(1H-Pyrrolo[2,3-B]Pyridin-1-yl)Pyrimidin-2-yl-Amino-Phenyl-Acrylamide Inhibitors of EGFR for Use in the Treatment of Brain Tumors

Abstract

The present invention relates generally to pharmaceutical products and methods of treatment. More specifically, the present invention provides small molecule EGFR inhibitors (e.g., EGFR tyrosine kinase inhibitor compounds) and pharmaceutical compositions thereof, and methods of their use in the treatment of various diseases and conditions, such as cancers of the central nervous system (e.g., primary and metastatic brain cancers) and lung cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 213,301, filed June 22, 2021, and U.S. Provisional Patent Application No. 63 / 257,907, filed October 20, 2021, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Many targeted therapies have demonstrated widespread success in other cancer types, but efficacy in GBM is limited, and the prognosis for patients with GBM remains grim.

[0003] More than 50% of glioblastomas harbor abnormal EGFR gene variants. Most of these EGFR variants arise via mutations in the extracellular domain. Among them, the most common EGFR variant (v), EGFRvIII (exon 2-7 deletion), has an in-frame extracellular domain truncation. It has been shown that EGFR-mutated GBM cells are likely dependent on EGFR signaling. Therefore, EGFR is an attractive therapeutic target in GBM.

[0004] Currently, in the United States, there are five EGFR tyrosine kinase inhibitors (TKIs, gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) approved by the Food and Drug Administration (FDA) for the treatment of EGFR-mutant lung cancer. Gefitinib and erlotinib are first-generation EGFR-TKIs that inhibit catalytic activity by competing with ATP for binding to the ATP-binding site on the kinase domain. Administration of gefitinib or erlotinib results in a marked improvement in patient survival over platinum chemotherapy. Second-generation EGFR inhibitors, afatinib and dacomitinib, irreversibly inhibit all four ErbB receptors, including EGFR. Thus, they are more potent inhibitors of EGFR, but with increased toxicity. Osimertinib, the only FDA-approved third-generation EGFR-TKI, is a covalent inhibitor designed to target EGFR resistance mutations that emerge with EGFR-TKI treatment.

[0005] These first- and second-generation EGFR-TKIs have been shown to inhibit the proliferation of GBM cells in preclinical experiments, but have not been effective in the clinical setting of GBM patients. There are two main reasons for their failure. First, the first- and second-generation EGFR-TKIs do not cross the blood-brain barrier (BBB). Meanwhile, the third-generation EGFR-TKI osimertinib has been reported to have activity against brain metastases of lung cancer with EGFR mutations and has higher brain penetration, and has been proposed for the treatment of EGFR-mutant GBM. Second, dose-limiting toxicities (DLTs) may prevent the approved EGFR-TKIs from being safe and effective drugs for patients with GBM. Unlike EGFR mutations in lung cancer, such as exon-19 deletions or L858R and T790M substitutions present in the intracellular kinase domain (KD), a common feature of EGFR variants in GBM is a mutant extracellular domain with a wild-type (WT) intracellular KD. Because of these complicating factors, it has so far not been possible to design truly targeted therapeutics that suppress EGFR signaling in central nervous system (CNS) tumors at concentrations that spare systemic WT EGFR function in vivo. Summary of the Invention

[0006] In certain aspects, the disclosure provides a method of treating glioblastoma multiforme, astrocytoma, congenital tumors of the brain, ependymoma, germinoma, glioma, gliomatosis, gliosarcoma, medulloblastoma, meningioma, meningeal sarcoma, oligodendroglioma, pinealoma, retinoblastoma, schwannoma, or spinal neurofibroma, comprising administering to a human subject in need thereof a therapeutically effective amount of a compound of formula I: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein the therapeutically effective amount is at least 100 mg / day; During the ceremony, Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0007] In certain embodiments, the method further comprises examining the subject's skin within one month after administration, and the subject does not exhibit skin lesions within one month after administration.

[0008] In certain embodiments, the method is a method of treating glioblastoma multiforme. In certain embodiments, the compound of formula I is characterized by a binding affinity to EGFR and / or mutant EGFR in a subject of 10 nM or less.

[0009] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the subject does not lose more than 10% of their body weight within one month after administration. A therapeutically effective amount of the compound may be administered to the subject daily for at least one month. The therapeutically effective amount may be 100 mg / day to 1000 mg / day, 100 mg / day to 800 mg / day, 100 mg / day to 500 mg / day, and / or 200 mg / day to 500 mg / day.

[0011] The method further comprises examining the subject's skin within one month after administration, wherein the subject does not exhibit a skin lesion within one month after administration. In some embodiments, the method further comprises examining the subject's skin within two months after administration, wherein the subject does not exhibit a skin lesion within two months after administration.

[0012] In some embodiments, these methods are methods for treating glioblastoma multiforme. Glioblastoma multiforme may be characterized by elevated levels of EGFR and / or mutant EGFR. In some embodiments, the compound of formula I is not a substrate for efflux transporters. In some embodiments, the compound of formula I is characterized by a binding affinity to EGFR and / or mutant EGFR in a subject of 10 nM or less, such as 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.15 nM or less, 0.12 nM or less, 0.11 nM or less, or 0.10 nM or less.

[0013] The methods can be methods of treating astrocytoma.

[0014] In some embodiments, Z1 and Z2 are each N, Z3 is CR8, R1 is H or NH2, R2 is H, R3 is (C1-C4)alkoxy, and R4 is NR9R 10 and R5 is NR 12 C(O)R 13 and / or R 15 is selected from (C1-C6)alkyl and (C1-C6)haloalkyl, and / or selected from methyl and CF3.

[0015] In some embodiments, R is H or halogen, R is (C-C) alkyl, and / or R 10 In some embodiments, R is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11In some embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In some embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0016] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0017] In yet another embodiment, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0018] In some embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0019] The compounds may be administered once daily, twice daily, or three times daily.

[0020] In some embodiments, the compound is administered systemically. In some embodiments, the compound is administered orally. In yet other embodiments, the compound is administered intravenously.

[0021] In some aspects, the disclosure provides a method for treating or reducing a brain tumor or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0022] In some aspects, the disclosure provides a method for inhibiting or reducing activity of epidermal growth factor receptor (EGFR) in a subject suffering from a brain tumor, comprising administering to the subject a therapeutically effective amount of a compound having the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, for use.

[0023] In some aspects, the disclosure provides a method for treating or reducing a brain disease or condition mediated by epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0024] In some embodiments, the brain tumor comprises a primary tumor. In some embodiments, the brain tumor comprises a metastatic tumor. In certain embodiments, the brain tumor is a glioblastoma.

[0025] In some embodiments, the therapeutically effective amount is in the range of about 0.1 to about 20 mg / kg of body weight per day, hi some such embodiments, the therapeutically effective amount is in the range of about 0.5 to about 5 mg / kg of body weight per day.

[0026] In another aspect, the invention generally relates to a pharmaceutical composition for treating brain tumors or related diseases or conditions, comprising a compound having the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0027] In some embodiments, the brain tumor comprises a primary tumor, such as a glioblastoma. In other aspects, the brain tumor comprises a metastatic tumor.

[0028] In yet another aspect, the disclosure provides a compound having the structural formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0029] In yet another aspect, the disclosure provides a pharmaceutical composition, comprising a compound having the structural formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, and a pharma- ceutically acceptable excipient, carrier, or diluent. In certain embodiments, the pharmaceutical composition is suitable for oral administration. In certain embodiments, the pharmaceutical composition is suitable for intravenous administration.

[0030] In some embodiments, the pharmaceutical composition is suitable for use in the treatment of a disease or condition selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0031] In yet another aspect, the present disclosure provides a unit dosage form comprising the pharmaceutical composition disclosed herein.

[0032] In yet another aspect, the disclosure provides a method for treating or alleviating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0033] In yet another aspect, the disclosure provides a method for inhibiting or reducing activity of EGFR in a subject suffering from a disease or condition associated with activity of EGFR, comprising administering to a subject in need thereof a therapeutic amount of a compound having the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0034] In yet another aspect, the disclosure provides a method for treating or reducing an EGFR-mediated disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0035] In further embodiments, the disease is a cancer, such as a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, head and neck squamous cell carcinoma, leukemia, lymphoma, and myeloma. In some such embodiments, the cancer comprises a primary tumor. In other such embodiments, the cancer comprises a metastatic tumor. In still other such embodiments, the cancer is glioblastoma. In still further such embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

[0036] In certain embodiments, the subject carries an EGFR mutation, such as a T790M EGFR mutation.

[0037] In some embodiments, the therapeutically effective amount is in the range of about 0.1 to about 20 mg / kg of body weight per day, such as in the range of about 0.5 to about 5 mg / kg of body weight per day.

[0038] In yet another aspect, the disclosure provides a method for treating or reducing brain tumor or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0039] In yet another aspect, the disclosure provides a method for inhibiting or reducing activity of EGFR in a subject suffering from a brain tumor, comprising administering to a subject in need thereof a therapeutic amount of a compound having the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0040] In yet another aspect, the disclosure provides a method for treating or reducing an EGFR-mediated brain disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0041] In some embodiments, the brain tumor comprises a primary tumor. In some embodiments, the brain tumor comprises a metastatic tumor. In certain embodiments, the brain tumor is a glioblastoma.

[0042] In yet another aspect, the disclosure relates to the use of a compound or pharmaceutical composition thereof for treating or reducing brain tumors or related diseases or conditions, wherein the compound has the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0043] In yet another aspect, the invention generally relates to the use of a compound or pharmaceutical composition thereof for inhibiting or reducing activity of EGFR in a subject suffering from a brain tumor, the compound having the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, for use.

[0044] In yet another aspect, the disclosure provides a use of a compound or pharmaceutical composition thereof for treating or reducing an EGFR-mediated brain disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0045] In some embodiments, the brain tumor comprises a primary tumor. In some embodiments, the brain tumor comprises a metastatic tumor. In yet other embodiments, the brain tumor is a glioblastoma.

[0046] In yet another aspect, the disclosure relates to the use of a compound or a pharmaceutical composition thereof for treating or reducing a disease or condition, wherein the compound has the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0047] In yet another aspect, the disclosure provides a use of a compound or a pharmaceutical composition thereof for inhibiting or reducing activity of EGFR in a subject suffering from a disease or condition associated with activity of EGFR, wherein the compound has the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0048] In yet another aspect, the disclosure relates to the use of a compound or a pharmaceutical composition thereof for treating or reducing a disease or condition mediated by EGFR, wherein the compound has the formula of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0049] In further embodiments, the disease is a cancer, such as a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, and myeloma. In some such embodiments, the brain tumor comprises a primary tumor. In other such embodiments, the brain tumor comprises a metastatic tumor. In still other such embodiments, the cancer is glioblastoma. In still other such embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).

