54 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 0.5 h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with Na2SO3 (aq.) (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (97:3) to afford 2-bromo-3- chloro(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 86.47%) as a white solid. LC-MS: (M+H)+ found: 254.1.
Figure imgf000405_0002
To a stirred solution of 2-bromo-3-chloro(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 3.93 mmol, 1.00 equiv) in 1,4-dioxane (15.00 mL) was added Pd(dppf)Cl2CH2Cl2 (320 mg, 0.39 mmol, 0.10 equiv), KOAc (1.16 g, 11.79 mmol, 3.00 equiv) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1,3,2-dioxaborolane (2.01 g, 7.86 mmol, 2.00 equiv) at room temperature. The mixture was stirred for overnight at 100 °C under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with DCM (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate (5 mL) then purified by silica gel column chromatography, eluting with PE/EA (0:100) to afford 3-chloro-4-oxo(6,6,7,7-2H4)-5H-pyrazolo[1,5- a]pyrazin-2-ylboronic acid (700 mg, 81.19%) as a white solid. LC-MS: (M+H)+ found: 220.2.
Figure imgf000406_0001
To a stirred solution of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (460 mg, 2.70 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added Na2CO3 (857 mg, 8.09 mmol, 3.00 equiv) in H2O (2.00 mL), Xphos Pd G2 (212 mg, 0.27 mmol, 0.10 equiv) and 3-chloro-4-oxo(6,6,7,7-2H4)-5H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (710 mg, 3.23 mmol, 1.20 equiv) at room temperature. The mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with MeCN (3 x 3 mL) and H2O (3 x 3 mL). Then the filter cake was washed with MeCN (2 x 2 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}(6,6,7,7-2H4)-5H- pyrazolo[1,5-a]pyrazin-4-one (700 mg, 83.81%) as a yellow solid. LC-MS: (M+H)+ found: 309.90.
Figure imgf000406_0002
To a stirred solution of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}(6,6,7,7-2H4)-5H- pyrazolo[1,5-a]pyrazin-4-one (460 mg, 1.49 mmol, 1.00 equiv) in DMF (7.00 mL) was added Cs2CO3 (968 mg, 2.97 mmol, 2.00 equiv), 3-chloro-2-methoxyaniline (234 mg, 1.49 mmol, 1.00 equiv) and EPhos Pd G4 (245 mg, 0.28 mmol, 0.20 equiv), the mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (94:6) to afford crude product, The crude product (400 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.05% TEA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 62% B in 7 min, 62% B; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-((3-chloro- 2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one-6,6,7,7-d4 (191.8 mg, 29.40%) as a light yellow solid. LC-MS: (M+H)+ found: 431.20. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.81 (d, 1H), 8.38 (s, 1H), 7.73 (d, 1H), 7.53 (s, 1H), 6.81 – 6.74 (m, 2H), 6.21 – 6.18 (m, 1H), 3.95 (s, 3H). Example 53.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 282)
Figure imgf000407_0001
To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (150 mg, 0.70 mmol, 1.00 equiv) and 7-chlorothieno[3,2-b]pyridine (236 mg, 1.40 mmol, 2.00 equiv) in 1,4-dioxane (4.00 mL) and H2O (0.80 mL) were added 2nd Generation XPhos Precatalyst (54 mg, 0.07 mmol, 0.10 equiv) and Na2CO3 (221 mg, 2.10 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (70 mg, 32.98%) as an off-white solid. LC-MS: (M+H)+ found: 304.85.
Figure imgf000408_0001
To a stirred solution of 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.20 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (36 mg, 0.04 mmol, 0.20 equiv) and Cs2CO3 (128 mg, 0.40 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added 2-(difluoromethoxy)-3-fluoroaniline (105 mg, 0.60 mmol, 3.00 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 2h at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (14.8 mg, 16.07%) as an off-white solid. LC-MS: (M+H)+ found: 445.90. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, 1H), 8.38 (s, 1H), 8.19 (d, 1H), 7.69 (d, 1H), 7.64 - 7.57 (m, 2H), 7.20 (t, 1H), 6.90 - 6.85(m, 1H), 6.66 - 6.61(m, 1H), 6.13 (d, 1H), 4.51 (t, 2H), 3.72 (s, 2H). Example 54.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 281)
Figure imgf000408_0002
To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.26 mmol, 1.00 equiv) and 2-(difluoromethoxy)-3- fluoroaniline (139 mg, 0.78 mmol, 3.00 equiv) in DMF (2.00 mL) were added Cs2CO3 (171 mg, 0.52 mmol, 2.00 equiv) and Ephos Pd G4 (48 mg, 0.05 mmol, 0.20 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford 50 mg crude product. The crude product was dissolved in MeCN (2 mL). The precipitated solids were collected by filtration and washed with MeCN (1 mL) to obtain 3- {[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (29.8 mg, 25.23%) as a white solid. LC-MS: (M+H)+ found: 447.20. 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.79 (d, 1H), 8.42 (d, 1H), 7.83 (d, 1H), 7.71 (s, 1H), 7.23 (t, 1H), 7.02 - 6.87 (m, 1H), 6.72 - 6.68 (m, 1H), 6.20 (d, 1H), 4.56 (t, 2H), 3.73 (s, 2H). Example 55.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 285)
Figure imgf000409_0001
To a stirred solution of 4-chloropyridine-3-carbaldehyde (300 mg, 2.12 mmol, 1.00 equiv) in DCM (20.00 mL) was added DAST (1.71 g, 10.60 mmol, 5.00 equiv) dropwise at -78 degrees C under argon atmosphere. The mixture was stirred for overnight from -78 degrees C to room temperature. The reaction was monitored by TLC. The resulting mixture was extracted with CH2Cl2 (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.
Figure imgf000410_0001
To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-ylboronic acid (200 mg, 0.93 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na2CO3 (295 mg, 2.79 mmol, 3.00 equiv) in H2O (1.00 mL), Xphos Pd G2 (73 mg, 0.09 mmol, 0.10 equiv) and 4-chloro-3-(difluoromethyl)pyridine (304 mg, 1.86 mmol, 2.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (97:3) to afford 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (220 mg, 65.84%) as a yellow solid. LC-MS: (M+H)+ found: 298.85.
Figure imgf000410_0002
To a stirred solution of 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.28 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs2CO3 (181 mg, 0.56 mmol, 2.00 equiv) , EPhos Pd G4 (26 mg, 0.02 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (44 mg, 0.28 mmol, 1.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 47% B in 8 min, 47% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3- (difluoromethyl)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.6 mg, 13.35%) as a white solid. LC-MS: (M+H)+ found 420.20. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.67 (d, 1H), 8.33 (s, 1H), 7.63 - 7.34 (m, 3H), 6.68 - 6.63 (m, 2H), 6.18 - 6.15 (m, 1H), 4.43 (t, 2H), 3.80 (s, 3H), 3.69 (t, 2H). Example 56.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 287)
Figure imgf000411_0001
To a stirred solution of 4-bromopyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 equiv) in DCM (11.00 mL) was added DAST (347 mg, 2.15 mmol, 2.00 equiv) in portions at - 78 °C under argon atmosphere. The mixture was stirred for overnight from -78 °C to room temperature. The reaction was monitored by TLC. The reaction was quenched with sat. sodium sulfite at 0 degrees C. The resulting mixture was extracted with 2-methoxy-2- methylpropane (3x10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.
Figure imgf000411_0002
To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na2CO3 (148 mg, 1.39 mmol, 3.00 equiv) in H2O (1.00 mL) , XPhos Pd G2 (37 mg, 0.05 mmol, 0.10 equiv) and 4-bromo-2-(difluoromethyl)pyridine (193 mg, 0.93 mmol, 2.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (97:3) to afford 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (75 mg, 54.09%) as a yellow solid. LC-MS: (M+H)+ found: 299.20.
Figure imgf000412_0001
To a stirred solution of 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.30 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs2CO3 (197 mg, 0.60 mmol, 2.00 equiv), Ephos Pd G4 (17 mg, 0.03 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 53% B in 10 min, 53% B; Wave Length: 220/254 nm; RT1(min): 8.00) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.8 mg, 8.51%) as a white solid. LC-MS: (M+H)+ found: 420.20. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.40 (s, 1H), 6.92 (t, 1H), 6.78 - 6.71 (m, 2H), 6.17 - 6.13 (m, 1H), 4.45 (t, 2H), 3.88 (s, 3H), 3.70 - 3.65 (m, 2H). Example 57.3-[(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 286)
Figure imgf000413_0001
To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) and 4-bromo-2-fluoropyridine (98 mg, 0.55 mmol, 1.20 equiv) in 1,4-dioxane (5.00 mL) and H2O (1.00 mL) were added 2nd Generation XPhos Precatalyst (39 mg, 0.05 mmol, 0.10 equiv) and Na2CO3 (147 mg, 1.38 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-chloro-2-(2-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (65 mg, 52.51%) as an off-white solid. LC-MS: (M+H)+ found: 266.90.
Figure imgf000413_0002
To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.23 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (41 mg, 0.04 mmol, 0.20 equiv) and Cs2CO3 (146 mg, 0.46 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2- methoxyaniline (35 mg, 0.23 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 5h at 50 °C. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford the crude product. The crude product (45 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 3- [(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.2 mg, 13.95%) as a white solid. LC-MS: (M+H)+ found: 388.20. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.24 (d, 1H), 7.67 (d, 1H), 7.39 (d, 2H), 6.84 - 6.71 (m, 2H), 6.19 - 6.15 (m, 1H), 4.43 (t, 2H), 3.89 (s, 3H), 3.67 (s, 2H). Example 58.2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 296)
Figure imgf000414_0001
To a mixture of 2-methoxy-4-nitroaniline (3.00 g, 17.84 mmol, 1.00 equiv) and Boc2O (20.00 mL) was added bis(trifluoromethanesulfonyloxy) scandio trifluoromethanesulfonate (439 mg, 0.89 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for overnight at 50 °C. Desired product could be detected by LCMS. The resulting mixture was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford N-tert-butyl-2-methoxy-4-nitroaniline (720 mg, 18.00%) as a yellow solid. LC-MS: (M+H)+ found: 168.90.
Figure imgf000415_0001
To a stirred solution of N-tert-butyl-2-methoxy-4-nitroaniline (1.53 g, 6.82 mmol, 1.00 equiv) in MeOH (20.00 mL) was added 10 % Pd/C (300 mg, 20 w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under hydrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered to afford N1-tert-butyl-2-methoxybenzene-1,4-diamine (1.08 g, 83.07%) as a yellow oil. LC-MS: (M+H)+ found: 195.00.
Figure imgf000415_0002
To a stirred solution of N1-tert-butyl-2-methoxybenzene-1,4-diamine (1.08 g, 5.54 mmol, 1.00 equiv) in DMF (10.00 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.03 g, 5.54 mmol, 1.00 equiv) at room temperature. The mixture was stirred at 80 °C under nitrogen atmosphere for 1h. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The residue was diluted with MeOH (10 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (3x10.00 mL). The filtrate was concentrated under reduced pressure to afford 5-[(1E)-{[4-( tert- butylamino)-3- methoxyphenyl] imino} methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione) (1.90 g, 98.29%) as a yellow solid. LC-MS: (M+H)+ found: 349.10.
Figure imgf000416_0001
Into hot (230 °C) diphenyl ether (100.00 mL) was added 5-[(1E)-{[4-(tert-butylamino)-3- methoxyphenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (2.00 g, 5.74 mmol, 1.00 equiv). The resulting mixture was stirred for 5 min at 230 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to 30 °C. The resulting mixture was diluted with n-hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (50.00 mL) to give 6-(tert-butylamino)-7- methoxyquinolin-4-ol (1.50 g, 95.48%) as a brown oil. LC-MS: (M+H)+ found: 247.00.
Figure imgf000416_0002
To a stirred solution of 6-(tert-butylamino)-7-methoxyquinolin-4-ol (1.40 g, 5.68 mmol, 1.00 equiv) in DMF (40.00 mL) was added PBr3 (1.69 g, 6.25 mmol, 1.10 equiv) dropwise at 0 degrees C under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated salt solution (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give to give 4-bromo- N-tert-butyl-7-methoxyquinolin-6-amine (200 mg, 10.81%) as a white solid. LC-MS: (M+H)+ found: 310.85.
Figure imgf000417_0001
To a stirred mixture of 4-bromo-N-tert-butyl-7-methoxyquinolin-6-amine (130 mg, 0.42 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (108 mg, 0.50 mmol, 1.20 equiv) in 1,4-dioxane (3.50 mL) and H2O (0.70 mL) was added 2nd Generation XPhos Precatalyst (33 mg, 0.04 mmol, 0.10 equiv) and Na2CO3 (133 mg, 1.26 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 2-[6-(tert-butylamino)-7- methoxyquinolin-4-yl]-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 77.32%) as an off-white solid. LC-MS: (M+H)+ found: 400.00.
Figure imgf000417_0002
To a stirred solution of 2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-chloro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.25 mmol, 1.00 equiv) and 3-chloro- 2-methoxyaniline (39 mg, 0.25 mmol, 1.00 equiv) in DMF (2.00 mL) were added Cs2CO3 (163 mg, 0.50 mmol, 2.00 equiv) and EPhos Pd G4 (23 mg, 0.02 mmol, 0.10 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 12 h at 50°C under argon atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 2-[6-(tert-butylamino)-7-methoxyquinolin-4- yl]-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (18.9 mg, 14.46%) as a solid. LC-MS: (M+H)+ found: 521.00. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 7.32 (d, 2H), 7.24 (s, 1H),6.73 - 6.51 (m, 2H), 6.60 (d, 1H), 4.83 (s, 1H),4.42 (d, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 3.71 (s, 2H), 1.56 (s, 9H). Example 59.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 274)
Figure imgf000418_0001
To a stirred solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (2.00 g, 10.10 mmol, 1.00 equiv) and Cs2CO3 (6.58 g, 20.20 mmol, 2.00 equiv) in dimethylformamide (20.00 mL) was added PMBCl (2.37 g, 15.15 mmol, 1.50 equiv) dropwise at 0 degrees C under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3x 50 mL). The combined organic layers were washed with saturated salt solution (3x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give 7-bromo- 1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.20 g, 33.61%) as a white solid. LC-MS: (M+H)+ found: 319.80.
Figure imgf000419_0001
To a solution of 7-bromo-1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.00 g, 3.14 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- ylboronic acid (0.81 g, 3.77 mmol, 1.20 equiv) in 1,4-dioxane (20.00 mL) and XPhos Pd G3 (0.27 g, 0.31 mmol, 0.10 equiv) were added Na2CO3 (1.00 g, 9.42 mmol, 3.00 equiv) in H2O (4.00 mL). After stirring for 20 min at 50 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to afford 3- chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (600 mg, 44.36%) as a white solid. LC-MS: (M+H)+ found: 408.95.
Figure imgf000419_0002
To a stirred solution of 3-chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.24 mmol, 1.00 equiv) and 3- fluoro-2-methoxyaniline (103 mg, 0.72 mmol, 3.00 equiv) in DMF (2.00 mL) were added Ephos Pd G4 (22 mg, 0.02 mmol, 0.10 equiv) and Cs2CO3 (159 mg, 0.48 mmol, 2.00 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 1h at room temperature under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (3%) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (90 mg, 64.49%) as a yellow green oil. LC-MS: (M+H)+ found: 514.10.
Figure imgf000420_0001
Into TFA (2.00 mL) was added 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (100 mg, 0.19 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 70 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 48% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (16.7 mg, 21.74%) as a white solid. LC-MS: (M+H)+ found: 394.25. 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.44 (d, 1H), 8.35 (d, 1H), 7.46 (d, 1H), 7.37 (s, 1H), 6.72 - 6.52 (m, 2H), 6.03 (d, 1H), 4.53 (d, 1H), 3.94 (s, 3H), 3.72 (s, 2H). Example 60.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxypyrido[3,2- d]pyrimidin-8-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 319)
Figure imgf000420_0002
To a stirred mixture of 8-bromo-2-methoxypyrido[3,2-d]pyrimidine (260 mg, 1.08 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (412 mg, 1.62 mmol, 1.50 equiv) in 1,4-dioxane (2.00 mL) was added Pd(dppf)Cl2CH2Cl2 (88 mg, 0.11 mmol, 0.10 equiv) and KOAc (319 mg, 3.25 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 100 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 70% gradient in 30 min; detector, UV 254 nm. to afford 2- methoxypyrido[3,2-d]pyrimidin-8-ylboronic acid (170 mg, 72.75%) as a white solid. LC-MS: (M+H)+ found: 206.20.
Figure imgf000421_0001
To a solution of 2-methoxypyrido[3,2-d]pyrimidin-8-ylboronic acid (79 mg, 0.39 mmol, 1.80 equiv) in 1,4-dioxane (3.00 mL) and H2O (0.50 mL) were added 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.22 mmol, 1.00 equiv), Na2CO3 (46 mg, 0.43 mmol, 2.00 equiv), XPhos Pd G2 (18 mg, 0.02 mmol, 0.10 equiv). The reaction was stirred for 2 h at 50 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (3%) to afford crude product (80 mg). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 7 min, 51% B; Wave Length: 254 nm; RT1(min): 6.1) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-2-{2-methoxypyrido[3,2-d]pyrimidin-8-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (37.8 mg, 38.63%) as a yellow solid. LC-MS: (M+H)+ found: 452.20. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.97 (d, 1H), 8.27 (s, 1H), 8.05 (d, 1H), 7.74 (s, 1H), 6.68 – 6.58 (m, 2H), 6.37-6.34 (m, 1H), 4.48 (t, 2H), 4.11 (s, 3H), 3.74 (s, 2H), 3.49 (s, 3H). Example 61.2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (compound 316)
Figure imgf000422_0001
A mixture of 3-methoxy-4-nitroaniline (5.00 g, 29.74 mmol, 1.00 equiv) and 5- (methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.64 g, 35.67 mmol, 1.20 equiv) in DMF (50.00 mL) was stirred for 1h at 80℃ under nitrogen atmosphere. The mixture was allowed to cool down to RT. The product was precipitated by the addition of MeOH (50 mL). The precipitated solids were collected by filtration and washed with MeOH (20 mL). This resulted in 5-[(1E)-[(3-methoxy-4-nitrophenyl)imino]methyl]-2,2- dimethyl-1,3-dioxane-4,6-dione (8.92 g, 93.08%) as a yellow solid. LC-MS: (M+H)+ found: 323.95.
Figure imgf000422_0002
To a stirred solution of diphenyl-ether (80.00 mL) was added 5-[(1E)-[(3-methoxy-4- nitrophenyl)imino]methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (1.60 g, 4.97 mmol, 1.00 equiv) dropwise at 230°C for 10 min. The product was precipitated by the addition of hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (100 mL) to afford 7-methoxy-6-nitroquinolin-4-ol (0.90 g, 82.33%) as a brown solid. LC-MS: (M+H)+ found: 220.90.
Figure imgf000423_0001
To a stirred solution of 7-methoxy-6-nitroquinolin-4-ol (0.95 g, 4.31 mmol, 1.00 equiv) in DMF (28.00 mL) were added PBr3 (1.28 g, 4.75 mmol, 1.10 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of saturated aqueous Na2CO3. The resulting mixture was extracted with EA (50ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH=30:1 to afford 4-bromo-7-methoxy-6- nitroquinoline (0.90 g, 73.69%) as a yellow solid. LC-MS: (M+H)+ found: 282.97
Figure imgf000423_0002
To a stirred mixture of 4-bromo-7-methoxy-6-nitroquinoline (300 mg, 1.06 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (273 mg, 1.27 mmol, 1.20 equiv) in 1,4-dioxane (10.00 mL) and H2O (2.00 mL) were added 2nd Generation XPhos Precatalyst (83 mg, 0.11 mmol, 0.10 equiv) and Na2CO3 (337 mg, 3.18 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 2 x 5 mL of water. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 3 mL). The resulting mixture was concentrated under reduced pressure to obtain 3- chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 78.27%) as a yellow solid. LC-MS: (M+H)+ found: 374.10.
Figure imgf000424_0001
To a stirred solution of 3-chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (280 mg, 0.75 mmol, 1.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (488 mg, 1.49 mmol, 2.00 equiv) and EPhos Pd G4 (137 mg, 0.15 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (317 mg, 2.25 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(7- methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (330 mg, 92.07%) as a yellow solid. LC-MS: (M+H)+ found: 479.15.
Figure imgf000424_0002
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(7-methoxy-6- nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.21 mmol, 1.00 equiv) in EtOH (2.50 mL) and H2O (0.50 mL) was added Fe (70 mg, 1.26 mmol, 6.00 equiv) and NH4Cl (67 mg, 1.26 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80 degrees C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 27% B in 8 min, 27% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (37.7 mg, 36.00%) as a yellow solid. LC-MS: (M+H)+ found: 449.25. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.32 - 7.25 (m, 2H), 7.20 (d, 2H), 6.45 - 6.31 (m, 2H), 5.92 (d, 1H), 5.37 (s, 2H), 4.43 (t, 2H), 3.93 (s, 3H), 3.75(s, 3H), 3.74 - 3.69 (m, 2H). Example 62. N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (compound 320)
Figure imgf000425_0001
To a stirred solution of 3-chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a] pyrazin-4-one (300 mg, 0.80 mmol, 1.00 equiv) in DMF (6 mL) were added Cs2CO3 (523 mg, 1.60 mmol, 2.00 equiv) and EPhos Pd G4 (147 mg, 0.16 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (126 mg, 0.80 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7- methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (160 mg, 40.28%) as a yellow solid. LC-MS: (M+H)+ found: 495.1.
Figure imgf000426_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-6- nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.30 mmol, 1.00 equiv) and Fe (101 mg, 1.82 mmol, 6.00 equiv) in EtOH (3.00 mL) and H2O (0.60 mL) were added NH4Cl (97 mg, 1.82 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with MeOH (3x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (140 mg, 99.35%) as an off-white solid. LC-MS: (M+H)+ found: 465.00.
Figure imgf000426_0002
To a stirred solution of 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.15 mmol, 1.00 equiv) in 4-methylmorpholine (0.50 mL) and THF (2.00 mL) was added acryloyl chloride (16 mg, 0.17 mmol, 1.15 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 0°C under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 44% B in 10 min, 44% B; Wave Length: 220/254 nm; RT1(min): 10.17) to afford N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4- oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (10.8 mg, 13.74%) as an off-white solid. LC-MS: (M+H)+ found: 518.95. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.03 (s, 1H), 8.72 (d, 1H), 8.38 (d, 1H), 7.45 (d, 2H), 7.23 (s, 1H), 6.81-6.73 (m,1H), 6.55-6.53 (m,1H), 6.46 (t, 1H), 6.31-6.26 (m,1H), 6.08-6.05 (m,1H), 5.78-5.75 (m,1H), 4.55 (t, 2H), 4.02 (s, 3H), 3.75-3.73 (m, 2H), 3.64 (s, 3H). Example 63. N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (compound 290)
Figure imgf000427_0001
To a stirred solution of 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.22 mmol, 1.00 equiv) in DMF (2.50 mL) and 4-methylmorpholine (0.50 mL) was added acryloyl chloride (23 mg, 0.25 mmol, 1.15 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14% B to 44% B in 10 min, 44% B; Wave Length: 220/254 nm; RT1(min): 11.32) to afford N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (17.4 mg, 15.48%) as an off-white solid. LC-MS: (M+H)+ found: 502.95. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.05 (s, 1H), 8.71 (d, 1H), 8.37 (d, 1H), 7.45 (d, 2H), 7.19 (s, 1H), 6.82-6.73 (m,1H), 6.45 – 6.26 (m, 3H), 5.90 (d, 1H), 5.77 (d, 1H), 4.45 (t, 2H), 4.02 (s, 3H), 3.73 (s, 2H), 3.67 (s, 3H). Example 64.3-[(3-chloro-2-methoxyphenyl)amino]-2-[7-methoxy-6- (methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 295)
Figure imgf000428_0001
To a solution of 2-methoxy-4-nitroaniline (2.00 g, 11.89 mmol, 1.00 equiv) in THF (50.00 mL) was added NaH (1.19 g, 29.74 mmol, 2.50 equiv, 60%) at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature. Then was added MeI (2.03 g, 14.27 mmol, 1.20 equiv) and stirred for overnight at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water at 0 degrees C. The mixture was extracted with EtOAc and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 46.15%) as a yellow solid. LC-MS: M+H found: 182.90
Figure imgf000429_0001
To a solution of 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 5.49 mmol, 1.00 equiv) in EA (50 mL) was added 10% Pd/C (115 mg, 10w/w%) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford crude product 2-methoxy-N1-methylbenzene-1,4-diamine (800 mg) as a yellow solid. LC-MS: M+H found: 153.10
Figure imgf000429_0002
A mixture of 2-methoxy-N1-methylbenzene-1,4-diamine (700 mg, 4.60 mmol, 1.00 equiv) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (942 mg, 5.06 mmol, 1.10 equiv) in DMF (7.00 mL). The resulting mixture was stirred for 1 h at 80 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-[(1E)-{[3-methoxy-4- (methylamino)phenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg, 53.23%) as a yellow solid. LC-MS: M+H found: 306.95.
Figure imgf000429_0003
A mixture of 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl- 1,3-dioxane-4,6-dione (650 mg, 2.12 mmol, 1.00 equiv) in diphenyl-ether (40 mL). The resulting mixture was stirred for 30 min at 230 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was down to room temperature and diluted with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford crude product 7-methoxy-6-(methylamino)quinolin-4-ol (550 mg) as a brown solid. LC-MS: M+H found: 205.05.
Figure imgf000430_0001
To a mixture of 7-methoxy-6-(methylamino)quinolin-4-ol (200 mg, 0.98 mmol, 1.00 equiv) in POCl3 (5.00 mL). The resulting mixture was stirred for 1 h at 100 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 4-chloro-7- methoxy-N-methylquinolin-6-amine (70 mg, 32.10%) as a yellow oil. LC-MS: M+H found: 222.90.
Figure imgf000430_0002
To a solution of 4-chloro-7-methoxy-N-methylquinolin-6-amine (130 mg, 0.58 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (151 mg, 0.70 mmol, 1.20 equiv) in dioxane (1.00 mL) and H2O (0.1 mL) were added AcOK (172 mg, 1.75 mmol, 3.00 equiv) and PCy3*HBF4 (43 mg, 0.12 mmol, 0.20 equiv), and Pd2(dba)3 (54 mg, 0.06 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 28.72%) as a yellow solid. LC-MS: M+H found: 357.90.
Figure imgf000431_0001
To a solution of 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (60 mg, 0.17 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (26 mg, 0.17 mmol, 1.00 equiv) in DMF (2.00 mL) were added EPhos Pd G4 (31 mg, 0.03 mmol, 0.20 equiv) and Cs2CO3 (109 mg, 0.34 mmol, 2.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 49% B in 8 min, 49% B; Wave Length: 254/220 nm; RT1(min): 7.53) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[7- methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.3 mg, 6.49%) as a yellow solid. LC-MS: M+H found: 479.25. 1H NMR (300 MHz, DMSO-d6) δ 8.41 (d, 1H), 8.30 (s, 1H), 7.39-7.27 (m, 2H), 7.20 (s, 1H), 7.00 (s, 1H), 6.63-6.43 (m, 2H), 6.20-6.07 (m, 1H), 5.81-5.66 (m, 1H), 4.44 (t, 2H), 3.94 (s, 3H), 3.79-3.63 (m, 5H), 2.79-2.64 (m, 3H). Example 65.3-[(3-fluoro-2-methoxyphenyl)amino]-2-[7-methoxy-6- (methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 315)
Figure imgf000432_0001
To a solution of 2-methoxy-4-nitroaniline (2.00 g, 11.9 mmol, 1.00 equiv) in THF (50 mL) was added NaH (1.19 g, 29.7 mmol, 2.5 equiv, 60%) at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature. Then was added MeI (2.03 g, 14.3 mmol, 1.2 equiv) and stirred for overnight at room temperature. The reaction was quenched with water at 0 degrees C. The mixture was extracted with EtOAc and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: (column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 2- methoxy-N-methyl-4-nitroaniline (1.00 g, 46.15%) as a yellow solid. LC-MS: M+H found: 182.90
Figure imgf000432_0002
To a solution of 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 5.49 mmol, 1.00 equiv) in EA (50 mL) was added 10% Pd/C (115 mg, 10 w/w%) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford crude product 2-methoxy-N1-methylbenzene-1,4-diamine (800 mg) as a yellow solid. LC-MS: M+H found: 153.10
Figure imgf000432_0003
A mixture of 2-methoxy-N1-methylbenzene-1,4-diamine (700 mg, 4.60 mmol, 1.00 equiv) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (942 mg, 5.06 mmol, 1.1 equiv) in DMF (7 mL). The resulting mixture was stirred for 1 h at 80 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 5-[(1E)- {[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg, 53.23%) as a yellow solid. LC-MS: M+H found: 306.95.
Figure imgf000433_0001
A mixture of 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl- 1,3-dioxane-4,6-dione (650 mg, 2.12 mmol, 1.00 equiv) in diphenyl-ether (40 mL). The resulting mixture was stirred for 30 min at 230 degrees C. The resulting mixture was down to room temperature and diluted with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford crude product 7-methoxy-6- (methylamino)quinolin-4-ol (550 mg) as a brown solid. LC-MS: M+H found: 205.05
Figure imgf000433_0002
To a mixture of 7-methoxy-6-(methylamino)quinolin-4-ol (200 mg, 0.979 mmol, 1.00 equiv) in POCl3 (5 mL). The resulting mixture was stirred for 1 h at 100 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 4-chloro- 7-methoxy-N-methylquinolin-6-amine (70 mg, 32.10%) as a yellow oil. LC-MS: M+H found: 222.90
Figure imgf000434_0001
To a solution of 4-chloro-7-methoxy-N-methylquinolin-6-amine (500 mg, 2.24 mmol, 1 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (580 mg, 2.69 mmol, 1.2 equiv) in dioxane (6 mL) and H2O (0.6 mL) were added AcOK (661 mg, 6.74 mmol, 3 equiv), PCy3HBF4 (165 mg, 0.449 mmol, 0.2 equiv) and Pd2(dba)3 (206 mg, 0.225 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-chloro-2-[7- methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 18.67%) as a yellow solid. LC-MS: M+H found: 357.90.
Figure imgf000434_0002
To a mixture of 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.196 mmol, 1 equiv), 3-fluoro-2-methoxyaniline (55.2 mg, 0.392 mmol, 2 equiv), Ephos Pd G4 (35.94 mg, 0.039 mmol, 0.2 equiv) and Cs2CO3 (127.49 mg, 0.392 mmol, 2 equiv) in DMF (1 mL) at room temperature under Ar atmosphere. The resulting mixture was stirred for 2 h at 50°C under Ar atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire Prep C18 OBD Column, 19*250 mm, 10μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 40% B in 7 min, 40% B; Wave Length: 254/220 nm; RT1(min): 5.98) to afford 3-[(3-fluoro-2- methoxyphenyl)amino]-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (17.2 mg, 19.01%) as a yellow solid. LC-MS: M+H found: 463.30 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 8.31 (s, 1H), 7.33-7.31 (m, 2H), 7.19 (s, 1H), 6.98 (s, 1H), 6.48-6.32 (m, 2H), 5.97 (d, 1H), 5.79-5.70 (m, 1H), 4.44 (t, 2H), 3.94 (s, 3H), 3.75 (s, 3H), 3.71 (s, 2H), 2.71 (d, 3H). Example 66.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 275)
Figure imgf000435_0001
To a solution of anise alcohol (860 mg, 6.19 mmol, 1.05 equiv) in DMF (10 mL) was added sodium hydride (260 mg, 6.50 mmol, 1.10 equiv, 60% in oil) at 0 degrees C. The mixture was stirred for 15 min.7-chlorothieno[3,2-b]pyridine (1.00 g, 5.90 mmol, 1.00 equiv) was added and the mixture was allowed to warm to RT and stirred for 1h. The reaction mixture was quenched by water and extracted with DCM (3*25 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 7- [(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.4 g, 87.53%) as a white solid. LC-MS: M+H+ found: 272.1.
Figure imgf000435_0002
A solution of 7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.30 g, 4.79 mmol, 1.00 equiv) in tetrahydrofuran (40 mL) was treated with n-BuLi (4.2 mL, 10.54 mmol, 2.20 equiv) for 1h at -78 degrees C under nitrogen atmosphere followed by the addition of carbon tetrabromide (1.59 g, 4.79 mmol, 1.00 equiv) dropwise at -78 degrees C. The resulting mixture was stirred for 1h at -78 degrees C under argon atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (40 mL) at 0 degrees C. The resulting mixture was extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-bromo-7-[(4- methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.2 g, 71.51%) as a white solid. LC-MS: (M+H)+ found: 350.0.
Figure imgf000436_0001
A mixture of 2-bromo-7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.10 g, 3.15 mmol, 1.00 equiv) in TFA (15 mL) and DCM (15 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product is recrystallized with ether and pentanes to afford 2- bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.2 g, 99.93%) as a white solid. LC-MS: (M+H)+ found: 230.0.
Figure imgf000436_0002
To a stirred mixture of 2-bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.10 g, 3.20 mmol, 1.00equiv) and NaOMe in MeOH (4.30 g, 15.99 mmol, 5.00 equiv, 30w/w%) in MeOH (30 mL) was added CuBr (70 mg, 0.48 mmol, 0.10 equiv) at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 61.18%) as a light brown solid. LC-MS: (M+H)+ found: 182.00.
Figure imgf000437_0001
A mixture of 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 2.93 mmol, 1.00 equiv) in phosphorus oxychloride (6 mL) was stirred for 2h at 90 degrees C under nitrogen atmosphere. The reaction was quenched by the addition of water/ice (30 mL) at 0 degrees C, treated with aqueous 50 % sodium hydroxide solution. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to afford 7-chloro-2-methoxythieno[3,2-b]pyridine (250 mg, 42.81%) as a white solid. LC-MS: (M+H)+ found: 199.90.
Figure imgf000437_0002
Into a 8 mL vial were added 7-chloro-2-methoxythieno[3,2-b]pyridine (40 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (102 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl2 (14 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL). The resulting mixture was stirred for 1 days at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 210.2.
Figure imgf000438_0001
To a stirred mixture of 2-bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.14 mmol, 1.00 equiv) and 2-methoxy-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (49 mg, 0.17 mmol, 1.20 equiv) in dioxane (1.0 mL) and H2O (0.2 mL) were added XPhos palladium(II) biphenyl-2-amine chloride (11 mg, 0.01 mmol, 0.10 equiv) and Na2CO3 (30 mg, 0.28 mmol, 2.00 equiv) in portions at room temperature under argon atmosphere.The resulting mixture was stirred for overnight at 50 degrees C under argon atmosphere. The resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 1:1) to afford 3-[(3- fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (11.7 mg, 18.87%) as a white solid. LC-MS: (M+H)+ found: 439.95. 1H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.42 (m, 2H), 7.47 (d, 1H), 7.36 (s, 1H), 6.63 – 6.73 (m, 2H), 6.58 – 6.55 (m, 1H), 5.98 – 5.96 (m, 1H), 4.47 – 4.45 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.69 (t, 2H) Example 67.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound (365)
Figure imgf000439_0001
Into a 8 mL vial were added 2-methoxythieno[3,2-b]pyridin-7-ylboronic acid (40 mg, 0.19 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (71 mg, 0.19 mmol, 1.00 equiv) and 2nd Generation XPhos Precatalyst (15 mg, 0.02 mmol, 0.10 equiv) and Na2CO3 (61 mg, 0.57 mmol, 3.00 equiv) and dioxane (2.0 mL) and H2O (0.4 mL) at room temperature. The resulting mixture was stirred for overnight at 50 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (50:1) to afford crude product (100 mg).The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 69% B in 10 min, 69% B; Wave Length: 254/220 nm; RT1(min): 5.63) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2- methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (17.2 mg, 19.62%) as a white solid. LC-MS: M+H+ found: 455.90. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.35 (t, 1H), 7.47 (d, 1H), 7.42 (s, 1H), 6.80 – 6.67 (m, 3H), 6.16 - 6.10 (m, 1H), 4.50 - 4.44 (m, 2H), 4.05 (s, 3H), 3.91 (s, 3H), 3.70 - 3.64 (m, 2H). Example 68.8-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}-1H-1,5-naphthyridin-2-one (compound 345)
Figure imgf000440_0001
To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (50.00 g, 292.21 mmol, 1.00 equiv) and PPh3 (91.97 g, 350.65 mmol, 1.20 equiv) in dry THF (500 mL) was added tert-butyl N-(2-hydroxyethyl)carbamate (56.52 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 20 min at 0 degrees C under argon atmosphere. Then, the above mixture was added DIAD (70.90 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at 0 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3-carboxylate (150 g, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 315.
Figure imgf000440_0002
To a stirred solution of methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole- 3-carboxylate (150 g, 477.25 mmol, 1.00 equiv) in DCM (200 mL) was added 4 M HCl in dioxane (600 mL) dropwise at 0 degrees C. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with CH2Cl2 (3x100 mL) to afford methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108 g, crude) as an off-white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 215.
Figure imgf000441_0001
To a stirred solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108.00 g, 504.25 mmol, 1.00 equiv) in toluene (1000 mL) was added TEA (102.05 g, 1.00 mol, 2.00 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at 100 degrees C under air atmosphere. The precipitated solids were collected by filtration and washed with DCM (3x50 mL) to afford 3-nitro-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (68 g, 74.04%) as an off-white solid. LC-MS: (M+H)+ found: 183.
Figure imgf000441_0002
To a stirred solution of 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.00 g, 82.36 mmol, 1.00 equiv) in methanol (150 mL) was added 10% wet Pd/C (5.00 g, 33w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under hydrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (4x100 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (12 g, 95.76%) as an off-white solid. LC-MS: (M+H)+ found:153.