[0050] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0051] [Figure 1A] Western blot analysis of 293-EGFRvIII cells with the indicated antibodies following treatment with Compound 1 or erlotinib at the indicated doses for 6 hours. [Figure 1B] Graph showing Western blot analysis of 293-EGFRvIII cells treated with Compound 1 for 6 hours at the indicated doses using antibodies against pEGFRvIII1068 and EGFRvIII to determine the IC50 for inhibition of pEGFRvIII1068.-Tubulin was used as a loading control. [Figure 1C] 1 is a graph showing the IC50 (μM) of Compound 1 and other EGFR-TKIs as indicated by the viability of 293-EGFRvIII cells. [Figure 2A] Figure 1 is a graph showing the viability of BT122 cells upon treatment with Compound 1 for 3 days at a dose titration of 0.156μM to 20μM for each drug. Also shown is a table summarizing the IC50 of Compound 1 and other EGFR inhibitors for BT112 cells. [Figure 2B] Figure 1 is a graph showing the viability of BT179 cells upon treatment with Compound 1 for 3 days at a dose titration of 0.156 μM to 20 μM for each drug. Also shown is a table summarizing the IC50 of Compound 1 and other EGFR inhibitors for BT179 cells. [Figure 2C] Figure 1 is a graph showing the viability of BT333 cells upon treatment with Compound 1 for 3 days at a dose titration of 0.156 μM to 20 μM for each drug. Also shown is a table summarizing the IC50 of Compound 1 and other EGFR inhibitors for BT333 cells. [Figure 3A] Graph showing Western blot analysis of U251-EGFRvIII cells treated with Compound 1 for 20 hours at the indicated doses using antibodies against pEGFRvIII1068 and EGFRvIII to determine the IC50 for inhibition of pEGFRvIII1068. IC50 is 0.174 μM. [Figure 3B] Graph showing U251-EGFRvIII cells treated with Compound 1 or other EGFR TKIs as indicated. IC50s for Compound 1 and other EGFR-TKIs are shown in the table below the curves. [Figure 3C] Figure 1 is a graph showing the proliferation of U251 cells upon treatment with Compound 1 and other EGFR inhibitors for 3 days at a dose titration of 0.156 μM to 20 μM for each drug. Also shown is a table summarizing the IC50 of Compound 1 and other EGFR inhibitors for U251 cells. [Figure 4A] A representative set of bioluminescence images of the first cohort of mice bearing U251-EGFRvIII at the indicated weeks after treatment with vehicle control (n=3), 37.5 mg / kg (QD, n=3) or 75 mg / kg (QD, n=2) of Compound 1. [Figure 4B] 1 is a bar graph showing quantification of the region of interest (ROI) in each mouse in the first cohort after 4 weeks of treatment compared to week zero, which was set as baseline. [Figure 4C]A representative set of bioluminescence images of a second cohort of mice bearing U251-EGFRvIII at the indicated times (weeks) after treatment with control (n=4), 37.5 mg / kg (QD, n=5) or 75 mg / kg (QD, n=5) of Compound 1. [Figure 4D] 1 is a bar graph showing quantification of the region of interest (ROI) in each mouse in the second cohort after 4 weeks of treatment compared to week zero, which was set as baseline. [Figure 4E] Kaplan-Meier survival analysis of U251-EGFRvIII xenograft-bearing mice from both cohorts treated with Compound 1 (37.5 mg / kg QD PO, n=8), Compound 1 (75 mg / kg QD PO, n=7), or vehicle control (n=7). Mean ± SD, *p<0.05, **p<0.01, Log-rank (Mantel-Cox) test. [Figure 4F] Body weight records of U251-EGFRvIII xenograft-bearing mice from both cohorts treated with Compound 1 (37.5 mg / kg QD PO, n=8), Compound 1 (75 mg / kg QD PO, n=7), or vehicle control (black line, n=7). Mean ± SD, *p<0.05, **p<0.01, Log-rank (Mantel-Cox) test. [Figure 5A] 13 shows the representation of genetic alterations in a syngeneic genetically engineered mouse model of glioblastoma driven by Cdkn2anull;Ptennull;hEGFRvIII as described in Example 5. [Figure 5B] Western blot analysis of primary mouse CPEvIII cells treated with Compound 1 for 1 day. [Figure 5C] Kaplan-Meier survival analysis of tumor-bearing mice treated with Compound 1 (75 mg / kg, PO QD, n=5) or vehicle control (n=6). *p<0.05 (p=0.017), Logrank (Mantel-Cox) test. [Figure 5D]IHC analysis of CPEvIII tumors harvested at endpoint from mice treated with Compound 1 or vehicle control. Scale bar, 100 μm. [Figure 5E] FIG. 1 is a graph showing the body weight of tumor-bearing mice treated with Compound 1 or vehicle control. [Figure 6A] Mice treated with osimertinib at 10-25 mg / kg / day are shown. [Figure 6B] Alternatively, mice treated with Compound 1 at 10-50 mg / kg / day are shown. [Figure 7] 1 shows the change in body weight over the course of treatment in mice treated with Compound 1 (25-50 mg / kg) or osmertinib (25 mg / kg). [Figure 8] 1 shows weight loss in female SCID mice bearing NSCLC brain metastases dosed with Compound 1 or osimertinib as described in Example 11. [Figure 9] 1 shows inhibition of brain metastases by both compounds described in Example 11. [Figure 10A] 1B shows bioluminescence images of GBM-bearing mice dosed with 100 mg / kg Compound 1 administered orally or control mice sacrificed 7 hours after treatment. [Figure 10B] 1 shows images of brain tissue from control and Compound 1-treated mice stained with hematoxylin and eosin (H&E). [Figure 10C] Shown is a control mimic plated onto a MALDI substrate along with brain tissue sections from control and Compound 1-treated mice. [Figure 10D] The signals observed from the mimic samples during MALDI-MSI analysis are shown. [Figure 10E] Normalized curves generated from the intensities observed for different concentrations of mimetic plated on a MALDI substrate are shown. [Figure 10F] 1 is an image of the observed intensity of a brain tissue sample. [Figure 10G] Absolute intensities observed from MALDI analysis of the mimetics are shown. [Figure 10H] Absolute intensities observed from MALDI analysis of brain tissue samples from mice treated with Compound 1 are shown. [Figure 10I] 1 shows an MSMS analysis of compound 1. [Figure 11] 1 shows kinase profiling results using AZD9291, Compound 1, and Compound 2 as discussed in Example 18. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] This application relates to small molecule EGFR-TKI compounds and pharmaceutical compositions thereof, and their use in the treatment of various diseases and conditions, including cancer, optionally cancer of the central nervous system (CNS) and lung cancer. In some non-limiting examples, the cancer is a primary or metastatic brain tumor. In other non-limiting examples, the cancer is a cancer of the CNS, such as glioblastoma (GBM), such as adult GBM with abnormal EGFR. In yet other non-limiting examples, the cancer is a lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

[0053] This application is based in part on the discovery of novel therapeutic agents, compositions, and methods for treating various diseases and conditions, including primary brain cancer (e.g., GBM), metastatic brain cancer, and lung cancer. Specifically, the present invention provides compounds 11 and 12, as shown below, and compositions and methods of use thereof, for treating GBM and other cancers with abnormal EGFR. Importantly, both compounds 11 and 12 have shown favorable pharmacokinetic (PK) and safety profiles with abnormal brain-specific distribution and accumulation. In the case of compound 11, the brain-to-plasma ratio was shown to be more than 20-fold at estimated steady state, in sharp contrast to other reported EGFR inhibitors.

[0054] In certain embodiments, methods are described herein for treating cancers of the central nervous system (CNS), such as GBM, such as adult GBM with aberrant EGFR, using a covalent EGFR-TKI, Compound 1. Preclinical efficacy studies have shown that Compound 1 is more effective than other EGFR-TKIs in blocking the growth of GBM tumor cells from both patient-derived and cultured human GBM cell lines with EGFR amplification and / or EGFRvIII mutations. In addition, Compound 1 administered as a single agent could attenuate the growth of orthotopic U251-EGFRvIII xenografts and extend the survival of tumor-bearing mice in a dose-dependent manner. Furthermore, Compound 1 inhibited phosphorylation of EGFR in GBM tumors derived from a novel genetically engineered mouse (GEM) model of GBM with EGFRvIII expression both in vitro and in vivo. Compound 1 also extended the survival of mice bearing orthotopic allografts of GBM. Notably, mice maintained stable weights during treatment with increasing doses of Compound 1 up to 75 mg / kg per day.

[0055] In certain embodiments, Compound 1 has a more favorable pharmacokinetic (PK) and safety profile than other reported EGFR inhibitors.

[0056] In certain embodiments, the present disclosure provides a compound having the structure of Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0057] In certain aspects, the disclosure provides a method of treating glioblastoma multiforme, astrocytoma, congenital tumors of the brain, ependymoma, germinoma, glioma, gliomatosis, gliosarcoma, medulloblastoma, meningioma, meningeal sarcoma, oligodendroglioma, pinealoma, retinoblastoma, schwannoma, or spinal neurofibroma, comprising administering to a human subject in need thereof a therapeutically effective amount of a compound of formula I: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein the therapeutically effective amount is at least 100 mg / day; During the ceremony, Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0058] In certain embodiments, the subject does not lose more than 10% of its body weight within one month after administration.In other embodiments, a therapeutically effective amount of the compound is administered to the subject daily for at least one month, and the subject does not lose more than 10% of its body weight within one month after daily administration.The change in the subject's body weight can be measured by any suitable means known in the art.

[0059] In certain embodiments, the therapeutically effective amount is between 100 mg / day and 1000 mg / day, such as between 100 mg / day and 800 mg / day, between 100 mg / day and 500 mg / day, or between 200 mg / day and 500 mg / day.

[0060] In certain embodiments, the method further comprises inspecting the subject's skin within one month after administration, and the subject does not exhibit skin lesions within one month after administration. In other embodiments, the method further comprises inspecting the subject's skin within two months after administration, and the subject does not exhibit skin lesions within two months after administration. As used herein, "inspecting the skin" of a subject can include visual observation by the subject himself / herself and / or a medical professional. If no skin lesions are observed when the skin is visually inspected by the subject himself / herself and / or a medical professional, the subject does not exhibit skin lesions.

[0061] In certain embodiments, the method is a method of treating glioblastoma multiforme. In some such embodiments, glioblastoma multiforme is characterized by elevated levels of EGFR and / or mutant EGFR. The level of EGFR in a subject (such as in a tumor of the subject) is elevated when it is above the level of EGFR in a healthy subject. EGFR is mutant when its amino acid sequence differs from that of wild-type EGFR. EGFR mutations associated with glioblastoma multiforme include those observed in the art, including, but not limited to, EGFRvIII, EGFR amplification, EGFR missense mutations, and EGFR polysomy. In other such embodiments, the compound of formula I is not a substrate for an efflux transporter. Efflux transporters are known in the art, including, but not limited to, P-gp and Bcrp. A compound is not a substrate for an efflux transporter if it does not bind to the efflux transporter with a binding affinity of more than 10 μM.

[0062] In some embodiments, compounds of formula I are characterized by a binding affinity to EGFR and / or mutant EGFR in a subject of 10 nM or less, such as 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.15 nM or less, 0.12 nM or less, 0.11 nM or less, or 0.10 nM or less. Binding affinity may be determined by any suitable method known in the art.

[0063] In another embodiment, the method is a method of treating astrocytoma.

[0064] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0065] In certain embodiments, R1 is H, such as H or NH2.

[0066] In certain embodiments, R3 is (C1-C4)alkoxy.

[0067] In certain embodiments, R4 is NR9R 10 It is.

[0068] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0069] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0070] In certain embodiments, R8 is H or halogen.

[0071] In certain embodiments, R9 is (C1-C4) alkyl.

[0072] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0073] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0074] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0075] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0076] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0077] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0078] In one particular embodiment, the p-toluenesulfonate salt of the compound has the following structure: [ka] ("Compound 1" tosylate or "Compound 1" p-toluenesulfonate)

[0079] In certain embodiments, the compound is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0080] In certain embodiments, the compound is Compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0081] In certain embodiments, the compound is administered once per day. In other embodiments, the compound is administered twice per day. In yet other embodiments, the compound is administered three times per day.

[0082] In certain embodiments, the compound is administered systemically. In some such embodiments, the compound is administered orally. In other such embodiments, the compound is administered intravenously.

[0083] In certain aspects, the disclosure provides a method for treating or reducing brain tumors or related diseases or conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0084] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0085] In certain embodiments, R1 is H, such as H or NH2.

[0086] In certain embodiments, R3 is (C1-C4)alkoxy.

[0087] In certain embodiments, R4 is NR9R 10 It is.

[0088] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0089] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0090] In certain embodiments, R8 is H or halogen.

[0091] In certain embodiments, R9 is (C1-C4) alkyl.

[0092] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0093] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0094] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0095] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0096] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0097] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0098] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0099] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0100] In certain embodiments, the brain tumor is a glioblastoma.

[0101] In certain embodiments, the compound is administered once per day. In other embodiments, the compound is administered twice per day. In yet other embodiments, the compound is administered three times per day.

[0102] In certain embodiments, the compound is administered systemically. In some such embodiments, the compound is administered orally. In other such embodiments, the compound is administered intravenously.

[0103] In another aspect, the disclosure provides a method for inhibiting or reducing activity of EGFR in a subject suffering from a brain tumor, comprising administering to the subject a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0104] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0105] In certain embodiments, R1 is H, such as H or NH2.

[0106] In certain embodiments, R3 is (C1-C4)alkoxy.

[0107] In certain embodiments, R4 is NR9R 10 It is.

[0108] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0109] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0110] In certain embodiments, R8 is H or halogen.

[0111] In certain embodiments, R9 is (C1-C4) alkyl.

[0112] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0113] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0114] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0115] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0116] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0117] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0118] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0119] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0120] In certain embodiments, the brain tumor is a glioblastoma.

[0121] In certain embodiments, the compound is administered once per day. In other embodiments, the compound is administered twice per day. In yet other embodiments, the compound is administered three times per day.

[0122] In certain embodiments, the compound is administered systemically. In some such embodiments, the compound is administered orally. In other such embodiments, the compound is administered intravenously.

[0123] In another aspect, the disclosure provides a method for treating or reducing an EGFR-mediated brain disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0124] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0125] In certain embodiments, R1 is H, such as H or NH2.

[0126] In certain embodiments, R3 is (C1-C4)alkoxy.

[0127] In certain embodiments, R4 is NR9R 10 It is.

[0128] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0129] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0130] In certain embodiments, R8 is H or halogen.

[0131] In certain embodiments, R9 is (C1-C4) alkyl.

[0132] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0133] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0134] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0135] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0136] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0137] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0138] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0139] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0140] In certain embodiments, the brain tumor is a glioblastoma.

[0141] In certain embodiments, the compound is administered once per day. In other embodiments, the compound is administered twice per day. In yet other embodiments, the compound is administered three times per day.

[0142] In certain embodiments, the compound is administered systemically. In some such embodiments, the compound is administered orally. In other such embodiments, the compound is administered intravenously.

[0143] In another aspect, the disclosure provides a pharmaceutical composition for treating brain tumors or related diseases or conditions, comprising a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, and a pharma- ceutically acceptable excipient, carrier, or diluent, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0144] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0145] In certain embodiments, R1 is H, such as H or NH2.

[0146] In certain embodiments, R3 is (C1-C4)alkoxy.

[0147] In certain embodiments, R4 is NR9R 10 It is.

[0148] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0149] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0150] In certain embodiments, R8 is H or halogen.

[0151] In certain embodiments, R9 is (C1-C4) alkyl.

[0152] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0153] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0154] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0155] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0156] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0157] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0158] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0159] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0160] In certain embodiments, the brain tumor is a glioblastoma.

[0161] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, and a pharma- ceutically acceptable excipient, carrier, or diluent, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0162] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0163] In certain embodiments, R1 is H, such as H or NH2.

[0164] In certain embodiments, R3 is (C1-C4)alkoxy.

[0165] In certain embodiments, R4 is NR9R 10 It is.

[0166] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0167] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0168] In certain embodiments, R8 is H or halogen.

[0169] In certain embodiments, R9 is (C1-C4) alkyl.

[0170] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0171] In certain embodiments, R4 is NR9R 10 and R9 and R10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0172] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0173] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0174] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0175] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0176] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0177] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0178] In certain embodiments, the pharmaceutical compositions are suitable for oral administration.

[0179] In certain embodiments, the pharmaceutical compositions are suitable for intravenous administration.

[0180] In certain embodiments, the pharmaceutical composition is suitable for use in the treatment of a disease or condition selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0181] In other aspects, the present disclosure provides a unit dosage form comprising the pharmaceutical composition disclosed herein.

[0182] In another aspect, the disclosure provides a method for treating or ameliorating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0183] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0184] In certain embodiments, R1 is H, such as H or NH2.

[0185] In certain embodiments, R3 is (C1-C4)alkoxy.

[0186] In certain embodiments, R4 is NR9R 10 It is.

[0187] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0188] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0189] In certain embodiments, R8 is H or halogen.

[0190] In certain embodiments, R9 is (C1-C4) alkyl.

[0191] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0192] In certain embodiments, R4 is NR9R 10and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0193] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0194] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0195] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0196] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0197] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0198] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0199] In another aspect, the disclosure provides a method for inhibiting or reducing activity of EGFR in a subject suffering from a disease or condition associated with activity of EGFR, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0200] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0201] In certain embodiments, R1 is H, such as H or NH2.

[0202] In certain embodiments, R3 is (C1-C4)alkoxy.

[0203] In certain embodiments, R4 is NR9R 10 It is.

[0204] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0205] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0206] In certain embodiments, R8 is H or halogen.

[0207] In certain embodiments, R9 is (C1-C4) alkyl.

[0208] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0209] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0210] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0211] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0212] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0213] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0214] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0215] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0216] In another aspect, the disclosure provides a method for treating or reducing an EGFR-mediated disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0217] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0218] In certain embodiments, R1 is H, such as H or NH2.

[0219] In certain embodiments, R3 is (C1-C4)alkoxy.

[0220] In certain embodiments, R4 is NR9R 10 It is.

[0221] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0222] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0223] In certain embodiments, R8 is H or halogen.

[0224] In certain embodiments, R9 is (C1-C4) alkyl.

[0225] In certain embodiments, R 10is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0226] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0227] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0228] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11Forms a 5- to 7-membered heterocycle optionally substituted with

[0229] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0230] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0231] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0232] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0233] In certain embodiments, the disease or condition is cancer.

[0234] In certain embodiments, the cancer is selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0235] In certain embodiments, the cancer is glioblastoma.

[0236] In certain embodiments, the cancer is lung cancer.

[0237] In certain embodiments, the cancer is NSCLC.

[0238] In certain embodiments, the cancer is SCLC.

[0239] In certain embodiments, the subject carries an EGFR mutation.

[0240] In certain embodiments, the subject carries a T790M EGFR mutation.

[0241] In yet another aspect, the disclosure provides a use of a compound or pharmaceutical composition thereof for treating or reducing brain tumors or related diseases or conditions, wherein the compound has the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0242] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0243] In certain embodiments, R1 is H, such as H or NH2.

[0244] In certain embodiments, R3 is (C1-C4)alkoxy.

[0245] In certain embodiments, R4 is NR9R 10 It is.

[0246] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0247] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0248] In certain embodiments, R8 is H or halogen.

[0249] In certain embodiments, R9 is (C1-C4) alkyl.

[0250] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0251] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0252] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0253] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0254] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0255] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0256] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0257] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0258] In certain embodiments, the use is for treating cancer.

[0259] In certain embodiments, the use is for treating a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0260] In certain embodiments, the use is for treating glioblastoma.

[0261] In certain embodiments, the use is for treating lung cancer.

[0262] In certain embodiments, the cancer is for treating non-small cell lung cancer NSCLC.

[0263] In another aspect, the disclosure provides a use of a compound or pharmaceutical composition thereof for inhibiting or reducing activity of EGFR in a subject suffering from a brain tumor, wherein the compound has the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0264] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0265] In certain embodiments, R1 is H, such as H or NH2.

[0266] In certain embodiments, R3 is (C1-C4)alkoxy.

[0267] In certain embodiments, R4 is NR9R 10 It is.

[0268] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0269] In certain embodiments, R15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0270] In certain embodiments, R8 is H or halogen.

[0271] In certain embodiments, R9 is (C1-C4) alkyl.

[0272] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0273] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0274] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0275] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0276] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0277] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0278] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0279] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0280] In certain embodiments, the use is for treating cancer.

[0281] In certain embodiments, the use is for treating a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0282] In certain embodiments, the use is for treating glioblastoma.

[0283] In certain embodiments, the use is for treating lung cancer.

[0284] In certain embodiments, the cancer is for treating non-small cell lung cancer NSCLC.

[0285] In yet another aspect, the disclosure provides a use of a compound or pharmaceutical composition thereof for treating or reducing an EGFR-mediated brain disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0286] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0287] In certain embodiments, R1 is H, such as H or NH2.

[0288] In certain embodiments, R3 is (C1-C4)alkoxy.

[0289] In certain embodiments, R4 is NR9R 10 It is.

[0290] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0291] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0292] In certain embodiments, R8 is H or halogen.

[0293] In certain embodiments, R9 is (C1-C4) alkyl.

[0294] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0295] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0296] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0297] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0298] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0299] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0300] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0301] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0302] In certain embodiments, the use is for treating cancer.

[0303] In certain embodiments, the use is for treating brain cancer.

[0304] In certain embodiments, the use is for treating glioblastoma.

[0305] In yet another aspect, the disclosure relates to the use of a compound or a pharmaceutical composition thereof for treating or reducing a disease or condition, wherein the compound has the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0306] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0307] In certain embodiments, R1 is H, such as H or NH2.

[0308] In certain embodiments, R3 is (C1-C4)alkoxy.

[0309] In certain embodiments, R4 is NR9R 10 It is.

[0310] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0311] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0312] In certain embodiments, R8 is H or halogen.

[0313] In certain embodiments, R9 is (C1-C4) alkyl.

[0314] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0315] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0316] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0317] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0318] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0319] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0320] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0321] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0322] In certain embodiments, the use is for treating cancer.

[0323] In certain embodiments, the use is for treating a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0324] In certain embodiments, the use is for treating glioblastoma.

[0325] In certain embodiments, the use is for treating lung cancer.

[0326] In certain embodiments, the cancer is for treating non-small cell lung cancer NSCLC.

[0327] In yet another aspect, the disclosure provides a use of a compound or pharmaceutical composition thereof for inhibiting or reducing activity of EGFR in a subject suffering from a disease or condition associated with activity of EGFR, wherein the compound has the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11 is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0328] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0329] In certain embodiments, R1 is H, such as H or NH2.

[0330] In certain embodiments, R3 is (C1-C4)alkoxy.

[0331] In certain embodiments, R4 is NR9R 10 It is.

[0332] In certain embodiments, R5 is NR 12 C(O)R 13 It is.

[0333] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0334] In certain embodiments, R8 is H or halogen.

[0335] In certain embodiments, R9 is (C1-C4) alkyl.

[0336] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0337] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0338] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0339] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0340] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0341] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0342] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0343] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0344] In certain embodiments, the use is for treating cancer.

[0345] In certain embodiments, the use is for treating a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0346] In certain embodiments, the use is for treating glioblastoma.

[0347] In certain embodiments, the use is for treating lung cancer.

[0348] In certain embodiments, the cancer is for treating non-small cell lung cancer NSCLC.

[0349] In yet another aspect, the disclosure provides a use of a compound or pharmaceutical composition thereof for treating or reducing a disease or condition mediated by EGFR, wherein the compound has the structure of Formula I: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof, wherein: Z1, Z2, and Z3 are each independently N or CR8, and at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R1 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, NH2, NH(C1-C4)alkyl, N((C1-C4)alkyl)2, or halogen; R2 is H or (C1-C6)alkyl; R3 is (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)haloalkyl, or halogen; R4 is NR9R 10 or containing 1 to 3 heteroatoms selected from N, O, and S, and one or more R 11 is a 5- to 7-membered heterocycle optionally substituted with R9 is H or (C1-C4) alkyl; R 10 is (C1-C4)alkyl, (C1-C4)alkyl-NH(C1-C4)alkyl, or (C1C4)alkyl-N((C1-C4)alkyl)2; Alternatively, R9 and R 10 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 forming a 5- to 7-membered heterocycle optionally substituted with Each R 11is independently (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or halogen; R5 is NR 12 C(O)R 13 or C(O)NR 12 R 13 and R 12 is H or (C1-C6)alkyl; R 13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula: [ka] During the ceremony, X3 is N; X1, X2, X4, X5, and X6 are each independently CH or CR 15 and Each R 15 is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, OH, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, or halogen.

[0350] In certain embodiments, Z1 and Z2 are each N and Z3 is CR8.

[0351] In certain embodiments, R1 is H, such as H or NH2.