Figure imgf000441_0003
To a stirred solution of 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 13.14 mmol, 1.00 equiv) in ACN (200 mL) in ACN (200 mL) was added NBS (2.34 g, 13.14 mmol, 1.00 equiv) at -30°C. The resulting mixture was stirred for 1h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (mobile phase, MeCN in water, 0% to 100% in 30 min) to afford 3-amino-2-bromo-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 65.85%) as yellow solid. LC-MS: (M+H)+ found: 231.
Figure imgf000442_0001
To a solution of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (800 mg, 3.46 mmol, 1.00 equiv) and Cs2CO3 (2256 mg, 6.92 mmol, 2.00 equiv) in DMF (15.00 mL) were added Ephos Pd G4 (477 mg, 0.52 mmol, 0.15 equiv) and 1-chloro-3-iodo-2- methoxybenzene (1115 mg, 4.15 mmol, 1.20 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (30:1) to afford 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 38.86%) as a yellow solid. LC-MS: (M+H)+ found: 371.
Figure imgf000442_0002
To a solution of 8-bromo-2-fluoro-1,5-naphthyridine (500 mg, 2.20 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (671 mg, 2.64 mmol, 1.20 equiv) in THF (10 mL) were added KOAc (540 mg, 5.51 mmol, 2.50 equiv) and Pd(dppf)Cl2*CH2Cl2 (179 mg, 0.22 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH3OH (10:1) to afford 6-fluoro-1,5-naphthyridin-4-ylboronic acid (200 mg, 47.31%) as a yellow solid. LC-MS: (M+H)+ found: 193.
Figure imgf000443_0001
To a solution of 6-fluoro-1,5-naphthyridin-4-ylboronic acid (62 mg, 0.32 mmol, 1.50 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (80 mg, 0.21 mmol, 1.00 equiv) in dioxane (1.0 mL) and H2O (0.1 mL) were added Na2CO3 (69 mg, 0.65 mmol, 3.00 equiv) and 2nd Generation XPhos precatalyst (17 mg, 0.02 mmol, 0.10 equiv). After stirring for 2h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH3OH (10:1) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-(6-fluoro-1,5-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 63.51%) as a yellow solid. LC-MS: (M+H)+ found: 439.
Figure imgf000443_0002
To a stirred solution of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-fluoro-1,5- naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.11 mmol, 1.00 equiv) in DMF (2.00 mL) and THF (5.00 mL), DMSO (0.2 mL) and H2O (1.5 mL) were added NaOH (9 mg, 0.23 mmol, 2.00 equiv). The resulting mixture was stirred for 5 h at 50 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 8-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}-1H-1,5-naphthyridin-2-one (15.2 mg, 29.01%) as a yellow solid. LC-MS: (M+H)+ found: 436.90. 1H NMR (300 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.50 – 8.36 (m, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.45 (s, 1H), 6.85 (d, 1H), 6.77 – 6.62 (m, 2H), 6.25 – 6.17 (m, 1H), 4.53 (t, 2H), 3.89 (s, 3H), 3.70 (d, 2H). Example 69.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy-1H-pyrrolo[3,2- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 299)
Figure imgf000444_0001
A solution of Trimethyloxonium tetrafluoroborate (78 mg, 0.53 mmol, 1.13 equiv) in chloroform (5 mL) was treated with 7-bromo-1H,3H-pyrrolo[3,2-b]pyridin-2-one (100 mg, 0.47 mmol, 1.00 equiv) for 10 min at 10 degrees C under nitrogen .The resulting mixture was stirred for 2 day at room temperature under nitrogen atmosphere. The resulting mixture was washed with 1x5 mL of EtOAc. The resulting mixture was extracted with EtOEt (3 x 10mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH 10:1) to afford 7-bromo-2-methoxy-1H-pyrrolo[3,2-b]pyridine (80 mg, 75.06%) as a light yellow solid. LC-MS: M+H+ found: 226.95.
Figure imgf000445_0001
Into a 8 mL vial were added 7-bromo-2-methoxy-1H-pyrrolo[3,2-b]pyridine (45 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (100 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl2*CH2Cl2 (16 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL) at room temperature. The resulting mixture was stirred for 2 h at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was used in the next step directly without further purification LC-MS : M+H found: 275.2.
Figure imgf000445_0002
Into a 20 mL vial were added 2-methoxy-1H-pyrrolo[3,2-b]pyridin-7-ylboronic acid (35 mg, 0.18 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (68 mg, 0.18 mmol, 1.00 equiv) and Na2CO3 (58 mg, 0.55 mmol, 3.00 equiv)and 2nd Generation XPhos Precatalyst (14 mg, 0.02 mmol, 0.10 equiv) and dioxane (3.5 mL) and H2O (0.7 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product (60 mg).The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy- 1H-pyrrolo[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (11.9 mg, 14.75%) as a yellow solid. LC-MS: M+H+ found: 439.25. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.29 (s, 1H), 7.34 – 7.21 (m, 2H), 6.80 – 6.69 (m, 2H), 6.67 (d, 1H), 6.19 – 6.13 (m, 1H), 4.92 (d, 1H), 4.46 (t, 2H), 3.88 (s, 3H), 3.68 (d, 3H), 3.61 (s, 2H). Example 70.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 364)
Figure imgf000446_0001
To a stirred solution of 4-bromo-3-iodopyridine (500 mg, 1.77 mmol, 1.00 equiv), palladium chloride; bis(triphenylphosphine) (124 mg, 0.18 mmol, 0.10 equiv), TEA (535 mg, 5.31 mmol, 3.0 equiv) in MeCN (6 mL) was added CuI (34 mg, 0.18 mmol, 0.10 equiv) and 1-(difluoromethyl)-1-ethynylcyclopropane (250 mg, 2.12 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (2x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20:1) to afford 4-bromo-3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridine (465 mg, 97.03%) as a yellow oil. LC-MS: M+H found: 272.0.
Figure imgf000447_0001
To a stirred solution of 4-bromo-3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}pyridine (300 mg, 1.10 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (420 mg, 1.16 mmol, 1.50 equiv), Pd2(dba)3.CHCl3 (100 mg, 0.11 mmol, 0.10 equiv) in dioxane (10 mL) was added PPh3 (28 mg, 0.11 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 degrees under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The resulting mixture was concentrated under reduced pressure to afford 3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (400 mg) as a yellow solid. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 320.1.
Figure imgf000447_0002
Into a 40-mL vial were placed 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), 3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridin-4-ylboronic acid (77 mg, 0.32 mmol, 1.20 equiv), Na2CO3 (86 mg, 0.81 mmol, 2.00 equiv), Pd(PPh3)4 (31.2 mg, 0.03 mmol, 0.10 equiv) in dioxane (5 mL) and H2O (1 mL). The resulting solution was stirred for overnight at 100 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (6 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2x1 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 7.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2- [1-(difluoromethyl)cyclopropyl]ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (46.9 mg, 36.0%) as a white solid. LC-MS: (M+H)+ found: 484.25. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.49 (d,1H), 8.30 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 6.67 (d, 2H), 6.15 (t, 1H), 5.76 (t, 1H), 4.39 (t, 2H), 3.80 (s, 3H), 3.67 (d, 2H), 1.35 – 1.10 (m, 4H). Example 71. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyaceta-mide (compound 333)
Figure imgf000448_0001
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.26 mmol, 1.00 equiv) and 1-(2,4- dimethoxyphenyl)methanamine (54 mg, 0.32 mmol, 1.2 equiv) in DMSO (3 mL) was added DIEA (522 mg, 4.03 mmol, 15 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (15 mL). The precipitated solids were collected by filtration and washed with water (3 x 5 mL). The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 10:1) to afford 2-(3-{[(2,4- dimethoxyphenyl)methyl]amino}pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 50.35%) as a light yellow solid. LC-MS: (M+H)+ found: 519.05.
Figure imgf000449_0001
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.19 mmol, 1.00 equiv) was added trifluoroacetaldehyde (2.00 mL) dropwise at 0 degrees C under air atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 368.95.
Figure imgf000450_0001
To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (55 mg, 0.14 mmol, 1.00 equiv) in pyridine (1 mL) was added methoxyacetyl chloride (32 mg, 0.29 mmol, 2 equiv) in DCM (0.5 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (1 mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 63% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyaceta-mide (8.8 mg, 13.18%) as an off-white solid. LC-MS: (M+H)+ found: 441.05. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.61 (s, 1H), 8.48 - 8.10 (m, 2H), 7.64 (d, 1H), 7.37 (s, 1H), 6.73 - 6.65 (m, 1H), 6.63 - 6.45 (m, 1H), 6.00 (d, 1H), 4.46 - 4.43 (m, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.72 (d, 2H), 3.49 (s, 3H). Example 72.3-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-[(2-hydroxy-2- methylpropyl)amino]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 334)
Figure imgf000451_0001
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.18 mmol, 1.00 equiv) and 1-amino-2- methylpropan-2-ol (1.00 mL) in DMSO (1.00 mL) was added DIEA (365 mg, 2.83 mmol, 15.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 220 nm; RT1(min): 5.9) to afford 3-[(3-fluoro-2- methoxyphenyl)amino]-2-[3-[(2-hydroxy-2-methylpropyl)amino]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.7 mg, 6.86%) as a white solid. LC-MS: (M+H)+ found: 441.10. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (t, J = 2.8 Hz, 1H), 8.11 (s, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.49 - 6.98 (m, 3H), 6.80 - 6.38 (m, 2H), 5.97 (dt, J = 8.2, 1.4 Hz, 1H), 4.62 (s, 1H), 4.37 (dd, J = 7.1, 5.0 Hz, 2H), 3.90 (s, 3H), 3.75 - 3.62 (m, 2H), 3.17 (d, J = 5.2 Hz, 2H), 1.23 (s, 6H). Example 73.2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 343)
Figure imgf000452_0001
A solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.40 mmol, 1.00 equiv) and DIEA (783 mg, 6.06 mmol, 15.00 equiv) in 2,2-dimethyl-1-propylamin (3 mL) and DMSO (2 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 36 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5;) to afford 2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20.60 mg, 11.51%) as a light yellow solid. LC-MS: M+H found: 439.10. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.31 (s, 1H), 7.11 (t, J = 5.3 Hz, 1H), 6.68 (m, J = 8.3, 6.0 Hz, 1H), 6.54 (m, J = 11.0, 8.3, 1.4 Hz, 1H), 5.97 (m, J = 8.3, 1.3 Hz, 1H), 4.39 (dd, J = 6.9, 5.3 Hz, 2H), 3.91 (d, J = 0.8 Hz, 3H), 3.69 (d, J = 7.5 Hz, 2H), 3.08 (d, J = 5.3 Hz, 2H), 1.04 (s, 9H) Example 74. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclopropanecarboxamide (compound 338)
Figure imgf000453_0001
Into a Volume were added 3-[(3-fluoro-2-methoxyphenyl) amino]-2-(3-fluoropyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), DIEA (522 mg, 4.04 mmol, 15.00 equiv), 1-(2,4-dimethoxyphenyl) methanamine (1.50 mL) and DMSO (1.50 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 50 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino] pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one(47 mg, 33.66%) as a light yellow solid. LC-MS: M+H found: 519.05.
Figure imgf000453_0002
To a stirred solution of 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino]pyridin-4-yl)-3-[(3- fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (47 mg, 0.09 mmol, 1.00 equiv) was added trifluoroacetaldehyde (2.00 mL) dropwise at 0 degrees C under air atmosphere. The resulting mixture was stirred for 2 h at 0 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. This resulted in 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2- methoxyphenyl) amino]-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (30 mg, 89.85%) as a light yellow solid. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 369.10.
Figure imgf000454_0001
To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (46 mg, 0.13 mmol, 1.00 equiv) in pyridine (1.50 mL) was added cyclopropanecarbonyl chloride (14 mg, 0.14 mmol, 1.10 equiv) in DCM (0.10 mL) dropwise at -30 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at -30 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 34% B in 8 min; Wave Length: 220 nm; RT1(min): 8) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3- yl)cyclopropanecarboxamide (5.80 mg, 10.64%) as a light yellow solid. LC-MS: (M+H)+ found: 437.05. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.25 (s, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.56 (d, J = 5.0 Hz, 1H), 7.37 (s, 1H), 6.74 – 6.44 (m, 2H), 6.08 (d, J = 8.1 Hz, 1H), 4.46 (t, J = 5.8 Hz, 2H), 3.89 (s, 3H), 3.71 (d, J = 6.8 Hz, 2H), 1.89 (p, J = 6.3 Hz, 1H), 0.83 (d, J = 6.1 Hz, 4H). Example 75. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methylpropanamide (compound 339)
Figure imgf000455_0001
To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) and propanoyl chloride, 2-methyl-(28.9 mg, 0.271 mmol, 2.00 equiv) in pyridine (2.0 mL) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.75) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2- methylpropanamide (4.2 mg,12.93%) as a white solid. LC-MS: (M+H)+ found: 438. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.25 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.33 (s, 1H), 6.64 (td, J = 8.2, 5.9 Hz, 1H), 6.52 (ddd, J = 10.0, 8.4, 1.5 Hz, 1H), 6.12 (dd, J = 8.2, 1.5 Hz, 1H), 4.42 (dd, J = 7.1, 5.0 Hz, 2H), 3.93 (s, 3H), 3.69 (ddd, J = 7.8, 4.8, 2.6 Hz, 2H), 2.75 – 2.57 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H). Example 76.2,2,2-trifluoro-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)acetamide; formic acid (compound 340)
Figure imgf000456_0001
A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in trifluoroacetic anhydride (2.00 mL) at RT under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperatur e under nitrogen atmosphere. The resulting mixture was concentrated under reduced press ure. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, 50% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 2,2,2-trifluoro-N- (4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-3-yl)acetamide; formic acid (10.4 mg, 15%) as a light yellow solid. LC-MS: (M+H)+ found: 465.25. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.91 (s, 1H), 8.51 – 8.05 (m, 2H), 7.71 (d, J = 5.2 Hz, 1H), 7.35 (s, 1H), 6.77 – 6.35 (m, 3H), 6.19 (dt, J = 7.9, 1.4 Hz, 1H), 4.35 (dd, J = 7.1, 5.0 Hz, 2H), 3.92 (s, 3H), 3.67 (ddd, J = 7.8, 4.9, 2.8 Hz, 2H). Example 77. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (compound 341)
Figure imgf000457_0001
A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in pyridine (2.00 mL) at 0 degrees C under argon atmosphere. To the above mixture was added cyclobutanecarbonyl chloride (32 mg, 0.27 mmol, 2.00 equiv) dropwise at 0 degrees C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (50mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 19% B to 35% B in 8 min, 35% B; Wave Length: 254/220 nm; RT1(min): 7.7) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (6.8 mg, 11.00%) as an off- white solid. LC-MS: (M+H)+ found: 451.05. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.31 (s, 1H), 8.37 (s, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 5.0 Hz, 1H), 7.34 (s, 1H), 6.87 - 6.26 (m, 2H), 6.08 (d, J = 8.1 Hz, 1H), 4.43 (t, J = 5.9 Hz, 2H), 3.90 (s, 3H), 3.70 (d, J = 6.6 Hz, 2H), 3.22 (d, J = 27.9 Hz, 1H), 2.21 (dq, J = 19.4, 9.6 Hz, 4H), 2.09 - 1.49 (m, 2H). Example 78. (1r,3r)-3-(dimethylamino)-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4- oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutane-1-carboxamide; formic acid (compound 342)
Figure imgf000458_0001
To a stirred solution of (1r,3r)-3-(dimethylamino)cyclobutane-1-carboxylic acid (60 mg, 0.41 mmol, 1.00 equiv) in THF (4 mL) was added oxalyl chloride (79 mg, 0.62 mmol, 1.5 equiv) and DMF (0.1 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under argon atmosphere. The reaction was monitored by TLC (DCM/MeOH = 5/1). The resulting mixture was used in the next step directly without further purification.
Figure imgf000458_0002
To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in pyridine (0.3 mL) was added (1r,3r)-3-(dimethylamino)cyclobutane-1-carbonyl chloride (65 mg, 0.40 mmol, 3 equiv) in DCM (0.5 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (1mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to 20% B in 8 min, 20% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford (1r,3r)-3-(dimethylamino)-N-(4-[3-[(3- fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin- 3-yl)cyclobutane-1-carboxamide; formic acid (14.4 mg, 18.84%) as an off-white solid. LC-MS: (M+H)+ found: 494.10. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.23 (s, 1H), 8.36 (d, 1H), 8.26 - 8.14 (m, 2H), 7.55 (d, 1H), 7.32 (s, 1H), 6.70 - 6.57 (m, 1H), 6.56 - 6.50 (m, 1H), 6.11 (d, 1H), 4.45 - 4.37 (m, 2H), 3.72 - 3.64 (m, 2H), 3.12 (m, 1H), 2.89 - 2.83 (m, 1H), 2.32 - 2.27 (m, 2H), 2.15 - 2.06 (m, 8H). Example 79.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 349)
Figure imgf000459_0001
To a stirred mixture of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(150 mg, 0.40 mmol, 1.00 equiv) and benzyl alcohol (7.77 mL) was added K2CO3 (334 mg, 2.42 mmol, 6 equiv) in portions at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 4 days at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue product was purified by reverse phase flash to afford 2-[3-(benzyloxy)pyridin-4- yl]-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (48 mg, 25.86%) as a light yellow solid. LC-MS: (M+H)+ found: 460.05.
Figure imgf000460_0001
To a stirred mixture of 2-[3-(benzyloxy)pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (40 mg, 0.087 mmol, 1.00 equiv) in HAc (5.00 mL) was added Pd/C (55 mg, 0.52 mmol, 6.00 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at room temperature under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to 42% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro- 2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (12.8 mg, 39.81%) as a white solid. LC-MS: (M+H)+ found: 370.25. 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.47 -7.94 (m, 3H), 7.50 (dd, J = 2.8, 1.8 Hz, 1H), 7.21 (s, 1H), 6.70 (td, J = 8.3, 6.0 Hz, 1H), 6.53 (ddd, J = 10.9, 8.3, 1.5 Hz, 1H), 6.00 (dt, J = 8.1, 1.3 Hz, 1H), 4.38 (dd, J = 7.1, 5.0 Hz, 2H), 3.90 (d, J = 0.8 Hz, 3H), 3.65 (dt, J = 7.7, 3.1 Hz, 2H). Example 80.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 354)
Figure imgf000460_0002
To a stirred mixture of 2-(3-fluoropyridin-4-yl)-3-iodo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (50 mg, 0.69 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (132 mg, 0.83 mmol, 1.2 equiv) in dioxane (2.50 mL) were added Cs2CO3 (454 mg, 1.39 mmol, 2 equiv) and Ephos Pd G4 (128 mg, 0.14 mmol, 0.20 equiv) in portions at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.7 mg, 10.53%) as a white solid. LC-MS: (M+H)+ found: 388.00. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J = 1.7 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 2.9 Hz, 1H), 7.93 (ddd, J = 10.3, 2.9, 1.7 Hz, 1H), 7.37 (s, 1H), 6.83 - 6.62 (m, 2H), 6.16 (dd, J = 6.4, 3.2 Hz, 1H), 4.42 (dd, J = 7.1, 5.0 Hz, 2H), 3.87 (s, 3H), 3.72 - 3.55 (m, 2H). Example 81.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 355)
Figure imgf000461_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.12 mmol, 1.00 equiv) in 2- methoxyethanol (5.00 mL) was added potassium methaneperoxoate potassium (125 mg, 0.90 mmol, 7.00 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 1.5 days at 150 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 54% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.1 mg, 14.15%) as a white solid. LC-MS: (M+H)+ found: 444.00. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J = 1.7 Hz, 1H), 8.25 (dd, J = 25.5, 2.7 Hz, 2H), 7.62 (dd, J = 2.8, 1.7 Hz, 1H), 7.33 (s, 1H), 6.89 - 6.56 (m, 2H), 6.15 (dd, J = 6.4, 3.3 Hz, 1H), 4.40 (dd, J = 7.1, 5.0 Hz, 2H), 4.17 - 3.98 (m, 2H), 3.86 (s, 3H), 3.75 - 3.44 (m, 4H), 3.30 (d, J = 19.3 Hz, 3H). Example 82.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 356)
Figure imgf000462_0001
To a stirred mixture of 3-bromo-4-chloropyridine (500 mg, 2.59 mmol, 1.00 equiv) and cyclopropylboronic acid (245 mg, 2.85 mmol, 1.10 equiv) and Cs2CO3 (1693 mg, 5.19 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (105 mg, 0.13 mmol, 0.05 equiv) in dioxane (10.0 mL) and H2O (2.0 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 100 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH2Cl2/MeOH 20/1) to afford 4-chloro-3-cyclopropylpyridine (290 mg, 72.66%) as a yellow oil. LC-MS: (M+H)+ found: 154.
Figure imgf000462_0002
To a stirred mixture of 4-chloro-3-cyclopropylpyridine (200 mg, 1.30 mmol, 1.00 equiv) and 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (235 mg, 1.30 mmol, 1.00 equiv) and Na2CO3 (413 mg, 3.90 mmol, 3 equiv) and XPhos palladium(II) biphenyl-2- amine chloride(102 mg, 0.13 mmol, 0.1 equiv) in dioxane (13.0 mL) and H2O (1.3 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h at 60 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by prep-TLC (CH2Cl2/MeOH 20:1) to afford 2-(3- cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (230 mg, 69.47%) as a yellow oil. LC-MS: (M+H)+ found: 255.
Figure imgf000463_0001
To a stirred mixture of 2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (200 mg, 0.786 mmol, 1.00 equiv) and dbdmh (337 mg, 1.18 mmol, 1.50 equiv) in AcOH (7.8 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by prep-TLC (CH2Cl2/MeOH 15:1) to afford 3-bromo-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 49.61%) as a white solid. LC-MS: (M+H)+ found: 333.
Figure imgf000463_0002
To a stirred mixture of 3-bromo-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) and Ephos Pd G4 (27 mg, 0.03 mmol, 0.10 equiv) and EPhos (32 mg, 0.06 mmol, 0.20 equiv) and Cs2CO3 (195 mg, 0.60 mmol, 2.00 equiv) in DMF (0.50 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.62) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.6 mg, 10.18%) as a red solid. LC-MS: (M+H)+ found: 410. 1H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.23 (m, 2H), 8.13 (s, 1H), 7.39 - 7.20 (m, 2H), 6.76 - 6.48 (m, 2H), 6.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.40 (dd, J = 7.1, 4.9 Hz, 2H), 3.77 (s, 3H), 3.68 (ddd, J = 7.6, 4.9, 2.7 Hz, 2H), 2.21 (tt, J = 8.5, 5.3 Hz, 1H), 1.00 - 0.81 (m, 2H), 0.79 - 0.62 (m, 2H). Example 83.3-[(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin-7- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 363)
Figure imgf000464_0001
A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 1.99 mmol, 1.00 equiv), bis(pinacolato)diboron (1 g, 3.99 mmol, 2.00 equiv) and KOAc (392 mg, 3.99 mmol, 2.00 equiv) in DME (20.00 mL) were added Pd(dppf)Cl2 CH2Cl2 (243 mg, 0.29 mmol, 0.15 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 100 degrees C under argon atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was washed with DCM (3 x 100 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The precipitated solids were collected by filtration and washed with ethyl acetate (3 x 5 mL). This resulted in 3-chloro- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (400 mg, 83.73%) as a brown yellow solid. LC-MS: (M+H)+ found: 216.0.
Figure imgf000465_0001
A mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (530 mg, 2.46 mmol, 1.00 equiv), 7-chloro-2-methylthieno[3,2-b]pyridine (542 mg, 2.95 mmol, 1.20 equiv), PCy3 (138 mg, 0.49 mmol, 0.20 equiv) and Cs2CO3 (2.4 g, 7.38 mmol, 3.00 equiv) in dioxane (20.00 mL) and H2O (4.00 mL) at room temperature under nitrogen atmosphere. To the above mixture was added Pd2(dba)3 (225 mg, 0.24 mmol, 0.10 equiv) under nitrogen atmosphere. The resulting mixture was stirred for additional overnight at 60 degrees C. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3- chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (210 mg, 25.70%) as a brown solid. LC-MS: (M+H)+ found: 319.0.
Figure imgf000466_0001
A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.31 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (88 mg, 0.62 mmol, 2.00 equiv), EPhos (83 mg, 0.15 mmol, 0.50equiv), EPhos Pd G4 (144 mg, 0.15 mmol, 0.50 equiv) and Cs2CO3 (306 mg, 0.94 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product. The product was precipitated by the addition of Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 48% B in 10 min, 48% B; Wave Length: 254/220 nm; RT1(min): 9.28). This resulted in 3-[(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (17.5 mg, 13.09%) as an off-white solid. LC-MS: (M+H)+ found: 423.95. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.0 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 5.0 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J = 1.4 Hz, 1H), 6.76 - 6.49 (m, 2H), 5.98 (dt, J = 8.1, 1.3 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.95 (s, 3H), 3.72 (dd, J = 6.9, 3.4 Hz, 2H), 2.65 (d, J = 1.2 Hz, 3H). Example 84.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-methylthieno[3,2-b]pyridin-7- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 362)
Figure imgf000467_0001
A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (80 mg, 0.25 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (79 mg, 0.50 mmol, 2.00 equiv), EPhos (67 mg, 0.12 mmol, 0.50 equiv), EPhos Pd G4 (115 mg, 0.12 mmol, 0.50 equiv) and Cs2CO3 (245 mg, 0.75 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product. The product was precipitated by Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 50% B in 10 min, 50% B; Wave Length: 220/254 nm; RT1(min): 9.0). This resulted in 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2- methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (9 mg, 8.01%) as an off-white solid. LC-MS: (M+H)+ found: 440.20. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.0 Hz, 1H), 8.36 (t, J = 2.8 Hz, 1H), 7.54 (d, J = 5.0 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J = 1.3 Hz, 1H), 6.78 - 6.67 (m, 2H), 6.13 (dd, J = 7.1, 2.5 Hz, 1H), 4.49 (dd, J = 7.1, 4.9 Hz, 2H), 3.92 (s, 3H), 3.71 (ddd, J = 7.9, 4.7, 2.6 Hz, 2H), 2.65 (d, J = 1.2 Hz, 3H). Example 85.3-[(3-fluoro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7- dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (compound 367)
Figure imgf000468_0001
To a stirred mixture of methyl 4-bromo-2H-pyrazole-3-carboxylate (1 g, 4.87 mmol, 1 equiv) and tert-butyl N-(2-hydroxy-2-methylpropyl)carbamate (1.85 g, 9.75 mmol, 2 equiv) in THF (20 mL) were added DIAD (1.78 g, 8.78 mmol, 1.8 equiv) and PPh3 (2.30 g, 8.78 mmol, 1.8 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (8:1) to afford methyl 4-bromo-2-{1-[(tert-butoxycarbonyl)amino]-2-methylpropan-2- yl}pyrazole-3-carboxylate (1.5 g, 81.73%) as a white solid. LC-MS: [M+H]+ found: 375.90.
Figure imgf000468_0002
A mixture of methyl 4-bromo-2-{1-[(tert-butoxycarbonyl)amino]-2-methylpropan-2- yl}pyrazole-3-carboxylate (2 g, 5.316 mmol, 1 equiv) in HCl (gas) in 1,4-dioxane (10 mL) and DCM (10 mL) was stirred for 1 h at 0 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in methyl 2-(1-amino-2-methylpropan-2-yl)-4-bromopyrazole-3- carboxylate (1.3 g, 88.57%) as a light yellow oil. LC-MS: [M+H]+ found: 275.90.
Figure imgf000468_0003
A mixture of methyl 2-(1-amino-2-methylpropan-2-yl)-4-bromopyrazole-3-carboxylate (1.3 g, 4.70 mmol, 1 equiv) and sodium methoxide (1.27 g, 23.54 mmol, 5 equiv) in methanol (13 mL) was stirred for 1 h at room temperature under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 3-bromo-7,7-dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (650 mg, 56.56%) as a white solid. LC-MS: [M+H]+ found: 244.00.
Figure imgf000469_0001
To a stirred mixture of 3-bromo-7,7-dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.22 mmol, 1 equiv) and 3-fluoro-2-methoxyaniline (520 mg, 3.68 mmol, 3 equiv) in DMF (10 mL) were added Ephos Pd G4 (338 mg, 0.36 mmol, 0.3 equiv) and Cs2CO3 (800 mg, 2.45 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 80.21%) as a yellow solid. LC-MS: [M-H]- found: 302.90.
Figure imgf000469_0002
A mixture of 3-[(3-fluoro-2-methoxyphenyl)amino]-7,7-dimethyl-5H,6H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 0.49 mmol, 1 equiv) and NBS (87 mg, 0.49 mmol, 1 equiv) in DMF (2 mL) was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford 3-[(4-bromo-3-fluoro-2-methoxyphenyl)amino]-7,7- dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (180 mg, 95.29%) as a yellow solid. LC-MS: [M+H]+ found: 383.00.
Figure imgf000470_0001
To a stirred mixture of 3-[(4-bromo-3-fluoro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (190 mg, 0.49 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (258 mg, 0.99 mmol, 2 equiv) in 1,4-dioxane (2 mL) and water (0.4 mL) were added XPhos palladium(II) biphenyl-2- amine chloride (39 mg, 0.05 mmol, 0.1 equiv) and Na2CO3 (157 mg, 1.48 mmol, 3 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 54% B in 8 min, 54% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 3- [(3-fluoro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7-dimethyl-5H,6H- pyrazolo[1,5-a]pyrazin-4-one (49.6 mg, 22.87%) as a light yellow solid. LC-MS: [M+H]+ found: 438.00. 1H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.98 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 3.95 (s, 3H), 3.49 (d, J = 2.8 Hz, 2H), 1.48 (s, 6H). Example 86.3-[(3-chloro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7- dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (compound 366)
Figure imgf000471_0001
To a stirred mixture of 3-bromo-7,7-dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.22 mmol, 1 equiv) and 3-chloro-2-methoxyaniline (290 mg, 1.84 mmol, 1.5 equiv) in DMF (10 mL) were added Ephos Pd G4 (112 mg, 0.12 mmol, 0.1 equiv) and Cs2CO3 (800 mg, 2.45 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 50.73%) as a yellow solid. LC-MS: [M-H]- found: 320.95.
Figure imgf000471_0002
A mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl-5H,6H-pyrazolo[1,5- a]pyrazin-4-one (190 mg, 0.59 mmol, 1 equiv) and NBS (105 mg, 0.59 mmol, 1 equiv) in DMF (2 mL) was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. sodium sulfite (aq.) at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (15:1) to afford 3-[(4-bromo-3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl-5H,6H- pyrazolo[1,5-a]pyrazin-4-one (200 mg, 84.49%) as a yellow solid. LC-MS: [M+H]+ found: 399.00.
Figure imgf000472_0001
To a stirred mixture of 7-bromothieno[3,2-b]pyridine (300 mg, 1.40 mmol, 1 equiv), bis(pinacolato)diboron (391 mg, 1.54 mmol, 1.1 equiv) and KOAc (206 mg, 2.10 mmol, 1.5 equiv) in 1,4-dioxane (6 mL) were added PCy3*HBF4 (36 mg, 0.098 mmol, 0.07 equiv) and Pd2(dba)3 (38 mg, 0.04 mmol, 0.03 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (1 x 4 mL). The filtrate directly used for the next step response. LC-MS: [M+H]+ found: 262.00.
Figure imgf000472_0002
To a stirred mixture of 3-[(4-bromo-3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (190 mg, 0.47 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (248 mg, 0.95 mmol, 2 equiv) in 1,4-dioxane (2 mL) and water (0.5 mL) were added XPhos palladium(II) biphenyl-2- amine chloride (37 mg, 0.048 mmol, 0.1 equiv) and Na2CO3 (100 mg, 0.95 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 54% B in 8 min, 54% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 3- [(3-chloro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7-dimethyl-5H,6H- pyrazolo[1,5-a]pyrazin-4-one (26.4 mg, 12.01%) as a white solid. LC-MS: [M+H]+ found: 454.00. 1H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.97 (s, 1H), 7.64 (d, J = 5.6 Hz, 1H), 7.41 – 7.27 (m, 3H), 3.88 (s, 3H), 3.49 (d, J = 2.8 Hz, 2H), 1.48 (s, 6H). Example 87. 3-[(3-chloro-2-methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 297)
Figure imgf000473_0001
A solution of imidazole (431 mg, 6.34 mmol, 6.00 equiv) in DCM (10 mL) was treated with SO2Cl2 (256 mg, 1.90 mmol, 1.8 equiv) for 30 min at -5 degrees C under nitrogen atmosphere followed by the addition of tert-butyl N-(1-hydroxy-2-methylpropan-2- yl)carbamate (200 mg, 1.05 mmol, 1.00 equiv) in portions at 0 degrees C. Desired product could be detected by TLC. The aqueous layer was extracted with CH2Cl2 (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4- dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (220 mg, 88.47%) as a colorless oil.
Figure imgf000473_0002
A mixture of tert-butyl 4,4-dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (240 mg, 1.02 mmol, 1.00 equiv), NaIO4 (218 mg, 1.00 mmol, 1.00 equiv) and RuCl3.H2O (0.11 mg, 0.001 mmol, 0.0005 equiv) in MeCN (10 mL) and H2O (7 mL) was stirred for 0.5 h at room temperature under air atmosphere. Desired product could be detected by TLC. The aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4-dimethyl-2,2-dioxo- 1,2lambda6,3-oxathiazolidine-3-carboxylate (170 mg, 66.32%) as a white solid.
Figure imgf000474_0001
A mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (500 mg, 2.43 mmol, 1 equiv) and Cs2CO3 (371 mg, 4.87 mmol, 2 equiv) in DMF (20.00 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]-2-methylpropyl}pyrazole-3-carboxylate (450 mg, 49.04%) as an off-white solid. LC-MS: (M-H)- found: 375.95.
Figure imgf000474_0002
A solution of methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino]-2- methylpropyl}pyrazole-3-carboxylate (450 mg, 1.19 mmol, 1 equiv) in DCM (4 mL) and HCl (gas) in 1,4-dioxane (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 275.80.
Figure imgf000475_0001
A mixture of methyl 2-(2-amino-2-methylpropyl)-5-bromopyrazole-3-carboxylate (430 mg, 1.55 mmol, 1 equiv) and sodium methoxide (420 mg, 7.78 mmol, 5 equiv) in methanol (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 2-bromo-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 81.56%) as an off-white solid. LC-MS: (M+H)+ found: 243.85.
Figure imgf000475_0002
A mixture of 2-bromo-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.22 mmol, 1 equiv) and NCS (196 mg, 1.47 mmol, 1.2 equiv) in DMF (10 mL) was stirred for overnight at 100 °C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford 2-bromo- 3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (330 mg, 96.40%) as a light yellow solid. LC-MS: [M+H]+ found: 277.80.
Figure imgf000476_0001
A mixture of 2-bromo-3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.18 mmol, 1 equiv), bis(pinacolato)diboron (68 mg, 0.27 mmol, 1.5 equiv), potassium acetate (52 mg, 0.54 mmol, 3 equiv) and Pd(dppf)Cl2 (13 mg, 0.018 mmol, 0.1 equiv) in dioxane (2 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found 326.00.
Figure imgf000476_0002
A mixture of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (200 mg, 1.17 mmol, 1 equiv), 3- chloro-6,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (458 mg, 1.40 mmol, 1.2 equiv), XPhos palladium(II) biphenyl-2-amine chloride (92 mg, 0.11 mmol, 0.1 equiv) and Na2CO3 (372 mg, 3.51 mmol, 3 equiv) in dioxane (5 mL) and water (1 mL) was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford 3-chloro-6,6-dimethyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (185 mg, 47.28%) as a yellow solid. LC-MS: (M+H)+ found: 333.90.
Figure imgf000477_0001
A solution of 3-chloro-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv) ,EPhos Pd G4 (27 mg, 0.03 mmol, 0.1 equiv) and Cs2CO3 (195 mg, 0.60 mmol, 2 equiv) in DMF (2 mL) was stirred for 2 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 64% B in 8 min, 64% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.2 mg, 5.24%) as a white solid. LC-MS: (M+H)+ found: 454.93. 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 6.80 - 6.73 (m, 2H), 6.22 - 6.15 (m, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 1.34 (s, 6H). Example 88.3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(3- methoxypropyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 303)
Figure imgf000477_0002
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.20 mmol, 1.00 equiv) and 3- methoxypropylamine (0.5 mL) in DMSO (1 mL) was added DIEA (399 mg, 3.09 mmol, 15 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 10 min, 40% B; Wave Length: 254/220 nm; RT1(min): 10.38) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-2-{3-[(3-methoxypropyl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.5 mg, 7.90%) as a white solid. LC-MS: (M+H)+ found: 457. 1H NMR (300 MHz, DMSO-d6) δ 1.84 (m, J = 6.5 Hz, 2H), 3.30 (d, J = 6.1 Hz, 5H), 3.45 (t, J = 6.1 Hz, 2H), 3.68 (q, J = 6.7, 4.9 Hz, 2H), 3.85 (s, 3H), 4.41 (dd, J = 7.1, 5.0 Hz, 2H), 6.11 (t, J = 4.8 Hz, 1H), 6.69 (dd, J = 8.3, 5.0 Hz, 3H), 7.2–7.4 (m, 2H), 7.72 (d, J = 5.0 Hz, 1H), 8.08 (s, 1H), 8.33 (t, J = 2.7 Hz, 1H) Example 89.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-cyclopropylethynyl)pyridin- 4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 185)
Figure imgf000478_0001
A mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (220 mg, 0.95 mmol, 1.00 equiv) in DCE (10.00 mL) was added 3-chloro-2-methoxyphenylboronic acid(425 mg, 2.29 mmol, 2.40 equiv), Cu(OAc)2 (190 mg, 1.05 mmol, 1.10 equiv), TEA (289 mg, 2.85 mmol, 3.00 equiv) in DCE (10.00 mL) was stirred overnight at room temperature under oxygen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 33.91%) as an off-white solid. LC-MS: [M+H]+ found: 372.90.