[0352] In certain embodiments, R3 is (C1-C4)alkoxy.

[0353] In certain embodiments, R4 is NR9R 10 It is.

[0354] In certain embodiments, R5 is NR12 C(O)R 13 It is.

[0355] In certain embodiments, R 15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl. In some such embodiments, R 15 is selected from methyl and CF3.

[0356] In certain embodiments, R8 is H or halogen.

[0357] In certain embodiments, R9 is (C1-C4) alkyl.

[0358] In certain embodiments, R 10 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl).

[0359] In certain embodiments, R4 is NR9R 10 and R9 and R 10 optionally contain, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0360] In certain embodiments, R 11 is (C1-C4) alkyl, R 12 is H and R 13 is (C2-C6)alkenyl. In other embodiments, R 11 is (C1-C4) alkyl, R 12 is (C1-C6) alkyl, R 13 is (C2-C6)alkenyl.

[0361] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: X1, X2, X4, X5, and X6 are each independently CR 15 and R 91 is (C1-C4) alkyl; R 101 is (C1-C4)alkyl-NH(C1-C4)alkyl or (C1-C4)alkyl-N((C1-C4)alkyl)2; Or, R 91 and R 101 optionally containing, together with the nitrogen atom to which they are attached, one or two additional heteroatoms selected from N, O, and S, and one or more R 11 Forms a 5- to 7-membered heterocycle optionally substituted with

[0362] In certain embodiments, the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0363] In certain embodiments, the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharma- ceutically acceptable salt thereof.

[0364] In certain embodiments, the compound of formula I is Compound 1: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0365] In certain embodiments, the compound of formula I is compound 2: [ka] or a pharma- ceutically acceptable form or isotopic derivative thereof.

[0366] In certain embodiments, the use is for treating cancer.

[0367] In certain embodiments, the use is for treating a cancer selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, renal cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, squamous cell carcinoma of the head and neck, leukemia, lymphoma, and myeloma.

[0368] In certain embodiments, the use is for treating glioblastoma.

[0369] In certain embodiments, the use is for treating lung cancer.

[0370] In certain embodiments, the cancer is for treating non-small cell lung cancer NSCLC.

[0371] definition Listed below are definitions of various terms used to describe this application. These definitions apply to the terms as they are used throughout this specification and claims, unless limited in specific instances either individually or as part of a larger group.

[0372] As used herein, "at least" a particular value is understood to mean that value and all values ​​greater than that value.

[0373] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. The term "consisting essentially of," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements and exclude other elements of any essential importance to the compositions and methods. For example, "consisting essentially of" refers to the administration of pharmacologically active agents that are explicitly recited and excludes pharmacologically active agents that are not explicitly recited. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharma- ceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, is intended to mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0374] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to be within the normal tolerance in the art, for example, within 2 standard deviations of the mean. "About" may be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​provided herein may be modified by the term about.

[0375] As used herein, the term "administration" of a disclosed compound includes delivery of a compound described herein, or a prodrug or other pharma- ceutically acceptable form thereof, to a subject using any suitable formulation or route of administration, as discussed herein.

[0376] The terms "disease," "disorder," and "condition" are used interchangeably unless otherwise indicated.

[0377] The terms "cancer" or "tumor" are used interchangeably herein to refer to diseases or disorders involving abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, brain cancer (e.g., glioblastoma), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, cholangiocarcinoma, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability high colorectal carcinoma).

[0378] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to accomplish its intended use, including but not limited to, the treatment of a disease, as set forth below.

[0379] In some embodiments, the amount is effective to detectably kill or inhibit the growth or spread of cancer cells, tumor size or number, or other measures of the level, stage, progression, or severity of cancer.

[0380] The therapeutically effective amount may vary depending on the intended use or the subject and disease state to be treated, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the weight and age of the patient, which can be easily determined by those skilled in the art. This term also applies to the dose that will induce a specific response in the target cells, such as reducing cell migration. The specific dose will vary depending on, for example, the specific compound selected, the species of the subject and their age / pre-existing health conditions or risk of health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered.

[0381] The term "alkyl," as used herein, in certain embodiments, refers to a saturated, straight- or branched-chain hydrocarbon radical containing 1 to 6 or 1 to 8 carbon atoms, respectively. Examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals, and examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.

[0382] The term "alkenyl," as used herein, in certain embodiments, refers to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 or 2 to 8 carbon atoms with at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0383] The term "alkynyl," as used herein, in certain embodiments, refers to a monovalent group derived from a hydrocarbon moiety containing 2 to 6 or 2 to 8 carbon atoms with at least one carbon-carbon triple bond. An alkynyl group may or may not be the point of attachment to another group. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0384] The term "alkoxy" refers to an --O-alkyl radical.

[0385] The term "aryl" as used herein, It refers to a mono- or polycyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.

[0386] The term "aralkyl," as used herein, refers to an alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0387] The term "cycloalkyl" as used herein refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. Examples of C3-C8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl; 12Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Monovalent groups derived from monocyclic or polycyclic carbocyclic ring compounds having at least one carbon-carbon double bond by removal of a single hydrogen atom are also contemplated. Examples of such groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

[0388] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic, or higher), fused or non-fused radical or ring system having at least one aromatic ring, of which 5 to 10 ring atoms, one ring atom is selected from S, O, and N, and 0, 1, or 2 ring atoms are additional heteroatoms independently selected from S, O, and N, and the remaining ring atoms are carbon. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, and the like.

[0389] The term "heteroaralkyl," as used herein, refers to an alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like.

[0390] The term "heterocyclyl" or "heterocycloalkyl," as used herein, refers to a non-aromatic 3-, 4-, 5-, 6-, or 7-membered ring, or bicyclic or tricyclic fused or non-fused system, where (i) each ring contains 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, and (v) any of the above rings may be fused to a benzene ring. Representative heterocycloalkyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0391] The term "alkylamino" refers to the structure -NH(C-C 12 alkyl), C1-C 12 Alkyl is as defined above.

[0392] The term "dialkylamino" refers to the structure -N(C-C 12 alkyl)2, C1-C 12 Alkyl is as defined above.

[0393] The term "acyl" includes residues derived from acids, including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates, and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxyacetyl, and the like.

[0394] According to the present application, any of the aryl, substituted aryl, heteroaryl, and substituted heteroaryl described herein can be any aromatic group. The aromatic group can be substituted or unsubstituted.

[0395] The terms "hal," "halo," and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0396] As described herein, the compounds of the present application may be optionally substituted with one or more substituents, as generally exemplified above, or as exemplified by the specific classes, subclasses, and species of the present application. It will be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether preceded by the term "optionally", refers to the replacement of a hydrogen radical in a given structure with the radical of a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specific group, the substituents may be either the same or different at all positions. "Optionally substituted", "optionally substituted alkyl", "optionally substituted "optionally substituted alkenyl", "optionally substituted alkynyl", "optionally substituted cycloalkyl", "optionally substituted cycloalkenyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted aralkyl", "optionally substituted heteroaralkyl", "optionally substituted heterocycloalkyl", and any other optionally substituted groups as used herein refer to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more hydrogen atoms thereon with substituents including, but not limited to, the following: -F, -CI, -Br, -I, -OH, protected hydroxy, -NO2, -CN, -NH2, protected amino, -NH-C1-C 12 -Alkyl, -NH-C2-C 12-Alkenyl, -NH-C2-C 12 -alkenyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -Dialkylamino, -Diarylamino, -Diheteroarylamino, -O-C1-C 12 -Alkyl, -O-C2-C 12 -alkenyl, -O-C2-C 12 -Alkenyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -Alkyl, -C(O)-C2-C 12 -alkenyl, -C(O)-C2-C 12 -Alkenyl, -C(O)-C3-C 12 -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -Alkyl, -CONH-C2-C 12 -alkenyl, -CONH-C2-C 12 -Alkenyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C 12 -Alkenyl, -OCO2-C2-C 12 -Alkenyl, -OCO2-C3-C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12 -Alkyl, -OCONH-C2-C 12 -Alkenyl, -OCONH-C2-C12 -alkenyl, -OCONH-C3-C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-C1-C 12 -Alkyl, -NHC(O)-C2-C 12 -alkenyl, -NHC(O)-C2-C 12 -Alkenyl, -NHC(O)-C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1-C 12 -Alkyl, -NHCO2-C2-C 12 -Alkenyl, -NHCO2-C2-C 12 -Alkenyl, -NHCO2-C3-C 12 -cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, NHC(O)NH2, -NHC(O)NH-C1-C 12 -Alkyl, -NHC(O)NH-C2-C 12 -Alkenyl, -NHC(O)NH-C2-C 12 -Alkenyl, -NHC(O)NH-C3-C 12 -Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1-C 12 -Alkyl, -NHC(S)NH-C2-C 12 -Alkenyl, -NHC(S)NH-C2-C 12 -Alkenyl, -NHC(S)NH-C3-C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 -Alkyl, -NHC(NH)NH-C2-C 12 -Alkenyl, -NHC(NH)NH-C2-C12 -Alkenyl, -NHC(NH)NH-C3-C 12 -Cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C1-C 12 -Alkyl, -NHC(NH)-C2-C 12 -Alkenyl, -NHC(NH)-C2-C 12 -Alkenyl, -NHC(NH)-C3-C 12 -Cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -Alkyl, -C(NH)NH-C2-C 12 -alkenyl, -C(NH)NH-C2-C 12 -Alkenyl, C(NH)NH-C3-C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -S(O)-C1-C 12 -Alkyl, -S(O)-C2-C 12 -Alkenyl, -S(O)-C2-C 12 -Alkenyl, -S(O)-C3-C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl-SO2NH2, -SO2NH-C1-C 12 -Alkyl, -SO2NH-C2-C 12 -Alkenyl, -SO2NH-C2-C 12 -Alkenyl, -SO2NH-C3-C 12 -cycloalkyl, -SONH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 -Alkyl, -NHSO2-C2-C 12 -Alkenyl, -NHSO2-C2-C 12 -Alkenyl, -NHSO2-C3-C 12 -cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -Arylalkyl, -Heteroaryl, -Heteroarylalkyl, -Heterocycloalkyl, -C3-C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C 12 -Alkyl, -S-C2-C 12 -Alkenyl, -S-C2-C 12 -Alkenyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl.

[0397] It is understood that the aryl, heteroaryl, alkyl, and the like can be further substituted.

[0398] As used herein, the term "EGFR" refers to epidermal growth factor receptor kinase.

[0399] The term "HER" or "Her" herein refers to human epidermal growth factor receptor kinase.

[0400] The term "subject" as used herein refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Thus, a subject refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, etc. Preferably, the subject is a human. When the subject is a human, the subject may be referred to herein as a patient. In some embodiments, the subject has an EGFR mutation. In other embodiments, the subject has a T790M EGFR mutation. In other embodiments, the subject has a deletion in exon 19 EGFR mutation. In some embodiments, the subject has a L858R / T790M EGFR mutation.

[0401] "Treat", "treating" and "treatment" refer to a method of alleviating or relieving a disease and / or its attendant symptoms.

[0402] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0403] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound formed by the process of the present application that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio; however, non-pharmaceutically acceptable salts may be useful in the preparation of pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts may be prepared in situ during the final isolation and purification of the compounds of the present application, or separately, such as by reacting a free base function with a suitable organic acid. When the compound is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N,N 1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine, etc. When the compound is basic, salts may be prepared from pharma- ceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetate, acetic acid, acid citrate, acid phosphate, ascorbate, benzenesulfonate, benzenesulfonate, benzoic acid, benzoate, bromide, bisulfate, bitartrate, camphorsulfonate, chloride, citrate, citric acid, ethanesulfonate, ethanesulfonic acid, formate, fumarate, fumaric acid, gentisinate, gluconate, gluconic acid, glucuronate, glutamate, glutamic acid, hydrobromide, hydrochloric acid, iodide, isethionate, isonicotinate, Examples of suitable acids include phosphate, lactate, lactic acid, maleate, maleic acid, malic acid, mandelic acid, methanesulfonic acid, methanesulfonate, mucic acid, nitrate, nitric acid, oleate, oxalate, pamoic acid, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), pantothenic acid, pantothenate, phosphate, phosphoric acid, saccharate, salicylate, succinic acid, succinate, sulfuric acid, sulfate, tannate, tartrate, tartaric acid, p-toluenesulfonate, toluenesulfonic acid (TsOH), etc. Particular embodiments include TsOH, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0404] Examples of pharma- ceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, tetrahydrofuran ... Representative salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0405] As used herein, the term "pharmaceutical acceptable ester" refers to an ester of a compound formed by the process of the present application, including those that hydrolyze in vivo and degrade readily in the human body to leave the parent compound or a salt thereof. Such esters can act as prodrugs as defined herein. Suitable ester groups include, for example, those derived from pharmaceutical acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or fewer carbon atoms. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic, phosphoric, phosphinic, sulfinic, sulfonic, and boronic acids. Examples of specific esters include, but are not limited to, formic, acetic, propionic, butyric, acrylic, and ethylsuccinic acids. Esters can be formed with hydroxy or carboxylic acid groups of the parent compound.

[0406] The term "pharmaceutically acceptable salts" as used herein refers to prodrugs of the compounds formed by the processes of the present application that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio and effective for their intended use, as well as, where possible, the zwitterionic forms of the compounds of the present application. As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to yield any compound depicted by the formulas of the present application. Various forms of prodrugs are described, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Prodrugs are discussed in Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002). Prodrugs may be inactive when administered to a subject but are converted to the active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in blood).In certain cases, prodrugs have improved physical and / or delivery properties compared to the parent compound. Prodrugs can increase the bioavailability of a compound when administered to a subject (e.g., by allowing enhanced absorption into the blood after oral administration) or enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced water solubility or active transport across the intestinal membrane relative to the parent compound. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. Exemplary advantages of a prodrug may include, but are not limited to, its physical properties, such as enhanced aqueous solubility for parenteral administration at physiological pH, or the ability to enhance absorption from the gastrointestinal tract, or the ability to enhance drug stability for long-term storage, as compared to the parent compound.

[0407] The present application also encompasses pharmaceutical compositions containing pharma- ceutically acceptable prodrugs of the compounds of the present application, and methods of treating disorders by administering the same. For example, compounds of the present application having free amino, amide, hydroxy, or carboxylic acid groups can be converted to prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked to a free amino, hydroxy, or carboxylic acid group of a compound of the present application via an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, commonly designated by their three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, decomosine, isodecomosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also encompassed. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate, and sulfate prodrugs of hydroxy groups. Also included is the derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or the acyl group is an amino acid ester as described above. This type of prodrug is described in J.Med.Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides, or phosphonamides. All of these prodrug moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups.

[0408] Combinations of substituents and variables envisioned by the application are only those that result in the formation of stable compounds. The term "stable," as used herein, refers to compounds that have sufficient stability to permit their manufacture and maintain compound integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject, formulation into a therapeutic product, intermediates for use in the manufacture of therapeutic compounds, intermediate compounds that can be isolated or stored, treatment of a disease or condition that is responsive to a therapeutic agent).

[0409] The present application also provides methods of using pharmaceutical compositions comprising a compound of formula (I), or a pharma- ceutically acceptable ester, salt, or prodrug thereof, in association with a pharma- ceutically acceptable carrier.

[0410] As used herein, the term "pharmacologically acceptable excipient, carrier, or diluent" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible materials used in pharmaceutical formulations. Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate, magnesium stearate, polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0411] Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The particular carrier, diluent, or excipient used will depend on the means and purpose for which the compounds described herein are formulated. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for administration to mammals (GRAS - Generally Recognized as Safe). In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulation may also include other types of excipients, such as one or more buffers, stabilizers, anti-adherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (e.g., enteric or sustained release) preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an elegant presentation of a medicament (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug).

[0412] In another aspect, the present application provides a kit comprising a compound capable of inhibiting EGFR activity selected from one or more compounds of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and instructions for use in the treatment of cancer.

[0413] Compounds of formula (I) and methods for their synthesis are described in US Pat. No. 10,266,517, which is incorporated herein by reference in its entirety.

[0414] Another embodiment is an isotopically labeled compound of any of the formulae depicted herein. Such compounds contain one or more isotopic atoms (e.g., 3 H, 2 H,14 C. 13 C. 18 , 35 S, 32 P, 125 I, and 131 I). Such compounds are useful in drug metabolism studies and in diagnostic and therapeutic applications.

[0415] The present disclosure includes salts of the compounds disclosed herein and their pharmaceutical compositions. The salts of the compounds of the present disclosure can be formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. The compounds of the present application can be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition salts of the compounds of the present application can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.

[0416] Alternatively, the salt forms of the compounds of the present application can be prepared using salts of the starting materials or intermediates.

[0417] The free acid or free base forms of the compounds of the present application can be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, the compounds of the present application in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds of the present application in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0418] Prodrug derivatives of the compounds of the present application can be prepared by methods known to those skilled in the art (see, for example, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985 for further details). For example, suitable prodrugs can be prepared by reacting a non-derivatized compound of the present application with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, paranitrophenyl carbonate, and the like).

[0419] The compounds of the present invention can be prepared by methods known in the art of organic synthesis, as described in part by the following synthetic schemes. In the schemes described below, it will be appreciated that protecting groups for sensitive or reactive groups are used where necessary in accordance with general chemical principles. Protected derivatives of the compounds of the present application can be prepared by means known to those skilled in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in TW Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999. These groups can be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selected processes, as well as the reaction conditions and the order of their execution, shall be consistent with the preparation of the compounds described herein.

[0420] The compounds described herein may be made from commercially available starting materials or may be synthesized using known organic, inorganic and / or enzymatic processes.

[0421] All abbreviations used in this application are found in "Protective Groups in Organic Synthesis" by John Wiley & Sons, Inc. or the MERCK INDEX by MERCK & Co., Inc., or other chemical books or chemical catalogs from chemical vendors such as Aldrich, or follow known usage in the art.

[0422] The synthesis of the compounds described herein can be readily accomplished by a synthetic chemist of ordinary skill in the art by reference to the exemplary syntheses and examples disclosed herein. Such methods can be carried out utilizing corresponding deuterated reagents and optionally other isotopically-containing reagents and / or intermediates to synthesize the compounds described herein, or by invoking standard synthetic protocols known in the art for introducing isotopic atoms into a chemical structure.

[0423] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by those of skill in the art, additional methods of synthesizing compounds having the formulas herein will be apparent to those of skill in the art. Additionally, the various synthetic steps can be performed in an alternating sequence or order to obtain the desired compounds. In addition, the solvents, temperatures, reaction times, etc. depicted herein are for illustrative purposes only, and one of skill in the art will recognize that the reaction conditions can be varied to produce the desired bridged macrocyclic products of the present application. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0424] After their preparation, the compounds of the invention are preferably isolated and purified to obtain compositions containing 95% by weight or more ("substantially pure") and then used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0425] As used herein, the term "isolated" or "substantially isolated" molecule (such as a polypeptide or polynucleotide) is a molecule that has been engineered to exist in greater concentrations than in nature or that has been removed from its natural environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified if at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of the non-subject antibody material with which it is naturally associated has been removed. For example, a polynucleotide or polypeptide that is naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials in its natural state is "isolated." Additionally, recombinant DNA molecules contained in a vector are considered isolated for purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include molecules that are synthetically produced. Additionally, vector molecules contained in a recombinant host cell are also isolated. Thus, not all "isolated" molecules need to be "purified."

[0426] As used herein, the term "purified," when used in reference to a molecule, means that the concentration of the purified molecule is increased relative to the molecules associated with it in its natural environment or the environment in which it was produced, discovered, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally do not include water, buffers, and reagents that are added to maintain the integrity of the purified molecule or to facilitate purification. By this definition, a material can be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0427] Some embodiments of the present invention include a method of inhibiting activity of EGFR in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0428] In some embodiments, the compounds described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions described herein, can inhibit the activity of EGFR containing one or more mutations. In some embodiments, the mutant EGFR contains one or more mutations selected from T790M, L718Q, L844Y, L858R, and Del. In some embodiments, the mutant EGFR contains a combination of mutations, the combination being selected from Del / L718Q, De1 / L844Y, Del / T790M, De1 / T790M / L718Q, De1 / T790M / L844Y, L858R / L718Q, L858R / L844Y, L858R / T790M, and L858R / T790M / L718Q. In some embodiments, the EGFR mutation is a T790M mutation. In other embodiments, the EGFR mutation is a deletion in exon 19. In certain embodiments, the EGFR mutation is an L858R / T790M mutation.

[0429] In some embodiments, a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, can inhibit the activity of an EGFR that contains one or more mutations, but does not affect the activity of wild-type EGFR.

[0430] Inhibition of EGFR containing one or more mutations, such as those described herein, rather than wild-type EGFR, provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, inflammation, arthritis, systemic lupus erythematosus, skin-related disorders, pulmonary disorders, cardiovascular disease, ischemia, neurodegenerative disorders, liver disease, gastrointestinal disorders, viral and bacterial infections, central nervous system disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy.

[0431] In some embodiments, drug-resistant EGFR mutations include sensitizing mutations such as Del and L858R.

[0432] In some embodiments, the present application provides compounds that inhibit the kinase activity of drug-resistant EGFR mutants that have sensitizing mutations (e.g., Del and L858R) and drug-resistant mutations (e.g., T790M, L718Q, and L844V) with less than a 10-fold difference in potency (e.g., as measured by IC50) relative to EGFR mutants that have sensitizing mutations but do not have drug-resistant mutations. In some embodiments, the difference in potency is less than about 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold.

[0433] In some embodiments, the disclosure provides compounds that are more potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387,785, and AZD9291, at inhibiting the activity of an EGFR that contains one or more mutations described herein, such as T790M, L718Q, L844Y, L858R, Del, or a combination thereof. For example, the compounds may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (e.g., as measured by IC50) than gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387,785, and AZD9291 at inhibiting the activity of an EGFR that contains one or more mutations described herein. In other embodiments, the present application provides compounds that are less potent than one or more known EGFR inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, WZ4002, HKI-272, CL-387,785, and AZD9291, at inhibiting the activity of EGFR containing one or more mutations described herein, such as T790M, L718Q, L844Y, L858R, Del, or combinations thereof.

[0434] The potency of a compound can be determined by IC50 value. A compound with a lower IC50 value is a more potent inhibitor than a compound with a higher IC50 value when determined under substantially similar conditions. In some embodiments, the substantially similar conditions include determining EGFR-dependent phosphorylation levels in 3T3 cells expressing wild-type EGFR, mutant EGFR, or any fragment thereof.

[0435] EGFR sensitizing mutations include, without limitation, L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19, and / or an insertion in exon 20. Drug-resistant EGFR variants can have drug-resistance mutations including, without limitation, T790M, T854A, L718Q, or D761Y.

[0436] An alternative method of measuring the effect on EGFR activity is to assay EGFR phosphorylation. Wild-type or mutant (L858R / T790M, Del / T790M, Del / T790M / L718Q, or L858R / T790M / L718Q) EGFR can be transfected into NIH-3T3 cells (which do not normally express endogenous EGFR) and the ability of inhibitors (using the concentrations listed above) to inhibit EGFR phosphorylation can be assayed. Cells are exposed to increasing concentrations of inhibitors for 6 hours and stimulated with EGFR for 10 minutes. The effect on EGFR phosphorylation is assayed by Western blotting using a phospho-specific (Y1068) EGFR antibody.

[0437] In some embodiments, the present invention provides a method of treating an EGFR-mediated disease in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments of the above-disclosed aspects, the EGFR-mediated disease is cancer.

[0438] In some embodiments, the present invention provides methods for treating lung cancer. In some embodiments, the present invention provides methods for treating non-small cell lung cancer (NSCLC). In some embodiments, the present invention provides methods for treating small cell lung cancer (SCLC).