Figure imgf000479_0001
A mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.26 mmol, 1.00 equiv), 3-(2-cyclopropylethynyl)pyridin-4- ylboronic acid (50 mg, 0.26 mmol, 1.00 equiv), Na2CO3 (57 mg, 0.52 mmol, 2.00 equiv) and XPhos Pd G2 (21 mg, 0.03 mmol, 0.10 equiv) in 1,4-dioxane (2.00 mL) and water (0.50 mL) was stirred for 2 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 46% B in 10 min, 46% B; Wave Length: 254 nm; RT1(min): 8.88) to afford 3-[(3-chloro- 2-methoxyphenyl)amino]-2-[3-(2-cyclopropylethynyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (11.3 mg, 9.62%) as a light yellow solid. LC-MS: (M+H)+ found: 434.00. 1H NMR (300 MHz, MeOD-d4) δ 8.40 (s, 1H), 8.28 (d, 1H), 7.41 - 7.39 (m, 1H), 6.59 - 6.46 (m, 2H), 6.13 -6.10 (m, 1H), 4.37 - 4.33 (m, 2H), 3.80 (s, 3H), 3.77 - 3.70 (m, 2H), 1.38 - 1.31 (m, 1H), 0.83 - 0.79 (m, 2H), 0.70 - 0.60(m, 2H). Example 90.3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 252)
Figure imgf000480_0001
A mixture of 4-bromo-6,7-dimethoxyquinoline (200 mg, 0.74 mmol, 1.00 equiv) in 1,4- dioxane (3.00 mL) was added bis(pinacolato)diboron (284 mg, 1.11 mmol, 1.50 equiv), KOAc (146 mg, 1.48 mmol, 2.00 equiv), Pd(dppf)Cl2 (54 mg, 0.07 mmol, 0.10 equiv). The reaction was stirred for overnight at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The precipitated solids were collected by filtration. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H) + found: 316.15.
Figure imgf000480_0002
A mixture of 6,7-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (100 mg, 0.32 mmol, 1.00 equiv), 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (141 mg, 0.38 mmol, 1.20 equiv), Na2CO3 (67 mg, 0.64 mmol, 2.00 equiv) and XPhos Pd G2 (24 mg, 0.03 mmol, 0.10 equiv) in 1,4- dioxane (5.00 mL) and water (1.00 mL) was stirred overnight at 80 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22% B to 42% B in 10 min, 42% B; Wave Length: 254/220 nm; RT1(min): 10.38) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7- dimethoxyquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (25.3 mg, 16.48%) as a white solid. LC-MS: (M+H)+ found: 480.00. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.32 (s, 1H), 7.62 (s, 1H), 7.45 (d, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 6.60 - 6.57 (m, 2H), 6.15 - 6.12 (m, 1H), 4.47 (t, 2H), 3.91 (s, 3H), 3.72 (s, 2H), 3.63 (s, 6H). Example 91.3-[(3-chloro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 221)
Figure imgf000481_0001
In a 250-mL round bottom flask, to a solution of 2,2,6,6-tetramethylpiperidine (4.73 g, 33.45 mmol, 1.10 equiv) in THF (30.00 mL) was added dropwise n-BuLi (2.05 g, 31.93 mmol, 1.05 equiv) solution (1.6 M in hexane, 20 mL) at -78 degrees C under N2 atmosphere. The reaction mixture was stirred at -78 degrees C for 10 mins. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. Then a solution of 4-chloro- 3-fluoropyridine (4.00 g, 30.41 mmol, 1.00 equiv) in 20 mL THF was added dropwise and the mixture was stirred for another 20 mins. The resulting mixture was stirred for 30min at -78 degrees C under nitrogen atmosphere. To the above mixture was added morpholine-4- carbaldehyde (3.68 g, 31.93 mmol, 1.05 equiv) dropwise over 10 min at -78 degrees C. The resulting mixture was stirred for additional 20 min at -78 degrees C. The reaction was quenched with ice water (1 mL). The resulting mixture was dried Na2SO4. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 4-chloro-3-fluoropyridine-2- carbaldehyde (1.50 g, 30.92%) as a yellow solid. LC-MS: (M+H)+ found: 158.9.
Figure imgf000481_0002
To a stirred solution of (4-methoxyphenyl)methanethiol (4.06 g, 26.33 mmol, 0.70 equiv) in THF (80.00 mL) was added t-BuOK (2.95 g, 26.33 mmol, 0.70 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0 degrees C under nitrogen atmosphere. To the above mixture was added 4-chloro-3-fluoropyridine- 2-carbaldehyde (6.00 g, 37.61 mmol, 1.00 equiv) dropwise over 20 min at -78 degrees C. The resulting mixture was stirred for additional 30min at 0 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (30:1) to afford 4-chloro-3-{[(4- methoxyphenyl)methyl] sulfanyl}pyridine-2-carbaldehyde (4.80 g, 43.45%) as a yellow oil. LC-MS: (M+H)+ found: 293.80.
Figure imgf000482_0001
To a stirred solution of 4-chloro-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine-2- carbaldehyde (18.00 g, 61.27 mmol, 1.00 equiv) in DCE (400 mL) was added SO2Cl2 (16.54 g, 1.23 mol, 2.00 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0 degrees C under nitrogen atmosphere. To the above mixture was added Ammonia (7.0 M Solution in MeOH, 44.00 mL, 308.00 mmol, 5.00 equiv) dropwise over 20 min at 0 degrees C. The resulting mixture was stirred for additional 1h at 0 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:4) to afford 7-chloro- [1,2]thiazolo[4,5-b]pyridine (2.50 g, 23.8%) as an off-white solid. LC-MS: (M+H)+ found: 171.0.
Figure imgf000482_0002
To a stirred mixture of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (3.60 g, 21.10 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (5.45 g, 25.32 mmol, 1.20 equiv) in 1,4-dioxane (100.00 mL) and H2O (20.00 mL) were added 2nd Generation XPhos Precatalyst (1.66 g, 2.11 mmol, 0.10 equiv) and Na2CO3 (6.71 g, 63.30 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 2 x 20 mL of water. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 20 mL). The resulting mixture was concentrated under reduced pressure to obtain 3-chloro-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(2.64 g, 40.9%) as a light yellow solid. LC-MS: (M+H)+ found: 305.90.
Figure imgf000483_0001
To a stirred solution of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (8.00 g, 26.17 mmol, 1.00 equiv) in DMF (80.00 mL) was added Cs2CO3 (17.05 g, 52.33 mmol, 2.00 equiv) and EPhos Pd G4 (4.81 g, 5.23 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (4.12 g, 26.17 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 62% B in 7 min, 62% B; Wave Length: 254/220 nm; RT1(min): 6.52) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4125 g, 21.34%) as an off-white solid. LC-MS: (M+H)+ found: 427.10. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.80 (d, 1H), 8.40 (d, 1H), 7.72 (d, 1H), 7.51 (s, 1H), 6.80 - 6.73 (m, 2H), 6.20 (d, 1H), 4.54 (t, 2H), 3.95 (s, 3H), 3.72 (s, 2H). Example 92.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 282)
Figure imgf000484_0001
To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (150 mg, 0.70 mmol, 1.00 equiv) and 7-chlorothieno[3,2-b]pyridine (236 mg, 1.40 mmol, 2.00 equiv) in 1,4-dioxane (4.00 mL) and H2O (0.80 mL) were added 2nd Generation XPhos Precatalyst (54 mg, 0.07 mmol, 0.10 equiv) and Na2CO3 (221 mg, 2.10 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (70 mg, 32.98%) as an off-white solid. LC-MS: (M+H)+ found: 304.85.
Figure imgf000484_0002
To a stirred solution of 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.20 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (36 mg, 0.04 mmol, 0.20 equiv) and Cs2CO3 (128 mg, 0.40 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added 2-(difluoromethoxy)-3-fluoroaniline (105 mg, 0.60 mmol, 3.00 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 2h at 50 degrees C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-{[2-(difluoromethoxy)-3- fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (14.8 mg, 16.07%) as an off-white solid. LC-MS: (M+H)+ found: 445.90. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, 1H), 8.38 (s, 1H), 8.19 (d, 1H), 7.69 (d, 1H), 7.64 - 7.57 (m, 2H), 7.20 (t, 1H), 6.90 - 6.85(m, 1H), 6.66 - 6.61(m, 1H), 6.13 (d, 1H), 4.51 (t, 2H), 3.72 (s, 2H). Example 93.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 281)
Figure imgf000485_0001
To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.26 mmol, 1.00 equiv) and 2-(difluoromethoxy)-3- fluoroaniline (139 mg, 0.78 mmol, 3.00 equiv) in DMF (2.00 mL) were added Cs2CO3 (171 mg, 0.52 mmol, 2.00 equiv) and Ephos Pd G4 (48 mg, 0.05 mmol, 0.20 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford 50 mg crude product. The crude product was dissolved in MeCN (2 mL). The precipitated solids were collected by filtration and washed with MeCN (1 mL) to obtain 3- {[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (29.8 mg, 25.23%) as a white solid. LC-MS: (M+H)+ found: 447.20. 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.79 (d, 1H), 8.42 (d, 1H), 7.83 (d, 1H), 7.71 (s, 1H), 7.23 (t, 1H), 7.02 - 6.87 (m, 1H), 6.72 - 6.68 (m, 1H), 6.20 (d, 1H), 4.56 (t, 2H), 3.73 (s, 2H). Example 94.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 285)
Figure imgf000486_0001
To a stirred solution of 4-chloropyridine-3-carbaldehyde (300 mg, 2.12 mmol, 1.00 equiv) in DCM (20.00 mL) was added DAST (1.71 g, 10.60 mmol, 5.00 equiv) dropwise at -78 degrees C under argon atmosphere. The mixture was stirred for overnight from -78 degrees C to room temperature. The reaction was monitored by TLC. The resulting mixture was extracted with CH2Cl2 (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.
Figure imgf000486_0002
To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-ylboronic acid (200 mg, 0.93 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na2CO3 (295 mg, 2.79 mmol, 3.00 equiv) in H2O (1.00 mL), Xphos Pd G2 (73 mg, 0.09 mmol, 0.10 equiv) and 4-chloro-3-(difluoromethyl)pyridine (304 mg, 1.86 mmol, 2.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (97:3) to afford 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (220 mg, 65.84%) as a yellow solid. LC-MS: (M+H)+ found: 298.85.
Figure imgf000487_0001
To a stirred solution of 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.28 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs2CO3 (181 mg, 0.56 mmol, 2.00 equiv) , EPhos Pd G4 (26 mg, 0.02 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (44 mg, 0.28 mmol, 1.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 47% B in 8 min, 47% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3- (difluoromethyl)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.6 mg, 13.35%) as a white solid. LC-MS: (M+H)+ found: 420.20. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.67 (d, 1H), 8.33 (s, 1H), 7.63 - 7.34 (m, 3H), 6.68 - 6.63 (m, 2H), 6.18 - 6.15 (m, 1H), 4.43 (t, 2H), 3.80 (s, 3H), 3.69 (t, 2H). Example 95.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 287)
Figure imgf000488_0001
To a stirred solution of 4-bromopyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 equiv) in DCM (11.00 mL) was added DAST (347 mg, 2.15 mmol, 2.00 equiv) in portions at -78 degrees C under argon atmosphere. The mixture was stirred for overnight from -78 degrees C to room temperature. The reaction was monitored by TLC. The reaction was quenched with sat. sodium sulfite at 0 degrees C. The resulting mixture was extracted with 2- methoxy-2-methylpropane (3x10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.
Figure imgf000488_0002
To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na2CO3 (148 mg, 1.39 mmol, 3.00 equiv) in H2O (1.00 mL), XPhos Pd G2 (37 mg, 0.05 mmol, 0.10 equiv), and 4-bromo-2-(difluoromethyl)pyridine (193 mg, 0.93 mmol, 2.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (97:3) to afford 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (75 mg, 54.09%) as a yellow solid. LC-MS: (M+H)+ found: 299.20.
Figure imgf000489_0001
To a stirred solution of 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.30 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs2CO3 (197 mg, 0.60 mmol, 2.00 equiv) , Ephos Pd G4 (17 mg, 0.03 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 53% B in 10 min, 53% B; Wave Length: 220/254 nm; RT1(min): 8.00) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.8 mg, 8.51%) as a white solid. LC-MS: (M+H)+ found: 420.20. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.40 (s, 1H), 6.92 (t, 1H), 6.78 - 6.71 (m, 2H), 6.17 - 6.13 (m, 1H), 4.45 (t, 2H), 3.88 (s, 3H), 3.70 - 3.65 (m, 2H). Example 96.3-[(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 286)
Figure imgf000490_0001
To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) and 4-bromo-2-fluoropyridine (98 mg, 0.55 mmol, 1.20 equiv) in 1,4-dioxane (5.00 mL) and H2O (1.00 mL) were added 2nd Generation XPhos Precatalyst (39 mg, 0.05 mmol, 0.10 equiv) and Na2CO3 (147 mg, 1.38 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 degrees C under argon atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-chloro- 2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (65 mg, 52.51%) as an off-white solid. LC-MS: (M+H)+ found: 266.90.
Figure imgf000490_0002
To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.23 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (41 mg, 0.04 mmol, 0.20 equiv) and Cs2CO3 (146 mg, 0.46 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2- methoxyaniline (35 mg, 0.23 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 5h at 50 degrees C. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford the crude product. The crude product (45 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 3- [(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.2 mg, 13.95%) as a white solid. LC-MS: (M+H)+ found: 388.20. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.24 (d, 1H), 7.67 (d, 1H), 7.39 (d, 2H), 6.84 - 6.71 (m, 2H), 6.19 - 6.15 (m, 1H), 4.43 (t, 2H), 3.89 (s, 3H), 3.67 (s, 2H). Example 97.2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 296)
Figure imgf000491_0001
To a mixture of 2-methoxy-4-nitroaniline (3.00 g, 17.84 mmol, 1.00 equiv) and Boc2O (20.00 mL) was added bis(trifluoromethanesulfonyloxy) scandio trifluoromethanesulfonate (439 mg, 0.89 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for overnight at 50 degrees C. Desired product could be detected by LCMS. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford N-tert-butyl-2-methoxy-4- nitroaniline (720 mg, 18.00%) as a yellow solid. LC-MS: (M+H)+ found: 168.90.
Figure imgf000491_0002
To a stirred solution of N-tert-butyl-2-methoxy-4-nitroaniline (1.53 g, 6.82 mmol, 1.00 equiv) in MeOH (20.00 mL) was added 10 % Pd/C (300 mg, 20 w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was filtered to afford N1-tert- butyl-2-methoxybenzene-1,4-diamine) (1.08 g, 83.07%) as a yellow oil. LC-MS: (M+H)+ found: 195.00.
Figure imgf000492_0001
To a stirred solution of N1-tert-butyl-2-methoxybenzene-1,4-diamine (1.08 g, 5.54 mmol, 1.00 equiv) in DMF (10.00 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.03 g, 5.54 mmol, 1.00 equiv) at room temperature. The mixture was stirred at 80 degrees C under nitrogen atmosphere for 1h. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The residue was diluted with MeOH (10 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (3x10.00 mL). The filtrate was concentrated under reduced pressure to afford 5-[(1E)- {[4- ( tert-butylamino)-3- methoxyphenyl] imino} methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione) (1.90 g, 98.29%) as a yellow solid. LC-MS: (M+H)+ found: 349.10.
Figure imgf000492_0002
Into a Diphenyl ether (100.00 mL) (230 degrees C) were added 5-[(1E)-{[4-(tert- butylamino)-3-methoxyphenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (2.00 g, 5.74 mmol, 1.00 equiv) at 230 degrees C. The resulting mixture was stirred for 5 min at 230 degrees C. The reaction was monitored by LCMS. The mixture was allowed to cool down to 30 degrees C. The resulting mixture was diluted with hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (50.00 mL) to give 6-(tert-butylamino)-7-methoxyquinolin-4-ol (1.50 g, 95.48%) as a brown oil. LC-MS: (M+H)+ found: 247.00.
Figure imgf000493_0001
To a stirred solution of 6-(tert-butylamino)-7-methoxyquinolin-4-ol (1.40 g, 5.68 mmol, 1.00 equiv) in DMF (40.00 mL) was added PBr3 (1.69 g, 6.25 mmol, 1.10 equiv) dropwise at 0 degrees C under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (3x 100 mL). The combined organic layers were washed with saturated salt solution (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give to give 4-bromo-N-tert-butyl- 7-methoxyquinolin-6-amine (200 mg, 10.81%) as a white solid. LC-MS: (M+H)+ found: 310.85.
Figure imgf000493_0002
To a stirred mixture of 4-bromo-N-tert-butyl-7-methoxyquinolin-6-amine (130 mg, 0.42 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (108 mg, 0.50 mmol, 1.20 equiv) in 1,4-dioxane (3.50 mL) and H2O (0.70 mL) was added 2nd Generation XPhos Precatalyst (33 mg, 0.04 mmol, 0.10 equiv) and Na2CO3 (133 mg, 1.26 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 degrees C under argon atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-chloro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 77.32%) as an off-white solid. LC-MS: (M+H)+ found: 400.00.
Figure imgf000494_0001
To a stirred solution of 2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-chloro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.25 mmol, 1.00 equiv) and 3-chloro- 2-methoxyaniline (39 mg, 0.25 mmol, 1.00 equiv) in DMF (2.00 mL) were added Cs2CO3 (163 mg, 0.50 mmol, 2.00 equiv) and EPhos Pd G4 (23 mg, 0.02 mmol, 0.10 equiv) dropwise at RT under Ar atmosphere. The resulting mixture was stirred for 12 h at 50degrees C under Ar atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 2-[6-(tert-butylamino)-7-methoxyquinolin-4- yl]-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (18.9 mg, 14.46%) as a solid. LC-MS: (M+H)+ found: 521.00. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 7.32 (d, 2H), 7.24 (s, 1H),6.73 - 6.51 (m, 2H), 6.60 (d, 1H), 4.83 (s, 1H),4.42 (d, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 3.71 (s, 2H), 1.56 (s, 9H). Example 98.3-[(3-chloro-2-methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 297)
Figure imgf000494_0002
A solution of Imidazole (431 mg, 6.36 mmol, 6.00 equiv) in DCM (10.00 mL) was treated with SO2Cl2 (257 mg, 1.91 mmol, 1.80 equiv) for 30 min at -5 degrees C under nitrogen atmosphere followed by the addition of tert-butyl N-(1-hydroxy-2-methylpropan-2- yl)carbamate (200 mg, 1.06 mmol, 1.00 equiv) in portions at 0 degrees C. Desired product could be detected by TLC. The aqueous layer was extracted with CH2Cl2 (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4- dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (220 mg, 88.47%) as a colorless oil.
Figure imgf000495_0001
A mixture of tert-butyl 4,4-dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (240 mg, 1.02 mmol, 1.00 equiv), NaIO4 (218 mg, 1.02 mmol, 1.00 equiv) and RuCl3.H2O (1 mg, 0.01 mmol, 0.005 equiv) in MeCN (10.00 mL) and H2O (7.00 mL) was stirred for 0.5 h at room temperature under air atmosphere. Desired product could be detected by TLC. The aqueous layer was extracted with CH2Cl2 (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4-dimethyl-2,2-dioxo- 1,2lambda6,3-oxathiazolidine-3-carboxylate (170 mg, 66.32%) as a white solid.
Figure imgf000495_0002
A mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (500 mg, 2.43 mmol, 1.00 equiv) in DMF (10.00 mL) was added Cs2CO3 (371 mg, 4.86 mmol, 2.00 equiv), tert-butyl 4,4- dimethyl-2,2-dioxo-1,2lambda6,3-oxathiazolidine-3-carboxylate(612 mg, 2.43 mmol, 1.00 equiv). The reaction was stirred for 2 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino]-2- methylpropyl}pyrazole-3-carboxylate (450 mg, 49.04%) as an off-white solid. LC-MS: [M+H]+ found: 375.95.
Figure imgf000496_0001
A solution of methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino]-2- methylpropyl}pyrazole-3-carboxylate (450 mg, 1.20 mmol, 1.00 equiv) in DCM (4.00 mL) and 4M HCl in 1,4-dioxane (4.00 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LC-MS: [M+H]+ found: 277.80.
Figure imgf000496_0002
A mixture of methyl 2-(2-amino-2-methylpropyl)-5-bromopyrazole-3-carboxylate (430 mg, 1.56 mmol, 1.00 equiv) in methanol (10.00 mL) was added sodium methoxide (421 mg, 7.80 mmol, 5.00 equiv) slowly at 0 °C. The reaction was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 2-bromo-6,6- dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 81.56%) as an off-white solid. LC-MS: [M+H]+ found: 243.85.
Figure imgf000497_0001
A mixture of 2-bromo-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.23 mmol, 1.00 equiv) and NCS (196 mg, 1.47 mmol, 1.20 equiv) in DMF (10.00 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford 2-bromo-3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (330 mg, 96.40%) as a light yellow solid. LC-MS: [M+H]+ found: 279.80.
Figure imgf000497_0002
A mixture of 2-bromo-3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.18 mmol, 1.00 equiv) bis(pinacolato)diboron (68 mg, 0.27 mmol, 1.50 equiv), potassium acetate (52 mg, 0.54 mmol, 3.00 equiv) and Pd(dppf)Cl2 (13 mg, 0.02 mmol, 0.10 equiv) in 1,4-dioxane (2.00 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. LC-MS: [M+H]+ found: 326.00.
Figure imgf000497_0003
A mixture of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (200 mg, 1.17 mmol, 1.00 equiv) 3- chloro-6,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (458 mg, 1.40 mmol, 1.20 equiv), XPhos palladium(II) biphenyl-2-amine chloride (92 mg, 0.12 mmol, 0.10 equiv) and Na2CO3 (372 mg, 3.52 mmol, 3.00 equiv) in dioxane (5.00 mL) and water (1.00 mL) was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford 3-chloro-6,6- dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (185 mg, 47.28%) as a yellow solid. LC-MS: [M+H]+ found: 333.90.
Figure imgf000498_0001
A solution of 3-chloro-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv), 3-chloro-2- methoxyaniline(47 mg, 0.30 mmol, 1.00 equiv) , EPhos Pd G4 (27 mg, 0.03 mmol, 0.10 equiv) and Cs2CO3 (195 mg, 0.60 mmol, 2.00 equiv) in DMF (2.00 mL) was stirred for 2 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 64% B in 8 min, 64% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (7.2 mg, 5.24%) as a white solid. LC-MS: (M+H)+ found: 454.93. 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, 1H), 8.50 (s, 1H), 7.76 (d, 1H), 7.56 (s, 1H), 6.80 - 6.73 (m, 2H), 6.22 - 6.15 (m, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 1.34 (s, 6H). Example 99.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 274)
Figure imgf000499_0001
To a stirred solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (2.00 g, 10.10 mmol, 1.00 equiv) and Cs2CO3 (6.58 g, 20.20 mmol, 2.00 equiv) in dimethylformamide (20.00 mL) was added PMBCl (2.37 g, 15.15 mmol, 1.50 equiv) dropwise at 0 degrees C under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature under N2 atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3x 50 mL). The combined organic layers were washed with saturated salt solution (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give 7-bromo- 1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.20 g, 33.61%) as a white solid. LC-MS: (M+H)+ found: 319.80.
Figure imgf000499_0002
To a solution of 7-bromo-1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.00 g, 3.14 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- ylboronic acid (0.81 g, 3.77 mmol, 1.20 equiv) in 1,4-dioxane (20.00 mL) and XPhos Pd G3 (0.27 g, 0.31 mmol, 0.10 equiv) were added Na2CO3 (1.00 g, 9.42 mmol, 3.00 equiv) in H2O (4.00 mL). After stirring for 20 min at 50 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to afford 3- chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (600 mg, 44.36%) as a white solid. LC-MS: (M+H)+ found: 408.95.
Figure imgf000500_0001
To a stirred solution of 3-chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.24 mmol, 1.00 equiv) and 3- fluoro-2-methoxyaniline (103 mg, 0.72 mmol, 3.00 equiv) in DMF (2.00 mL) were added Ephos Pd G4 (22 mg, 0.02 mmol, 0.10 equiv) and Cs2CO3 (159 mg, 0.48 mmol, 2.00 equiv) dropwise at RT under argon atmosphere. The resulting mixture was stirred for 1h at room temperature under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (3%) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (90 mg, 64.49%) as a yellow green oil. LC-MS: (M+H)+ found: 514.10.
Figure imgf000500_0002
Into a TFA (2.00 mL) was added 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (100 mg, 0.19 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 70 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 48% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (16.7 mg, 21.74%) as a white solid. LC-MS: (M+H)+ found: 394.25. 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.44 (d, 1H), 8.35 (d, 1H), 7.46 (d, 1H), 7.37 (s, 1H), 6.72 - 6.52 (m, 2H), 6.03 (d, 1H), 4.53 (d, 1H), 3.94 (s, 3H), 3.72 (s, 2H). Example 100.2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (compound 316)
Figure imgf000501_0001
A mixture of 3-methoxy-4-nitroaniline (5.00 g, 29.74 mmol, 1.00 equiv) and 5- (methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.64 g, 35.67 mmol, 1.20 equiv) in DMF (50.00 mL) was stirred for 1h at 80°C under N2 atmosphere. The mixture was allowed to cool down to RT. The product was precipitated by the addition of MeOH (50 mL). The precipitated solids were collected by filtration and washed with MeOH (20 mL). This resulted in 5-[(1E)-[(3-methoxy-4-nitrophenyl)imino]methyl]-2,2-dimethyl-1,3- dioxane-4,6-dione (8.92 g, 93.08%) as a yellow solid. LC-MS: (M+H)+ found: 323.95.
Figure imgf000502_0001
To a stirred solution of diphenyl-ether (80.00 mL) was added 5-[(1E)-[(3-methoxy-4- nitrophenyl)imino]methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (1.60 g, 4.97 mmol, 1.00 equiv) dropwise at 230°C for 10 min. The product was precipitated by the addition of hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (100 mL) to afford 7-methoxy-6-nitroquinolin-4-ol (0.90 g, 82.33%) as a brown solid. LC-MS: (M+H)+ found: 220.90.
Figure imgf000502_0002
To a stirred solution of 7-methoxy-6-nitroquinolin-4-ol (0.95 g, 4.31 mmol, 1.00 equiv) in DMF (28.00 mL) were added PBr3 (1.28 g, 4.75 mmol, 1.10 equiv) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred for 30 min at room temperature under N2 atmosphere. The reaction was quenched by the addition of Na2CO3 Saturated aqueous. The resulting mixture was extracted with EA (50ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH=30:1 to afford 4-bromo-7-methoxy-6- nitroquinoline (0.90 g, 73.69%) as a yellow solid. LC-MS: (M+H)+ found: 282.97
Figure imgf000502_0003
To a stirred mixture of 4-bromo-7-methoxy-6-nitroquinoline (300 mg, 1.06 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (273 mg, 1.27 mmol, 1.20 equiv) in 1,4-dioxane (10.00 mL) and H2O (2.00 mL) were added 2nd Generation XPhos Precatalyst (83 mg, 0.11 mmol, 0.10 equiv) and Na2CO3 (337 mg, 3.18 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 2 x 5 mL of water. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 3 mL). The resulting mixture was concentrated under reduced pressure to obtain 3- chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 78.27%) as a yellow solid. LC-MS: (M+H)+ found: 374.10.
Figure imgf000503_0001
To a stirred solution of 3-chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (280 mg, 0.75 mmol, 1.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (488 mg, 1.49 mmol, 2.00 equiv) and EPhos Pd G4 (137 mg, 0.15 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (317 mg, 2.25 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 3-[(3- fluoro-2-methoxyphenyl)amino]-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (330 mg, 92.07%) as a yellow solid. LC-MS: (M+H)+ found: 479.15.
Figure imgf000504_0001
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(7-methoxy-6- nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.21 mmol, 1.00 equiv) in EtOH (2.50 mL) and H2O (0.50 mL) was added Fe (70 mg, 1.26 mmol, 6.00 equiv) and NH4Cl (67 mg, 1.26 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80 degrees C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 27% B in 8 min, 27% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (37.7 mg, 36.00%) as a yellow solid. LC-MS: (M+H)+ found: 449.25. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.32 - 7.25 (m, 2H), 7.20 (d, 2H), 6.45 - 6.31 (m, 2H), 5.92 (d, 1H), 5.37 (s, 2H), 4.43 (t, 2H), 3.93 (s, 3H), 3.75(s, 3H), 3.74 - 3.69 (m, 2H). Example 101.3-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-[(2-hydroxy-2- methylpropyl)amino]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 334)
Figure imgf000505_0001
To a stirred solution of 2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(2.00 g, 9.26 mmol, 1.00 equiv) in 1,4-dioxane(24.00 mL) and water(6.00 mL) were added 3- fluoropyridin-4-ylboronic acid(1.57 g, 11.10 mmol, 1.20 equiv) and Pd(dppf)Cl2*CH2Cl2(0.75 g, 9.26 mmol, 0.10 equiv) and K3PO4(5.89 g, 27.78 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 3h at 60 degrees C. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(1.6 g, 74.4%) as a light-yellow solid. LC-MS: (M+H)+ found: 233.08.
Figure imgf000505_0002
To a stirred solution of 2-(3-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(1.00 g, 4.30 mmol, 1.00 equiv) in HOAc(21.00 mL) was added 1,3-Dibromo-5,5- dimethylhydantoin (1.85 g, 6.459 mmol, 1.50 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 60 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The reaction was quenched with sat. Na2SO3 (aq.) (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 7 with saturated Na2CO3 (aq.). The precipitated solids were collected by filtration and washed with EtOAc (3x50 mL) to obtain 3-bromo-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(1.3 g, 96.9%) as a light– yellow solid. LC-MS: (M+H)+ found: 310.99.
Figure imgf000506_0001
To a stirred solution of 3-bromo-2-(3-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one(600 mg, 1.93 mmol, 1.00 equiv) in 1,4-dioxane(10.00 mL) were added EPhos Pd G4(354 mg, 0.38 mmol, 0.20 equiv) and Cs2CO3(1.25 g, 3.86 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline(816 mg, 5.78 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred overnight at 50 degrees C. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(500 mg, 74.7%) as an off- white solid. LC-MS: (M+H)+ found: 372.13.
Figure imgf000506_0002
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.19 mmol, 1.00 equiv) and 1-amino-2- methylpropan-2-ol (1.00 mL) in DMSO (1.00 mL) was added DIEA (365 mg, 2.84 mmol, 15.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 220 nm; RT1(min): 5.9) to afford 3-[(3-fluoro- 2-methoxyphenyl)amino]-2-[3-[(2-hydroxy-2-methylpropyl)amino]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.7 mg, 6.86%) as a white solid. LC-MS: (M+H)+ found: 441.10. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.10 (s, 1H), 7.66 (d, 1H), 7.41 (d, 1H), 7.29 (s, 1H), 7.03(t, 1H), 6.70 – 6.45 (m, 2H), 5.96 (d, 1H), 4.61 (s, 1H), 4.36 (t, 2H), 3.89 (s, 3H), 3.67 (s, 2H), 3.16 (d, 2H), 1.21 (s, 6H). Example 102.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 349)
Figure imgf000507_0001
To a stirred mixture of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(150 mg, 0.40 mmol, 1.00 equiv) and benzyl alcohol(7.00 mL) was added K2CO3(334 mg, 2.42 mmol, 6.00 equiv) in portions at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 4 days at 120 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue product was purified by Prep-MPLC to afford 2-[3- (benzyloxy)pyridin-4-yl]-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (48 mg, 25.86%) as a light yellow solid. LC-MS: M+H found: 460.05.
Figure imgf000508_0001
To a stirred mixture of 2-[3-(benzyloxy)pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (40 mg, 0.087 mmol, 1.00 equiv) in HOAc (5.00 mL) was added 10% Pd/C (55 mg) at room temperature under argon atmosphere. The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The resulting mixture was stirred for 4 h at room temperature under hydrogen atmosphere. The mixture was filtered through a Celite pad. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to 42% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (12.8 mg, 39.81%) as a white solid. LC-MS: (M+H)+ found: 370.25. 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.39 (d, 1H), 8.25(s, 1H), 8.02(d, 1H) 7.50- 7.48 (m, 1H), 7.20 (s, 1H), 6.76-6.62 (m, 1H), 6.58-6.48 (m, 1H), 5.99 (d, 1H), 4.37 (t, 2H), 3.89 (s, 3H), 3.64 (s, 2H). Example 103.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 354)
Figure imgf000508_0002
To a stirred mixture of 2-(3-fluoropyridin-4-yl)-3-iodo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (50 mg, 0.69 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (132 mg, 0.84 mmol, 1.2 equiv) in 1,4-dioxane (2.50 mL) were added Cs2CO3 (455 mg, 1.39 mmol, 2.00 equiv) and Ephos Pd G4 (128 mg, 0.14 mmol, 0.20 equiv) at room temperature under argon atmosphere. The mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford the crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro- 2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(5.7 mg,10.53%) as a white solid. LC-MS: M+H found: 388.00. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, 1H), 8.51 (d, 1H), 8.30 (s, 1H), 7.98-7.88 (m, 1H), 7.36 (s, 1H), 6.78 -6.69 (m, 2H), 6.19-6.11 (m, 1H), 4.41 (t, 2H), 3.86 (s, 3H), 3.66(s, 2H). Example 104.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 355)
Figure imgf000509_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in 2- methoxyethanol (5.00 mL) was added Potassium carbonate (126 mg, 0.90 mmol, 7.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 1.5 days at 150 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 54% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2- methoxyethoxy)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.1 mg, 14.15%) as a white solid. LC-MS: M+H found: 444.00. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.28 (s, 1H), 8.20(d, 1H), 764-7.59 (m, 1H), 7.32 (s, 1H), 6.78 - 6.69 (m, 2H), 6.8-6.12 (m, 1H), 4.39 (t, 2H), 4.10-4.02 (m, 2H), 3.85 (s, 3H), 3.65 (s, 1H), 3.60-3.52(m, 3H), 3.26(s, 3H). Example 105.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-[[(2R)-oxolan-2- ylmethyl]amino]pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 105a)
Figure imgf000510_0001
Into a 8-mL sealed tube, was placed 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.32 mmol, 1.00 equiv), DMSO (3.00 mL), DIEA (626 mg, 4.85 mmol, 15.00 equiv), 1-[(2R)-oxolan-2- yl]methanamine (1.50 mL). The resulting solution was stirred for 2 days at 120 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 25% B to 50% B in 8 min, 50% B; Wave Length: 254 nm; RT1(min): 5.7) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]- 2-(3-[[(2R)-oxolan-2-ylmethyl]amino]pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (19.6 mg, 13.31%) as an off-white solid. LC-MS: (M+H)+ found: 453.10. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.13 (s, 1H), 7.71-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.29 (s, 1H), 6.95-6.91 (m, 1H), 6.80-6.61 (m, 1H), 6.55-6.45 (m, 1H), 6.01-5.82 (m, 1H), 4.40-4.36 (m, 2H), 4.11-4.08 (m, 1H), 3.89-3.83 (m, 4H), 3.73-3.61 (m, 3H), 3.40- 3.24 (m, 2H), 2.03-1.86 (m, 3H), 1.69-1.62 (m, 1H). Example 106.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-[[(2s)-oxolan-2- ylmethyl]amino]pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 105b)
Figure imgf000511_0001
Into a 8-mL sealed tube, was placed 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.32 mmol, 1.00 equiv), DMSO (3.00 mL), DIEA (626 mg, 4.85 mmol, 15.00 equiv), 1-[(2s)-oxolan-2- yl]methanamine (1.50 mL). The resulting solution was stirred for 2 days at 120 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 25% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1(min): 7.03) to afford 3-[(3-fluoro-2- methoxyphenyl)amino]-2-(3-[[(2s)-oxolan-2-ylmethyl]amino]pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (20.9 mg, 14.26%) as a white solid. LC-MS: (M+H)+ found: 453.10. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.13 (s, 1H), 7.71-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.29 (s, 1H), 6.95-6.91 (m, 1H), 6.69-6.61 (m, 1H), 6.56-6.45 (m, 1H), 6.05-5.89 (m, 1H), 4.38 (t, 2H), 4.11-4.08 (m, 1H), 3.89-3.83 (m, 4H), 3.75-3.61 (m, 3H), 3.40-3.24 (m, 2H), 2.03-1.86 (m, 3H), 1.69-1.62 (m, 1H). Example 107.3-[(3-chloro-2-methoxyphenyl)amino]-2-[7-methoxy-6- (methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 295)
Figure imgf000512_0001
To a solution of 2-methoxy-4-nitroaniline (2.00 g, 11.89 mmol, 1.00 equiv) in THF (50.00 mL) was added NaH (1.19 g, 29.74 mmol, 2.50 equiv, 60%) at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature. Then was added MeI (2.03 g, 14.27 mmol, 1.20 equiv) and stirred for overnight at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water at 0 degrees C. The mixture was extracted with EtOAc and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 46.15%) as a yellow solid. LC-MS: M+H found: 182.90.
Figure imgf000512_0002
To a solution of 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 5.49 mmol, 1.00 equiv) in EA (50 mL) was added 10% Pd/C (115 mg, 10 w/w%) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford crude product 2-methoxy-N1-methylbenzene-1,4-diamine (800 mg) as a yellow solid. LC-MS: M+H found: 153.10.
Figure imgf000513_0001
A mixture of 2-methoxy-N1-methylbenzene-1,4-diamine (700 mg, 4.60 mmol, 1.00 equiv) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (942 mg, 5.06 mmol, 1.10 equiv) in DMF (7.00 mL) was stirred for 1 h at 80 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl] imino}methyl]- 2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg, 53.23%) as a yellow solid. LC-MS: M+H found: 306.95.
Figure imgf000513_0002
A mixture of 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl- 1,3-dioxane-4,6-dione (650 mg, 2.12 mmol, 1.00 equiv) in diphenyl-ether (40 mL) was stirred for 30 min at 230 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford crude product 7-methoxy-6-(methylamino)quinolin-4-ol (550 mg) as a brown solid. LC-MS: M+H found: 205.05.
Figure imgf000513_0003
To a mixture of 7-methoxy-6-(methylamino)quinolin-4-ol (200 mg, 0.98 mmol, 1.00 equiv) in POCl3 (5.00 mL) was stirred for 1 h at 100 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 4-chloro-7-methoxy-N- methylquinolin-6-amine (70 mg, 32.10%) as a yellow oil. LC-MS: M+H found: 222.90.
Figure imgf000514_0001
To a solution of 4-chloro-7-methoxy-N-methylquinolin-6-amine (130 mg, 0.58 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (151 mg, 0.70 mmol, 1.20 equiv) in dioxane (1.00 mL) and H2O (0.1 mL) were added AcOK (172 mg, 1.75 mmol, 3.00 equiv) and PCy3.HBF4 (43 mg, 0.12 mmol, 0.20 equiv) and Pd2(dba)3 (54 mg, 0.06 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-chloro- 2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 28.72%) as a yellow solid. LC-MS: M+H found: 357.90.
Figure imgf000514_0002
To a solution of 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (60 mg, 0.17 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (26 mg, 0.17 mmol, 1.00 equiv) in DMF (2.00 mL) were added EPhos Pd G4 (31 mg, 0.03 mmol, 0.20 equiv) and Cs2CO3 (109 mg, 0.34 mmol, 2.00 equiv) at 50 degrees C under argon atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 49% B in 8 min, 49% B; Wave Length: 254/220 nm; RT1(min): 7.53) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[7- methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.3 mg, 6.49%) as a yellow solid. LC-MS: M+H found: 479.25. 1H NMR (300 MHz, DMSO-d6) δ 8.41 (d, 1H), 8.30 (s, 1H), 7.39-7.27 (m, 2H), 7.20 (s, 1H), 7.00 (s, 1H), 6.63-6.43 (m, 2H), 6.20-6.07 (m, 1H), 5.81-5.66 (m, 1H), 4.44 (t, 2H), 3.94 (s, 3H), 3.79-3.63 (m, 5H), 2.79-2.64 (m, 3H). Example 108.2,2,2-trifluoro-N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-yl]pyridin-3-yl)acetamide; formic acid (compound 340)
Figure imgf000515_0001
A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.13 mmol, 1.00 equiv) in trifluoroacetic anhydride(2.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, 50% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 2,2,2-trifluoro-N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a] pyrazin-2-yl]pyridin-3-yl)acetamide; formic acid (10.4 mg, 15%) as a light yellow solid. LC-MS: (M+H)+ found: 465.25. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.91 (s, 1H), 8.51 – 8.38 (m, 2H), 7.71 (d, 1H), 7.35 (s, 1H), 6.77 – 6.35 (m, 3H), 6.19 – 6.11 (m, 1H), 4.47 – 4.32 (m, 2H), 3.92 (s, 3H), 3.68 – 3.66 (m, 2H). Example 109. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (compound 341)
Figure imgf000516_0001
A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.13 mmol, 1.00 equiv) in Pyridine(2.00 mL) at 0 degrees C under argon atmosphere. To the above mixture was added cyclobutanecarbonyl chloride (32 mg, 0.27 mmol, 2.00 equiv) dropwise at 0 degrees C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (50mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 19% B to 35% B in 8 min, 35% B; Wave Length: 254/220 nm; RT1(min): 7.7) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (6.8 mg, 11.00%) as a off-white solid. LC-MS: (M+H)+ found: 451.05. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.31 (s, 1H), 8.37 (s, 1H), 8.21 (d, 1H), 7.58 (d, 1H), 7.34 (s, 1H), 6.87 – 6.26 (m, 2H), 6.08 (d, 1H), 4.43 (t, 2H), 3.90 (s, 3H), 3.70 (t, 2H), 3.56 – 3.29 (m, 1H), 2.31 – 2.16 (m, 4H), 2.09 – 1.82 (m, 2H). Example 110.3-[(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin- 7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 363)
Figure imgf000517_0001
A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 1.99 mmol, 1.00 equiv), bis(pinacolato)diboron (1.04 g, 3.99 mmol, 2.00 equiv) and KOAc (392 mg, 3.99 mmol, 2.00 equiv) in DME (20.00 mL) were added Pd(dppf)Cl2*CH2Cl2 (243 mg, 0.29 mmol, 0.15 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 100 degrees C under argon atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was washed with 3x100 mL of DCM. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100mL). The precipitated solids were collected by filtration and washed with ethyl acetate (3x5 mL). This resulted in 3-chloro- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (400 mg, 83.73%) as a brown- yellow solid. LC-MS: (M+H)+ found: 216.0.
Figure imgf000517_0002
A mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (530 mg, 2.46 mmol, 1.00 equiv) ,7-chloro-2-methylthieno[3,2-b]pyridine (542 mg, 2.95 mmol, 1.20 equiv), PCy3(138 mg, 0.49 mmol, 0.20 equiv) and Cs2CO3 (2.4 g, 7.38 mmol, 3.00 equiv) in dioxane (20.00 mL) and H2O (4.00 mL) at room temperature under nitrogen atmosphere. To the above mixture was added Pd2(dba)3 (225 mg, 0.24 mmol, 0.10 equiv) under nitrogen atmosphere. The resulting mixture was stirred for additional overnight at 60 degrees C. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 spherical column; mobile phase, MeOH in water, 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (210mg,25.70%) as a brown solid. LC-MS: (M+H)+ found: 319.0.
Figure imgf000518_0001
A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.31 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (88 mg, 0.62 mmol, 2.00 equiv), EPhos (83 mg, 0.15 mmol, 0.50 equiv), EPhos Pd G4 (144 mg, 0.15 mmol, 0.50 equiv) and Cs2CO3 (306 mg, 0.94 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product. The product was purified by prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 48% B in 10 min, 48% B; Wave Length: 254/220 nm; RT1(min): 9.28. This resulted in 3- [(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (17.5 mg, 13.09%) as a off-white solid. LC-MS: (M+H)+ found: 423.95. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H), 8.36 (t, 1H), 7.54 (d, 1H), 7.39 (s, 1H), 7.28 (d, 1H), 6.76 – 6.49 (m, 2H), 5.98 – 5.96 (m, 1H), 4.49 – 4.55 (m, 2H), 3.95 (s, 3H), 3.73 – 3.68 (m, 2H), 2.65 (d, 3H). Example 111.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-methylthieno[3,2-b]pyridin-7- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 362)
Figure imgf000519_0001
A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (80 mg, 0.25 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (79 mg, 0.50 mmol, 2.00 equiv), EPhos (67 mg, 0.12 mmol, 0.50 equiv), EPhos Pd G4 (115 mg, 0.12 mmol, 0.50 equiv) and Cs2CO3 (245 mg, 0.75 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product. The product was precipitated by Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 50% B in 10 min, 50% B; Wave Length: 220/254 nm; RT1(min): 9.0. This resulted in 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2- methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (9 mg, 8.01%) as a off-white solid. LC-MS: (M+H)+ found: 440.20. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H), 8.36 (t, 1H), 7.54 (d, 1H), 7.45 (s, 1H), 7.29 (d, 1H), 6.78 – 6.67 (m, 2H), 6.13 – 6.10 (m, 1H), 4.50 – 4.46 (m, 2H), 3.92 (s, 3H), 3.74 – 3.68 (m, 2H), 2.65 (d, 3H). Example 112.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2-[1- (difluoromethyl)cyclopropyl] ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 364)
Figure imgf000520_0001
To a stirred solution of 4-bromo-3-iodopyridine (500 mg, 1.77 mmol, 1.00 equiv), palladium chloride; bis(triphenylphosphine) (124 mg, 0.18 mmol, 0.10 equiv), TEA (535 mg, 5.31 mmol, 3.00 equiv) in MeCN (6 mL) was added CuI (34 mg, 0.18 mmol, 0.10 equiv) and 1-(difluoromethyl)-1-ethynylcyclopropane (1.17 g, 2.12 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (2x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20:1) to afford 4-bromo-3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridine (490 mg, 99%) as a yellow oil. LC-MS: M+H+ found: 272.
Figure imgf000520_0002
To a stirred solution of 4-bromo-3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}pyridine (300 mg, 1.10 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (420 mg, 1.16 mmol, 1.50 equiv), Pd2(dba)3.CHCl3 (100 mg, 0.11 mmol, 0.10 equiv) in dioxane (10 mL) was added PPh3 (28 mg, 0.11 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 degrees under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The resulting mixture was concentrated under reduced pressure to afford 3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (400 mg) as a yellow solid. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 320.1.
Figure imgf000521_0001
Into a 40-mL vial were placed 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), 3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridin-4-ylboronic acid (77 mg, 0.32 mmol, 1.20 equiv), Na2CO3 (86 mg, 0.81 mmol, 2.00 equiv), Pd(PPh3)4 (31 mg, 0.03 mmol, 0.10 equiv) in dioxane (5 mL) and H2O (1 mL). The resulting solution was stirred for overnight at 100 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (6 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2x1 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 7.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2-[1- (difluoromethyl)cyclopropyl] ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (46.9 mg, 36.0%) as a white solid. LC-MS: (M+H)+ found: 484.25. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.49 (d, 1H), 8.30 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 6.67 (d, J = 4.8 Hz, 2H), 6.15 (t, 1H), 5.76 (t, 1H), 4.41 – 4.37 (m, 2H), 3.80 (s, 3H), 3.69 – 3.66 (m, 2H), 1.26 – 1.13 (m, 4H). Example 113.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 228)
Figure imgf000522_0001
A mixture of 3-chloro-2-{[1,2] thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (120 mg, 0.39 mmol, 1.00 equiv) in DMF (4.00 mL) were added 3-fluoro- 2-methoxyaniline (110 mg, 0.78 mmol, 2.00 equiv), EPhos (104 mg, 0.19 mmol, 0.50 equiv), EPhos Pd G4 (180 mg, 0.19 mmol, 0.50 equiv)and Cs2CO3 (383 mg, 1.17 mmol, 3.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (40:1) to afford crude product. The crude product (35 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 50% B in 8 min; Wave Length: 254/220 nm; RT1(min): 8;) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.2 mg, 5.04%) as a off-white solid. LC-MS: (M+H)+ found: 411.25. 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.81 (d, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.48 (s, 1H), 6.89 – 6.53 (m, 2H), 6.08 – 6.03 (m, 1H), 4.56 – 4.52 (m, 2H), 3.98 (s, 3H), 3.74 – 3.70 (m, 2H). Example 114.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 275)
Figure imgf000523_0001
To a solution of anise alcohol (860 mg, 6.19 mmol, 1.05 equiv) in DMF (10 mL) was added sodium hydride (260 mg, 6.50 mmol, 1.10 equiv, 60% in oil) at 0 degrees C. The mixture was stirred for 15 min.7-chlorothieno[3,2-b]pyridine (1.00 g, 5.90 mmol, 1.00 equiv) was added and the mixture was allowed to warm to RT and stirred for 1h. The reaction mixture was quenched by water and extracted with DCM (3*25 mL). The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 7-[(4- methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.4 g, 87.53%) as a white solid. LC-MS: M+H+ found: 272.1.
Figure imgf000523_0002
A solution of 7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.30 g, 4.79 mmol, 1.00 equiv) in tetrahydrofuran (40 mL) was treated with n-BuLi (4.2 mL, 10.54 mmol, 2.20 equiv) for 1h at -78 degrees C under nitrogen atmosphere followed by the addition of carbon tetrabromide (1.59 g, 4.79 mmol, 1.00 equiv) dropwise at -78 degrees C. The resulting mixture was stirred for 1h at -78 degrees C under argon atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (40 mL) at 0 degrees C. The resulting mixture was extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 2-bromo-7-[(4- methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.2 g, 71.51%) as a white solid. LC-MS: (M+H)+ found: 350.0.
Figure imgf000524_0001
A mixture of 2-bromo-7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.10 g, 3.15 mmol, 1.00 equiv) in TFA (15 mL) and DCM (15 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product is recrystallized with ether and pentanes to afford 2- bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.2 g, 99.93%) as a white solid. LC-MS: (M+H)+ found: 230.0.
Figure imgf000524_0002
To a stirred mixture of 2-bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.10 g, 3.20 mmol, 1.00equiv) and NaOMe in MeOH (4.30 g, 15.99 mmol, 5.00 equiv, 30w/w%) in MeOH (30 mL) was added CuBr (70 mg, 0.48 mmol, 0.10 equiv) at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 61.18%) as a light brown solid. LC-MS: (M+H)+ found:182.00.
Figure imgf000524_0003
A mixture of 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 2.93 mmol, 1.00 equiv) in phosphorus oxychloride (6 mL) was stirred for 2h at 90 degrees C under nitrogen atmosphere. The reaction was quenched by the addition of Water/Ice (30 mL) at 0degrees C, treated with aqueous 50 % sodium hydroxide solution. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to afford 7-chloro-2-methoxythieno[3,2-b]pyridine (250 mg, 42.81%) as a white solid. LC-MS: (M+H)+ found:199.90.
Figure imgf000525_0001
Into a 8 mL vial were added 7-chloro-2-methoxythieno[3,2-b]pyridine (40 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (102 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl2 (14 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL). The resulting mixture was stirred for 1 days at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 210.2.
Figure imgf000525_0002
To a stirred mixture of 2-bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.14 mmol, 1.00 equiv) and 2-methoxy-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (49 mg, 0.17 mmol, 1.20 equiv) in dioxane (1.0 mL) and H2O (0.2 mL) were added XPhos palladium(II) biphenyl-2-amine chloride (11 mg, 0.01 mmol, 0.10 equiv) and Na2CO3 (30 mg, 0.28 mmol, 2.00 equiv) in portions at room temperature under argon atmosphere.The resulting mixture was stirred for overnight at 50 degrees C under argon atmosphere. The resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford 3-[(3- fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (11.7 mg, 18.87%) as a white solid. LC-MS: (M+H)+ found: 439.95. 1H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.42 (m, 2H), 7.47 (d, 1H), 7.36 (s, 1H), 6.63 – 6.73 (m, 2H), 6.58 – 6.55 (m, 1H), 5.98 – 5.96 (m, 1H), 4.47 – 4.45 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.69 (t, 2H) Example 115.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 365)
Figure imgf000526_0001
Into a 8 mL vial were added 2-methoxythieno[3,2-b]pyridin-7-ylboronic acid (40 mg, 0.19 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (71 mg, 0.19 mmol, 1.00 equiv) and 2nd Generation XPhos Precatalyst (15 mg, 0.02 mmol, 0.10 equiv) and Na2CO3 (61 mg, 0.57 mmol, 3.00 equiv) and dioxane (2.0 mL) and H2O (0.4 mL) at room temperature. The resulting mixture was stirred for overnight at 50 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (50:1) to afford crude product (100 mg).The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 69% B in 10 min, 69% B; Wave Length: 254/220 nm; RT1(min): 5.63) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2- methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (17.2 mg, 19.62%) as a white solid. LC-MS: M+H+ found: 455.90. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.35 (t, 1H), 7.47 (d, 1H), 7.42 (s, 1H), 6.80 – 6.67 (m, 3H), 6.16 - 6.10 (m, 1H), 4.50 - 4.44 (m, 2H), 4.05 (s, 3H), 3.91 (s, 3H), 3.70 - 3.64 (m, 2H). Example 116.8-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}-1H-1,5-naphthyridin-2-one (compound 345)
Figure imgf000527_0001
To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (50.00 g, 292.21 mmol, 1.00 equiv) and PPh3 (91.97 g, 350.65 mmol, 1.20 equiv) in dry THF (500 mL) was added tert-butyl N-(2-hydroxyethyl)carbamate (56.52 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 20 min at 0 degrees C under argon atmosphere. Then, the above mixture was added DIAD (70.90 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at 0 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3-carboxylate (150 g, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 315.
Figure imgf000528_0001
To a stirred solution of methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole- 3-carboxylate (150 g, 477.25 mmol, 1.00 equiv) in DCM (200 mL) was added 4 M HCl in dioxane (600 mL) dropwise at 0 degrees C. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with CH2Cl2 (3x100 mL) to afford methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108 g, crude) as an off-white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 215.
Figure imgf000528_0002
To a stirred solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108.00 g, 504.25 mmol, 1.00 equiv) in toluene (1000 mL) was added TEA (102.05 g, 1.00 mol, 2.00 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at 100 degrees C under air atmosphere. The precipitated solids were collected by filtration and washed with DCM (3x50 mL) to afford 3-nitro-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (68 g, 74.04%) as an off-white solid. LC-MS: (M+H)+ found: 183.
Figure imgf000529_0001
To a stirred solution of 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.00 g, 82.36 mmol, 1.00 equiv) in methanol (150 mL) was added 10% wet Pd/C (5.00 g, 33w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under hydrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (4x100 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (12 g, 95.76%) as an off-white solid. LC-MS: (M+H)+ found:153.
Figure imgf000529_0002
To a stirred solution of 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 13.14 mmol, 1.00 equiv) in ACN (200 mL) in ACN (200 mL) was added NBS (2.34 g, 13.14 mmol, 1.00 equiv) at -30°C. The resulting mixture was stirred for 1h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (mobile phase, MeCN in water, 0% to 100% in 30 min) to afford 3-amino-2-bromo-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (2.00 g, 65.85%) as yellow solid. LC-MS: (M+H)+ found: 231.
Figure imgf000529_0003
To a solution of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (800 mg, 3.46 mmol, 1.00 equiv) and Cs2CO3 (2256 mg, 6.92 mmol, 2.00 equiv) in DMF (15.00 mL) were added Ephos Pd G4 (477 mg, 0.52 mmol, 0.15 equiv) and 1-chloro-3-iodo-2- methoxybenzene (1115 mg, 4.15 mmol, 1.20 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (30:1) to afford 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 38.86%) as a yellow solid. LC-MS: (M+H)+ found: 371.
Figure imgf000530_0001
To a solution of 8-bromo-2-fluoro-1,5-naphthyridine (500 mg, 2.20 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (671 mg, 2.64 mmol, 1.20 equiv) in THF (10 mL) were added KOAc (540 mg, 5.51 mmol, 2.50 equiv) and Pd(dppf)Cl2*CH2Cl2 (179 mg, 0.22 mmol, 0.10 equiv). After stirring for 2hrs at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH3OH (10:1) to afford 6-fluoro- 1,5-naphthyridin-4-ylboronic acid (200 mg, 47.31%) as a yellow solid. LC-MS: (M+H)+ found: 193.
Figure imgf000530_0002
To a solution of 6-fluoro-1,5-naphthyridin-4-ylboronic acid (62 mg, 0.32 mmol, 1.50 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (80 mg, 0.21 mmol, 1.00 equiv) in dioxane (1.0 mL) and H2O (0.1 mL) were added Na2CO3 (69 mg, 0.65 mmol, 3.00 equiv) and 2nd Generation XPhos precatalyst (17 mg, 0.02 mmol, 0.10 equiv) . After stirring for 2h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH3OH (10:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-fluoro- 1,5-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 63.51%) as a yellow solid. LC-MS: (M+H)+ found: 439.
Figure imgf000531_0001
To a To a stirred solution of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-fluoro-1,5- naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.11 mmol, 1.00 equiv) in DMF (2.00 mL) and THF (5.00 mL), DMSO (0.2 mL) and H2O (1.5 mL) were added NaOH (9 mg, 0.23 mmol, 2.00 equiv). The resulting mixture was stirred for 5h at 50 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 8-{3-[(3- chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1H-1,5- naphthyridin-2-one (15.2 mg, 29.01%) as a yellow solid. LC-MS: (M+H)+ found: 436.90. 1H NMR (300 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.50 – 8.36 (m, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.45 (s, 1H), 6.85 (d, 1H), 6.77 – 6.62 (m, 2H), 6.25 – 6.17 (m, 1H), 4.53 (t, 2H), 3.89 (s, 3H), 3.70 (d, 2H). Example 117.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy-1H-pyrrolo[3,2- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 299)
Figure imgf000532_0001
A solution of Trimethyloxonium tetrafluoroborate (78 mg, 0.53 mmol, 1.13 equiv) in chloroform (5 mL) was treated with 7-bromo-1H,3H-pyrrolo[3,2-b]pyridin-2-one (100 mg, 0.47 mmol, 1.00 equiv) for 10 min at 10 degrees C under nitrogen .The resulting mixture was stirred for 2 days at room temperature under nitrogen atmosphere. The resulting mixture was washed with 1x5 mL of EtOAc. The resulting mixture was extracted with EtOEt (3 x 10mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH 10:1) to afford 7-bromo- 2-methoxy-1H-pyrrolo[3,2-b]pyridine (80 mg, 75.06%) as a light yellow solid. LC-MS: M+H+ found 226.95.
Figure imgf000532_0002
Into a 8 mL vial were added 7-bromo-2-methoxy-1H-pyrrolo[3,2-b]pyridine (45 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (100 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl2.CH2Cl2 (16 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL) at room temperature. The resulting mixture was stirred for 2 h at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. After filtration, the filtrate was concentrated under reduced pressure The crude product (50 mg) was used in the next step directly without further purification LC-MS : M+H found: 275.2.
Figure imgf000533_0001
Into a 20 mL vial were added 2-methoxy-1H-pyrrolo[3,2-b]pyridin-7-ylboronic acid (35 mg, 0.18 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (68 mg, 0.18 mmol, 1.00 equiv) and Na2CO3 (58 mg, 0.55 mmol, 3.00 equiv)and 2nd Generation XPhos Precatalyst (14 mg, 0.02 mmol, 0.10 equiv) and dioxane (3.5 mL) and H2O (0.7 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford crude product (60 mg).The crude product (60 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy-1H-pyrrolo[3,2- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (11.9 mg, 14.75%) as a yellow solid. LC-MS: M+H+ found: 439.25. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.29 (s, 1H), 7.34 – 7.21 (m, 2H), 6.80 – 6.69 (m, 2H), 6.67 (d, 1H), 6.19 – 6.13 (m, 1H), 4.92 (d, 1H), 4.46 (t, 2H), 3.88 (s, 3H), 3.68 (d, 3H), 3.61 (s, 2H). Example 118.3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(3- methoxypropyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 303)
Figure imgf000534_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl )amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.21 mmol, 1.00 equiv) and 3- methoxypropylamine (0.50 mL) in DMSO (1.00 mL) was added DIEA (400 mg, 3.15 mmol, 15.00 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 10 min, 40% B; Wave Length: 254/220 nm; RT1(min): 10.38) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(3-methoxypropyl)amino]pyridin- 4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.5 mg, 7.90%) as a white solid. LC-MS: (M+H)+ found: 457.00. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.08 (s, 1H), 7.72 (d, 1H), 7.42-7.30 (m, 2H), 6.81-6.49 (m, 3H), 6.19-6.02 (m, 1H), 4.41 (m, 2H), 3.85 (s, 3H), 3.70-3.55 (m, 2H), 3.51-3.39 (m, 2H), 3.29-3.17 (m, 5H), 1.98-1.70(m, 2H). Example 119. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyacetamide (compound 333)
Figure imgf000535_0001
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv) and 1-(2,4- dimethoxyphenyl)methanamine (54 mg, 0.32 mmol, 1.20 equiv) in DMSO (3.00 mL) was added DIEA (522 mg, 4.04 mmol, 15.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (15 mL). The precipitated solids were collected by filtration and washed with water (3x5 mL). The residue was purified by Prep-TLC (CH2Cl2/MeOH 10:1) to afford 2-(3-{[(2,4- dimethoxyphenyl)methyl]amino}pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a light yellow solid(70.0 mg, 50.35%). LC-MS: (M+H)+ found: 519.05.
Figure imgf000535_0002
To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.19 mmol, 1.00 equiv) was added TFA (2.00 mL) dropwise at 0 degrees C. The resulting mixture was stirred for 2h at 50 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 368.95.
Figure imgf000536_0001
To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (55 mg, 0.15 mmol, 1.00 equiv) in Pyridine (1.00 mL) was added methoxyacetyl chloride (32 mg, 0.30 mmol, 2.00 equiv) in DCM (0.50 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of MeOH (1mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 63% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyaceta-mide (8.8 mg, 13.18%) as an off-white solid. LC-MS: (M+H)+ found: 441.05. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.61 (s, 1H), 8.48-8.10 (m, 2H), 7.64 (d, 1H), 7.37 (s, 1H), 6.75-6.60 (m, 1H), 6.59-6.47 (m, 1H), 6.00 (d, 1H), 4.65-4.37 (m, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.72 (s, 2H), 3.49 (s, 3H). Example 120.3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(2- methoxyethyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 332)
Figure imgf000537_0001
To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.21 mmol, 1.00 equiv) and DIEA (400 mg, 3.15 mmol, 15.00 equiv) in ethanamine, 2-methoxy- (0.50 mL) and DMSO (1.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(2- methoxyethyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.9 mg, 5.84%) as a white solid. LC-MS: (M+H)+ found: 443.30. 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.29 (m, 1H), 8.12 (s, 1H), 7.72 (d, 1H), 7.41 (d, 1H), 7.33 (s, 1H), 6.97-6.92 (m, 1H), 6.73-6.61 (m, 2H), 6.12-6.04 (m, 1H), 4.46-4.28 (m, 2H), 3.90 (s, 3H), 3.62-3.73 (m, 2H), 3.61-3.55 (m, 2H), 3.42-3.36 (m, 2H), 3.33 (s, 3H). Example 121. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methylpropanamide (compound 339)
Figure imgf000538_0001
To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.14 mmol, 1.00 equiv) and propanoyl chloride, 2-methyl-(30 mg, 0.27 mmol, 2.00 equiv) in Pyridine (2.00 mL) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.75) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2- methylpropanamide(4.2 mg,12.93%) as a white solid. LC-MS: (M+H)+ found: 439.05. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.25 (s, 1H), 8.36 (d, 1H), 8.21 (d, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.33 (s, 1H), 6.68-6.60 (m, 1H), 6.59-6.45 (m, 1H), 6.14-6.10 (m, 1H), 4.61-4.30 (m, 2H), 3.93 (s, 3H),3.72-3.60 (m, 2H), 2.75-2.57 (m, 1H), 1.16 (s, 6H). Example 122. N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (compound 337)
Figure imgf000539_0001
To a stirring solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazine-4-on (60 mg, 0.16 mmol, 1.00 equiv) in pyridine were added Ac2O (33 mg, 0.33 mmol, 2.00 equiv) in 0.5 ml DCM dropwise at degree C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen. The crude product (70 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13% B to 43% B in 7 min, 43% B; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (13.2 mg, 18.38%) as white solid. LC-MS: (M+H)+ found: 411.05. 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.14 (s, 1H), 8.36 (t, 1H), 8.24 (d, 1H), 7.55 (d, 1H), 7.33 (s, 1H), 6.64-6.47 (m, 2H), 6.07 (d, 1H), 4.44 (t, 2H), 3.89 (s, 3H), 3.69 (t, 2H), 2.34 (s, 3H). Example 123. (1r,3r)-3-(dimethylamino)-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4- oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutane-1-carboxamide; formic acid (compound 342)
Figure imgf000539_0002
To a stirred solution of (1r,3r)-3-(dimethylamino)cyclobutane-1-carboxylic acid (60 mg, 0.42 mmol, 1.00 equiv) in THF (4.00 mL) was added oxalyl chloride (80 mg, 0.63 mmol, 1.50 equiv) and DMF (0.10 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under argon atmosphere. The reaction was monitored by TLC (DCM/MeOH = 5/1). The resulting mixture was used in the next step directly without further purification.
Figure imgf000540_0001
To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.14 mmol, 1.00 equiv) in Pyridine (0.30 mL) was added (1r,3r)-3-(dimethylamino)cyclobutane-1-carbonyl chloride (66 mg, 0.41 mmol, 3.00 equiv) in DCM (0.50 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (1 mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to 20% B in 8 min, 20% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford (1r,3r)-3- (dimethylamino)-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutane-1-carboxamide; formic acid (14.4 mg, 18.84%) as a off-white solid. LC-MS: (M+H)+ found: 494.10 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.23 (s, 1H), 8.36 (d, 1H), 8.26-8.14 (m, 2H), 7.55 (d, 1H), 7.32 (s, 1H), 6.69-6.60 (m, 1H), 6.55-6.49 (m, 1H), 6.11 (d, 1H), 4.69- 4.31 (m, 2H), 3.90 (s, 3H), 3.72-3.64 (m, 2H), 3.15-3.10 (m, 1H), 2.90-2.81 (m, 1H), 2.35- 2.27 (m, 2H), 2.12-2.01 (m, 8H). Example 124. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclopropanecarboxamide (compound 338)
Figure imgf000541_0001
Into a Volume were added 3-[(3-fluoro-2-methoxyphenyl) amino]-2-(3-fluoropyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), DIEA (522 mg, 4.04 mmol, 15.00 equiv), 1-(2,4-dimethoxyphenyl) methanamine (1.50 mL) and DMSO (1.50 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 50 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino] pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one(47 mg,33.66%) as a light yellow solid. LC-MS: (M+H)+ found: 519.05.
Figure imgf000542_0001
To a stirred solution of 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino]pyridin-4-yl)-3-[(3- fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (47 mg, 0.09 mmol, 1.00 equiv) was added TFA (2.00 mL) dropwise at 0 degrees C under air atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)+ found: 369.10.
Figure imgf000542_0002
To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (46 mg, 0.13 mmol, 1.00 equiv) in pyridine (1.50 mL) was added cyclopropanecarbonyl chloride (14 mg, 0.14 mmol, 1.10 equiv) in DCM (0.10 mL) dropwise at -30 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at -30 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 7 min; Wave Length: 254/220 nm; RT1(min): 6.32;) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3- yl)cyclopropanecarboxamide (5.80 mg, 10.64%) as a light yellow solid. LC-MS: (M+H)+ found: 437.05. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.25 (s, 1H), 8.38-8.22 (m, 2H), 7.56 (d, 1H), 7.37 (s, 1H), 6.74-6.44 (m, 2H), 6.11-5.98 (m, 1H), 4.46 (t, 2H), 3.89 (s, 3H), 3.71 (d, 2H), 1.90-1.76 (m, 1H), 0.89-0.76 (m, 4H). Example 125.2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 343)
Figure imgf000543_0001
A solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.40 mmol, 1.00 equiv) and DIEA (783 mg, 6.06 mmol, 15.00 equiv) in 2,2-dimethyl-1-propylamin (3 mL) and DMSO (2 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 36 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5;) to afford 2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20.60 mg, 11.51%) as a light yellow solid. LC-MS: (M+H)+ found: 439.10 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.67 (d, 1H), 7.47 (d, 1H), 7.31 (s, 1H), 7.11 (t, 1H), 6.70-6.61 (m, 1H), 6.60-6.49 (m, 1H), 5.99-5.91 (m, 1H), 4.49- 4.30 (m, 2H), 3.91 (s, 3H), 3.69 (d, 2H), 3.08 (d, 2H), 1.04 (s, 9H). Example 126.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 356)
Figure imgf000544_0001
To a stirred mixture of 3-bromo-4-chloropyridine(500 mg, 2.60 mmol, 1.00 equiv) and cyclopropylboronic acid (246 mg, 2.86 mmol, 1.10 equiv) and Cs2CO3(1.69 g, 5.20 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2(106 mg, 0.13 mmol, 0.05 equiv) in dioxane(10.0 mL) and H2O(2.0 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 100 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH2Cl2/MeOH 20:1) to afford 4- chloro-3-cyclopropylpyridine (290 mg, 72.66%) as a yellow oil. LC-MS: (M+H)+ found: 154.1.
Figure imgf000544_0002
To a stirred mixture of 4-chloro-3-cyclopropylpyridine(200 mg, 1.30 mmol, 1.00 equiv) and 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid(236 mg, 1.30 mmol, 1.00 equiv) and Na2CO3(414 mg, 3.90 mmol, 3.00 equiv) and XPhos palladium(II) biphenyl-2- amine chloride(102 mg, 0.13 mmol, 0.10 equiv) in dioxane(13.0 mL) and H2O(1.3 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h at 60 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH2Cl2/MeOH 20:1) to afford 2-(3- cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (230 mg, 69.47%) as a yellow oil. LC-MS: (M+H)+ found: 254.9.
Figure imgf000545_0001
To a stirred mixture of 2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one(200 mg, 0.77 mmol, 1.00 equiv) and 1,3-Dibromo-5,5-dimethylhydantoin (337 mg, 1.18 mmol, 1.50 equiv) in AcOH(7.8 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to afford 3-bromo-2-(3-cyclopropylpyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130.00 mg, 49.61%) as a white solid. LC-MS: (M+H)+ found: 334.8.
Figure imgf000545_0002
To a stirred mixture of 3-bromo-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) and Ephos Pd G4 (28 mg, 0.03 mmol, 0.10 equiv) and EPhos(32 mg, 0.06 mmol, 0.20 equiv) and Cs2CO3 (196 mg, 0.60 mmol, 2.00 equiv) in DMF (0.50 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.62) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.6 mg, 10.18%) as a red solid. LC-MS: (M+H)+ found: 410.25. 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.23 (m, 2H), 8.13 (s, 1H), 7.39-7.20 (m, 2H), 6.76-6.48 (m, 2H), 6.09-6.21 (m, 1H), 4.30-4.43 (m, 2H), 3.77 (s, 3H), 3.70-3.61(m, 2H), 2.21-2.10 (m, 1H), 1.00-0.81 (m, 2H), 0.79-0.62 (m, 2H). Example 127.2-(2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 335)
Figure imgf000546_0002
To a solution of 2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.00 g, 4.629 mmol, 1.00 equiv) and tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl]carbamate (1.78 g, 5.555 mmol, 1.20 equiv) in dioxane (10.00 mL) and H2O (2.00 mL) were added K2CO3 (1.28 g, 9.258 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (0.75 g, 0.926 mmol, 0.20 equiv).After stirring for 2 h at 80 degrees C under a nitrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with EA (20 mL). The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4- [4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (1.05 g, 68.87%) as a white solid. LC-MS: M+H found: 330.
Figure imgf000546_0001
To a stirred solution of tert-butyl N-(4-[4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (1.00 g, 3.036 mmol, 1.00 equiv)in DMF (20.00 mL)was added NBS (0.54 g, 3.036 mmol, 1.00 equiv) in portions at 0 degrees C. The resulting mixture was stirred for 2h at 80degrees C.The resulting mixture was filtered, the filter cake was washed with H2O and EA.The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin- 2-yl)carbamate (700 mg, 56.47%) as a white solid. LC-MS: M+H found: 408.
Figure imgf000547_0001
To a solution tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (200.00 mg, 0.490 mmol, 1.00 equiv)of and 3-chloro-2- methoxyaniline (154.41 mg, 0.980 mmol, 2.00 equiv) in THF (4.00 mL)were added t- BuONa (70.62 mg, 0.735 mmol, 1.50 equiv)and Pd PEPPSI IPentCl (42.16 mg, 0.049 mmol, 0.10 equiv). After stirring for 4h at 80degrees C under a nitrogen atmosphere. The resulting mixture was diluted with H2O (20mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl]pyridin-2-yl)carbamate (30 mg, 12.63%) as a pink solid. LC-MS: M+H found: 485.
Figure imgf000548_0001
To a stirred solution of tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (30.00 mg) in DCM (6.00 mL)was added TFA (2.00 mL)dropwise at rt . The resulting mixture was stirred for 2h at rt. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150mm 5um; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3* H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min, 50% B; Wave Length: 254; 220 nm; RT1(min): 6.97) to afford 2- (2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (6.0 mg, 25.0%) as a light yellow solid. LC-MS: M+H found: 385. 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.02 (s, 2H), 6.79 (t, J = 8.1 Hz, 1H), 6.65 (dd, J = 8.0, 1.5 Hz, 1H), 6.31 (dd, J = 8.2, 1.5 Hz, 1H), 5.94 (s, 2H), 4.35 (dd, J = 7.1, 5.1 Hz, 2H), 3.84 (s, 3H), 3.61 (ddd, J = 7.7, 4.7, 2.6 Hz, 2H). Example 129.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H-imidazo[4,5- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 336)
Figure imgf000548_0002
To a stirred solution of methyl 4-nitro-2H-pyrazole-3-carboxylate (5.00 g, 29.221 mmol, 1.00 equiv) and tert-butyl N-(2-bromoethyl)carbamate (9.82 g, 43.831 mmol, 1.5 equiv) in DMF (50.00 mL) were added K2CO3 (8.08 g, 58.441 mmol, 2 equiv) and NaI (2.19 g, 14.610 mmol, 0.5 equiv) at rt . Then the solution was stirred at rt about 16 h.The resulting mixture was diluted with water (50mL) and was washed with EA (4x50mL). The filtrate was concentrated under reduced pressure and get the methyl 2-[2-[(tert- butoxycarbonyl)amino]ethyl]-4-nitropyrazole-3-carboxylate about 11.8 g as a white solid. LC-MS: M+Na found: 337.10.
Figure imgf000549_0001
To a stirred solution of methyl 2-[2-[(tert-butoxycarbonyl)amino]ethyl]-4-nitropyrazole- 3-carboxylate (6.00 g) and HCl(gas)in 1,4-dioxane (20.00 mL) in DCM (40.00 mL) ,and then the solution was stirred at rt about 2h. The resulting mixture was extracted with DCM, the combined organic layers were washed with saturation NaHCO3, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and get the methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate about 4.2 g as a yellow solid. LC-MS: M+H found: 215.20.