[0439] Administering a compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein to a mammal includes any suitable delivery method. The most suitable administration means for a particular patient depends on the nature and severity of the disease or condition being treated, or the nature of the treatment being used, and the nature of the active compound. Administering a compound or a pharma- ceutically acceptable form thereof (e.g., a salt), or a pharmaceutical composition described herein to a mammal includes administering a compound or a pharma- ceutically acceptable form thereof (e.g., a salt), or a pharmaceutical composition described herein to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administering a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition to a mammal also includes administering to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally, a compound described herein or a pharma- ceutically acceptable salt thereof that is metabolized to a pharmaceutical composition in or on the body of the mammal.

[0440] Thus, the compounds described herein or their pharma- ceutically acceptable salts, or pharmaceutical compositions, may be administered systemically, for example, orally, in combination with a pharma- ceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the food of the patient's diet. For oral therapeutic administration, the compounds described herein or their pharma- ceutically acceptable salts, or pharmaceutical compositions may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary and may be from about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions may be such that an effective dosage level will be obtained.

[0441] Compositions for parenteral injection include pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0442] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial activity may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0443] The compounds of the present invention can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present composition in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p.33 et seq.

[0444] Useful dosages of the compounds described herein can be determined by comparing their in vitro activity in animal models, and in vivo activity. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated herein by reference.

[0445] The amount of the compounds described herein required for use in a treatment may vary depending on the particular salt selected, as well as the route of administration, the nature of the condition being treated, and the age and condition of the patient, and may ultimately be at the discretion of the attending physician or clinician. In general, the total daily dose of the compositions of the invention administered to a human or other mammalian host in single or divided doses may be, for example, in an amount of about 0.1 to about 20 mg / kg body weight, about 0.5 to about 5 mg / kg body weight, or about 5 to about 10 mg / kg body weight per day. In some embodiments, a dose of 5 mg / kg or less may be appropriate. The desired dose may be conveniently presented in a single dose or as divided doses administered at suitable intervals. The compounds described herein may be conveniently administered in unit dosage form, for example, containing about 25 mg to about 500 mg, about 50 mg to about 300 mg, or about 100 mg to about 250 mg of active ingredient per unit dosage form.

[0446] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (i) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, such as glycerol, and (iv) disintegrants, such as agar, calcium carbonate, and the like. The granules are mixed with corn, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders such as paraffin, (vi) absorption enhancers such as quaternary ammonium compounds, (vii) wetting agents such as cetyl alcohol and glycerol monostearate, (viii) adsorbents such as kaolin and bentonite, and (ix) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared using coatings and shells such as enteric coatings and others known in the art.

[0447] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of these substances.In addition to such inert diluents, the composition may also contain additional agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, or aromatic agents.

[0448] The exemplary pharmaceutical dosage form for injection or infusion may include sterile aqueous solution or dispersion, or sterile powder containing active ingredient that is suitable for extemporaneous preparation of sterile injectable or injectable solution or dispersion.In all cases, the final dosage form must be sterile, fluid and stable under the conditions of manufacture and storage.Sterile injectable solution can be prepared by incorporating the required amount of active compound in a suitable solvent, together with various other ingredients listed above as necessary, and then sterilizing by filtration.In the case of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains a powder of the active ingredient present in the solution previously sterile-filtered, plus any additional desired ingredients.

[0449] The materials, compositions, and components disclosed herein may be used in, in conjunction with, or in the preparation of, or are products of, the disclosed methods and compositions. When combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that each is specifically contemplated and described herein, although specific reference to each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed. For example, when a method is disclosed and discussed, and a number of modifications that may be made to a number of molecules contained in the method are discussed, any and all combinations and permutations of the method and possible modifications are expressly contemplated, unless specifically indicated to the contrary. Likewise, any subset or combination of these is specifically contemplated and disclosed. This concept applies to all aspects of this disclosure, including but not limited to steps in methods using the disclosed compositions. Thus, when there are various additional steps that can be performed, it is understood that each of these additional steps can be performed at any particular method step or combination of method steps of the disclosed method, and each such combination or subset of combinations should be considered to be specifically contemplated and disclosed.

[0450] The disclosed methods may include a kit that includes a compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, and instructions that may describe administering the compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein to a cell or a subject. This should be construed to include other embodiments of kits known to those of skill in the art, such as a kit that includes a solvent (such as sterile) for dissolving or suspending the compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, prior to administering the compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein to a cell or a subject. In some embodiments, the subject may be a human.

[0451] The compounds of the present application may be conveniently prepared, or formed during the process of the present application, as solvates (e.g., hydrates). Hydrates of the compounds of the present application may be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran, or methanol.

[0452] Acids and bases useful in the methods herein are known in the art. Acid catalysts can be any acidic chemical, inorganic in nature (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic in nature (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). Acids are useful in either catalytic or stoichiometric amounts to promote chemical reactions. Bases can be any basic chemical, inorganic in nature (e.g., sodium bicarbonate, potassium hydroxide) or organic in nature (e.g., triethylamine, pyridine). Bases are useful in either catalytic or stoichiometric amounts to promote chemical reactions.

[0453] In addition, in certain embodiments, some of the compounds of the present application have one or more double bonds or one or more asymmetric centers. Such compounds may occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z-biisomeric forms, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. All such isomeric forms of the compounds are expressly included in the present application. Optical isomers may be prepared from their respective optically active precursors by the procedures described herein or by resolving racemic mixtures. Resolution may be carried out in the presence of a resolving agent, by chromatography, or by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution may be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). The compounds of the present application may also be represented in multiple tautomeric forms, and in such cases, the present application expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, and the present application expressly includes all such reaction products). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. The configurations of carbon-carbon double bonds appearing herein are selected for convenience only, and are not intended to designate a particular configuration unless expressly stated in the text, and thus a carbon-carbon double bond arbitrarily shown as trans herein may be cis, trans, or a mixture of the two in any ratio. All such isomeric forms of such compounds are expressly included in the present application. All crystalline forms of the compounds described herein are expressly included in the present application.

[0454] In other embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof may contain asymmetric carbon atoms, for example, as a result of deuterium substitution or otherwise. Thus, the compounds of the present invention may exist as either individual enantiomers or mixtures of two enantiomers. Thus, the compounds of the present invention may exist as either racemic or scalemic mixtures, or as each individual stereoisomer substantially free of other possible stereoisomers. As used herein, the term "substantially free of other stereoisomers" means that less than 25% of other stereoisomers are present, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers, and most preferably less than 2% of other stereoisomers. Methods for obtaining or synthesizing individual enantiomers for a given compound are known in the art and may be applied to the final compound or starting material or intermediates where feasible.

[0455] In this specification, the structural formula of a compound may conveniently represent a specific isomer in some cases, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, etc. In addition, the compound represented by the formula may have crystal polymorphism. It should be noted that any crystal form, mixture of crystal forms, or anhydrides or hydrates thereof are included in the scope of the present application. Furthermore, the so-called metabolites generated by the in vivo decomposition of the present compound are included in the scope of the present application.

[0456] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonds of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or often optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0457] A carbon atom bonded to four nonidentical substituents is termed a "chiral center."

[0458] "Chiral isomer" means a compound having at least one chiral center. Compounds having two or more chiral centers can exist either as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ordered according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385, errata 511, Cahn et al.,Angew.Chem.1966,78,413, Cahn and Ingold,J.Chem.Soc.1951(London),612, Cahn et al.,Experientia 1956, 12, 81, Cahn, J. Chem. Educ. 1964, 41, 116).

[0459] "Geometric isomers" refers to diastereomers whose existence benefits from hindrance of rotation about a double bond. These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog priority rules.

[0460] Furthermore, the structures and other compounds discussed in this application include all atropic isomers thereof. An "atropic isomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers benefit from the restriction of rotation caused by the hindrance of rotation of large groups around a central bond for their existence. Such atropic isomers typically exist as mixtures, although as a result of recent advances in chromatographic techniques, it has been possible in selected cases to separate mixtures of two atropic isomers.

[0461] In accordance with the present invention, isomeric mixtures containing any of a variety of isomeric ratios can be utilized.For example, when only two isomers are combined, mixtures containing isomeric ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention.Those skilled in the art will readily recognize that similar ratios are contemplated for more complex isomeric mixtures.

[0462] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting mixture of diastereomers separated, and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereoisomers formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

[0463] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switch of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0464] Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar molecule reacting with one of the hydroxyl groups (-OH) in the same molecule, resulting in the cyclic (ring-shaped) form exhibited by glucose. Common tautomeric pairs are ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism, amine-enamine, and enamine-enamine in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine).

[0465] Additionally, the compounds of the present application, for example, salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0466] Solvates and polymorphs of the compounds of the invention are also contemplated herein. "Solvate" means a solvation form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. The solvate may be of the disclosed compound or a pharma- ceutically acceptable salt thereof. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance, where the water retains its molecular state as H2O. Solvates of the compounds of the invention include, for example, hydrates. Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and its solvates, as well as mixtures thereof.

[0467] The present application is intended to include all isotopes of atoms present in the present compounds. Isotopes 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 C-13 and C-14. Isotopically labeled compounds are also within the scope of the present disclosure. As used herein, "isotopically labeled compounds" refers to compounds of the present disclosure, including pharmaceutical salts and prodrugs thereof, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature, each as described herein. Examples of isotopes that may be incorporated into compounds of the present disclosure include, respectively, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl.

[0468] By isotopically labelling the compounds of the present disclosure, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, may afford certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. The presently disclosed isotopically-labeled compounds, including pharmaceutical salts, esters, and prodrugs thereof, may be prepared by any means known in the art.

[0469] Furthermore, hydrogen, which is normally abundant ( 1 Substitution of hydrogen (H) with heavier isotopes, such as deuterium, can provide certain therapeutic advantages, resulting, for example, from improved absorption, distribution, metabolism, and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. Benefits also typically abound. 12 C 13 C. (See WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431.)

[0470] It is understood that the compounds of the present application may be represented as different tautomeric forms, and where the compounds have tautomeric forms, all tautomeric forms are intended to be included within the scope of the present application, and the naming of the compounds does not exclude any tautomeric forms.

[0471] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by those of skill in the art, additional methods of synthesizing compounds having the formulas herein will be apparent to those of skill in the art. Additionally, the various synthetic steps can be performed in an alternating sequence or order to obtain the desired compounds. In addition, the solvents, temperatures, reaction times, etc. depicted herein are for illustrative purposes only, and one of skill in the art will recognize that variations in reaction conditions can produce the desired bridged macrocyclic products of the present application. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0472] The compounds of the present application may be modified by appending various functional groups via any of the synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those that enhance biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), enhance oral availability, increase solubility to allow administration by injection, alter metabolism, and alter excretion rate.

[0473] The compounds of the present application are defined herein by their chemical structures and / or chemical names. If a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0474] The recitation of a listing of chemical groups within any definition of a variable herein includes the definition of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. EXAMPLES

[0475] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, compositions, materials, devices, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0476] Various aspects regarding the synthesis, characterization, and formulation of N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Compound 1) can be found, for example, in Gray et al., U.S. Patent Application Publication No. 2017 / 0362204(A1). [ka] .

[0477] Materials and Methods Brain exposure A comparative evaluation of brain exposure of Compound 1 and Gefitinib following a single oral (PO) or intravenous (IV) dose to Sprague Dawley rats was performed by Inotiv. Protocol is available upon request.

[0478] cell culture HEK293 and U251 cells were maintained in DMEM supplemented with 10% fetal bovine serum (FBS) and 100 μg / ml penicillin-streptomycin. Mouse neural stem cells (NSCs) were grown in NeuroCult Growth Medium (mouse) (StemCell Technologies) supplemented with 20 ng / ml EGF. Primary mouse glioma cells (CPEvIII) were cultured in NeuroCult Growth Medium (mouse) (StemCell Technologies) supplemented with 20 ng / ml EGF, 10 ng / ml FGF, and 0.0002% heparin. Primary human glioblastoma lines BT112, BT179, and BT333 were maintained in NeuroCult Growth Medium (human) (StemCell Technologies) containing 20 ng / ml EGF, 10 ng / ml FGF, and 0.0002% heparin.