Figure imgf000549_0002
To a stirred solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (4.20 g, 19.610 mmol, 1.00 equiv) and K2CO3 (9.49 g, 68.635 mmol, 3.50 equiv) in EtOH (40.00 mL, 688.541 mmol, 35.11 equiv). The solution was stirred at 50 degrees C about 16h. The resulting mixture was diluted with water (50 mL) and was washed with EA (4 x 50 mL). The combined organic layers were washed with saturated salt solution (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and get the 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 650 mg as a white solid. LC-MS: M+H found: 183.10.
Figure imgf000550_0001
Into a 100 mL Stand-up flask were added 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (0.6 g) , Pd/C (0.26 g) and EtOH (35.00 mL) at rt. Then replace the hydrogen and attach the stand-up flask to the hydrogen packet. The solution was stirred at rt for 16h.The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain crude product 3-amino-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (520 mg) as a white solid. LC-MS: M+H found: 153.10.
Figure imgf000550_0002
To a stirred solution of 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500.00 mg, 3.286 mmol, 1.00 equiv) in MeCN (5.00 mL) were added NBS (643.36 mg, 3.615 mmol, 1.10 equiv) dropwise at 0 degrees C. Then the solution was stirred at rt about 30 min. The resulting mixture was diluted with water (50 mL) and was washed with EA (4 x 50 mL). The combined organic layers was concentrated under reduced pressure and get the 3- amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 370 mg(yield = 49%) as a yellow solid. LC-MS: M+H found: 231.
Figure imgf000550_0003
A mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.00 mg, 0.043 mmol, 1.00 equiv) and 3-chloro-2-methoxyphenylboronic acid (9.68 mg, 0.052 mmol, 1.20 equiv), Cu(OAc)2 (8.65 mg, 0.048 mmol, 1.1 equiv), Et3N (13.14 mg, 0.130 mmol, 3 equiv) in DCE (0.50 mL) was stirred for 12h at 25 °C under oxygen atmosphere. The residue was dissolved in water (10 mL).The resulting mixture was extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH=15/1) to afford 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5 mg, 29.53%) as a white solid. LC-MS: M+H found: 371.05.
Figure imgf000551_0001
To a stirred solution of 7-bromo-1H,3H-imidazo[4,5-b]pyridin-2-one (325.00 mg, 1.519 mmol, 1.00 equiv) and bis(pinacolato)diboron (771.23 mg, 3.037 mmol, 2.00 equiv) in DMF (4.00 mL, 51.687 mmol, 44.25 equiv) were added KOAc (298.07 mg, 3.037 mmol, 2.00 equiv) and Pd(dppf)Cl2 (222.22 mg, 0.304 mmol, 0.20 equiv)at RT under N2 atmosphere. Then, the solution was stirred at 150 degrees C in microwave. The resulting mixture was diluted with 5ml of DMF and filtrated. Then, The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 1% to 100% gradient in 10 min; detector, UV 254 nm to afford 2-oxo-1H,3H-imidazo[4,5-b]pyridin-7-ylboronic acid (138 mg, 66.02%) as a brown solid. LC-MS: M+H found: 180.05.
Figure imgf000551_0002
To a stirred mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.00 mg, 0.108 mmol, 1.00 equiv) and 2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-ylboronic acid (38.52 mg, 0.215 mmol, 2 equiv) in THF (0.40 mL) and H2O (0.10 mL) were added K2CO3 (29.75 mg, 0.216 mmol, 2.00 equiv) and XPhos Pd G3 (18.22 mg, 0.022 mmol, 0.2 equiv) in portions at RT under N2 atmosphere. The resulting mixture was stirred for 16 hours at 80 degrees C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (1x110 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA and MeOH 50:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.8 mg, 8.17%) as a off-white solid. LC-MS: M+H found: 426.2 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 10.46 (s, 1H), 8.30 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J = 5.6 Hz, 1H), 6.74 – 6.68 (m, 2H), 6.13 (p, J = 4.1 Hz, 1H), 4.46 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.68 (q, J = 6.6, 4.8 Hz, 2H). Example 130.3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxy-1,7-naphthyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 350)
Figure imgf000552_0001
To a stirred mixture of 6-methoxy-1H-1,7-naphthyridin-4-one (300 mg, 1.703 mmol, 1.00 equiv) and phosphorus oxychloride (3 mL, 19.567 mmol, 11.49 equiv) for 2 hours at 100 degrees C under N2 atmosphere. The reaction was quenched with H2O at 0 degrees C. The aqueous layer was extracted with EA and H2O 3x1150 mL). The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 4-chloro-6-methoxy-1,7-naphthyridine (120 mg, 36.21%) as a light yellow oil. LC-MS: M+H found: 194.95.
Figure imgf000553_0001
To a stirred mixture of 4-chloro-6-methoxy-1,7-naphthyridine (360 mg, 1.850 mmol, 1.00 equiv) and 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (1100.79 mg, 3.700 mmol, 2 equiv) in dioxane (4 mL, 47.216 mmol, 25.53 equiv) and H2O (1 mL, 55.508 mmol, 30.01 equiv) were added Pd(dppf)Cl2CH2Cl2 (150.69 mg, 0.185 mmol, 0.1 equiv) and K2CO3 (511.29 mg, 3.700 mmol, 2 equiv) in portions at RT. The resulting mixture was stirred for 2 hours at 80 degrees C under N2 atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH= 10:1) to afford 3-chloro-2-(6- methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (320 mg, 52.46%) as a light yellow solid. LC-MS: M+H found: 330.2.
Figure imgf000553_0002
To a stirred mixture of 3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.607 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (114.71 mg, 0.728 mmol, 1.2 equiv) in dioxane (5.00 mL) were added Cs2CO3 (592.87 mg, 1.821 mmol, 3.00 equiv) and EPhos (32.44 mg, 0.061 mmol, 0.10 equiv) and EPhos Pd G4 (55.71 mg, 0.061 mmol, 0.10 equiv) in portions at RT under N2 atmosphere. The resulting mixture was stirred for 16 hours at 50 degrees C under N2 atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (1x1 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6- methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (37.0 mg, 13.57%) as a light yellow solid. LC-MS: M+H found: 451.0. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.9 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.44 (s, 1H), 6.61 (dd, J = 8.1, 1.5 Hz, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.49 (dd, J = 7.1, 5.0 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 3.77 – 3.69 (m, 2H). Example 131. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 351)
Figure imgf000554_0001
To a solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.399 mmol, 1.00 equiv) and 1H-pyrazolo[3,4-b]pyridin-4-ylboronic acid (78.06 mg, 0.000 mmol, 1.20 equiv) in dioxane (2.00 mL) and H2O (0.40 mL) were added K2CO3 (110.35 mg, 0.798 mmol, 2.00 equiv) and Pd(dppf)Cl2*CH2Cl2 (32.52 mg, 0.040 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (400 mg, 69.41%) as a yellow solid. LC-MS: M+H found: 289
Figure imgf000555_0001
To a solution of 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (400.00 mg, 1.386 mmol, 1.00 equiv) in DMF (8.00 mL)was added NaH (66.50 mg, 1.663 mmol, 1.20 equiv, 60%) at 0 degrees C. The mixture was stirred for 15 min. [2-(chloromethoxy)ethyl]trimethylsilane (277.19 mg, 1.663 mmol, 1.20 equiv)was added and the mixture was allowed to warm to RT and stirred for 2 h.The reaction was quenched with H2O (50 ml) at 0 degrees C. The resulting mixture was filtered, the filter cake was washed with H2O (30 mL). The filter cake was concentrated under reduced pressure to afford 3-chloro-5-[[2-(trimethylsilyl)ethoxy]methyl]-2-(1-[[2- (trimethylsilyl)ethoxy]methyl] pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 40.61%) as a yellow solid. LC-MS: M+H found: 549.
Figure imgf000555_0002
To a solution of 3-chloro-5-{[2-(trimethylsilyl)ethoxy]methyl}-2-(1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 0.910 mmol, 1 equiv) and 3-chloro-2-methoxyaniline (286.95 mg, 1.820 mmol, 2 equiv) in DMF (12.50 mL, 161.452 mmol, 177.42 equiv) were added Cs2CO3 (593.24 mg, 1.820 mmol, 2 equiv) and EPhos Pd G4 (418.12 mg, 0.455 mmol, 0.5 equiv), EPhos (486.87 mg, 0.910 mmol, 1 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-5-{[2- (trimethylsilyl)etho xy]methyl}-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyridin-4-yl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200 mg, 14.98%) as a brown solid. LC-MS: M+H found: 670.
Figure imgf000556_0001
To a stirred solution of 3-[(3-chloro-2-methoxyphenyl)amino]-5-[[2- (trimethylsilyl)ethoxy]methyl]-2-(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazolo[3,4- b]pyridin-4-yl)-6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200.00 mg) in HCl (gas )in 1,4- dioxane (5.00 mL) at rt. The resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL). EDA(1 ml) was added at 0 degrees C. The resulting mixture was stirred for 2 h at rt.The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EA (3 x 30mL). The combined organic layers were washed with brine (1 x 20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford crude product. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 51% B in 7 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.37) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H- pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4 mgˈ11.4%) as a white solid. LC-MS: M+H found: 410. 1H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 6.72 – 6.64 (m, 2H), 6.21 – 6.12 (m, 1H), 4.41 (t, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H). Example 132. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 352)
Figure imgf000557_0001
To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (380.95 mg, 1.768 mmol, 2.00 equiv) and 4-chlorothieno[2,3-b]pyridine (150.00 mg, 0.884 mmol, 1.00 equiv) in dioxane (5.00 mL, 59.020 mmol, 66.74 equiv) and H2O (1.00 mL, 0.056 mmol, 0.06 equiv) were added Pd(dppf)Cl2 (64.70 mg, 0.088 mmol, 0.10 equiv) and K2CO3 (244.42 mg, 1.768 mmol, 2.00 equiv) at rt under N2 atmosphere. Then, the solution was stirred at 80 degrees C for 2 h. The mixture was diluted with 300 ml water and filtrate the solid to afford 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (109 mg, 40.45%) as a black solid. LC-MS: M+1 found: 304.95.
Figure imgf000557_0002
To a stirred solution of 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (130.00 mg, 0.427 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (134.46 mg, 0.853 mmol, 2 equiv) in DMF (7.00 mL, 0.008 mmol, 0.25 equiv) were added Cs2CO3 (277.98 mg, 0.853 mmol, 2.00 equiv), EPhos (228.13 mg, 0.427 mmol, 1.00 equiv) and EPhos Pd G4 (195.92 mg, 0.213 mmol, 0.50 equiv) at rt under N2 atmosphere. Then, the solution was stirred at 50 degrees C for 2 h. The resulting mixture was diluted with water (50 mL) and washed with 3×40 ml of EA. The filtrate was concentrated under reduced pressure.The residue was purified by reverse flash chromatography with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.62) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3- b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.9 mg, 3.25%) as a yellow solid. LC-MS: M+1 found: 425.9. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.44 (s, 1H), 6.67 (dd, J = 8.1, 1.8 Hz, 1H), 6.63 (t, J = 7.9 Hz, 1H), 6.12 (dd, J = 7.8, 1.8 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.85 (s, 3H), 3.70 (s, 2H). Example 133. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7- yl}-5H,6H,7H-pyrazolo [1,5-a]pyrazin-4-one (compound 353)
Figure imgf000558_0001
A solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 2.00 mmol, 1.00 equiv) and bis(pinacolato)diboron (1013.81 mg, 3.99 mmol, 2.00 equiv), KOAc (489.77 mg, 4.99 mmol, 2.50 equiv) and Pd(dppf)Cl2 (146.06 mg, 0.200 mmol, 0.1 equiv) in DME (30.00 mL, 309.92 mmol,) was stirred 2h at 100°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was filtered; the filter cake was washed with DCM (2x210ml). The filtrate was concentrated under reduced pressure. The residue was dissolved in EA (5ml). The resulting mixture was filtered; the filter cake was washed with EA (2x210ml). The filtrate was concentrated under reduced pressure to afford crude product 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-ylboronic acid (800 mg) as a black oil. LC-MS: (M+H) + found: 216.3.
Figure imgf000559_0001
To a solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol, 1.00 equiv) in DMF (5 mL, 64.61 mmol, 25.59 equiv) was added sodium hydride (60% in oil, 90.98 mg) at 0 degrees C. The mixture was stirred for 15 min. [2- (chloromethoxy)ethyl]trimethylsilane (547.25 mg, 3.28 mmol, 1.30 equiv) was added and the mixture was allowed to warm to RT and stirred for 3h. The reaction mixture was quenched with water and extracted with DCM (3*25 mL). The residue was purified by prep-TLC (DCM:MeOH =15:1) to afford 7-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine(400 mg, 48.26%) as a brown solid. LC-MS: (M+H)+ found: 328.1.
Figure imgf000559_0002
To a solution of 7-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine (400 mg, 1.22 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-ylboronic acid (787.36 mg, 3.65 mmol, 3 equiv) in dioxane (20.00 mL) and H2O (4.00 mL) were added K2CO3 (420.99 mg, 3.045 mmol, 2.5 equiv) and Pd(dppf)Cl2 (89.15 mg, 0.122 mmol, 0.10 equiv) . After stirring for 5h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro- 2-(1-{[2-(trimethylsilyl) ethoxy] methyl}pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (250 mg, 48.97%) as a brown solid. LC-MS: (M+H)+ found: 419.3.
Figure imgf000560_0001
To a solution of 3-chloro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3- b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.477 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (112.85 mg, 0.716 mmol, 1.5 equiv) in DMF (10.00 mL) and EPhos (127.65 mg, 0.238 mmol, 0.5 equiv) were added Cs2CO3 (388.84 mg, 1.192 mmol, 2.50 equiv) and EPhos Pd G4 (219.25 mg, 0.239 mmol, 0.50 equiv) . After stirring for 3h at 50°C under a nitrogen atmosphere, the resulting mixture was extracted with EA (3x50ml). The combined organic layers were washed with brine (3x20ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. the resulting mixture was concentrated under reduced pressure. The residue was purified three times by prep-TLC (DCM:MeOH 20:1) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-2-[(2Z)-3-[(E)-(2-iminoethylidene) amino]prop-2-en- 1-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20 mg, purity:50%) as off-white solid. LC-MS: (M+H)+ found: 540.4.
Figure imgf000560_0002
To a stirred solution of 3-[(3-chloro-2-methoxyphenyl) amino]-2-(1-{[2-(trimethylsilyl) ethoxy] methyl} pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg) in HCl of dioxane (2.5 mL) at RT under N2 atmosphere for 2h. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3x15ml), dried over anhydrous Na2SO4. After extraction, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 10 min, 45% B; Wave Length: 254/220 nm; RT1(min): 9.42) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3- b]pyridin-7-yl}-5H,6H,7H-pyrazolo [1,5-a]pyrazin-4-one (7.1 mg, 1.9 %) as a white solid. LC-MS: (M+H)+ found: 410.2. 1H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 3.6 Hz, 2H), 7.47 (d, J = 4.7 Hz, 1H), 6.80 – 6.67 (m, 2H), 6.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.54 (dd, J = 7.0, 5.1 Hz, 2H), 3.92 (s, 3H), 3.73 (s, 2H). Example 134. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 357)
Figure imgf000561_0001
To a solution of 4-chloro-6-methoxyquinoline (150.00 mg, 0.775 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (965.46 mg, 3.1 mmol, 4.00 equiv) in dioxane (5.00 mL) and H2O (1.00 mL) were added K2CO3 (214.13 mg, 1.550 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (63.11 mg, 0.078 mmol, 0.10 equiv). After stirring for 2h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (100mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)-3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 43.55%) as a brown solid. LC-MS: M+H found: 343.
Figure imgf000562_0001
To a solution of (7S)-3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.438 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (285.16 mg, 0.876 mmol, 2.00 equiv), EPhos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.85) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (44.4 mg, 21.70%)as a light yellow solid. LC-MS: M+H found: 464. 1H NMR (400 MHz, DMSO-d6):δ 8.70 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.0, 1.5 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.13 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.60 (m, 1H), 3.83 (s, 3H), 3.80 (dd, J = 8.0, 3.9 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.1, 8.5, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 135. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 358)
Figure imgf000563_0001
To a solution of 4-bromo-6-methoxyquinoline (200 mg, 0.840 mmol, 1.00 equiv) and (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (654.33 mg, 2.100 mmol, 2.5 equiv) in DMF (2mL) were added K2CO3 (290.25 mg, 2.100 mmol, 2.5 equiv) and Pd(dppf)Cl2 (61.47 mg, 0.084 mmol, 0.10 equiv). After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (15:1) to afford (7R)-3-chloro-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo [1,5-a]pyrazine-4-one(150 mg 66.9%) a brown solid. LC-MS: M+H found: 343.0.
Figure imgf000563_0002
To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs2CO3 (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2x120ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH 15:1) to afford the crude product. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.82) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(15mg 98.2%) as a as a white solid. LC-MS: M+H found: 464.0. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 2.9 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.62 (m, 1H), 3.82 (s, 3H), 3.79 (dd, J = 8.1, 4.1 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.2, 8.4, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 136. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 359)
Figure imgf000564_0001
To a solution of (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazine-4-one (651.62 mg, 2.092 mmol, 2.5 equiv) and 4-bromo-6-methoxy-1,7-naphthyridine (200 mg, 0.837 mmol, 1.00 equiv) in DMF (10 mL) were added K2CO3 (289.05 mg, 2.092 mmol, 2.5 equiv) and Pd(dppf)Cl2 (61.21 mg, 0.084 mmol, 0.1 equiv) . After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (15:1) to afford the (7R)-3-chloro-2-(6-methoxy- 1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg 73.2%) as a brown solid. LC-MS: M+H found: 344.0.
Figure imgf000565_0001
To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs2CO3 (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50ml). The combined organic layers were washed with brine (2x1 20ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=15:1) to afford the crude product (50mg, 78%). The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(8.1mg 99.4%) as a white solid. LC-MS: M+H found: 464.95. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 7.77 – 7.70 (m, 2H), 7.48 (s, 1H), 6.65 – 6.58 (m, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.1 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.96 (s, 3H), 3.77 (t, J = 3.8 Hz, 1H), 3.53 ̢ 3.43 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H). Example 137. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxy-1,7- naphthyridin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 253)
Figure imgf000566_0001
To a solution of 4-chloro-6-methoxy-1,7-naphthyridine (150.00 mg, 0.771 mmol, 1.00 equiv)and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (960.55 mg, 3.083 mmol, 4.00 equiv) in dioxane (5.00 mL) and H2O (1.00 mL) were added K2CO3 (213.04 mg, 1.541 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (62.79 mg, 0.077 mmol, 0.10 equiv). After stirring for 2h at 80degrees C under a nitrogen atmosphere. The resulting mixture was diluted with H2O (100mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)-3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150 mg, 46.82%) as a brown solid. LC-MS: M+H found: 344.
Figure imgf000567_0001
To a solution of (7S)-3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.582 mmol, 1.00 equiv)and 3- chloro-2-methoxyaniline (183.38 mg, 1.164 mmol, 2 equiv) in DMF (5.00 mL) were added EPhos Pd G4 (267.20 mg, 0.291 mmol, 0.5 equiv)EPhos (311.14 mg, 0.582 mmol, 1 equiv) and Cs2CO3 (379.11 mg, 1.164 mmol, 2.00 equiv) . After stirring for 2h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- TLC(DCM:MeOH=15:1) and Prep-HPLC(Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 60% B in 7 min, 60% B; Wave Length: 254/220 nm; RT1(min): 6.57) to afford (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-2-(6-methoxy-1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (75.3 mg, 27.51%) as a light yellow solid. LC-MS: M+H found: 465. 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.80 (d, J = 4.3 Hz, 1H), 8.35 (t, J = 2.9 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.48 (s, 1H), 6.62 (dd, J = 8.1, 1.6 Hz, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.10 (dd, J = 8.1, 1.6 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 3.77 (d, J = 7.9 Hz, 1H), 3.48 (ddd, J = 13.3, 8.2, 2.3 Hz, 1H), 1.60 (d, J = 6.5 Hz, 3H). Example 138. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 361)
Figure imgf000568_0001
To a solution of 4-bromo-6,7-dimethoxyquinoline (150.00 mg, 0.559 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (697.26 mg, 2.236 mmol, 4.00 equiv)in dioxane (5.00 mL) and H2O (1.00 mL) were added K2CO3 (154.64 mg, 1.118 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (45.58 mg, 0.056 mmol, 0.10 equiv). After stirring for 2h at 80degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H2O (100mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x20mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 68.61%) as a brown solid. LC-MS: M+H found: 373
Figure imgf000568_0002
To a solution of (7S)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.402 mmol, 1.00 equiv)and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (285.16 mg, 0.876 mmol, 2.00 equiv), EPhos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) and Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 6.60) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (42.8 mg, 21.43%) as a light yellow solid. LC-MS: M+H found: 494. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 4.7 Hz, 1H), 8.37 – 8.32 (m, 1H), 7.86 (s, 1H), 7.47 (d, J = 4.9 Hz, 2H), 7.39 (s, 1H), 6.61 (dd, J = 8.0, 1.5 Hz, 1H), 6.53 (t, J = 8.1 Hz, 1H), 6.11 (dd, J = 8.1, 1.6 Hz, 1H), 4.66 (ddd, J = 8.6, 6.4, 4.4 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.78-3.72 (m, 4H), 3.48 (ddd, J = 13.0, 8.6, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 139. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 360)
Figure imgf000569_0001
To a solution of 4-bromo-6,7-dimethoxyquinoline (300 mg, 1.119 mmol, 1 equiv) and (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (552.28 mg, 2.797 mmol, 2.5 equiv) in DMF (6 mL)were added K2CO3 (386.61 mg, 2.797 mmol, 2.50 equiv) and Pd(dppf)Cl2 (122.81 mg, 0.168 mmol, 0.15 equiv) . After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (20:1) to afford (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (300 mg, 90.8%) as a brown solid. LC-MS: M+H found: 373.00.
Figure imgf000570_0001
To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.805 mmol, 1 equiv), Cs2CO3 (655.47 mg, 2.013 mmol, 2.5 equiv) and 3-chloro-2-methoxyaniline (380.46 mg, 2.414 mmol, 3.00 equiv) in DMF (5 mL) was added EPhos Pd G4 (369.58 mg, 0.403 mmol, 0.5 equiv) and EPhos (215.17 mg, 0.403 mmol, 0.5 equiv) dropwise at 50°C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 30ml). The combined organic layers were washed with brine (3x220ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 59% B in 7 min, 59% B; Wave Length: 254/220 nm; RT1(min): 6.42) to afford(7R)-3-[(3-chloro-2- methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (10.3 mg, 98.4%) as a white solid. LC-MS: M+H found: 494.00. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.7 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.49 – 7.41 (m, 2H), 7.37 (s, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.2 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.77 (m, 4H), 3.50 (d, J = 10.5 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 140. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-[thien [3,2- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 239b)
Figure imgf000571_0001
To a solution of 7-chlorothieno[3,2-b]pyridine (300 mg, 1.769 mmol, 1.00 equiv) and (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (872.91 mg, 4.422 mmol, 2.5 equiv) in DMF (5 mL, 1.769 mmol, 1.00 equiv) were added K2CO3 (611.06 mg, 4.422 mmol, 2.5 equiv) and Pd(dppf)Cl2 (194.11 mg, 0.265 mmol, 0.15 equiv) . After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (25:1) to afford (7R)-3-chloro-7-methyl-2-{thieno[3,2-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (350 mg, 35.2%) as a black solid. LC-MS: M+H found: 318.90.
Figure imgf000571_0002
To a stirred solution of (7R)-3-chloro-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.627 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (197.75 mg, 1.254 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs2CO3 (613.25 mg, 1.882 mmol, 3 equiv) in portions at 50°C under N2 atmosphere. The resulting mixture was extracted with EA (2 x 50ml). The combined organic layers were washed with NaCl (2x250ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-[thien [3,2-b]pyridin-7-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (25.3 mg, 98.2%) as a white solid. LC-MS: M+H found: 439.95. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.22 – 8.14 (m, 2H), 7.60 (dd, J = 8.6, 5.3 Hz, 2H), 7.50 (s, 1H), 6.78 – 6.68 (m, 2H), 6.14 (dd, J = 7.6, 2.0 Hz, 1H), 4.67 (ddd, J = 9.1, 6.5, 4.5 Hz, 1H), 3.93 (s, 3H), 3.75 (dt, J = 12.9, 4.2 Hz, 1H), 3.52 – 3.43 (m, 1H), 1.67 (d, J = 6.4 Hz, 3H). Example 141. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-[thieno[3,2- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 239a)
Figure imgf000572_0001
To a solution of 7-chlorothieno[3,2-b]pyridine (100.00 mg, 0.590 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (367.35 mg, 1.179 mmol, 2.00 equiv) in dioxane (5.00 mL) and H2O (1.00 mL) were added K2CO3 (162.95 mg, 1.179 mmol, 2.00 equiv) and Pd(dppf)Cl2 CH2Cl2 (48.02 mg, 0.059 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H2O (50mL) and EA (50 mL).The resulting mixture was filtered, the filter cake was washed with H2O (10mL). The filterate was concentrated under reduced pressure to afford (7S)- 3-chloro-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (140 mg, 74.50%) as a dark grey solid. LC-MS: M+H found: 319.
Figure imgf000573_0001
To a solution of (7S)-3-chloro-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (120.00 mg, 0.376 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (118.65 mg, 0.752 mmol, 2.00 equiv) in DMF (5.00 mL) were added EPhos Pd G4 (172.89 mg, 0.188 mmol, 0.50 equiv),EPhos (201.32 mg, 0.376 mmol, 1.00 equiv)and Cs2CO3 (245.30 mg, 0.753 mmol, 2.00 equiv).After stirring for 2 h at 50 degrees C under a nitrogen atmosphere,The resulting mixture was diluted with H2O (100mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford crude product.The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 71% B in 8 min, 71% B; Wave Length: 254/220 nm; RT1(min): 6.93) to afford (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (46.0 mg, 27.11%) as a white solid. LC-MS: M+H found: 440. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, J = 4.9 Hz, 1H), 8.39 (dd, J = 4.1, 1.9 Hz, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.9, 5.3 Hz, 2H), 7.50 (s, 1H), 6.80 – 6.68 (m, 2H), 6.14 (dd, J = 7.6, 2.0 Hz, 1H), 4.74 – 4.61 (m, 1H), 3.93 (s, 3H), 3.75 (dt, J = 13.0, 4.2 Hz, 1H), 3.47 (ddd, J = 13.2, 9.2, 1.9 Hz, 1H), 1.68 (d, J = 6.5 Hz, 3H). Example 142. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 247b)
Figure imgf000574_0001
To a stirred solution of 2,2,6,6-tetramethylpiperidine (11.81 g, 83.631 mmol, 1.1 equiv) in THF (40 mL) was added n-BuLi (5.11 g, 79.829 mmol, 1.05 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at -5 degrees C under argon atmosphere. Then, the mixture was cooled to -78 degrees C. To the above mixture was added a solution of 4-chloro-3-fluoropyridine (5 g, 38.014 mmol, 1.00 equiv) in THF (40mL) dropwise and stirred for 2 h at -78 degrees C. Then, a solution of DMF (5.84 g, 79.829 mmol, 1.05 equiv) in THF (40 mL) was added into the above mixture. The resulting mixture was stirred for additional 1 h at -78 degrees C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (20 mL) at 0 degrees C.The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2:1) to afford 4-chloro-3-fluoropyridine-2- carbaldehyde (9.5g) as a yellow liquid. LC-MS: M+H found: 159.
Figure imgf000574_0002
To a stirred solution of 4-chloro-3-fluoropyridine-2-carbaldehyde (5 g, 28.833 mmol, 1.00 equiv) and (4-methoxyphenyl)methanethiol (4.45 g, 28.853 mmol, 1.00 equiv) in THF (125.00 mL, 1542.854 mmol, 53.51 equiv) was added t-BuOK (3.24 g, 28.833 mmol, 1 equiv) in portions at 0 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered; the filter cake was washed with ethyl acetate (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (50:1) to afford 4-chloro-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine-2- carbaldehyde (4.5 g, 53.13%) as a yellow solid. LC-MS: M+H found: 294.
Figure imgf000575_0001
To a stirred solution of 4-chloro-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine-2- carbaldehyde (4.5 g, 15.318 mmol, 1.00 equiv) in DCE (102.28 mL, 1291.920 mmol, 84.34 equiv) was added SO2Cl2 (2.48 mL, 30.636 mmol, 2 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. To the above mixture was added NH3(g) in MeOH (10.94 mL, 76.590 mmol, 5 equiv) dropwise over 5 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 7- chloro-[1,2]thiazolo[4,5-b]pyridine (800 mg, 27.86%) as a yellow solid. LC-MS: M+H found: 171.
Figure imgf000575_0002
Into a 8-mL sealed tube was placed 7-chloro-[1,2]thiazolo[4,5-b]pyridine (350 mg, 2.051 mmol, 1.00 equiv) in diaxone/H2O(3mL; 5:1), (7S)-3-chloro-7-methyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2556.70 mg, 8.204 mmol, 4 equiv) , Pd2(dba)3 (187.86 mg, 0.205 mmol, 0.1 equiv) , PCy3 (57.53 mg, 0.205 mmol, 0.1 equiv) and Cs2CO3 (2005.22 mg, 6.153 mmol, 3 equiv) . The resulting solution was stirred at 60oC for 2h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MeOH (3x5 mL) to afford (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 45.73%) as a grey solid LC-MS: M+H found: 320.
Figure imgf000576_0001
Into a 20-mL sealed tube was placed 3-chloro-2-methoxyaniline (221.78 mg, 1.407 mmol, 3 equiv) in DMF (2 mL), (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) , Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv) and EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (25:1). The semi-pure product was further purified by Prep-Flash-HPLC with the following conditions: (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 72% B in 8 min, 72% B; Wave Length: 254/220 nm; RT1(min): 6.85). This resulted in (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (87 mg) as an off-white solid. LC-MS: M+H found: 441. 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.81 (d, J = 4.7 Hz, 1H), 8.44 (d, J = 3.4 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 6.86 – 6.72 (m, 2H), 6.20 (dd, J = 7.3, 2.3 Hz, 1H), 4.72 (ddd, J = 10.7, 6.5, 4.4 Hz, 1H), 3.96 (s, 3H), 3.75 (dt, J = 13.3, 4.3 Hz, 1H), 3.49 (dd, J = 13.0, 9.6 Hz, 1H), 1.72 (d, J = 6.4 Hz, 3H). Example 143. (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 368)
Figure imgf000577_0001
Into a 20-mL sealed tube was placed (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv) and Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (25:1). The semi-pure product was purified by Prep-Flash-HPLC with the following conditions: (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 6.60). This resulted in 67 mg of (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]- 7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (67.8 mg, 33.10%) as a white solid LC-MS: M+H found: 425. 1H NMR (300 MHz, DMSO-d6) δ 9.31 (d, J = 1.4 Hz, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H), 6.78 – 6.68 (m, 1H), 6.66 – 6.57 (m, 1H), 6.05 (d, J = 8.1 Hz, 1H), 4.97 – 4.51 (m, 1H), 3.98 (s, 3H), 3.81 – 3.67 (m, 1H), 3.56 – 3.40 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 144. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 247a)
Figure imgf000578_0001
To a stirred solution of (7R)-2-bromo-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2 g, 8.693 mmol, 1 equiv) in DMF (20 mL) was added NCS (1.28 g, 9.586 mmol, 1.10 equiv) . The resulting mixture was stirred for 2 h at 50oC. The reaction was monitored by LCMS. The resulting mixture was diluted with H2O (200 mL). The resulting mixture was filtered and the filter cake was washed with H2O (20mL). The filter cake was concentrated under reduced pressure to afford (7R)-2-bromo-3-chloro-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (2 g, 86.98%) as a white solid. LC-MS: M+H found: 266.
Figure imgf000578_0002
To a solution of bis(pinacolato)diboron (480.02 mg, 1.890 mmol, 1.00 equiv) and (7R)- 2-bromo-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 1.890 mmol, 1.00 equiv) in DME (5.00 mL) were added KOAc (371.03 mg, 3.780 mmol, 2 equiv) and Pd(dppf)Cl2 (414.94 mg, 0.567 mmol, 0.3 equiv). After stirring for 16 h at 100°C under a nitrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with DCM .The filtrate was concentrated under reduced pressure and diluted with EA .The resulting mixture was filtered, the filter cake was washed with EA .The filtrate was concentrated under reduced pressure to afford (7R)-3-chloro-7-methyl-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (1.5 g, crude) as a black solid. LC-MS: M+H found: 230.
Figure imgf000579_0001
Into a 8-mL sealed tube was placed (7R)-3-chloro-7-methyl-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (403.43 mg, 1.758 mmol, 1 equiv) in diaxone/H2O(3mL; 5:1), 7-chloro-[1,2]thiazolo[4,5-b]pyridine (300 mg, 1.758 mmol, 1.00 equiv) , Pd2(dba)3 (161.02 mg, 0.176 mmol, 0.1 equiv) , PCy3 (49.31 mg, 0.176 mmol, 0.1 equiv) and Cs2CO3 (1718.76 mg, 5.274 mmol, 3 equiv). The resulting solution was stirred at 60oC for 2h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MeOH (3x5 mL) to afford (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (300 mg, 53.35%) as a grey solid. LC-MS: M+H found: 171.
Figure imgf000579_0002
To a solution of (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv)Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv) and 3-chloro-2-methoxyaniline (221.78 mg, 1.407 mmol, 3 equiv) in DMF (1.5 mL) were added EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv), EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) and Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, the resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (25:1). The crude product was purified by Prep-Flash-HPLC with following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 67% B in 10 min, 67% B; Wave Length: 254/220 nm; RT1(min): 8.77). This resulted in (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (39.6 mg, 19.11%) as a white solid. LC-MS: M+H found: 441. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.55 (s, 1H), 6.84 – 6.73 (m, 2H), 6.20 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H), 3.95 (s, 3H), 3.75 (d, J = 12.7 Hz, 1H), 3.54 – 3.44 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 145. (7R)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 369)
Figure imgf000580_0001
Into a 20-mL sealed tube was placed (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv), EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) and Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (30:1). The semi-pure product was purified by Prep-Flash-HPLC with following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.95). This resulted in (7R)-3-[(3-fluoro-2- methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (53.6 mg, 26.81%) as a white solid LC-MS: M+H found: 425. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.42 (s, 1H), 7.68 (d, J = 4.9 Hz, 1H), 7.49 (s, 1H), 6.74 (q, J = 7.8 Hz, 1H), 6.62 (t, J = 9.8 Hz, 1H), 6.05 (d, J = 8.3 Hz, 1H), 4.69 (d, J = 10.2 Hz, 1H), 3.98 (s, 3H), 3.75 (d, J = 13.2 Hz, 1H), 3.54 – 3.43 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 146. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 257b)
Figure imgf000581_0001
To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (500 mg, 2.439 mmol, 1.00 equiv) and 2-bromoacetonitrile (351.05 mg, 2.927 mmol, 1.2 equiv) in ACN (5 mL, 95.123 mmol, 39.00 equiv) was added Cs2CO3 (1589.28 mg, 4.878 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 5 hours at room temperature under N2 atmosphere. The resulting mixture was diluted with H2O (40 mL), The aqueous layer was extracted with EtOAc (50 mL) for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (4:1) to afford methyl 5-bromo-2- (cyanomethyl)pyrazole-3-carboxylate (500 mg, 84.00%) as a light yellow solid. LC-MS: (M+H)+ found: 244.1.
Figure imgf000581_0002
A mixture of methyl 5-bromo-2-(cyanomethyl)pyrazole-3-carboxylate (500 mg, 2.049 mmol, 1.00 equiv), pyridin-4-ylboronic acid (377.75 mg, 3.074 mmol, 1.5 equiv), K3PO4 (869.77 mg, 4.098 mmol, 2 equiv) and Pd(dppf)Cl2 (299.82 mg, 0.410 mmol, 0.2 equiv) in 1,4-dioxane (6 mL, 70.825 mmol, 34.57 equiv) and H2O (1.5 mL, 83.263 mmol, 40.64 equiv) was stirred for 2h at 80°C under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H2O (50 mL), The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (3:1) to afford methyl 2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole- 3-carboxylate (250 mg, 50.37%) as a light yellow solid. LC-MS: (M+H)+ found: 243.0.
Figure imgf000582_0001
Into a 50 mL round-bottom flask were added methyl 2-(cyanomethyl)-5-(pyridin-4- yl)pyrazole-3-carboxylate (450 mg, 1.858 mmol, 1 equiv), 2-bromoethyl methyl ether (309.84 mg, 2.230 mmol, 1.2 equiv) and DMF (20 mL) at 0°C. The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaH (44.58 mg, 1.858 mmol, 1 equiv) was added, The mixture was stirred 2 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (3:2) to afford methyl 2-(1-cyano-3-methoxypropyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (100 mg, 17.92%) as a yellow solid. LC-MS: (M+H)+ found: 301.0.
Figure imgf000582_0002
To a mixture of methyl 2-(1-cyano-3-methoxypropyl)-5-(pyridin-4-yl)pyrazole-3- carboxylate (400 mg, 1.332 mmol, 1 equiv) in MeOH (20 mL) was added CoCl2 (518.81 mg, 3.996 mmol, 3 equiv)at 0°C. The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaBH4 (503.91 mg, 13.320 mmol, 10 equiv) was added. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with NH4Cl (50 mL), The aqueous layer was extracted with EtOAc 50mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:1) to afford 7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (170 mg, 46.87%) as a yellow solid. LC-MS: (M+H)+ found: 273.0.
Figure imgf000583_0001
Into a 25 mL round-bottom flask were added 7-(2-methoxyethyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (140 mg, 0.514 mmol, 1 equiv), Br2 (90.38 mg, 0.565 mmol, 1.1 equiv), KOAc (75.69 mg, 0.771 mmol, 1.5 equiv) and HOAc (5 mL) at room temperature, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H2O (30 mL), The aqueous layer was extracted with EtOAc 30 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (2:1) to afford 3-bromo-7-(2- methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 55.38%) as a yellow solid. LC-MS: (M+H)+ found: 350.9.
Figure imgf000584_0001
A mixture of 3-bromo-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (90 mg, 0.256 mmol, 1 equiv), 3-chloro-2-methoxyaniline (60.58 mg, 0.384 mmol, 1.5 equiv), EPhos Pd G4 (23.54 mg, 0.026 mmol, 0.1 equiv), EPhos (13.70 mg, 0.026 mmol, 0.1 equiv) and Cs2CO3 (166.99 mg, 0.512 mmol, 2 equiv) in 1,4-dioxane (5 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. After the reaction. The resulting mixture was diluted with H2O (30 mL), The aqueous layer was extracted with EtOAc 30 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (2:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 45.60%) as a yellow solid. LC-MS: (M+H)+ found: 428.0.
Figure imgf000584_0002
3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.117 mmol, 1.00 equiv) was used for chiral separation(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 67% B in 8 min, 67% B; Wave Length: 254/220 nm; RT1(min): 8), and 2 peak was splitted from the material, the first peak is the product (7R)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (13.2 mg, 26.22%), This resulted in (7R)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (13.2 mg, 26.22%) as a yellow solid. LC-MS: (M+H)+ found: 428.2. 1H NMR (300 MHz, Chloroform-d) δ 8.56 (d, J = 5.2 Hz, 2H), 7.72 (d, J = 5.2 Hz, 2H), 7.16 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 8.1 Hz, 1H), 6.18 (d, J = 8.1 Hz, 1H), 5.87 (s, 1H), 4.65 (s, 1H), 4.06 (s, 3H), 3.98 (d, J = 13.0 Hz, 1H), 3.71 (s, 1H), 3.63 (t, J = 5.8 Hz, 2H), 3.41 (s, 3H), 2.55 – 2.43 (m, 1H), 2.15 (dd, J = 14.3, 7.1 Hz, 1H). Example 147. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 257a)
Figure imgf000585_0001
3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.117 mmol, 1.00 equiv) was used for chiral separation(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 67% B in 8 min, 67% B; Wave Length: 254/220 nm; RT1(min): 8), and 2 peak was splitted from the material, the first peak is the product (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.9 mg, 25.59%), This resulted in (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.9 mg, 25.59%) as a yellow solid. LC-MS: (M+H)+ found: 428.3 1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.72 (s, 2H), 7.16 (s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.65 (s, 1H), 6.18 (d, J = 8.2 Hz, 1H), 5.94 (s, 1H), 4.65 (s, 1H), 4.06 (s, 3H), 3.98 (d, J = 12.6 Hz, 1H), 3.71 (s, 1H), 3.63 (t, J = 5.8 Hz, 2H), 3.41 (s, 3H), 2.49 (s, 1H), 2.15 (s, 1H). Example 148. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 283)
Figure imgf000586_0001
Into a 100 mL round-bottom flask were added methyl 2-(cyanomethyl)-5-(pyridin-4- yl)pyrazole-3-carboxylate (2 g, 8.256 mmol, 1 equiv), tert-butyl 2-bromoacetate (2.42 g, 12.384 mmol, 1.5 equiv) and THF (50 mL) at 0°C. The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaH (0.20 g, 8.256 mmol, 1 equiv) was added. The mixture was stirred 2 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (2:1) to afford methyl 2-[3- (tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole-3-carboxylate (1.1 g, 37.38%) as a yellow solid. LC-MS: M+H found: 357.1.
Figure imgf000586_0002
To a mixture of methyl 2-[3-(tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole- 3-carboxylate (1.1 g, 3.087 mmol, 1 equiv) in MeOH (20 mL) was added CoCl2 (1.20 g, 9.261 mmol, 3 equiv) at 0°C . The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaBH4 (1.17 g, 30.870 mmol, 10 equiv) was added, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with NH4CL (50 mL),The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:1) to afford tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl]acetate (400 mg, 39.47%) as a yellow solid. LC-MS: (M+H)+ found: 329.0.
Figure imgf000587_0001
To a mixture of tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7- yl]acetate (500 mg, 1.523 mmol, 1 equiv) and KOAc (224.16 mg, 2.284 mmol, 1.5 equiv) in HOAc (10 mL) was added Br2 (267.67 mg, 1.675 mmol, 1.1 equiv) at room temperature. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H2O (40 mL), The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (2:1) to afford tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-7-yl]acetate (420 mg, 67.73%) as a yellow solid. LC-MS: (M+H)+ found: 406.9.
Figure imgf000588_0001
A mixture of tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl]acetate (420 mg, 1.031 mmol, 1 equiv), 3-chloro-2-methoxyaniline (243.79 mg, 1.546 mmol, 1.5 equiv), EPhos Pd G4 (94.73 mg, 0.103 mmol, 0.1 equiv), EPhos (55.15 mg, 0.103 mmol, 0.1 equiv) and Cs2CO3 (672.01 mg, 2.062 mmol, 2 equiv) in 1,4- dioxane (10 mL) at room temperature, The mixture was stirred 3 h at 80°C under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H2O (40 mL),The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:1) to afford tert-butyl 2-{3-[(3- chloro-2-methoxyphenyl)amino]-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl}acetate (200 mg, 40.07%) as a yellow solid. LC-MS: (M+H)+ found: 484.0.
Figure imgf000588_0002
To a mixture of tert-butyl 2-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7-yl}acetate (200 mg, 0.413 mmol, 1 equiv) in THF (10 mL) was added CH3MgBr(in 3M Et2O) (1.239 mL, 1.239 mmol, 3 equiv) at 0°C, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. After the reaction, The resulting mixture was concentrated to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- oxopropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 68.18%) as a yellow solid. LC-MS: (M+H)+ found: 426.0.
Figure imgf000589_0002
To a mixture of d3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-oxopropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.282 mmol, 1 equiv) in THF (10 mL) was added CH3Li (0.846 mL, 0.846 mmol, 3 equiv) at 0°C, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. After the reaction, the resulting mixture was diluted with NH4Cl (30 mL),The aqueous layer was extracted with EtOAc 40 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:2) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40 mg, 32.12%) as a yellow solid. LC-MS: (M+H)+ found: 442.3.
Figure imgf000589_0001
3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)- HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81), and 2 peak was splitted from the material, the prepeak is the product (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 14.93%). This resulted in (7S)-3-[(3- chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 14.93%) as a white solid. LC-MS: (M+H)+ found: 442.3. 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 2H), 7.82 (s, 2H), 7.24 (s, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 5.95 (s, 1H), 4.76 (s, 1H), 4.37 – 3.39 (m, 5H), 2.95 (s, 1H), 2.46 (d, J = 15.0 Hz, 1H), 2.03 (s, 1H), 1.42 (s, 6H). Example 149. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 284)
Figure imgf000590_0001
3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81), and 2 peak was splitted from the material, the postpeak is the product (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.7 mg, 14.99%). This resulted in (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.7 mg, 14.99%)as a white solid. LC-MS: (M+H)+ found: 442.3. 1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.79 (s, 2H), 7.24 (s, 1H), 6.83 (dd, J = 8.1, 1.4 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.15 (dd, J = 8.1, 1.4 Hz, 1H), 5.96 (s, 1H), 4.75 (p, J = 6.0 Hz, 1H), 4.06 (s, 3H), 4.02 – 3.89 (m, 1H), 3.79 (ddd, J = 13.0, 7.7, 2.6 Hz, 1H), 3.00 (s, 1H), 2.51 – 2.42 (m, 1H), 2.03 (dd, J = 14.9, 6.3 Hz, 1H), 1.42 (d, J = 1.4 Hz, 6H). Example 150. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 279)
Figure imgf000591_0001
To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (6 g, 29.267 mmol, 1.00 equiv) and DIEA (11.35 g, 87.801 mmol, 3 equiv) in DCM (60.00 mL, 943.861 mmol, 32.25 equiv) were added SEM-Cl (6.83 g, 40.974 mmol, 1.4 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (50:1) to afford methyl 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (5.68 g, 57.89%) as a white oil. LCMS: [M-H]+ found: 335.
Figure imgf000591_0002
To a mixture of methyl 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.73 g, 8.143 mmol, 1.00 equiv) and pyridin-4-ylboronic acid (3.00 g, 24.429 mmol, 3 equiv) in dioxane (83 mL, 979.739 mmol, 120.32 equiv) and H2O (8.3 mL, 460.719 mmol, 56.58 equiv) were added K3PO4 (3.46 g, 16.286 mmol, 2 equiv) and Pd(dppf)Cl2*CH2Cl2 (1.33 g, 1.629 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE/EA (2:1) to afford methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.23 g, 82.13%) as a brown solid. LCMS: [M-H]+ found: 334.
Figure imgf000592_0001
To a stirred mixture of methyl 5-(pyridin-4-yl)-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.2 g, 6.597 mmol, 1.00 equiv)methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.2 g, 6.597 mmol, 1.00 equiv) were added TFA (20 mL, 269.261 mmol, 40.81 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).This resulted in methyl 5-(pyridin-4-yl)-2H-pyrazole- 3-carboxylate (1.83 g, 136.51%) as a light yellow solid.The crude product/ resulting mixture was used in the next step directly without further purification. LCMS: [M-H]+ found: 204.
Figure imgf000592_0002
To a stirred mixture of methyl 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.38 g, 6.791 mmol, 1.00 equiv) in CH2Cl2 (15.50 mL, 243.865 mmol, 35.91 equiv) were added NBS (1.21 g, 6.791 mmol, 1.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). This resulted in methyl 4-bromo- 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 73.08%) as a white solid.The crude product/ resulting mixture was used in the next step directly without further purification. LCMS: [M-H]+ found: 282.
Figure imgf000593_0002
To a stirred mixture of methyl 4-bromo-5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 4.963 mmol, 1.00 equiv) and 2-bromoacetonitrile (0.71 g, 5.956 mmol, 1.2 equiv) in MeCN (30 mL) were added K2CO3 (1.37 g, 9.926 mmol, 2.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-bromo-2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole-3- carboxylate as a white solid. LCMS: [M-H]+ found: 321.
Figure imgf000593_0001
A mixture of (HCHO)n (2.10 g, 46.70 mmol, 6 equiv) in dimethylamine (23.35mL, 2M in THF, 6 equiv) was stirred for 2h and added to a mixture of methyl 4-bromo-2- (cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (2.5 g, 7.785 mmol, 1.00 equiv) in DMF (25 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min at 100 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE / EA (0:1) to afford methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4- yl)pyrazole-3-carboxylate (460 mg, 15.62%) as a yellow solid. LCMS: [M-H]+ found: 378.
Figure imgf000594_0002
Methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4-yl)pyrazole-3- carboxylate (200 mg, 0.529 mmol, 1.00 equiv) and CoCl2 (205.97 mg, 1.587 mmol, 3 equiv) in MeOH (10.00 mL, 247.091 mmol, 467.09 equiv) were added NaBH4 (60.02 mg, 1.587 mmol, 3 equiv) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue/crude product was purified by reverse phase flash with the following conditions () to afford 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (90 mg, 48.60%) as a yellow solid. LCMS: [M-H]+ found: 350.
Figure imgf000594_0001
To a mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs2CO3 (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The crude product was purified by Pre-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.0 mg, 6.10%) as a white solid. LCMS: [M-H]+ found: 427. 1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.68 (d, J = 5.2 Hz, 2H), 7.14 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.64 (t, J = 8.1 Hz, 1H), 6.17 (dd, J = 8.1, 1.4 Hz, 1H), 5.86 (s, 1H), 4.64 (s, 1H), 4.05 (s, 3H), 3.98 (s, 2H), 2.94 (dd, J = 35.1, 22.1 Hz, 2H), 2.49 (s, 6H). Example 151. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]- 2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 280)
Figure imgf000595_0001
To a stirred mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs2CO3 (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The residue/crude product was purified by reverse phase flash with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7- [(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.6 mg) as a white solid. LCMS: [M-H]+ found: 427. 1H NMR (300 MHz, Chloroform-d) δ 8.65 – 8.48 (m, 2H), 7.66 (d, J = 5.8 Hz, 2H), 7.15 (s, 1H), 6.79 (dd, J = 8.1, 1.4 Hz, 1H), 6.61 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.4 Hz, 1H), 6.06 (s, 1H), 4.76 – 4.53 (m, 1H), 4.02 (s, 5H), 3.31 (s, 2H), 2.82 (s, 6H). Example 152. (R)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 288)
Figure imgf000596_0001
To a stirred mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv) in MeCN (100 mL) were added NCS (6.51 g, 48.778 mmol, 1 equiv). The resulting mixture was stirred for 2h at 80 degree C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid. LC-MS: M+H found: 239.0
Figure imgf000596_0002
To a stirred mixture of methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate (11.4 g, 47.609 mmol, 1.00 equiv) in MeOH (100 mL) was added NaOH (20 mL, 500.036 mmol, 10.50 equiv) at room temperature. The resulting mixture was stirred for overnight at 60 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid as an off-white solid.
Figure imgf000597_0001
To a stirred mixture of 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid (10 g, 44.360 mmol, 1.00 equiv) and oxalyl chloride (11.26 g, 88.720 mmol, 2 equiv) in DCM (100 mL) was added DMF (2 mL, 25.844 mmol, 0.58 equiv) dropwise at room temperature. The resulting mixture was stirred for 0.6 h at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under vacuum. To the above mixture was added Et3N (13.47 g, 133.080 mmol, 3 equiv) and 1,1,1-trifluoro-3-{[(4- methoxyphenyl)methyl]amino}propan-2-ol (11.06 g, 44.360 mmol, 1 equiv) in DCM (100 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2Cl2 (3 x 150 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 5-bromo-4-chloro- N-[(4-methoxyphenyl)methyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)-2H-pyrazole-3- carboxamide as a yellow solid. LC-MS: M+H found: 456.00.
Figure imgf000597_0002
To a stirred mixture of 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3- trifluoro-2-hydroxypropyl)-2H-pyrazole-3-carboxamide (6 g, 13.139 mmol, 1.00 equiv) and Et3N (3.99 g, 39.417 mmol, 3 equiv) in DCM (100 mL) was added TsCl (5.01 g, 26.278 mmol, 2 equiv) in DCM(20 ml) dropwise at 0 degree C .The resulting mixture was stirred for 0.5 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (300 mL) at room temperature. The aqueous layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (100 mL).To the above mixture was added K2CO3 (5.45 g, 39.417 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 100 degree C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 438.00.
Figure imgf000598_0001
The 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.5 g) was dissolved in trifluoroacetaldehyde (20 mL).The resulting mixture was stirred for 3 h at 60°C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified/basified/neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc to afford 2-bromo-3-chloro-7- (trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one) as a yellow solid. LC-MS: M+H found: 318.00.
Figure imgf000599_0001
To a stirred mixture of 2-bromo-3-chloro-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (1.7 g, 5.338 mmol, 1.00 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isothiazolo[4,5-b]pyridine (1.44 g, 10.676 mmol, 2 equiv) in dioxane (10 mL) and H2O (2 mL) were added Na2CO3 (1.13 g, 10.676 mmol, 2 equiv) and XPhos Pd G3 (0.90 g, 1.068 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120°C under nitrogen atmosphere.The resulting mixture was extracted with CH2Cl2 (3 x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (1:3) to afford 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 374.00.
Figure imgf000599_0002
To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (490 mg, 1.311 mmol, 1.00 equiv) and 3-fluoro- 2-methoxyaniline (222.06 mg, 1.573 mmol, 1.2 equiv) in dioxane (10 mL) were added Cs2CO3 (854.35 mg, 2.622 mmol, 2 equiv) and EPhos Pd G4 (120.43 mg, 0.131 mmol, 0.1 equiv) and EPhos (70.12 mg, 0.131 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 60 degree C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 mg) was purified by Prep- HPLC with the following conditions(Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 8 min, 63% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 479.00.
Figure imgf000600_0001
The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38). Obtained (R)-3-((3-fluoro-2-methoxyphenyl)amino)- 2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. LC-MS: M+H found: 479.00. 1H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 5.1 Hz, 1H), 7.28 (s, 1H), 6.69 – 6.60 (m, 2H), 6.01 (t, J = 4.6 Hz, 1H), 5.89 (d, J = 4.6 Hz, 1H), 5.24 – 5.16 (m, 1H), 4.32 – 4.23 (m, 1H), 4.13 (m, J = 1.7 Hz, 4H). Example 153. (S)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 289)
Figure imgf000601_0001
To a stirred mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv) in MeCN (100 mL) were added NCS (6.51 g, 48.778 mmol, 1 equiv). The resulting mixture was stirred for 2h at 80 degree C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid. LC-MS: M+H found: 239.00
Figure imgf000601_0002
To a stirred mixture of methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate (11.4 g, 47.609 mmol, 1.00 equiv) in MeOH (100 mL) was added NaOH (20 mL, 500.036 mmol, 10.50 equiv) at room temperature. The resulting mixture was stirred for overnight at 60 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid as an off-white solid. LC-MS: M+H found: 225.00.
Figure imgf000601_0003
To a stirred mixture of 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid (10 g, 44.360 mmol, 1.00 equiv) and oxalyl chloride (11.26 g, 88.720 mmol, 2 equiv) in DCM (100 mL) was added DMF (2 mL, 25.844 mmol, 0.58 equiv) dropwise at room temperature. The resulting mixture was stirred for 0.6 h at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under vacuum. To the above mixture was added Et3N (13.47 g, 133.080 mmol, 3 equiv) and 1,1,1-trifluoro-3-{[(4- methoxyphenyl)methyl]amino}propan-2-ol (11.06 g, 44.360 mmol, 1 equiv) in DCM (100 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2Cl2 (3 x 150 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 5-bromo-4-chloro- N-[(4-methoxyphenyl)methyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)-2H-pyrazole-3- carboxamide as a yellow solid. LC-MS: M+H found: 456.00.
Figure imgf000602_0001
To a stirred mixture of 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3- trifluoro-2-hydroxypropyl)-2H-pyrazole-3-carboxamide (6 g, 13.139 mmol, 1.00 equiv) and Et3N (3.99 g, 39.417 mmol, 3 equiv) in DCM (100 mL) was added TsCl (5.01 g, 26.278 mmol, 2 equiv) in DCM(20 ml) dropwise at 0 degree C .The resulting mixture was stirred for 0.5 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (300 mL) at room temperature. The aqueous layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (100 mL).To the above mixture was added K2CO3 (5.45 g, 39.417 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 100 degree C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (3x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 438.00.
Figure imgf000603_0001
The 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.5 g) was dissolved in trifluoroacetaldehyde (20 mL).The resulting mixture was stirred for 3 h at 60°C .Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified/basified/neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc to afford 2-bromo-3-chloro-7- (trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one) as a yellow solid. LC-MS: M+H found: 318.00.
Figure imgf000603_0002
To a stirred mixture of 2-bromo-3-chloro-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (1.7 g, 5.338 mmol, 1.00 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isothiazolo[4,5-b]pyridine (1.44 g, 10.676 mmol, 2 equiv) in dioxane (10 mL) and H2O (2 mL) were added Na2CO3 (1.13 g, 10.676 mmol, 2 equiv) and XPhos Pd G3 (0.90 g, 1.068 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120°C under nitrogen atmosphere.The resulting mixture was extracted with CH2Cl2 (3 x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (1:3) to afford 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 374.00.
Figure imgf000604_0001
To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (490 mg, 1.311 mmol, 1.00 equiv) and 3-fluoro- 2-methoxyaniline (222.06 mg, 1.573 mmol, 1.2 equiv) in dioxane (10 mL) were added Cs2CO3 (854.35 mg, 2.622 mmol, 2 equiv) and EPhos Pd G4 (120.43 mg, 0.131 mmol, 0.1 equiv) and EPhos (70.12 mg, 0.131 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 60 degree C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 mg) was purified by Prep- HPLC with the following conditions(Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 8 min, 63% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 479.00.
Figure imgf000605_0001
The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38). Obtained (S)-3-((3-fluoro-2-methoxyphenyl)amino)- 2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. LC-MS: M+H found: 479.00. 1H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.23 (s, 1H), 6.66 – 6.57 (m, 2H), 6.09 – 5.98 (m, 2H), 5.18 (m, J = 6.0 Hz, 1H), 4.25 (m, J = 14.2, 5.1 Hz, 1H), 4.17 – 4.03 (m, 4H). Example 154.3-((3-chloro-2-methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 291)
Figure imgf000605_0002
A mixture of (3-chloro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)boronic acid (1.80 g, 8.37 mmol, 1.00 equiv), 4-bromo-2-fluoropyridine (1.46 g, 8.37 mmol, 1.00 equiv), K3PO4 (5.37 g, 25.1 mmol, 3.00 equiv), Pd(dppf)Cl2 (0.67 g, 0.83 mmol, 0.1 equiv) and water (1 mL) in 1,4-dioxane (10 mL) was stirred for 12 h at 100 degrees C. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (4:1) to afford 3-chloro-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.9 g, 36%) as yellow oil. LC-MS: M+H found: 267.0.
Figure imgf000606_0001
To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (900.00 mg, 3.36 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (689 mg, 4.36 mmol, 1.3 equiv), and Cs2CO3 (2.18 g, 6.72 mmol, 2.00 equiv) in 1,4-dioxane (10.00 mL) were added EPhos (387 mg, 0.67 mmol, 0.20 equiv) and EPhos Pd G4 (300 mg, 0.33 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc /Petroleum ether 1:3) to afford 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (400 mg, 31%) as a yellow solid. LC-MS: (M+H)+ found: 388.
Figure imgf000606_0002
To a stirred solution of 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100.00 mg, 0.26 mmol, 1.00 equiv), 1- methyl-1H-pyrazol-4-amine (38 mg, 0.39 mmol, 1.5 equiv) in 1,4-dioxane(1.00 mL) was added 3N HCl (0.1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 110 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-((3-chloro-2- methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (20.7 mg, 17%) as a white solid. LC-MS: (M+H)+ found: 465. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.27 (s, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.78 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 5.2 Hz, 1H), 6.78-6.74 (m, 2H), 6.17-6.15 (m, 1H), 4.38 (t, J = 6 Hz, 2H), 3.88 (s 3H), 3.76 (s, 3H), 3.65 (s, 2H). Example 155. rac-(6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 278)
Figure imgf000607_0001
To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv), tert-butyl N-(1-hydroxypropan-2-yl)carbamate (10.26 g, 58.534 mmol, 1.2 equiv) and PPh3 (19.19 g, 73.167 mmol, 1.5 equiv) in THF (200 mL) was added DIAD (14.79 g, 73.167 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (7:1) to afford methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 90.56%) as a white solid. LC-MS: M+H found: 362.15.
Figure imgf000608_0001
To a stirred solution of methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 44.172 mmol, 1.00 equiv) in DCM (120 mL) was added HCl (gas) in 1,4-dioxane (30 mL, 822.797 mmol, 18.63 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with CH2Cl2 (3 x 20 mL). This resulted in methyl 2-(2-aminopropyl)-5-bromopyrazole-3-carboxylate (10.5 g, 90.69%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 262.2.
Figure imgf000608_0002
To a stirred solution of methyl 2-(2-aminopropyl)-5-bromopyrazole-3-carboxylate (10 g, 38.152 mmol, 1.00 equiv) in EtOH (20 mL) was added Et3N (11.58 g, 114.456 mmol, 3 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with EtOH (3 x 20 mL). This resulted in 2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8 g, 91.14%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 230.
Figure imgf000609_0001
A solution of 2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6 g, 26.080 mmol, 1.00 equiv) and NCS (3.48 g, 26.080 mmol, 1 equiv) in DMF (200 mL) was stirred for 3 h at 60 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (5:1) to afford 2-bromo-3- chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6.5 g, 94.23%) as a white solid. LC-MS: (M+H)+ found: 264.0.
Figure imgf000609_0002
To a stirred solution of 2-bromo-3-chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (400 mg, 1.512 mmol, 1 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2]thiazolo[4,5-b]pyridine (594.60 mg, 2.268 mmol, 1.5 equiv) in were added Na2CO3 (320.56 mg, 3.024 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst (237.96 mg, 0.302 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-chloro-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (280 mg, 57.90%) as a light yellow solid. LC-MS: (M+H)+ found: 264.0.
Figure imgf000610_0001
To a stirred solution of 3-chloro-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 0.407 mmol, 1.00 equiv), 3-chloro-2- methoxyaniline (76.89 mg, 0.488 mmol, 1.2 equiv) and Cs2CO3 (264.92 mg, 0.814 mmol, 2 equiv) in dioxane (5 mL) were added EPhos Pd G4 (37.34 mg, 0.041 mmol, 0.1 equiv) and EPhos (43.48 mg, 0.081 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 55% B in 9 min, 55% B; Wave Length: 254/220 nm; RT1(min): 8.85) and Prep-Chiral-HPLC with the following conditions(Column: (R, R)- WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)- HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 38 min; Wave Length: 220/254 nm; RT1(min): 27.906; RT2(min): 32.398) to afford rac- (6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (0.8 mg, 0.45%) as a white solid. LC-MS: (M+H)+ found: 441.20. 1H NMR (300 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.15 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.16 (d, J = 8.1 Hz, 1H), 5.83 (s, 1H), 4.63 (d, J = 9.1 Hz, 1H), 4.21 (d, J = 9.7 Hz, 2H), 4.09 (s, 3H), 1.50 (d, J = 5.5 Hz, 3H). Example 156. rac-(6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 277)
Figure imgf000611_0001
To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv), tert-butyl N-(1-hydroxypropan-2-yl)carbamate (10.26 g, 58.534 mmol, 1.2 equiv) and PPh3 (19.19 g, 73.167 mmol, 1.5 equiv) in THF (200 mL) was added DIAD (14.79 g, 73.167 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (7:1) to afford methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 90.56%) as a white solid. LC-MS: M+H found: 362.15.
Figure imgf000612_0001
To a stirred solution of methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 44.172 mmol, 1.00 equiv) in DCM (120 mL) was added HCl (gas) in 1,4-dioxane (30 mL, 822.797 mmol, 18.63 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with CH2Cl2 (3 x 20 mL). This resulted in methyl 2-(2-aminopropyl)-5-bromopyrazole-3-carboxylate (10.5 g, 90.69%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 262.2.
Figure imgf000612_0002
To a stirred solution of methyl 2-(2-aminopropyl)-5-bromopyrazole-3-carboxylate (10 g, 38.152 mmol, 1.00 equiv) in EtOH (20 mL) was added Et3N (11.58 g, 114.456 mmol, 3 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with EtOH (3 x 20 mL). This resulted in 2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8 g, 91.14%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 230.
Figure imgf000613_0001
A solution of 2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6 g, 26.080 mmol, 1.00 equiv) and NCS (3.48 g, 26.080 mmol, 1 equiv) in DMF (200 mL) was stirred for 3 h at 60 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (5:1) to afford 2-bromo-3- chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6.5 g, 94.23%) as a white solid. LC-MS: (M+H)+ found: 264.0.
Figure imgf000613_0002
To a stirred solution of 2-bromo-3-chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (400 mg, 1.512 mmol, 1 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2]thiazolo[4,5-b]pyridine (594.60 mg, 2.268 mmol, 1.5 equiv) in 1,4-dioxane(5 mL) were added Na2CO3 (320.56 mg, 3.024 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst (237.96 mg, 0.302 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-chloro-6-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (280 mg, 57.90%) as a light yellow solid. LC-MS: (M+H)+ found: 320.
Figure imgf000614_0001
To a stirred solution of 3-chloro-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 0.407 mmol, 1.00 equiv), 3-chloro-2- methoxyaniline (76.89 mg, 0.488 mmol, 1.2 equiv) and Cs2CO3 (264.92 mg, 0.814 mmol, 2 equiv) in dioxane (5 mL) were added EPhos Pd G4 (37.34 mg, 0.041 mmol, 0.1 equiv) and EPhos (43.48 mg, 0.081 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 55% B in 9 min, 55% B; Wave Length: 254/220 nm; RT1(min): 8.85) and Prep-Chiral-HPLC with the following conditions(Column: (R, R)- WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)- -HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 38 min; Wave Length: 220/254 nm; RT1(min): 27.906; RT2(min): 32.398) to afford rac-(6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6.4 mg, 3.57%) as a white solid. LC-MS: (M+H)+ found: 441.20. 1H NMR (300 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.15 (s, 1H), 6.89 – 6.80 (m, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.21 – 6.12 (m, 1H), 5.88 (s, 1H), 4.63 (d, J = 9.1 Hz, 1H), 4.26 – 4.17 (m, 2H), 4.09 (s, 3H), 1.49 (d, J = 5.7 Hz, 3H). Example 157.3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 344)
Figure imgf000615_0001
A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (500.00 mg, 1.996 mmol, 1.00 equiv), pyridin-4-ylboronic acid (368.05 mg, 2.994 mmol, 1.50 equiv), Pd(dppf)Cl2 (146.06 mg, 0.200 mmol, 0.10 equiv) and K2CO3 (827.64 mg, 5.988 mmol, 3.00 equiv) in 1,4-dioxane (10.00 mL) and water (1.00 mL) was stirred for overnight at 70 degrees C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (40:1) to afford 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (200 mg, 40.29%) as a yellow solid. LC-MS: M+H found: 249.
Figure imgf000615_0002
A mixture of 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.402 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (95.07 mg, 0.603 mmol, 1.50 equiv), EPhos Pd G4 (36.94 mg, 0.040 mmol, 0.10 equiv), EPhos (21.51 mg, 0.040 mmol, 0.10 equiv) and K2CO3 (166.73 mg, 1.206 mmol, 3.00 equiv) in 1,4-dioxane (1.00 mL) and Toluene (1.00 mL) was stirred for overnight at 60 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.58) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one(35.6mg,23.87%) as a white solid. LC-MS: (M+H)+ found: 370. 1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.69 (d, J = 5.1 Hz, 2H), 7.08 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.73 – 6.50 (m, 2H), 6.19 (dd, J = 8.1, 1.5 Hz, 1H), 4.46 (dd, J = 7.1, 5.0 Hz, 2H), 4.05 (s, 3H), 3.94 – 3.75 (m, 2H). Example 158.3-[(3-chloro-2-methoxyphenyl) amino]-2-{1H-pyrrolo[3,2-b] pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 346)
Figure imgf000616_0001
A mixture of 7-bromo-1H-pyrrolo[3,2-b] pyridine (500 mg, 2.538 mmol, 1.00 equiv), Boc2O (664.59 mg, 3.046 mmol, 1.2 equiv) and DMAP (31.00 mg, 0.254 mmol, 0.1 equiv) in THF (10 mL, 123.430 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 7-bromopyrrolo[3,2-b] pyridine-1-carboxylate (700 mg, 92.83%) as a brown oil. LC-MS: M+H found: 297.
Figure imgf000617_0001
A mixture of tert-butyl 7-bromopyrrolo[3,2-b]pyridine-1-carboxylate (700 mg, 2.356 mmol, 1.00 equiv), 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (841.13 mg, 2.827 mmol, 1.2 equiv), Pd(DtBPF)Cl2 (153.53 mg, 0.236 mmol, 0.1 equiv) and K2CO3 (976.71 mg, 7.068 mmol, 3 equiv) in 1,4- dioxane (15 mL, 170.251 mmol) was stirred for 4 h at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}pyrrolo[3,2- b]pyridine-1-carboxylate (500 mg, 54.73%) as a white solid. LC-MS: (M+H)+ found: 388.
Figure imgf000617_0002
A mixture of tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2- yl}pyrrolo [3,2-b]pyridine-1-carboxylate (200 mg, 0.516 mmol, 1.00 equiv) , EPhos Pd G4 (47.37 mg, 0.052 mmol, 0.1 equiv)and Cs2CO3 (504.08 mg, 1.548 mmol, 3 equiv) in 1,4-dioxane (4 mL) was stirred for overnight at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (50:1) to afford tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1- carboxylate (35 mg, 13.33%) as a white solid. LC-MS: (M+H)+ found: 509.
Figure imgf000618_0001
A mixture of tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1-carboxylate (50 mg, 0.098 mmol, 1.00 equiv) and TFA (56.01 mg, 0.490 mmol, 5 equiv) in DCM (1 mL, 15.730 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro-2-methoxyphenyl) amino]- 2-{1H-pyrrolo[3,2-b] pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (37 mg, 92.12%) as a yellow solid. LC-MS: (M+H)+ found: 409. 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.26 (d, J = 5.1 Hz, 1H), 7.70 (t, J = 3.1 Hz, 1H), 7.42 – 7.33 (m, 2H), 6.77 – 6.65 (m, 2H), 6.65 – 6.58 (m, 1H), 6.16 (dd, J = 6.8, 2.9 Hz, 1H), 4.51 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.72 (s, 2H). Example 159.3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 347)
Figure imgf000619_0001
3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane(5 mL) and H2O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs2CO3(438 mg), PCy3(37.7 mg) and Pd2(dba)3 (123.1 mg) was added, the reaction was stirred for 12 hours, the reaction was stirred for 12 hours under N2 atmosphere.The resulting mixture was concentrated under reduced pressure.The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3- chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (116.1 mg, 48.50%) as a light yellow solid. LC-MS: M+H found: 300.
Figure imgf000619_0002
3-chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(100 mg) was dissolved in DMF(5 mL), 3-chloro-2-methoxyaniline(105 mg), Cs2CO3(326 mg), EPhos Pd G4(306 mg) and EPhos (89 mg) was added, the reaction was stirred for 4 hours under N2 atmosphere.The resulting mixture was concentrated under reduced pressure.The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3*H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (24.7 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 421. 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.08 (d, J = 4.6 Hz, 1H), 8.73 (d, J = 5.8 Hz, 1H), 8.37 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 7.46 (s, 1H), 6.57 (dt, J = 15.8, 7.7 Hz, 2H), 6.17 (d, J = 7.8 Hz, 1H), 4.52 (s, 2H), 3.75 (s, 2H), 3.68 (s, 3H). Example 160.3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-1,6-naphthyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 348)
Figure imgf000620_0001
3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs2CO3(438 mg), PCy3(37.7 mg) and Pd2(dba)3 (123.1 mg) was added. The reaction was stirred for 12 hours under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-chloro-2-(7-methoxy-1,6- naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (102.1 mg, 45.50%) as a light yellow solid. LC-MS: M+H found: 330.