[0479] Compounds and Reagents Gefitinib and erlotinib were purchased from Selleck Chemicals. Lapatinib was purchased from MedChemexpress. Osimertinib (AZD9291) was obtained from a commercial source. Compound 1 was synthesized by Pharmaron (Wang et al., bioRxiv, 2020.2003.2009.984500). For in vitro studies, the compound was dissolved in DMSO. For in vivo studies, compound 1 was dissolved in 10% NMP / 90% PEG300 and administered by gavage at 37.5 mg / kg or 75 mg / kg per day.

[0480] Western blot analysis Western blot analysis was performed as previously described (Ni, J., et al. (2012). Cancer discovery 2, 425-433; Ni, J., et al. (2016). Nature medicine 22, 723-726; Ni, J., et al. (2017). Neurooncology 19, 22-30). Anti-pEGFR-1068 (#3777), anti-pEGFR-1173 (#4407), anti-EGFR (#4267), anti-pERK1 / 2 (#9101), anti-ERK1 / 2 (#9102), anti-S6RP (#2211), and anti-S6RP (#2217) antibodies were purchased from Cell Signaling Technology. Anti-a-tubulin antibody was purchased from Sigma.

[0481] Cell viability assay Cells were seeded in 96-well plates at a density of 1,000 cells per well and treated with 2-fold serial dilutions of compounds at a starting concentration of 20 μM. Cell viability was assessed 3 days after treatment with CellTiter-Glo (Promega). Curve fitting analysis and IC50 value determination were performed using GraphPad Prism8.

[0482] mouse Ptenf / f (from Dr. Hong Wu, UCLA) mice were backcrossed to the C57BL / 6 strain background for 10 generations. They were then crossed with Cdkn2a-null (Ink4a- / -; / Arf- / -) mice (Ni et al., 2017) on the C57BL / 6 background to generate Cdkn2a-null;Ptenf / f mice. ICR-SCID mice were purchased from Taconic. All animal experiments were performed in accordance with the NIH Animal Use Guidelines and protocols approved by the Dana-Farber Cancer Institute Animal Care and Use Committee (IACUC).

[0483] Intracranial injection of cells Cells (100,000 cells resuspended in 1 μl PBS) were injected intracranially into the right striatum (0 mm anterior, 2 mm lateral, and 2.5 mm ventral to bregma) of 8-10 week old ICR-SCID mice. Animals were monitored daily for the development of neurological deficits.

[0484] Primary mouse CPEvIII glioma Neural stem cells (NSCs) from E14.5 embryonic mouse (Cdkn2a-null; Ptenf / f) striatum were isolated and cultured as previously described (Rietze, RL, and Reynolds, BA (2006). Methods in enzymology 419, 3-23). ​​NSCs were infected twice with adenovirus (University of Iowa) expressing Cre recombinase (AdCre; MOI50) to knock out floxed Pten. Cells were then transduced with a retrovirus (from Dr. Charles Stiles, DFCI) expressing EGFRvIII (pBabe-puro-EGFRvIII) and selected with 1 μg / ml puromycin. The resulting cells (Cdkn2a-null; Ptennull; EGFRvIII, termed CPEvIII) are capable of forming gliomas after transplantation into mouse brain. Tumors were then isolated and mechanically dissociated for growth in vitro and in vivo.

[0485] Bioluminescence imaging Cells were transduced with lentiviral luciferase (HIV-Luc-zsGreen, addgene#39196). Bioluminescence signals from luciferase-expressing cells in live mice were recorded 10 min after intraperitoneal injection of D-luciferin (80 mg / kg) (Gold Biotechnology) using an IVIS Lumina III imaging system (PerkinElmer). Signals were analyzed with Living Image Software (PerkinElmer).

[0486] statistical analysis Statistical analysis of animal survival was determined by the log-rank (Mantel-Cox) test (Prism). Data were considered statistically significant when P<0.05.

[0487] Example 1. In vitro activity of Compound 1 in HEK293 cells expressing EGFRvIII Since EGFRvIII is the most common EGFR variant in GBM, the effect of compound 1 on the activity of EGFRvIII was tested. HEK293-EGFRvIII cells (293-EGFRvIII) stably expressing EGFRvIII were generated. Compound 1 reduced the phosphorylation of EGFRvIII (pEGFRvIIIY1068 and pEGFRvIIIY1173) at both tyrosine sites 1068 and 1173, as well as the phosphorylation of downstream signaling molecules ERK1 and ERK2 (ERK1 / 2), in a dose-dependent manner comparable to that of erlotinib (Figure 1A). Further dose titration revealed that the IC50 value of compound 1 on EGFRvIII phosphorylation was 0.19 μM (Figure 1B). Furthermore, compound 1 reduced the viability of 293-EGFRvIII cells with an IC50 of 1.48 μM, which was lower than those of erlotinib (IC50 4.83 μM), gefitinib (IC50 15.67 μM), and osimertinib (IC50 2.19 μM) (Figure 1C).

[0488] Example 2. In vitro activity of Compound 1 against GBM patient-derived cell lines harboring EGFR amplification and / or mutations Patient-derived glioblastoma cell lines characterized by EGFR amplification (EGFRamp) and / or mutations (PDCL BT112, BT179, and BT333) were cultured and treated with compound 1, erlotinib, gefitinib, or lapatinib, a type II EGFR TKI that is highly active against GBM EGFR variants in vitro (Vivanco, I., et al. (2012). Cancer discovery 2,458-471). Lapatinib more aggressively suppressed survival of GBM patient-derived cells in vitro than the type I EGFR TKIs erlotinib and gefitinib (Figures 2A-2C). Notably, compound 1 was the most potent TKI within this group, as indicated by its greater efficacy in reducing survival of these PDCLs at the lowest IC50 values ​​(Table 1). [Table 1]

[0489] Example 3. In vitro activity of Compound 1 against human GBM U251 cells expressing EGFRvIII In parallel, conventional human GBM U251 cell line was used as a surrogate model for both in vitro and in vivo studies. U251 cells were engineered to stably express EGFRvIII via retroviral-mediated gene transfer (U251-EGFRvIII). Compound 1 was able to dose-dependently reduce EGFRvIII phosphorylation in U251-EGFRvIII cells in culture with an IC50 value of 0.174 μM (Figures 3A and 3B). Examination of the effect of compound 1 along with other EGFR-TKIs on the viability of U251-EGFRvIII cells revealed that, similar to their effects on 293-EGFRvIII cells (Figures 1A-1C), compound 1 and osimertinib (AZD9291 or Tagrisso®) were equally potent in inhibiting the viability of U251-EGFRvIII cells, with IC50 values ​​of 1.52 μM and 2.64 μM, respectively, whereas erlotinib and gefitinib showed much higher IC50 values ​​of 13.65 μM and 20.35 μM, respectively (Figure 3C and Table 2). [Table 2]

[0490] Example 4. In vivo activity of Compound 1 against the orthotopic xenograft model GBM U251-EGFRvIII To evaluate the in vivo activity of Compound 1 in GBM with mutant EGFR, luciferase-expressing U251-EGFRvIII GBM cells were generated to facilitate monitoring of drug response in vivo by bioluminescence imaging analysis. When luminescence signals were detectable, mice bearing orthotopic U251-EGFRvIII tumors were randomized into three treatment groups: vehicle control, 37.5 mg / kg Compound 1, or 75 mg / kg Compound 1. Two independent experiments were performed. In both cohorts, treatment with Compound 1 reduced the luminescence signal and dose-dependently extended the survival of mice bearing orthotopic U251-EGFRvIII tumors (Figures 4A-4D). Median survival times were 68 days for control mice, 80 days for mice treated with 37.5 mg / kg Compound 1, and 89.5 days for mice treated with 75 mg / kg Compound 1 (Figure 4E). All mice appeared normal with no significant weight loss during the treatment period (Figure 4F), suggesting that compound 1 is active in U251-EGFRvIII orthotopic tumors and is well tolerated in mice.

[0491] Example 5. In vitro and in vivo activity of Compound 1 on a genetically engineered mouse (GEM) model of GBM In GBM, EGFR mutations frequently coexist with CDKN2A deletion and PTEN deficiency (Brennan, CW, et al. (2013). Cell 155, 462-477; Cancer Genome Atlas Research, N. (2008). Nature 455, 1061-1068). A syngeneic genetically engineered mouse (GEM) model of GBM driven by double simultaneous deletion of Cdkn2a and Pten with EGFRvIII expression (designated CPEvIII) has been generated. Figure 5A shows the genetic changes observed in these genes in GBM. Primary CPEvIII tumor cells were isolated, cultured as neurospheres, and allografted intracranially in mice. As shown in Figure 5B, compound 1 significantly reduced phosphorylation of EGFRvIII, ERK1 / 2, and S6RP in a dose-dependent manner in vitro and in neurosphere cultures. Compound 1 (75 mg / kg, QD) also extended the survival of mice bearing intracranial orthotopic implants of CPEvIII, with median survival of 25.5 days for control mice and 33 days for mice treated with compound 1, p=0.017 (Figure 5C). Immunohistochemistry (IHC) analysis of pEGFR in tumors harvested from mice at endpoint revealed that phosphorylation levels of EGFRvIII were reduced in mice treated with compound 1 (Figure 5D). Compound 1 was also well tolerated in this cohort of mice, with no significant loss of body weight observed during compound 1 treatment (Figure 5E). Taken together, these results suggest that compound 1 has activity against CPEvIII GBM tumor cells both in vitro and in vivo.

[0492] Example 6. Comparative evaluation of brain exposure of Compound 1 and gefitinib following administration to Sprague Dawley rats Compound 1 and gefitinib were administered as a single oral (PO) dose (30 mg / kg or 50 mg / kg, respectively) to Sprague Dawley rats.

[0493] Compound 1 and gefitinib were also administered via intravenous infusion to 9-week-old (± weeks) male Sprague Dawley rats, with each mouse having two surgically implanted catheters (femoral and jugular veins, respectively) for blood sampling and IV dosing. Compound 1 and gefitinib formulations were prepared within 24 hours of dosing. A single 5-hour IV infusion was administered to each animal, which were then clinically observed twice (30 minutes to 1 hour after dosing, and at the end of the study (T Terminal Blood samples were collected from each animal at 5 time points over a 5-hour infusion period (5 min, 1 h, 2 h, 3 h and T Terminal ) and processed to plasma. Brains were harvested in Tterminal (blotted, weighed, and flash frozen) to compare brain exposure.

[0494] Genfitinib concentrations from plasma and brain from animals of group 1 were quantified by LC-MS / MS. Compound 1 and metabolite (M38) concentrations from plasma and brain from animals of group 2 were quantified by LC-MS / MS. Non-compartmental analysis was performed using Phoenix WinNonlin or Watson LIMS with provided PK parameters including, but not limited to, estimated concentration at T=0 (C0), total body clearance (CL), predicted volume of distribution at steady state (Vss), elimination half-life, maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve over the dosing interval (AUC0-t), and brain and plasma ratios were calculated.

[0495] The results of the study in orally and IV dosed mice are shown in Tables 3 and 4, respectively. [Table 3] [Table 4]

[0496] Example 7. Brain permeability of Compound 1 Data obtained in previously published reports on the brain permeability of EGFR TKIs in GBM were compared with the brain permeability data described herein (Table 5). The comparison shows that gefitinib, erlotinib, afatinib, and vicinpro failed to effectively treat GBM, and the efficacy of osimertinib was not determined. Each of these drugs, along with the vicinpro formulation, appeared to be substrates of P-gp and Bcrp (efflux transporter proteins). In contrast, a significant increase in brain permeability was observed for compound 1 versus the other drugs, suggesting that compound 1 is not a substrate of efflux transporter proteins. [Table 5]

[0497] Example 8. Kinase profiling of compound 1 EGFR amplification and / or mutations are common in GBM, estimated to occur in more than 50% of patients. Therefore, the binding affinity of Compound 1 to wtEGFR and several mutant forms was characterized and compared to that of the second generation kinase inhibitor osimertinib (Table 6). [Table 6]

[0498] Example 9. Compound 1 has less skin toxicity than osimertinib Mice were treated with osimertinib (10-25 mg / kg / day) or compound 1 (10-50 mg / kg / day) and visually observed for skin toxicity (osimertinib, Figure 6A; compound 1, Figure 6B).