Figure imgf000621_0001
3-Chloro-2-(7-methoxy-1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(100 mg) was dissolved in DMF (10 mL), and 3-chloro-2-methoxyaniline (96 mg), Cs2CO3 (296 mg), EPhos Pd G4(139 mg) and EPhos (81 mg) was added. The reaction mixture was stirred for 12 hours under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (46.1 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 451. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.37 (s, 1H), 7.54 – 7.42 (m, 2H), 7.22 (s, 1H), 6.67 – 6.50 (m, 2H), 6.16 (dd, J = 7.9, 1.7 Hz, 1H), 4.50 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.78 (s, 3H), 3.99 (s, 2H). 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). 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 μL 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.45 μL of stock solution is transferred to a 384 polypropylene plate (pp-plate). Perform 3-fold, 10-point dilution via transferring 15 μL compound into 30 μL DMSO using a TECAN (EVO200) liquid handler. 2.2 Spin plates at room temperature at 1,000 RPM for 1 minute. 2.3 Transfer 120 nL of diluted compound from compound source plate into the cell plate. 2.4 After compound treatment for 72 hours, perform CTG detection for compound treatment plates as described in "Detection" section. 3 Detection 3.1 Plates are removed from incubators and equilibrated at room temperature for 15 minutes. 3.2 Thaw the CellTiter Glo reagents and allow to equilibrate to room temperature before the experiment. 3.3 Add 40 μL of CellTiter-Glo reagent into each well (at 1:1 to culture medium). Then place the plates at room temperature for 30 min followed by reading on EnVision. 4 Data analysis 4.1 Inhibition activity is calculated following the formula below: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC) where HC is obtained from cells treated with 0.1% DMSO only; and LC is obtained from culture medium only. 4.22. Calculate the IC50 by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom)/(1 + 10^((LogIC50 - X)*HillSlope)) The IC50 date are included in Table 6 and Table 7. EXAMPLE B. Inhibitor Activity on EGFR phosphorylation (pEGFR) 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. CUTO14 cells were obtained from Dr. Robert C. Doebele at the University of Colorado. The IC50 date are included in Table 6 and Table 7. 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 μL 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 μL of stock solution is transferred to a 384 polypropylene plate (pp-plate). Perform 3-fold, 10-point dilution via transferring 15 μL compound into 30 μL DMSO using a TECAN (EVO200) liquid handler. 2.2 Spin plates at room temperature at 1,000 RPM for 1 minute. 2.3 Transfer 5 nL of diluted compound from compound source plate into the cell plate. 2.4 After compound treatment for 2 hours, perform pEGFR detection by AlphaLISA for compound treatment plates as described in "Detection" section. 3 Detection by pEGFR AlphaLISA (Perkin-Elmer) 3.1 Plates are removed from incubators and equilibrated at room temperature for 10 minutes, and media was removed 3.210 μL of lysis buffer is added and plates shaken at 600 rpm for 1 hr. 3.3 Prepare acceptor mix just before use and dispense 5 μL of acceptor mix to all the wells. Shake 350 rpm for 1hr in the dark 3.4 Prepare donor mix under low light conditions prior to use. Dispense 5 μL of donor mix to all the wells. Mix well on the shaker, seal and wrap in aluminum foil and incubate 1.5 hrs at room temperature in the dark 3.5 Transfer 18.5 μL mixture to OptiPlate 384, and read using an Envision. The IC50 date are included in Table 6 and Table 7. Table 6. IC50 Data for EGFR Activity and Inhibitor Activity on EGFR phosphorylation (pEGFR)1
Figure imgf000624_0001
Figure imgf000625_0001
Figure imgf000626_0001
Figure imgf000627_0001
1 “+++” indicates that IC50 < 100 nM; “++” indicates that 100 nM <= IC50 < 1000 nM; “+” indicates that IC50 >= 1000 nM. “NA” indicates that the IC50 data is not available for this compound; Table 7. IC50 Data for EGFR Activity and Inhibitor Activity on EGFR phosphorylation (pEGFR) - continued1
Figure imgf000627_0002
Figure imgf000628_0001
1 “+++” indicates that IC50 < 100 nM; “++” indicates that 100 nM <= IC50 < 1000 nM; “+” indicates that IC50 >= 1000 nM. “NA” indicates that the IC50 data is not available for this compound;

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I):
Figure imgf000629_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc; X1 is –(X2)m-L1-R5, wherein: m is 0 or 1; X2 is selected from the group consisting of: • -O-, -N(RN)-, or –S(O)0-2; •
Figure imgf000630_0001
• -C(=O)O-*, -C(=O)N(RN)-*, or –S(O)1-2N(RN)-*; • -OC(=O)-*, -N(RN)C(=O)-*, or –N(RN)S(O)1-2-*; and • -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, or – N(RN)S(O)1-2N(RN)-*, wherein the asterisk represents point of attachment to L1; L1 is selected from the group consisting of: a bond and C1-10 alkylene optionally substituted with from 1-6 Ra; R5 is selected from the group consisting of: • H; • halo; • -OH; • -NReRf; • -C1-6 alkoxy or -S(O)0-2(C1-6 alkyl), each optionally substituted with from 1-6 Ra; • -Rg; • -L5-Rg; • -Rg2-RW or -Rg2-RY; • -L5-Rg2-RW or –L5-Rg2-RY; and • -RW provided that: when L1 is a bond, then R5 is selected from the group consisting of: H, -Rg, -Rg2- RW, and -Rg2-RY; and X1 is other than H, -OH, or NH2; L5 is selected from the group consisting of: –O-, -S(O)0-2, -NH, and -N(Rd)-; RW is –LW-W, wherein LW is C(=O), S(O)1-2, OC(=O)*, NHC(=O)*, NRdC(=O)*, NHS(O)1-2*, or NRdS(O)1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C2-6 alkenyl; C2-6 alkynyl; or C3-10 allenyl, each of which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 Rc, wherein x is 1 or 2; and y is an integer from 1 to 6; RY is selected from the group consisting of: -Rg and -(Lg)g-Rg; each of R1c, R2a, R2b, R3a, and R3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH2; -CN; -Rb; -Lb-Rb; -C1-6 alkoxy or - C1-6 thioalkoxy, each optionally substituted with from 1-6 Ra; -NReRf; -Rg; and -(Lg)g-Rg; provided that R1c is other than halo, –CN, or –C(O)OH; or two of variables R1c, R2a, R2b, R3a, and R3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R1c)- when –N(R1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(Rd), O, and S(O)0-2; and • 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, Rc, and RW; or one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is Rg; each occurrence of Ra is independently selected from the group consisting of: – OH; -halo; –NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(C1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); and cyano; each occurrence of Rb is independently C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with from 1-6 Ra; each occurrence of Lb is independently C(=O); C(=O)O; S(O)1-2; C(=O)NH*; C(=O)NRd*; S(O)1-2NH*; or S(O)1-2N(Rd)*, wherein the asterisk represents point of attachment to Rb; each occurrence of Rc is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)1-2(C1-4 alkyl); -S(O)(=NH)(C1-4 alkyl); -NReRf; –OH; -S(O)1-2NR’R’’; -C1-4 thioalkoxy; -NO2; -C(=O)(C1-10 alkyl); -C(=O)O(C1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF5; each occurrence of Rd is independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(C1-4 alkyl); - C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Re and Rf is independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(C1-4 alkyl); -C(O)O(C1-4 alkyl); -CONR’R’’; -S(O)1-2NR’R’’; -S(O)1-2(C1-4 alkyl); -OH; and C1-4 alkoxy; each occurrence of Rg is independently selected from the group consisting of: • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; • 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(Rd), 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 Rc; • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc; each occurrence of Lg is independently selected from the group consisting of: -O-, -NH-, -NRd , -S(O)0-2, C(O), and C1-3 alkylene optionally substituted with from 1-3 Ra; each g is independently 1, 2, or 3; each Rg2 is a divalent Rg group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C1-4 alkyl; and each occurrence of RN is independently H, C1-3 alkyl, or C3-6 cycloalkyl.
2. The compound of claim 1, wherein Ring C is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with X1 and further optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with X1 and further optionally substituted with from 1-4 Rc.
3. The compound of claims 1 or 2, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-4 Rc.
4. The compound of any one of claims 1-3, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc.
5. The compound of any one of claims 1-4, wherein Ring C is monocyclic heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(Rd), and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc.
6. The compound of any one of claims 1-5, wherein Ring C is pyridyl or pyrimidyl, each of which is substituted with X1 and further optionally substituted with from 1-3 Rc.
7. The compound of any one of claims 1-6, wherein Ring C is
Figure imgf000634_0001
wherein n is 0, 1, or 2.
8. The compound of any one of claims 1-6, wherein Ring C is
Figure imgf000635_0001
, wherein n is 0, 1, or 2.
9. The compound of any one of claims 1-6, wherein Ring C is
Figure imgf000635_0002
wherein n is 0, 1, or 2.
10. The compound of any one of claims 1-3, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc.
11. The compound of any one of claims 1-3 or 10, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc.
12. The compound of any one of claims 1-3 or 10-11, wherein: (i) 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc; (ii) Ring C is selected from the group consisting of: quinolinyl; naphthyridinyl such as 1,5-naphthyridin-4-yl; and pyridopyrimidinyl, such as pyrido[3,2-d]pyrimidin-4-yl, each of which is substituted with X1 and further optionally substituted with from 1-3 Rc; or (iii) Ring C is selected from the group consisting of:
Figure imgf000636_0001
Figure imgf000636_0005
and each of which is optionally substituted with c
Figure imgf000636_0004
from 1-2 R .
13. The compound of any one of claims 1-3 or 10-11, wherein: (i) Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is substituted with X1 and further optionally substituted with from 1-3 Rc; for example, Ring C is
Figure imgf000636_0002
. (ii) Ring C is thieno[3,2-b]pyridyl, which is substituted with X1 and further optionally substituted with from 1-3 Rc; or (iii) Ring C is which is optionally substituted with fro c
Figure imgf000636_0003
m 1-2 R.
14. The compound of any one of claims 1-13, wherein m is 1.
15. The compound of any one of claims 1-13, wherein m is 0.
16. The compound of any one of claims 1-14, wherein X2 is -O-, -N(RN)-, or – S(O)0-2.
17. The compound of any one of claims 1-14 or 16, wherein X2 is –O-.
18. The compound of any one of claims 1-14 or 16, wherein X2 is –N(RN)-.
19. The compound of any one of claims 1-14, 16, or 18, wherein X2 is –N(H)-.
20. The compound of any one of claims 1-14, wherein X2 is
Figure imgf000637_0001
21. The compound of any one of claims 1-14, wherein X2 is selected from the group consisting of: -OC(=O)-*, -N(RN)C(=O)-*, and –N(RN)S(O)1-2-*.
22. The compound of any one of claims 1-14 or 21, wherein X2 is - N(RN)C(=O)-*, such as –N(H)C(=O)-*.
23. The compound of any one of claims 1-14 or 21, wherein X2 is –N(RN)S(O)1- 2-*, such as –N(H)S(O)2-*.
24. The compound of any one of claims 1-14, wherein X2 is selected from the group consisting of: -OC(=O)N(RN)-*, -N(RN)C(=O)O-*, -N(RN)C(=O)N(RN)-*, and – N(RN)S(O)1-2N(RN)-.
25. The compound of any one of claims 1-14 or 24, wherein X2 is - N(RN)C(=O)O-*, such as –N(H)C(=O)O-*.
26. The compound of any one of claims 1-14 or 24, wherein X2 is – N(H)C(=O)N(RN)-*, such as –N(H)C(=O)N(C1-3 alkyl)-*.
27. The compound of any one of claims 1-26, wherein L1 is C1-10 alkylene optionally substituted with from 1-6 Ra.
28. The compound of any one of claims 1-27, wherein L1 is C1-3 alkylene optionally substituted with from 1-6 Ra.
29. The compound of any one of claims 1-28, wherein L1 is C1-3 alkylene.
30. The compound of any one of claims 1-29, wherein L1 is –CH2-.
31. The compound of any one of claims 1-29, wherein L1 is –CH(Me)-, such as
Figure imgf000638_0001
or
Figure imgf000638_0002
32. The compound of any one of claims 1-29, wherein L1 is –CH2CH2-.
33. The compound of any one of claims 1-27, wherein L1 is C3-8 alkylene optionally substituted with from 1-6 Ra.
34. The compound of any one of claims 1-27 or 33, wherein L1 is branched C3- 6 alkylene optionally substituted with from 1-6 Ra.
35. The compound of any one of claims 1-27 or 33-34, wherein L1 is branched C3-6 alkylene.
36. The compound of any one of claims 1-27 or 33-35, wherein L1 is selected from the group consisting of:
Figure imgf000638_0003
and
Figure imgf000638_0004
wherein aa is the point of attachment to R5.
37. The compound of any one of claims 1-26, wherein L1 is a bond.
38. The compound of any one of claims 1-36, wherein R5 is selected from the group consisting of: -OH; -NReRf; and C1-6 alkoxy or -S(O)0-2(C1-6 alkyl) each optionally substituted with from 1-6 Ra.
39. The compound of any one of claims 1-36 or 38, wherein R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra.
40. The compound of any one of claims 1-36 or 38-39, wherein R5 is C1-3 alkoxy, such as methoxy.
41. The compound of any one of claims 1-36 or 38, wherein R5 is -S(O)0-2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra.
42. The compound of any one of claims 1-36, 38, or 41, wherein R5 is – S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra.
43. The compound of any one of claims 1-36, 38, or 41-42, wherein R5 is – S(O)2(C1-3 alkyl).
44. The compound of any one of claims 1-37, wherein R5 is –Rg.
45. The compound of any one of claims 1-37 or 44, wherein R5 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(Rd), 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 Rc.
46. The compound of any one of claims 1-37 or 44-45, wherein R5 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(Rd), 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 Rc.
47. The compound of any one of claims 1-37 or 44-46, wherein R5 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(Rd), 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 Rc.
48. The compound of any one of claims 1-37 or 44-47, wherein R5 is
Figure imgf000640_0001
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.
49. The compound of any one of claims 1-37 or 44-48, wherein R5 is
Figure imgf000640_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); and x1 and x2 are each independently 0, 1, or 2.
50. The compound of claims 48 or 49, wherein x1 is 0.
51. The compound of any one of claims 48-50, wherein Xa is –O-.
52. The compound of any one of claims 1-37 or 44-51, wherein R5 is
Figure imgf000640_0003
such as
Figure imgf000640_0008
or
Figure imgf000640_0007
53. The compound of any one of claims 1-37 or 44-51, wherein R5 is
Figure imgf000640_0004
such as
Figure imgf000640_0005
or
Figure imgf000640_0006
54. The compound of any one of claims 48-50, wherein Xa is N(H) or N(Rd), such as N(Rd), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl).
55. The compound of any one of claims 1-37, 44-50, or 54, wherein R5 is selected from the group consisting of:
Figure imgf000641_0001
, such as
Figure imgf000641_0002
or
Figure imgf000641_0018
;
Figure imgf000641_0017
(e.g.,
Figure imgf000641_0016
), such as
Figure imgf000641_0015
(e.g.,
Figure imgf000641_0003
) or
Figure imgf000641_0011
(e.g.,
Figure imgf000641_0012
) ;
Figure imgf000641_0013
, such as
Figure imgf000641_0014
or
Figure imgf000641_0004
; and , such as
Figure imgf000641_0008
or
Figure imgf000641_0009
, optionally wherein Rd is d
Figure imgf000641_0010
C1-4 alkyl or wherein R is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl).
56. The compound of claims 48 or 49, wherein x1 is 1 or 2.
57. The compound of any one of claims 48-49 or 56, wherein Xa is –O-.
58. The compound of any one of claims 1-37, 44-49, or 56-57, wherein R5 is selected from the group consisting of:
Figure imgf000641_0006
such as
Figure imgf000641_0007
or
Figure imgf000641_0019
;
Figure imgf000641_0020
; and
Figure imgf000641_0005
59. The compound of any one of claims 48-49 or 56, wherein Xa is N(H) or N(Rd), such as N(Rd), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl).
60. The compound of any one of claims 1-37, 44-49, 56, or 59, wherein R5 is
Figure imgf000642_0001
61. The compound of any one of claims 1-37 or 44-47, wherein R5 is
Figure imgf000642_0002
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2.
62. The compound of any one of claims 1-37, 44-47, or 61, wherein R5 is selected from the group consisting of:
Figure imgf000642_0003
Figure imgf000642_0004
optionally wherein Rd is C1-4
Figure imgf000642_0005
alkyl, such as methyl.
63. The compound of any one of claims 1-37 or 44-46, wherein R5 is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc.
64. The compound of any one of claims 1-37, 44-46, or 63, wherein R5 is
Figure imgf000642_0006
65. The compound of any one of claims 1-37 or 44, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
66. The compound of any one of claims 1-37, 44, or 65, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
67. The compound of any one of claims 1-37, 44, or 65-66, wherein R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-3 Rc.
68. The compound of any one of claims 1-37, 44, or 65-67, wherein R5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd.
69. The compound of any one of claims 1-37, 44, or 65-68, wherein R5 is selected from the group consisting of:
Figure imgf000643_0001
Figure imgf000643_0002
70. The compound of any one of claims 1-37, 44, or 65-66, wherein R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
71. The compound of any one of claims 1-37, 44, 65-66, or 70, wherein R5 is selected from the group consisting of:
Figure imgf000644_0003
Figure imgf000644_0001
72. The compound of any one of claims 1-37, 44, or 65, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
73. The compound of any one of claims 1-37, 44, 65, or 72, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
74. The compound of any one of claims 1-37, 44, 65, or 72-73, wherein R5 is selected from the group consisting of: each optionally substituted
Figure imgf000644_0002
with from 1-2 Rc.
75. The compound of any one of claims 1-37, 44, 65, or 72, wherein R5 is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is
Figure imgf000645_0001
o .
76. The compound of any one of claims 1-37 or 44, wherein R5 is phenyl optionally substituted with from 1-2 Rc, such as unsubstituted phenyl.
77. The compound of any one of claims 1-37 or 44, wherein R5 is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
78. The compound of any one of claims 1-37, 44, or 77, wherein R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
79. The compound of any one of claims 1-37, 44, or 77-78, wherein R5 is C3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.
80. The compound of any one of claims 1-37, 44, or 77-78, wherein R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1-4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc.
81. The compound of any one of claims 1-37, 44, 77-78, or 80, wherein R5 is selected from the group consisting of:
Figure imgf000645_0002
Figure imgf000646_0001
82. The compound of any one of claims 1-37, wherein R5 is H or halo, such as H.
83. The compound of claims 1-37, wherein R5 is RW.
84. The compound of any one of claims 1-37, wherein R5 is -Rg2-RW or -Rg2- RY., optionally wherein R5 is –Rg2-RW.
85. The compound of any one of claims 1-37 or 83-84, wherein the –Rg2 group present in R5 is heterocyclylene 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(Rd), 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 Rc.
86. The compound of any one of claims 1-37 or 83-85, wherein the –Rg2 group present in R5 is
Figure imgf000646_0002
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW or RY; and x1 and x2 are each independently 0, 1, or 2.
87. The compound of claim 86, wherein x1 is 0.
88. The compound of any one of claims 1-37 or 83-86, wherein the –Rg2 group present in R5 is selected from the group consisting of:
Figure imgf000646_0003
Figure imgf000647_0001
Figure imgf000647_0002
wherein bb is the point of attachment to RW or RY.
89. The compound of any one of claims 1-37 or 83-85, wherein the –Rg2 group present in R5 is
Figure imgf000647_0004
such as
Figure imgf000647_0003
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW or RY.
90. The compound of any one of claims 1-37, 83-85, or 89, wherein the –Rg2 group present in R5 is selected from the group consisting of:
Figure imgf000647_0005
such as
Figure imgf000647_0006
wherein bb is the point of attachment to RW or RY; and optionally wherein Rd is C1-4 alkyl, such as methyl.
91. The compound of any one of claims 1-37 or 83-85, wherein the Rg2 group present in R5 is bicyclic heterocyclylene including from 6-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein Rg2 is
Figure imgf000648_0004
, wherein bb is the point of attachment to RW or RY.
92. The compound of any one of claims 1-37 or 83-91, wherein the RW present in R5 is –C(=O)-W, –S(O)2-W, or –NH-C(=O)-W, such as wherein RW is –C(=O)-W or – NH-C(=O)-W.
93. The compound of claim 92, wherein W is C2-6 alkenyl or C2-6 alkynyl optionally substituted with from 1-3 Ra.
94. The compound of claims 92 or 93, wherein RW is
Figure imgf000648_0001
Figure imgf000648_0003
; ; , ;
Figure imgf000648_0002
95. The compound of any one of claims 1-13, wherein m is 0 or 1; X2 is –O-, -N(RN)-, N N
Figure imgf000648_0005
, –N(R )C(=O)-*, or -N(R )S(O)2-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf.
96. The compound of claim 95, wherein R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra.
97. The compound of claims 95 or 96, wherein R5 is C1-3 alkoxy.
98. The compound of claim 95, wherein R5 is S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra.
99. The compound of claims 95 or 98, wherein R5 is S(O)2(C1-3 alkyl).
100. The compound of any one of claims 1-13, wherein: m is 0 or 1; X2 is –O-, -N(RN)-, N N
Figure imgf000649_0001
, –N(R )C(=O)*, or -N(R )S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 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(Rd), 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 Rc.
101. The compound of claim 100, wherein R5 is
Figure imgf000649_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.
102. The compound of claim 100, wherein R5 is
Figure imgf000649_0003
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); and x1 and x2 are each independently 0, 1, or 2.
103. The compound of claims 101 or 102, wherein x1 is 0.
104. The compound of any one of claims 101-103, wherein Xa is –O-.
105. The compound of any one of claims 100-104, wherein R5 is
Figure imgf000650_0005
such as ; or whe 5
Figure imgf000650_0006
rein R is
Figure imgf000650_0007
106. The compound of any one of claims 101-103, wherein Xa is N(Rd), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl).
107. The compound of any one of claims 100-103 or 106, wherein R5 is selected from the group consisting of:
Figure imgf000650_0001
, ;
Figure imgf000650_0004
, optionally wherein Rd is d
Figure imgf000650_0002
C1-4 alkyl or wherein R is C(=O)(C1-4 alkyl) or S(O)2(C1- 4 alkyl).
108. The compound of claims 101 or 102, wherein x1 is 1 or 2.
109. The compound of any one of claims 100-102 or 108, wherein R5 is selected from the group consisting of:
Figure imgf000650_0003
110. The compound of claim 100, wherein R5 is
Figure imgf000651_0004
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2.
111. The compound of claims 100 or 110, wherein R5 is selected from the group consisting of:
Figure imgf000651_0005
Figure imgf000651_0006
optionally wherein Rd is C1-4 alkyl, such as methyl.
112. The compound of claim 100, wherein R5 is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein R5 is
Figure imgf000651_0002
such as
Figure imgf000651_0001
113. The compound of any one of claims 1-13, wherein: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000651_0003
, –N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc.
114. The compound of claim 113, wherein R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-3 Rc.
115. The compound of claims 113 or 114, wherein R5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd, such as
Figure imgf000652_0001
116. The compound of claim 113, wherein R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as
Figure imgf000652_0002
Figure imgf000652_0003
117. The compound of claim 113, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
118. The compound of claims 113 or 117, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is selected from the group consisting of:
Figure imgf000653_0001
each optionally substituted with from 1-2 Rc.
119. The compound of claim 113, wherein R5 is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is
Figure imgf000653_0002
120. The compound of claim 113, wherein R5 is phenyl optionally substituted with from 1-2 Rc, such as unsubstituted phenyl.
121. The compound of any one of claims 1-13, wherein: m is 0 or 1; X2 is –O-, -N(RN)-, , –N(RN)C(=O)*, or N
Figure imgf000653_0003
-N(R )S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
122. The compound of claim 121, wherein R5 is C3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.
123. The compound of claim 121, wherein R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1-4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc, such as: wherein R5 is selected from the group consisting of:
Figure imgf000654_0002
Figure imgf000654_0003
124. The compound of any one of claims 1-13, wherein: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000654_0001
, –N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is –Rg2-RW, wherein: the -Rg2 of R5 is heterocyclylene 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(Rd), 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 Rc; and -RW is –C(=O)-W or –S(O)2-W.
125. The compound of claim 124, wherein Rg2 is
Figure imgf000655_0001
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0.
126. The compound of claims 124 or 125, wherein Rg2 is selected from the group consisting of:
Figure imgf000655_0002
, such as
Figure imgf000655_0003
or
Figure imgf000655_0004
such as
Figure imgf000655_0005
or
Figure imgf000655_0008
; (e.g.,
Figure imgf000655_0009
), such as
Figure imgf000655_0006
(e.g.,
Figure imgf000655_0012
wherein bb is the point of attachment to W
Figure imgf000655_0010
R .
127. The compound of claim 124, wherein Rg2 is
Figure imgf000655_0007
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW.
128. The compound of claims 124 or 127, wherein Rg2 is selected from the group consisting of: such as
Figure imgf000655_0011
or , wherein bb is the point of at W
Figure imgf000656_0004
Figure imgf000656_0005
tachment to R ; and optionally wherein Rd is C1-4 alkyl, such as methyl.
129. The compound of claim 124, wherein Rg2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein Rg2 is
Figure imgf000656_0006
, such as or wherein bb is
Figure imgf000656_0007
Figure imgf000656_0008
the point of attachment to RW.
130. The compound of any one of claims 124-129, wherein RW is –C(=O)-W.
131. The compound of any one of claims 124-130, wherein W is C2-6 alkenyl optionally substituted with from 1-3 Ra.
132. The compound of any one of claims 124-131, wherein RW is
Figure imgf000656_0001
or
Figure imgf000656_0002
, such as
Figure imgf000656_0003
.
133. The compound of any one of claims 95-132, wherein m is 1.
134. The compound of any one of claims 95-133, wherein X2 is –O-.
135. The compound of any one of claims 95-133, wherein X2 is -N(RN)-, such as –N(H)-.
136. The compound of any one of claims 95-133, wherein X2 is
Figure imgf000657_0001
.
137. The compound of any one of claims 95-133, wherein X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*, such as –N(H)C(=O)* or –N(H)S(O)2-*.
138. The compound of any one of claims 95-132, wherein m is 0.
139. The compound of any one of claims 1-13, wherein: m is 1; X2 is –N(RN)C(=O)-*, -N(RN)C(=O)O-* or -N(RN)C(=O)N(RN)-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is H.
140. The compound of claim 139, wherein X2 is -N(RN)C(=O)-*, such as – N(H)C(=O)-*.
141. The compound of claim 139, wherein X2 is selected from the group consisting of -N(RN)C(=O)N(RN)-*, such as –N(H)C(=O)N(RN)-*; and -N(RN)C(=O)O- *, such as –N(H)C(=O)O-*.
142. The compound of any one of claims 95-141, wherein L1 is CH2.
143. The compound of any one of claims 95-141, wherein L1 is –CH(Me)-.
144. The compound of any one of claims 95-141, wherein L1 is –CH2CH2-.
145. The compound of any one of claims 100-138, wherein L1 is a bond.
146. The compound of any one of claims 1-13, wherein: m is 1; X2 is –O-, -N(RN)-, N N
Figure imgf000657_0002
, –N(R )C(=O)*, or -N(R )S(O)2-*; L1 is branched C3-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; –NReRf; and H.
147. The compound of claim 146, wherein R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra.
148. The compound of claims 146 or 147, wherein R5 is C1-3 alkoxy.
149. The compound of claim 146, wherein R5 is S(O)2(C1-6 alkyl) optionally substituted with from 1-6 Ra.
150. The compound of any one of claims 146-149, wherein X2 is –O-.
151. The compound of any one of claims 146-149, wherein X2 is -N(RN)-, such as –N(H)-.
152. The compound of any one of claims 146-149, wherein X2 is
Figure imgf000658_0001
.
153. The compound of any one of claims 146-149, wherein X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*, such as –N(H)C(=O)-* or –N(H)S(O)2-*.
154. The compound of any one of claims 146-153, wherein L1 is branched C3-6 alkylene.
155. The compound of any one of claims 146-154, wherein L1 is selected from the group consisting of: and
Figure imgf000658_0002
Figure imgf000658_0003
wherein aa is the point of attachment to R5.
156. The compound of claims 1 or 2, wherein Ring C is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc.
157. The compound of any one of claims 1-2 or 156, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
158. The compound of any one of claims 1-2 or 156-157, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-3 Rc.
159. The compound of any one of claims 1-2 or 156-158, wherein Ring C is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd.
160. The compound of any one of claims 1-2 or 156-159, wherein Ring C is selected from the group consisting of:
Figure imgf000659_0001
, such as
Figure imgf000659_0002
161. The compound of any one of claims 1-2 or 156-157, wherein 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
162. The compound of any one of claims 1-2, 156-157, or 161, wherein Ring C is: (i) selected from the group consisting of:
Figure imgf000660_0001
Figure imgf000660_0008
(ii) selected from the group consisting of:
Figure imgf000660_0002
and
Figure imgf000660_0003
(iii) selected from the group consisting of:
Figure imgf000660_0004
and
Figure imgf000660_0005
, wherein the Rc present in Ring C is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl optionally substituted with from 1-3 independently selected halo; or (iv) selected from the group consisting of: and
Figure imgf000660_0006
wherein the
Figure imgf000660_0007
Rc present in Ring C is selected from the group consisting of: halo and C1-3 alkyl optionally substituted with from 1-3 Ra, optionally wherein the Rc is –F, -Cl, or C1-3 alkyl optionally substituted with from 1-3 independently selected halo.
163. The compound of any one of claims 1-2 or 156, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
164. The compound of any one of claims 1-2, 156, or 163, wherein Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
165. The compound of claim 164, wherein Ring C is attached to
Figure imgf000661_0001
via a 5-membered ring.
166. The compound of any one of claims 1-2, 156, or 163-165, wherein Ring C is selected from the group consisting of:
Figure imgf000661_0002
Figure imgf000661_0003
, and
Figure imgf000661_0005
Figure imgf000661_0004
.
167. The compound of claim 164, wherein Ring C is attached to
Figure imgf000662_0005
via a 6-membered ring.
168. The compound of any one of claims 1-2, 156, 164, or 167, wherein Ring C is:
Figure imgf000662_0006
, wherein Z0 is N or CH (e.g., CH); and Ring D is an aromatic or partially unsaturated (e.g., aromatic) ring including 5 ring atoms, wherein from 1-3 (e.g., 1 or 2) ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(Rd), O, and S(O)0-2, wherein Ring D is optionally substituted with from 1-2 Rc.
169. The compound of any one of claims 1-2, 156, 163-164, or 167-168, wherein Ring C is selected from the group consisting of:
Figure imgf000662_0001
, , ,
Figure imgf000662_0002
, , , , , ,
Figure imgf000662_0003
, and
Figure imgf000662_0004
, each further optionally substituted with from 1-2 Rc.
170. The compound of any one of claims 1-2, 156, 163-164, or 167-168, wherein Ring C is selected from the group consisting of:
Figure imgf000663_0006
Figure imgf000663_0005
and .
171. The compound of any one of claims 1-2, 156, or 163, wherein Ring C is: (i) 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), and N(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc; (ii) selected from the group consisting of:
Figure imgf000663_0004
Figure imgf000663_0003
, , , , , and
Figure imgf000663_0002
or (iii) selected from the group consisting of:
Figure imgf000663_0007
and
Figure imgf000663_0001
172. The compound of claims 1 or 2, wherein Ring C 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc, such as: wherein Ring C is 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(Rd), 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 Rc, such as wherein Ring C is tetrahydropyranyl, such as
Figure imgf000664_0001
.
173. The compound of any one of claims 1-172, wherein each occurrence of Rc present on one or more ring atoms of Ring C is independently selected from the group consisting of: C1-3 alkyl; C1-3 alkyl substituted with from 1-3 Ra; halo; cyano; NReRf, such as NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, or NHC(=O)C1-3 alkyl; -OH; C1-4 alkoxy; and C1-4 haloalkoxy.
174. The compound of any one of claims 1-173, wherein R1c is H.
175. The compound of any one of claims 1-174, wherein R2a and R2b are H.
176. The compound of any one of claims 1-174, wherein from 1-2, such as 1, of R2a and R2b is a substituent other than H.
177. The compound of any one of claims 1-174 or 176, wherein one of R2a and R2b is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl; and the other of R2a and R2b is H.
178. The compound of any one of claims 1-174 or 176, wherein one of R2a and R2b is Rg; and the other of R2a and R2b is H.
179. The compound of any one of claims 1-174, 176, or 178, wherein one of R2a and R2b is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R2a and R2b is H.
180. The compound of any one of claims 1-174, wherein R2a and R2b, 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(Rd), 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 Rc.
181. The compound of any one of claims 1-174 or 180, wherein R2a and R2b 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 Rc.
182. The compound of any one of claims 1-181, wherein R3a and R3b are H.
183. The compound of any one of claims 1-181, wherein from 1-2, such as 1, of R3a and R3b is a substituent other than H.
184. The compound of any one of claims 1-181 or 183, wherein one of R3a and R3b is Rb; and the other of R3a and R3b is H.
185. The compound of any one of claims 1-181 or 183-184, wherein one of R3a and R3b is C1-3 alkyl optionally substituted with from 1-3 Ra; and the other of R3a and R3b is H.
186. The compound of any one of claims 1-181 or 183-185, wherein one of R3a and R3b is C1-3 alkyl; and the other of R3a and R3b is H.
187. The compound of any one of claims 1-181 or 183-186, wherein one of R3a and R3b is methyl, ethyl, or isopropyl; and the other of R3a and R3b is H.
188. The compound of any one of claims 1-181 or 183-185, wherein one of R3a and R3b is C1-3 alkyl substituted with from 1-3 independently selected halo; and the other of R3a and R3b is H.
189. The compound of any one of claims 1-181, 183-185, or 188, wherein one of R3a and R3b is –CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CH2F; and the other of R3a and R3b is H.
190. The compound of any one of claims 1-181 or 183-185, wherein one of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; and the other of R3a and R3b is H.
191. The compound of any one of claims 1-181, 183-185, or 190, wherein one of R3a and R3b is –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, - CH2OEt, -CH2CH2OCHF2, -CH2NReRf (e.g., -CH2N(CF3)Me), or –CH2CH2NReRf (e.g., - CH2CH2NMe2); and the other of R3a and R3b is H.
192. The compound of any one of claims 1-181 or 183, wherein one of R3a and R3b is Rg or –(Lg)g-Rg; and the other of R3a and R3b is H.
193. The compound of any one of claims 1-181, 183, or 192, wherein one of R3a and R3b is selected from the group consisting of: heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and C3-6 cycloalkyl optionally substituted with from 1-4 Rc; and the other of R3a and R3b is H.
194. The compound of any one of claims 1-181, 183, or 192-193, wherein one of R3a and R3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with Rd; and the other of R3a and R3b is H.
195. The compound of any one of claims 1-181, 183, or 192, wherein one of R3a and R3b is –(C1-3 alkylene)-Rg or -(C1-3 alkylene)-O-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H.
196. The compound of any one of claims 1-181, 183, 192, or 195, wherein one of R3a and R3b is –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H.
197. The compound of any one of claims 1-181, 183, 192, or 195-196, wherein one of R3a and R3b is –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with Rd; and the other of R3a and R3b is H; optionally, wherein one of R3a and R3b is selected from the group consisting of: such as or ; , such
Figure imgf000668_0004
Figure imgf000668_0001
Figure imgf000668_0002
Figure imgf000668_0003
as or
Figure imgf000668_0005
; , such as
Figure imgf000668_0006
or
Figure imgf000668_0007
; and
Figure imgf000668_0008
198. The compound of any one of claims 1-181 or 183, wherein R3a and R3b are each independently selected Rb.
199. The compound of any one of claims 1-181, 183, or 198, wherein R3a and R3b are each independently selected C1-3 alkyl which is optionally substituted with from 1- 3 Ra.
200. The compound of any one of claims 1-181, 183, or 198-199, wherein R3a and R3b are each independently C1-3 alkyl, such as methyl.
201. The compound of any one of claims 1-181, wherein R3a and R3b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • 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(Rd), O, and S(O)0-2; and • 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 Rc.
202. The compound of any one of claims 1-181 or 201, wherein R3a and R3b 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 Rc.
203. The compound of any one of claims 1-181 or 201-202, wherein R3a and R3b together with the Ring B ring atom to which each is attached form a fused cyclopropyl or cyclobutyl.
204. The compound of any one of claims 1-181 or 201, wherein R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc.
205. The compound of any one of claims 1-181, 201, or 204, wherein R3a and R3b, together with the Ring B ring atom to which each is attached, form: (i)
Figure imgf000669_0001
, or
Figure imgf000669_0002
; (ii)
Figure imgf000669_0003
or
Figure imgf000669_0004
; (iii) any group in (ii), wherein Rd is C1-3 alkyl optionally substituted with from 1-3 independently selected halo; (iv) any group in (ii), wherein Rd is C1-3 alkyl substituted with from 1-3 independently selected halo; or (v) any group in (ii), wherein Rd is –CH2CF3.
206. The compound of any one of claims 1-181, wherein R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with RW and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc.
207. The compound of any one of claims 1-181 or 206, wherein R3a and R3b together with the Ring B ring atom to which each is attached, form: (i)
Figure imgf000670_0001
, , or
Figure imgf000670_0002
; (ii) any group of (i), wherein RW is –LW-W, wherein LW is C(=O) or S(O)2; and RW is C2-6 alkenyl which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 hybridized carbon atom; (iii) any group of (i), wherein RW is
Figure imgf000670_0003
or
Figure imgf000670_0004
or (iv) , whe W
Figure imgf000670_0006
rein R is
Figure imgf000670_0005
208. The compound of any one of claims 201-207, wherein R1c, R2a, and R2b are each H.
209. The compound of any one of claims 1-174, wherein one of R2a and R2b and one of R3a and R3b taken together with the Ring B ring atoms 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(Rd), 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 Rc.
210. The compound of any one of claims 1-174 or 209, wherein one of R2a and R2b and one of R3a and R3b taken together with the Ring B ring atoms to which each is attached, form a fused saturated ring of 3-8 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(Rd), O, and S(O)0-2; and x wherein the fused saturated ring of 3-8 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
211. The compound of any one of claims 1-174 or 209-210, wherein one of R2a and R2b and one of R3a and R3b taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 cycloalkyl which is optionally substituted with from 1-2 Rc, such as: wherein one of R2a and R2b and one of R3a and R3b taken together with the Ring B ring atoms to which each is attached, form a fused cyclopropyl or cyclobutyl.
212. The compound of any one of claims 1-174, wherein one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached.
213. The compound of any one of claims 209-212, wherein the other of R2a and R2b and the other of R3a and R3b are each H.
214. The compound of any one of claims 209-212, wherein the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: Rb, Rg, and –(Lg)g-Rg.
215. The compound of any one of claims 209-212 or 214, wherein the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc.
216. The compound of any one of claims 209-212 or 214-215, wherein the other of R2a and R2b is H; and the other of R3a and R3b is: (i) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; or (ii) –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, -CH2OEt, - CH2CH2OCHF2, -CH2NReRf (e.g., -CH2N(CF3)Me), or –CH2CH2NReRf (e.g., - CH2CH2NMe2).
217. The compound of any one of claims 209-212 or 214-215, wherein the other of R2a and R2b is H; and the other of R3a and R3b is: (i) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; (ii) –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, -CH2CH(Me)OMe, -CH2OEt, or -CH2CH2OCHF2; or (iii) –CH2OMe or –CH2CH2OMe.
218. The compound of any one of claims 209-217, wherein R1c is –H.
219. The compound of any one of claims 1-173, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl optionally substituted with from 1-3 Ra; and the other of R3a and R3b is H; and optionally each Ra substituent present in R3a or R3b is independently selected from the group consisting of: halo, C1-4 alkoxy, and C1-4 haloalkoxy.
220. The compound of any one of claims 1-173 or 219, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl; and the other of R3a and R3b is H.
221. The compound of any one of claims 1-173 or 219, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl substituted with from 1-3 independently selected halo; and the other of R3a and R3b is H.
222. The compound of any one of claims 1-173 or 219, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; and the other of R3a and R3b is H.
223. The compound of any one of claims 1-173, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is –Rg, –(C1-3 alkylene)-Rg, or –(C1-3 alkylene)-O-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H.
224. The compound of any one of claims 1-173, wherein R1c, R2a, and R2b are each H; and R3a and R3b taken together with the Ring B ring carbon 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 Rc.
225. The compound of any one of claims 1-173, wherein R1c, R2a, and R2b are each H; and R3a and R3b taken together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc.
226. The compound of any one of claims 1-225, wherein Ring A is
Figure imgf000674_0001
wherein each RcB is an independently selected Rc; and m is 0, 1, 2, 3, or 4.
227. The compound of claim 226, wherein m is 1, 2, or 3.
228. The compound of claims 226 or 227, wherein m is 1 or 2, such as 2.
229. The compound of any one of claims 1-228, wherein Ring A is
Figure imgf000675_0002
or (e.g., cB c
Figure imgf000675_0003
Figure imgf000675_0004
), wherein each R is an independently selected R .
230. The compound of any one of claims 226-229, wherein each RcB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo.
231. The compound of any one of claims 1-228, wherein Ring A is
Figure imgf000675_0001
, wherein RcB1 is Rc; and RcB2 is H or Rc, optionally wherein RcB1 and RcB2 are each independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo.
232. The compound of claim 231, wherein RcB1 is halo, such as –F or –Cl, such as –F.
233. The compound of claim 231, wherein RcB1 is C1-3 alkyl or C1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein RcB1 is methyl, – CHF2, or –CF3.
234. The compound of any one of claims 231-233, wherein RcB2 is selected from the group consisting of: halo; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo.
235. The compound of any one of claims 231-234, wherein RcB2 is C1-4 alkoxy or C1-4 haloalkoxy.
236. The compound of any one of claims 231-234, wherein RcB2 is selected from the group consisting of cyano; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein RcB2 is cyano, methyl, ethyl, -CHF2, -CF3, or -CH2CHF2.
237. The compound of any one of claims 1-225, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo.
238. The compound of any one of claims 1-225 or 237, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo.
239. The compound of any one of claims 1-225 or 237-238, wherein Ring A is selected from the group consisting of:
Figure imgf000676_0001
, , ,
Figure imgf000676_0002
and each of which is further optionally substituted
Figure imgf000676_0003
with Rc.
240. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a):
Figure imgf000677_0001
Formula (I-a) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
241. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-b):
Figure imgf000677_0002
Formula (I-b) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
242. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-c):
Figure imgf000677_0003
Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
243. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-d):
Figure imgf000678_0002
Formula (I-d) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
244. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-e):
Figure imgf000678_0001
Formula (I-e) or a pharmaceutically acceptable salt thereof.
245. The compound of any one of claims 240-244, wherein m is 0 or 1; X2 is –O-, -N(RN)-, –N(RN)C(=O)-*, or -N(RN
Figure imgf000678_0003
)S(O)2-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf.
246. The compound of claim 245, wherein R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra, such as wherein R5 is C1-3 alkoxy.
247. The compound of claim 245, wherein R5 is S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra, such as wherein R5 is S(O)2(C1-3 alkyl).
248. The compound of any one of claims 240-244, wherein: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000679_0003
–N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 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(Rd), 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 Rc.
249. The compound of claim 248, wherein R5 is
Figure imgf000679_0001
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.
250. The compound of claim 248, wherein R5 is
Figure imgf000679_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); and x1 and x2 are each independently 0, 1, or 2.
251. The compound of claims 249 or 250, wherein x1 is 0.
252. The compound of any one of claims 249-251, wherein Xa is –O-.
253. The compound of any one of claims 248-252, wherein R5 is
Figure imgf000680_0001
, such as or whe 5
Figure imgf000680_0005
rein R is
Figure imgf000680_0006
254. The compound of any one of claims 249-251, wherein Xa is N(Rd), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl).
255. The compound of any one of claims 248-251 or 254, wherein R5 is selected from the group consisting of:
Figure imgf000680_0003
Figure imgf000680_0007
, optionally wherein Rd is C d
Figure imgf000680_0004
1-4 alkyl or wherein R is C(=O)(C1-4 alkyl) or S(O)2(C1- 4 alkyl).
256. The compound of claims 249 or 250, wherein x1 is 1 or 2.
257. The compound of any one of claims 248-250 or 256, wherein R5 is selected from the group consisting of:
Figure imgf000680_0002
258. The compound of claim 248, wherein R5 is
Figure imgf000681_0005
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2.
259. The compound of claims 248 or 258, wherein R5 is selected from the group consisting of:
Figure imgf000681_0006
, ; ,
Figure imgf000681_0007
optionally wherein Rd is C1-4 alkyl, such as methyl.
260. The compound of claim 248, wherein R5 is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein R5 is
Figure imgf000681_0004
or
Figure imgf000681_0002
such as
Figure imgf000681_0003
261. The compound of any one of claims 240-244, wherein: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000681_0001
–N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is selected from the group consisting of: • 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc; and • C6-10 aryl optionally substituted with from 1-4 Rc.
262. The compound of claim 261, wherein R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-3 Rc.
263. The compound of claims 261 or 262, wherein R5 is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd, such as
Figure imgf000682_0001
Figure imgf000682_0002
264. The compound of claim 261, wherein R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as
Figure imgf000682_0003
Figure imgf000682_0004
265. The compound of claim 261, wherein R5 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is selected from the group consisting of: , each optio c
Figure imgf000683_0002
nally substituted with from 1-2 R .
266. The compound of claim 261, wherein R5 is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as wherein R5 is
Figure imgf000683_0001
267. The compound of claim 261, wherein R5 is phenyl optionally substituted with from 1-2 Rc, such as unsubstituted phenyl.
268. The compound of any one of claims 240-244, wherein: m is 0 or 1; X2 is –O-, -N(RN)-, –N(RN)C(=O)*, or N
Figure imgf000683_0003
-N(R )S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
269. The compound of claim 268, wherein R5 is C3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.
270. The compound of claim 268, wherein R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1-4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc, such as: wherein R5 is selected from the group consisting of:
Figure imgf000684_0001
g such as
Figure imgf000684_0002
g g
Figure imgf000684_0003
271. The compound of any one of claims 240-244, wherein: m is 0 or 1; X2 is –O-, -N(RN)-,
Figure imgf000684_0004
, –N(RN)C(=O)*, or -N(RN)S(O)2-*; L1 is a bond or C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is –Rg2-RW, wherein: the -Rg2 of R5 is heterocyclylene 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(Rd), 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 Rc; and -RW is –C(=O)-W or –S(O)2-W.
272. The compound of claim 271, wherein Rg2 is
Figure imgf000684_0005
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0.
273. The compound of claims 271 or 272, wherein Rg2 is selected from the group consisting of:
Figure imgf000685_0004
Figure imgf000685_0005
, wherein bb is the point of attachment t W
Figure imgf000685_0006
o R .
274. The compound of claim 271, wherein Rg2 is
Figure imgf000685_0001
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW.
275. The compound of claims 271 or 274, wherein Rg2 is selected from the group consisting of:
Figure imgf000685_0002
; , wherein bb is the point of attac W
Figure imgf000685_0003
hment to R ; and optionally wherein Rd is C1-4 alkyl, such as methyl.
276. The compound of claim 271, wherein Rg2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein Rg2 is
Figure imgf000686_0002
, such as
Figure imgf000686_0003
, wherein bb is the point of attachment to RW.
277. The compound of any one of claims 271-276, wherein RW is –C(=O)-W.
278. The compound of any one of claims 271-277, wherein W is C2-6 alkenyl optionally substituted with from 1-3 Ra.
279. The compound of any one of claims 271-278, wherein RW is
Figure imgf000686_0001
or
Figure imgf000686_0004
, such as
Figure imgf000686_0005
280. The compound of any one of claims 240-279, wherein m is 1.
281. The compound of any one of claims 240-280, wherein X2 is –O-.
282. The compound of any one of claims 240-280, wherein X2 is -N(RN)-, such as –N(H)-.
283. The compound of any one of claims 240-280, wherein X2 is
Figure imgf000686_0006
284. The compound of any one of claims 240-280, wherein X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*, such as –N(H)C(=O)* or –N(H)S(O)2-*.
285. The compound of any one of claims 240-279, wherein m is 0.
286. The compound of any one of claims 240-244, wherein: m is 1; X2 is –N(RN)C(=O)-*, -N(RN)C(=O)O-* or -N(RN)C(=O)N(RN)-*; L1 is C1-3 alkylene optionally substituted with from 1-3 Ra; and R5 is H.
287. The compound of claim 286, wherein X2 is -N(RN)C(=O)-*, such as – N(H)C(=O)-*.
288. The compound of claim 286, wherein X2 is selected from the group consisting of -N(RN)C(=O)N(RN)-*, such as –N(H)C(=O)N(RN)-*; and -N(RN)C(=O)O- *, such as –N(H)C(=O)O-*.
289. The compound of any one of claims 240-288, wherein L1 is CH2.
290. The compound of any one of claims 240-288, wherein L1 is –CH(Me)-.
291. The compound of any one of claims 240-288, wherein L1 is –CH2CH2-.
292. The compound of any one of claims 240-244 or 248-285, wherein L1 is a bond.
293. The compound of any one of claims 240-244, wherein: m is 1; X2 is –O-, -N(RN)-, N N
Figure imgf000687_0001
, –N(R )C(=O)*, or -N(R )S(O)2-*; L1 is branched C3-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: H; C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf.
294. The compound of claim 293, wherein R5 is C1-6 alkoxy optionally substituted with from 1-6 Ra, such as wherein R5 is C1-3 alkoxy.
295. The compound of claim 293, wherein R5 is S(O)2(C1-6 alkyl) which is optionally substituted with from 1-6 Ra.
296. The compound of any one of claims 293-295, wherein X2 is –O-.
297. The compound of any one of claims 293-295, wherein X2 is -N(RN)-, such as –N(H)-.
298. The compound of any one of claims 293-295, wherein X2 is
Figure imgf000688_0004
.
299. The compound of any one of claims 293-295, wherein X2 is –N(RN)C(=O)* or -N(RN)S(O)2-*, such as –N(H)C(=O)-* or –N(H)S(O)2-*.
300. The compound of any one of claims 240-244 or 293-299, wherein L1 is branched C3-6 alkylene.
301. The compound of any one of claims 240-244 or 293-299, wherein L1 is selected from the group consisting of:
Figure imgf000688_0002
, and , wherein aa is the point of attachme 5
Figure imgf000688_0003
nt to R .
302. The compound of claim 1, wherein the compound is a compound of Formula (I-f):
Figure imgf000688_0001
Formula (I-f) or a pharmaceutically acceptable salt thereof, wherein: Ring C1 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
303. The compound of claim 302, wherein Ring C1 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-3 Rc.
304. The compound of claims 302 or 303, wherein Ring C1 is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 Rc, and wherein a ring nitrogen atom is optionally substituted with Rd.
305. The compound of claim 302, wherein Ring C1 is selected from the group consisting of:
Figure imgf000689_0001
, such as wherein Ring C1 is:
Figure imgf000689_0002
306. The compound of claim 302, wherein 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc.
307. The compound of claims 302 or 306, wherein Ring C1 is selected from the group consisting of:
Figure imgf000690_0005
, and
Figure imgf000690_0006
308. The compound of any one of claims 302 or 306-307, wherein Ring C1 is: (i) selected from the group consisting of:
Figure imgf000690_0007
and
Figure imgf000690_0004
, wherein the Rc present in Ring C is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl optionally substituted with from 1-3 independently selected halo; or (ii) selected from the group consisting of:
Figure imgf000690_0002
and
Figure imgf000690_0003
wherein the Rc present in Ring C is selected from the group consisting of: halo and C1-3 alkyl optionally substituted with from 1-3 Ra, optionally wherein the Rc is –F, -Cl, or C1-3 alkyl optionally substituted with from 1-3 independently selected halo.
309. The compound of claim 1, wherein the compound is a compound of Formula (I-g):
Figure imgf000690_0001
Formula (I-g) 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
310. The compound of claim 309, wherein Ring C2 is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.
311. The compound of claims 309 or 310, wherein Ring C2 is selected from the group consisting of:
Figure imgf000691_0001
Figure imgf000692_0005
Figure imgf000692_0004
, each further optionally substituted with from 1-2 Rc; or (iii)
Figure imgf000692_0001
312. The compound of claim 309, wherein: (i) 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), and N(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc; (ii) Ring C2 is selected from the group consisting of:
Figure imgf000692_0002
,
Figure imgf000692_0003
(iii) Ring C2 is selected from the group consisting of:
Figure imgf000693_0001
;
Figure imgf000693_0002
;
313. The compound of claim 1, wherein the compound is a compound of Formula (I-h):
Figure imgf000693_0003
Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: Ring C3 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(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X1 and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
314. The compound of claim 313, wherein Ring C3 is 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(Rd), 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 Rc, such as wherein Ring C is tetrahydropyranyl, such as
Figure imgf000693_0004
315. The compound of any one of claims 302-314, wherein each occurrence of Rc present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 is independently selected from the group consisting of: C1-3 alkyl; C1-3 alkyl substituted with from 1-3 Ra; halo; cyano; NReRf, such as NH2, NH(C1-3 alkyl), or N(C1-3 alkyl)2; -OH; C1-4 alkoxy; and C1-4 haloalkoxy.
316. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a1):
Figure imgf000694_0001
Formula (I-a1) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is heterocyclyl including from 4-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc.
317. The compound of claim 316, wherein R5 is
Figure imgf000694_0002
which is optionally substituted with from 1-2 Rc, wherein Xa is O, N(H), or N(Rd); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.
318. The compound of claim 317, wherein x1 is 0.
319. The compound of claims 317 or 318, wherein Xa is –O-.
320. The compound of any one of claims 316-319, wherein R5 is
Figure imgf000695_0001
, such as ; or w 5
Figure imgf000695_0006
herein R is
Figure imgf000695_0007
321. The compound of claims 317 or 318, wherein Xa is N(Rd), optionally wherein Rd is C1-4 alkyl or wherein Rd is C(=O)(C1-4 alkyl) or S(O)2(C1-4 alkyl).
322. The compound of any one of claims 316-318 or 321, wherein R5 is selected from the group consisting of:
Figure imgf000695_0002
Figure imgf000695_0003
) ; , ; , , optionally wherein d d
Figure imgf000695_0004
R is C1-4 alkyl or wherein R is C(=O)(C1-4 alkyl) or S(O)2(C1- 4 alkyl).
323. The compound of claim 317, wherein x1 is 1 or 2.
324. The compound of any one of claims 316-317 or 323, wherein R5 is selected from the group consisting of:
Figure imgf000695_0005
325. The compound of claim 316, wherein R5 is
Figure imgf000696_0001
which is optionally substituted with from 1-2 Rc, wherein Xb and Xc are each independently selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2.
326. The compound of claims 316 or 325, wherein R5 is selected from the group
Figure imgf000696_0002
g , ; ,
Figure imgf000696_0003
optionally wherein Rd is C1-4 alkyl, such as methyl.
327. The compound of claim 316, wherein R5 is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein R5 is
Figure imgf000696_0004
Figure imgf000696_0005
328. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a2):
Figure imgf000697_0003
Formula (I-a2) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is selected from the group consisting of: • 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(Rd), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 Rc; and • C6 aryl optionally substituted with from 1-4 Rc.
329. The compound of claim 328, wherein R5 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 Rc, such as: wherein R5 is
Figure imgf000697_0001
Figure imgf000697_0002
330. The compound of claim 328, wherein R5 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(Rd), and wherein the heteroaryl is optionally substituted with from 1-4 Rc, such as
Figure imgf000698_0001
Figure imgf000698_0002
, , ,
331. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a3):
Figure imgf000698_0003
Formula (I-a3) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.
332. The compound of claim 331, wherein R5 is C3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.
333. The compound of claim 331, wherein R5 is C3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C1-4 alkyl; C1-4 alkyl substituted with Ra, such as C1-4 alkyl substituted with C1-4 alkoxy; C1-4 alkoxy; and C1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 Rc, such as: wherein R5 is selected from the group consisting of:
Figure imgf000699_0003
Figure imgf000699_0001
334. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a4):
Figure imgf000699_0002
Formula (I-a4) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R5 is –Rg2-RW, wherein: the -Rg2 of R5 is heterocyclylene 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(Rd), 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 Rc; and -RW is –C(=O)-W or –S(O)2-W.
335. The compound of claim 334, wherein Rg2 is
Figure imgf000700_0001
which is optionally substituted with from 1-2 Rc, wherein bb is the point of attachment to RW; and x1 and x2 are each independently 0, 1, or 2.
336. The compound of claim 335, wherein x1 is 0.
337. The compound of any one of claims 334-336, wherein Rg2 is selected from the group consisting of:
Figure imgf000700_0005
, ; ,
Figure imgf000700_0002
, wherein bb is the point of att W
Figure imgf000700_0003
achment to R .
338. The compound of claim 334, wherein Rg2 is
Figure imgf000700_0004
which is optionally substituted with from 1-2 Rc; Xb is selected from the group consisting of: O, N(H), N(Rd), and S(O)0-2; and bb is the point of attachment to RW.
339. The compound of claims 334 or 338, wherein Rg2 is selected from the group consisting of:
Figure imgf000701_0001
such as or ; and , such as
Figure imgf000701_0002
Figure imgf000701_0003
Figure imgf000701_0004
or , wher W
Figure imgf000701_0005
Figure imgf000701_0006
ein bb is the point of attachment to R ; and optionally wherein Rd is C1-4 alkyl, such as methyl.
340. The compound of claim 334, wherein Rg2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc, such as wherein Rg2 is
Figure imgf000701_0007
, such as , or
Figure imgf000701_0011
, wherein bb is
Figure imgf000701_0012
the point of attachment to RW.
341. The compound of any one of claims 334-340, wherein RW is –C(=O)-W.
342. The compound of any one of claims 334-341, wherein W is C2-6 alkenyl optionally substituted with from 1-3 Ra.
343. The compound of any one of claims 334-342, wherein RW is
Figure imgf000701_0008
or
Figure imgf000701_0009
, such as
Figure imgf000701_0010
344. The compound of claim 1, wherein the compound is a compound of Formula (I-a5):
Figure imgf000702_0001
Formula (I-a5) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; L1 is C1-6 alkylene optionally substituted with from 1-6 Ra; and R5 is selected from the group consisting of: H; C1-6 alkoxy or S(O)2(C1-6 alkyl) each optionally substituted with from 1-6 Ra; -OH; and –NReRf.
345. The compound of claim 344, wherein L1 is branched C3-6 alkylene.
346. The compound of claims 344 or 345, wherein L1 is selected from the group consisting of:
Figure imgf000702_0002
and
Figure imgf000702_0003
, wherein aa is the point of attachment to R5.
347. The compound of any one of claims 344-346, wherein R5 is H.
348. The compound of claim 1, wherein the compound is a compound of Formula (I-g1):
Figure imgf000703_0001
Formula (I-g1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Y1, Y2, and Y3 are each independently selected from the group consisting of: N, NH, NRd, CH, CRc, CX1, O, and S; and each is independently a single bond or a double bond, provided that the 5-membered ring including Y1, Y2, and Y3 is heteroaryl; and from 0-1 of Y1, Y2, and Y3 is selected from the group consisting of: O, S, and CRX1.
349. The compound of claim 348, wherein Y1 is S.
350. The compound of claims 348 or 349, wherein Y2 is selected from the group consisting of: N, CH, CRc, and CX1.
351. The compound of any one of claims 348-350, wherein Y2 is CH or CRc.
352. The compound of any one of claims 348-350, wherein Y2 is N.
353. The compound of any one of claims 348-352, wherein Y3 is selected from the group consisting of CH and CRc.
354. The compound of any one of claims 348-353, wherein Y3 is CH.
355. The compound of claim 348, wherein Y1 is S; and Y2 and Y2 are each CH.
356. The compound of claim 348, wherein Y1 is S; Y2 is N; and Y3 is CH.
357. The compound of claim 348, wherein Y1 is S; Y2 is CRc; and Y3 is CH.
358. The compound of any one of claims 348-351, 353-354, or 357, wherein the Rc group present in Y2 is selected from the group consisting of: (i) C1-6 alkyl; (ii) halo; and (iii) C1-6 alkyl substituted with from 1-6 independently selected Ra.
359. The compound of claim 358, wherein the Rc group present in Y2 is selected from the group consisting of: (i) C1-3 alkyl (e.g., methyl); (ii) halo (e.g., -F); and (iii) C1-3 alkyl substituted with from 1-3 independently selected halo (e.g., Rc is – CHF2 ) .
360. The compound of claim 1 or 348, wherein the compound is a compound of Formula (I-g1-1):
Figure imgf000704_0001
Formula (I-g1-1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1, such as 0.
361. The compound of any one of claims 240-360, wherein R1c is H.
362. The compound of any one of claims 240-361, wherein R2a and R2b are H.
363. The compound of any one of claims 240-361, wherein from 1-2, such as 1, of R2a and R2b is a substituent other than H.
364. The compound of any one of claims 240-361 or 363, wherein one of R2a and R2b is C1-3 alkyl optionally substituted with from 1-3 Ra, such as C1-3 alkyl (e.g., methyl) ; and the other of R2a and R2b is H.
365. The compound of any one of claims 240-361 or 363, wherein one of R2a and R2b is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R2a and R2b is H.
366. The compound of any one of claims 240-361, wherein R2a and R2b 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 Rc.
367. The compound of any one of claims 240-366, wherein R3a and R3b are H.
368. The compound of any one of claims 240-366, wherein from 1-2, such as 1, of R3a and R3b is a substituent other than H.
369. The compound of any one of claims 240-366 or 368, wherein one of R3a and R3b is C1-3 alkyl optionally substituted with from 1-3 Ra; and the other of R3a and R3b is H.
370. The compound of any one of claims 240-366 or 368-369, wherein one of R3a and R3b is C1-3 alkyl optionally substituted with from 1-3 independently selected halo, such as –CH3, –CH2F, -CH2CH2F, or –CHF2; and the other of R3a and R3b is H.
371. The compound of any one of claims 240-366 or 368-369, wherein one of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf, such as wherein one of R3a and R3b is –CH2OMe, -CH2CH2OMe, -CH(Me)CH2OMe, - CH2CH(Me)OMe, -CH2OEt, -CH2NReRf (e.g., -CH2N(CF3)Me), or –CH2CH2NReRf (e.g., -CH2CH2NMe2); and the other of R3a and R3b is H.
372. The compound of any one of claims 240-366 or 368, wherein one of R3a and R3b is selected from the group consisting of: heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and C3-6 cycloalkyl optionally substituted with from 1-4 Rc; and the other of R3a and R3b is H.
373. The compound of any one of claims 240-366 or 368, one of R3a and R3b is –(C1-3 alkylene)-Rg or –(C1-3 alkylene)-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H.
374. The compound of any one of claims 240-366, wherein R3a and R3b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 or 4 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 Rc.
375. The compound of any one of claims 240-366, wherein R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc.
376. The compound of any one of claims 240-366, wherein R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with RW and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc.
377. The compound of any one of claims 240-366 or 376, wherein R3a and R3b together with the Ring B ring atom to which each is attached, form: (i)
Figure imgf000707_0001
, , ; (ii) any group of (i), wherein RW is –LW-W, wherein LW is C(=O) or S(O)2; and RW is C2-6 alkenyl which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 hybridized carbon atom; or (iii) any group of (i), wherein RW is or
Figure imgf000707_0003
; or
Figure imgf000707_0002
(iv) , wherein RW is
Figure imgf000707_0004
Figure imgf000707_0005
378. The compound of any one of claims 240-361, wherein one of R2a and R2b and one of R3a and R3b taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 (e.g., C3 or C4) cycloalkyl which is optionally substituted with from 1-2 Rc.
379. The compound of any one of claims 240-361, wherein one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached.
380. The compound of claims 378 or 379, wherein the other of R2a and R2b and the other of R3a and R3b are each H.
381. The compound of claims 378 or 379, wherein the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: Rb, Rg, and –(Lg)g- Rg.
382. The compound of any one of claims 378-379 or 381, wherein the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc.
383. The compound of any one of claims 378-379 or 381-382, wherein the other of R2a and R2b is H; and the other of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf.
384. The compound of any one of claims 240-360, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl optionally substituted with from 1-3 Ra; and the other of R3a and R3b is H, optionally each Ra substituent present in R3a or R3b is independently selected from the group consisting of: halo, C1-4 alkoxy, and C1-4 haloalkoxy.
385. The compound of any one of claims 240-360 or 384, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; and the other of R3a and R3b is H.
386. The compound of any one of claims 240-360, wherein R1c, R2a, and R2b are each H; and R3a and R3b are independently selected C1-3 alkyl.
387. The compound of any one of claims 240-360, wherein R1c, R2a, and R2b are each H; one of R3a and R3b is –Rg, –(C1-3 alkylene)-Rg, or –(C1-3 alkylene)-O-Rg, optionally wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc; and the other of R3a and R3b is H.
388. The compound of any one of claims 240-360, wherein R1c, R2a, and R2b are each H; and R3a and R3b taken together with the Ring B ring carbon 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 Rc.
389. The compound of any one of claims 240-360, wherein R1c, R2a, and R2b are each H; and R3a and R3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 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(Rd), O, and S(O)0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and Rc.
390. The compound of any one of claims 240-360, wherein R1c, R2a, and R2b are each H; and R3a and R3b together with the Ring B ring atom to which each is attached, form: (i)
Figure imgf000710_0001
(ii) any group of (i), wherein RW is –LW-W, wherein LW is C(=O) or S(O)2; and RW is C2-6 alkenyl which is optionally substituted with from 1-3 Ra and further optionally substituted with Rg, wherein W is attached to LW via an sp2 hybridized carbon atom; or (iii) any group of (i), wherein RW is
Figure imgf000710_0002
.
391. The compound of any one of claims 240-360, wherein R1c is H; one of R2a and R2b and one of R3a and R3b taken together with the Ring B ring atoms to which each is attached, form a fused C3-6 (e.g., C3 or C4) cycloalkyl which is optionally substituted with from 1-2 Rc; and the other of R2a and R2b and the other of R3a and R3b are each H.
392. The compound of any one of claims 240-360, wherein R1c is H; one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached; and the other of R2a and R2b and the other of R3a and R3b are each H.
393. The compound of any one of claims 240-360, wherein R1c is H; one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R2a and R2b is H; and the other of R3a and R3b is selected from the group consisting of: (i) C1-3 alkyl; (ii) C1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C1-3 alkyl substituted with C1-4 alkoxy, C1-4 haloalkoxy, or NReRf; (iv) C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy; or (v) –Rg, –CH2-Rg, –CH2CH2Rg, or –CH2-O-Rg, wherein the Rg group of R3a or R3b is: C3-6 cycloalkyl optionally substituted with from 1-4 Rc, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), 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 Rc.
394. The compound of any one of claims 240-360, wherein R1c is H; one of R2a and R2b and one of R3a and R3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R2a and R2b is H; and the other of R3a and R3b is C1-3 alkyl substituted with C1-4 alkoxy or C1-4 haloalkoxy.
395. The compound of any one of claims 240-394, wherein Ring A is , wherein each RcB is an independently c
Figure imgf000711_0001
selected R ; and m is 0, 1, 2, 3, or 4.
396. The compound of claim 395, wherein m is 1 or 2, such as 2.
397. The compound of any one of claims 240-396, wherein Ring A is
Figure imgf000712_0004
or
Figure imgf000712_0005
(e.g., ), wherein each RcB is an independently
Figure imgf000712_0006
selected Rc.
398. The compound of any one of claims 395-397, wherein each RcB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C1-4 alkoxy; C1-4 haloalkoxy; C1-3 alkyl; and C1-3 alkyl substituted with from 1-6 independently selected halo.
399. The compound of any one of claims 240-398, wherein Ring A is selected from the group consisting of:
Figure imgf000712_0001
, and
Figure imgf000712_0003
.
Figure imgf000712_0002
400. The compound of any one of claims 240-394, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo.
401. The compound of any one of claims 240-394 or 400, wherein 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(Rd), O, and S(O)0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of Rc and oxo, such as: wherein Ring A is selected from the group consisting of:
Figure imgf000713_0001
Figure imgf000713_0002
, and
Figure imgf000713_0003
, each of which is further optionally substituted with Rc.
402. The compound of any one of claims 7-9, 240-244, or 316-401, wherein n is 0.
403. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.
404. A pharmaceutical composition comprising a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable diluent or carrier.
405. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
406. 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 any one of claims 1-403, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
407. A method of treating an EGFR-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR- associated cancer a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
408. A method of treating an EGFR-associated cancer in a subject, the method comprising: (a) determining that the cancer in the subject is an EGFR-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
409. A method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, 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.
410. The method of claims 406 or 408, wherein the step of determining that the cancer in the subject is an EGFR-associated cancer includes performing an assay to detect dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same in a sample from the subject.
411. The method of claim 410, further comprising obtaining a sample from the subject.
412. The method of claim 411, wherein the sample is a biopsy sample.
413. The method of any one of claims 410-412, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).
414. The method of claim 413, wherein the FISH is break apart FISH analysis.
415. The method of claim 413, wherein the sequencing is pyrosequencing or next generation sequencing.
416. The method of any one of claims 406, 409, or 410, wherein 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 mutations in the EGFR gene.
417. The method of claim 416, wherein the one or more point mutations in an EGFR gene results in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 1a and 1b.
418. The method of claim 417, wherein the one or more point mutations is selected from the mutations in Table 1a and 1b (e.g., L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon 20).
419. The method of claim 417, wherein the one or more point mutations is an EGFR inhibitor resistance mutation (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).
420. The method of claim 417, wherein the one or more point mutations in an EGFR gene include a deletion in exon 19 of a human EGFR gene.
421. The method of claim 417, wherein the one or more mutations is an EGFR insertion in exon 20 of a human EGFR gene.
422. The method of claim 421, wherein the insertion in exon 20 of a human EGFR gene is selected from: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
423. The method of claims 421 or 422, wherein the insertion in exon 20 of a human EGFR gene is selected from: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP.
424. The method of any one of claims 406-408 and 410-423, wherein the EGFR- associated cancer is selected from the group consisting of: oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, gastrointestinal cancer, central or peripheral nervous system tissue cancer, an endocrine or neuroendocrine cancer, a hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, renal cancer, biliary cancer, pheochromocytomaLi-Fraumeni tumor, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, osteogenic sarcoma tumors, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer and skin cancer.
425. The method of any one of claims 407, 408, and 410-424, wherein the EGFR-associated cancer is selected from the group consisting of: lung cancer, pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, glioblastoma, or breast cancer.
426. The method of claim 424 or 425, wherein the lung cancer is non-small cell lung cancer.
427. The method of any one of claims 405-426, wherein the cancer is a HER2- associated cancer.
428. The method of claim 427, wherein the HER2-associated cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.
429. The method of any one of claims 427 and 428, wherein determining that the cancer in the subject is a HER2-associated cancer includes performing an assay to detect dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same in a sample from the subject.
430. The method of claim 429, further comprising obtaining a sample from the subject.
431. The method of claim 430, wherein the sample is a biopsy sample.
432. The method of any one of claims 429-431, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).
433. The method of claim 432, wherein the sequencing is pyrosequencing or next generation sequencing.
434. The method of any one of claims 428-433, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is one or more point mutations in the HER2 gene.
435. The method of claim 434, wherein the one or more point mutations in a HER2 gene results in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3.
436. The method of claim 435, wherein the one or more point mutations is selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I).
437. The method of any one of claims 405-436, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
438. The method of any one of claims 405-437, further comprising administering an additional therapy or therapeutic agent to the subject.
439. The method of claim 438, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted- therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, and angiogenesis-targeted therapies.
440. The method of claim 439, wherein said additional therapeutic agent is selected from one or more kinase targeted therapeutics.
441. The method of claim 440, wherein said additional therapeutic agent is a tyrosine kinase inhibitor.
442. The method of claim 441, wherein said additional therapeutic agent is a second EGFR inhibitor.
443. The method of any one of claims 438-442, wherein said additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.
444. The method of claim 438, wherein said additional therapeutic agent is a second compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
445. The method of claim 438, wherein said additional therapeutic agent is a HER2 inhibitor.
446. The method of claim 445, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib, KU004, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788.
447. The method of any one of claims 438-446, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered simultaneously as separate dosages.
448. The method of any one of claims 438-446, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered as separate dosages sequentially in any order.
449. A method of treating a subject having a cancer, wherein the method comprises: (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 compound of any one of claims 1-403 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 increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); or (d) administering additional doses of the first EGFR inhibitor of step (a) to the subject if the subject has not been determined to have a cancer cell that 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).
450. The method of claim 449, wherein the anticancer agent in step (c) is a second EGFR inhibitor, an immunotherapy, a HER2 inhibitor, or a combination thereof.
451. The method of claim 449, wherein the anticancer agent in step (c) is the first EGFR inhibitor administered in step (a).
452. The method of claim 449, wherein the subject is administered additional doses of the first inhibitor of EGFR of step (a), and the method further comprises (e) administering another anticancer agent to the subject.
453. The method of claim 452, wherein the anticancer agent of step (e) is a second EGFR inhibitor, an immunotherapy, or a combination thereof.
454. The method of claim 452, wherein the anticancer agent of step (e) is a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof.
455. The method of any one of claims 449-454, wherein 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, T854A).
456. A method of treating an EGFR-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR- associated cancer that has one or more EGFR inhibitor resistance mutations a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
457. A method of treating an EGFR-associated cancer in a subject, the method comprising: (a) determining that the cancer in the subject has one or more EGFR inhibitor resistance mutations; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
458. A method of treating a subject having a cancer, wherein the method 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 compound of any one of claims 1-403 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 increased resistance to a cancer cell or tumor to treatment with the first modulator of EGFR that was previously administered to the subject; or (c) administering additional doses of the first modulator of EGFR to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR modulator resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first modulator of EGFR previously administered to the subject.
459. The method of claim 458, wherein the anticancer agent of step (b) is a second EGFR innhibitor, an immunotherapy, a HER2 inhibitor, or a combination thereof.
460. The method of claim 458, wherein the anticancer agent of step (b) is the first EGFR inhibitor previously administered to the subject.
461. The method of claim 458, wherein the subject is administered additional doses of the first EGFR inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.
462. The method of claim 461, wherein the anticancer agent of step (d) is a second EGFR inhibitor, an immunotherapy, or a combination thereof.
463. The method of claim 461, wherein the anticancer agent of step (d) is a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof.
464. The method of claim 462, wherein the second EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.
465. The method of any one of claims 456-464, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
466. The method of any one of claims 456-465, wherein 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.
467. The method of claim 466, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is one or more point mutations in the HER2 gene.
468. The method of claim 467, wherein the one or more point mutations in a HER2 gene results in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3.
469. The method of claim 468, wherein the one or more point mutations is selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I).
470. A method for modulating EGFR in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof.
471. The method of claim 470, wherein the contacting occurs in vivo.
472. The method of claim 470, wherein the contacting occurs in vitro.
473. The method of any one of claims 470-472, wherein the mammalian cell is a mammalian cancer cell.
474. The method of claim 473, wherein the mammalian cancer cell is a mammalian EGFR-associated cancer cell.
475. The method of any one of claims 470-473, wherein the cell has a dysregulation of an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same.
476. The method of claim 475, wherein 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 mutations in the EGFR gene.
477. The method of claim 476, wherein the one or more point mutations in an EGFR gene results in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 1a and 1b.
478. The method of claim 476, wherein the one or more point mutations is selected from the mutations in Table 1a and 1b (e.g., L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon 20).
479. The method of claim 476, wherein the one or more point mutations is an EGFR inhibitor resistance mutation (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).
480. The method of claim 476, wherein the one or more point mutations in an EGFR gene include a deletion in exon 19 of a human EGFR gene.
481. The method of claim 476, wherein the one or more point mutations is an EGFR insertion in exon 20 of a human EGFR gene.
482. The method of claims 476 or 481, wherein the insertion in exon 20 of a human EGFR gene is selected from: A767_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.
483. The method of claim 482, wherein the insertion in exon 20 of a human EGFR gene is selected from: 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.
484. 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 any one of claims 1-403, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
485. A method of treating a HER2-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a HER2-associated cancer a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
486. A method of treating a HER2-associated cancer in a subject, the method comprising: (a) determining that the cancer in the subject is a HER2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
487. A method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, 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.
488. The method of any one of claims 484 and 486, wherein the step of determining that the cancer in the subject is a HER2-associated cancer includes performing an assay to detect dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same in a sample from the subject.
489. The method of claim 488, further comprising obtaining a sample from the subject.
490. The method of claim 489, wherein the sample is a biopsy sample.
491. The method of any one of claims 484-490, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).
492. The method of claim 491, wherein the FISH is break apart FISH analysis.
493. The method of claim 491, wherein the sequencing is pyrosequencing or next generation sequencing.
494. The method of any one of claims 484-488, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is one or more point mutations in the HER2 gene.
495. The method of claim 494, wherein the one or more point mutations in a HER2 gene results in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3.
496. The method of claim 494, wherein the one or more point mutations is selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I).
497. The method of any one of claims 484-488, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is an insertion in exon 20 of the human HER2 gene.
498. The method of claim 497, wherein the insertion in exon 20 of the human HER2 gene is deletions at an amino acid position selected from: 774, 775, 776, 777, 778, and 780.
499. The method of claim 498, wherein the insertion in exon 20 of a human HER2 gene is selected from: 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.
500. The method of any one of claims 485, 486, and 488, wherein the HER2- associated cancer is selected from the group consisting of: colon cancer, lung cancer, or breast cancer.
501. The method of claim 500, wherein the lung cancer is non-small cell lung cancer.
502. The method of any one of claims 487-501, further comprising administering an additional therapy or therapeutic agent to the subject.
503. The method of claim 502, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted- therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies and angiogenesis-targeted therapies.
504. The method of claim 502, wherein said additional therapeutic agent is a second compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.
505. The method of claim 502, wherein said additional therapeutic agent is selected from one or more kinase targeted therapeutics.
506. The method of claim 502, wherein said additional therapeutic agent is a tyrosine kinase inhibitor.
507. The method of claim 502, wherein said additional therapeutic agent is an EGFR inhibitor.
508. The method of claim 502, wherein said additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.
509. The method of claim 502, wherein said additional therapeutic agent is a HER2 inhibitor.
510. The method of claim 509, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib, KU004, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788.
511. The method of any one of claims 505-510, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered simultaneously as separate dosages.
512. The method of any one of claims 505-510, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered as separate dosages sequentially in any order.
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