[0499] Example 10. Compound 1 has a larger therapeutic window than osimertinib Figure 7 shows the body weight over the course of treatment for mice treated with Compound 1 (25-50 mg / kg) or osimertinib (25 mg / kg). Mice treated with osimertinib (25 mg / kg) reached the study endpoint within one month due to a significant loss in body weight.

[0500] Example 11. Effect of Compound 1 and Osimertinib on NSCLC Brain Metastases Female SCID mice bearing non-small cell lung cancer (NSCLC) brain metastases were dosed with compound 1 (25-50 mg / kg) or osimertinib (AZD9291, 25 mg / kg). Reduction of brain metastases was observed in all treated animals relative to control post-treatment. However, as shown in Table 1 and Figure 8, mice in the AZD9291 group reached the study endpoint at 4 weeks with loss of body weight and skin lesions, and therefore did not show prolonged survival. However, mice treated with compound 1 had a median survival of 80.5 days (25 mg / kg) or more than 100 days (50 mg / kg) (Table 7). These data indicate that compound 1 has a larger therapeutic window for the treatment of NSCLC brain metastases (Figure 9). [Table 7]

[0501] Example 12: Imaging of tissues from mice treated with Compound 1 To image drugs in brain tissue more sensitively, matrix-assisted laser desorption / ionization mass spectrometry imaging (MALDI-MSI) technology was used. Briefly, GBM-bearing mice and control mice were dosed with 100 mg / kg of compound 1 administered orally and sacrificed 7 hours after treatment. Brain tissue was acquired and imaged using bioluminescence (FIG. 10A) and stained with hematoxylin and eosin (H&E) (FIG. 10B), with results that are compared to images acquired using MALDI-MSI.

[0502] Tissue sections were prepared and deposited onto the MALDI matrix (80 mg / mL) SuperDHB (sDHB) matrix, which is a 9:1 mixture of 2,5-dihydroxybenzoic acid (DHB) and 2-hydroxy-5-methoxybenzoic acid, 70:30 MeOH, and 0.1% trifluoroacetic acid (TFA). The tissue-MALDI sample preparation system (TM-Sprayer) parameters were 75 °C, 10 psi, and a flow rate of 0.18 mL / min.

[0503] The control mimic was placed on a MALDI substrate along with brain tissue sections from control and treated mice (FIGS. 10C, 10D) and subjected to MALDI-MSI. FIG. 10E shows the normalized curve generated from the observed intensities for the different concentrations. FIG. 10F is an image of the observed intensities for the brain tissue samples. FIGs. 10G and 10H show the absolute intensities observed for brain tissue samples from mice treated with mimic and compound 1. FIG. 10I shows the MSMS analysis of compound 1.

[0504] Example 13: Further testing Compound 1 and its active / major metabolite, Compound 2, were evaluated in multiple in vitro and in vivo pharmacology studies to assess target responses in lung and brain models. Kinase selectivity was also investigated.

[0505] Compound 1 and / or compound 2 (active / major metabolites) were evaluated for off-target activity in a large panel of receptors and ion channels, including the human ether-a-go-go-related gene (hERG) assay. Compound 1 was comprehensively evaluated in Good Laboratory Practice (GLP) safety pharmacology studies, including studies of cardiovascular, respiratory, and central nervous system function.

[0506] Pharmacokinetic / toxicokinetic (mouse / rat / dog), comparative protein binding, P450 inhibition and induction, transporter profiling, comparative in vitro metabolism and in vivo metabolism (rat) studies were performed with Compound 1. CNS exposure was assessed by oral and intravenous administration. Rats and dogs are metabolically and pharmacologically relevant species for the nonclinical development program.

[0507] The toxicity of Compound 1 and its major metabolite via metabolism, Compound 2, was evaluated in dose-ranging and 4-week oral GLP studies in rats and dogs. All GLP studies were performed using the tosylate salt, lot number A05993-056LB. Phase 1 clinical studies will be conducted with drug substance, lot number NB-Compound 1-A-3. Impurities in the clinical lot were qualified in GLP toxicity studies. The drug product contains only pure drug substance in capsules.

[0508] Pharmacology Compound 1 has been thoroughly evaluated in primary, secondary, and safety pharmacology studies, as shown in Table 8. [Table 8]

[0509] Pharmacology Overview Compound 1 and its active metabolite, Compound 2, were evaluated in multiple in vitro and in vivo studies to assess on-target and off-target pharmacology.

[0510] Compound 1 and Compound 2 (major metabolites) were evaluated on a panel of 468 human kinases and disease-associated mutant variants. Compound 1 and Compound 2 bound to several non-mutated kinases at less than 1% of control. The data suggest that Compound 1 and its major metabolites do not exhibit significant non-selective kinase binding to wild-type proteins. Targeted non-mutated kinases included in Compound 1: MAST1, PAK4, PDGFRB, and ULK3, and in the case of Compound 1-M38: ERBB2, JAK3 (JH1 domain catalytic), MKNK2, MTOR, OSR1, and TNK1. Although there is some variability between Compound 1 and Compound 2, it is clear that both compounds are highly effective at binding to a large panel of mutant kinases. Binding constants (Kd) of less than 100 nM were observed for ALK, EGFR, and FLT3 mutants. The binding constant to wild-type EGFR was 4.9 nM. Binding constants of less than 1 nM were evident for compound 1 with EGFR (E746A-740del, L858R-T790M, and T790M) double and single mutants, and compound 2 showed similar activity with EGFR (L858R-T790M, T790M) double and single mutants.

[0511] In HEK293 cells stably expressing EGFRvIII (the most common EGFR variant in human GBM), compound 1 dose-dependently reduced phosphorylation of EGFRvIII (pEGFRvIII) at tyrosine sites 1068 and 1173, as well as the phosphorylation of downstream signaling molecules ERK1 and ERK2 (ERK1 / 2). Further dose titration revealed an IC50 of 0.19 μM for compound 1 against pEGFRvIII (Table 4-2). Compound 1 also reduced viability in HEK293-EGFRvIII cells with an IC50 of 1.48 μM, which was similar to osimertinib but 3-fold and 10-fold more active than erlotinib and gefitinib.

[0512] In a human GBM cell line (U251 cells) stably expressing EGFRvIII, compound 1 reduced pEGFR with an IC50 of 0.17 μM (Table 9). In this study, compound 1 reduced cell viability (IC 50 1.5 μM) was compared with osimertinib (IC 50 2.6 μM), but cell survival was 9-fold and 13-fold lower than with erlotinib and gefitinib.

[0513] In three primary patient-derived GBM cell lines harboring EGFR amplification and / or mutations in a neurosphere culture system, compound 1 was the most potent inhibitor of cell viability with IC50s ranging from 0.89 to 3.28 μM when compared with erlotinib, gefitinib, or lapatinib. [Table 9]

[0514] To evaluate the in vivo activity of Compound 1 in GBM with mutant EGFR, U251 cells were generated to stably express EGFRvIII (U251-EGFRvIII) via retroviral-mediated gene transfer. U251-EGFRvIII cells were further engineered to express luciferase to facilitate monitoring of drug response in vivo by bioluminescence imaging analysis. In a pilot in vivo orthotopic study with U251-EGFRvIII cells (luciferase expression) implanted in the brain, mice were treated starting on day 28 after implantation, and luminescence signals were detected in the brain on day 28. Compound 1 doses were 0 (n=7), 37.5 (n=8), and 75 (n=7) mg / kg / QD. There was no weight loss during the study. Median survival was 68 days for control, 80 days for low dose, and 89.5 days for high dose Compound 1. These data suggest that Compound 1 was safe and effective in this pilot study.

[0515] In GBM, EGFR mutations frequently coexist with Cdkn2a deletion and Pten deficiency (Brennan 2013). In a genetically engineered mouse model of GBM driven by dual simultaneous deletion of Cdkn2a and Pten with EGFRvIII expression (CPEvIII model), primary CPEvIII tumor cells were cultured as neurospheres and implanted intracranially in mice. Compound 1 significantly reduced phosphorylation of EGFRvIII, ERK1 / 2, and S6RP in neurosphere cultures in vitro in a dose-dependent manner. Compound 1 (75 mg / kg, QD) also extended the survival of mice bearing intracranial implants of CPEvIII, with median survival of 25.5 days for control mice and 33 days for mice treated with compound 1, p=0.017 (Table 10). At termination, immunohistochemistry analysis of pEGFR in tumors harvested from mice revealed reduced levels of EGFRvIII phosphorylation in mice treated with Compound 1. Compound 1 was also well tolerated in this cohort of mice, with no significant loss in body weight observed during treatment with Compound 1. Collectively, these results suggest that Compound 1 has activity against CPEvIII GBM tumor cells both in vitro and in vivo. [Table 10]

[0516] One of the key features of Compound 1 that distinguishes it from all competitors is its exceptional distribution into brain tissue. The brain / plasma ratio of Compound 1 is approximately 20 in rats with continuous infusion. A recent study of the brain distribution of competing EGFR-TKIs shows that gefitinib has 27% brain penetration, erlotinib 13.7%, and osimertinib 180% (Kim 2019). The same study also showed that the five approved EGFR-TKIs are subject to extensive efflux transport. In contrast, current Crimson in vitro data indicates that Compound 1 is not a transporter substrate, but rather a weak inhibitor of breast cancer resistance protein (BCRP) and lacks inhibition of P-glycoprotein (P-gp).

[0517] Taken together, the data suggest that Compound 1 has impressive in vitro and in vivo activity in models of GBM.

[0518] In an in vitro non-small cell lung cancer (NSCLC) cell proliferation assay using PC9GR4 cells carrying the Ex19del / T790M double mutation and H1975 cells carrying the L858R / T790M double mutation, compound 1 exhibited an IC 50 and an IC of 4.39 nM in PC9GR4 cell lines 50 and inhibited proliferation (Wang 2020).

[0519] Compound 1 was also evaluated in xenograft models of lung tumor cell lines with EGFR single and double mutations in mice. Studies in NOD.SCID mice with SQ human lung grafts (H1975 cells: EGFR L858R-T790M and PC-9 cells: EGFR Ex19Del) demonstrated that oral Compound 1 (30 or 50 mg / kg) was effective and safe. Antitumor activity was demonstrated in the H1975 and PC-9 models with plasma concentrations of Compound 1 of 800 ng / mL (1.6 μM) and 1500 ng / mL (3.1 μM) at 4 hours post-dosing, respectively. Substantial tumor regression (essentially a cure) occurred in H1975 lung tumor grafts over the course of the study.

[0520] Safety pharmacology studies indicate no respiratory or CNS risks. In a cardiovascular (CV) dog study, one of four dogs showed signs of reversible ventricular conduction disturbances 10-24 hours after the high dose (100 mg / kg) of compound 1. This arrhythmia was not associated with maximum plasma concentration (Cmax) or Tmax of either the parent or metabolite. No clear link to the test article could be identified. Given the unexplained reversible heart rate in this high dose (100 mg / kg) telemetry dog, routine electrocardiogram (ECG) monitoring in Phase 1 is recommended.

[0521] hERG IC 50 is IC100 ~30 μM and 1.9 μM (925 ng / mL), whereas for compound 1, doses up to 100 mg / kg and an estimated single dose C of 2618 ng / mL (5.4 μM) max , and for compound 1-M38, C max In a high fidelity dog ​​CV telemetry study (Spence 1998, Miyazaki 2002) with approximately 367 ng / mL (0.75 μM), there was no QTc signal and no adverse effects on blood pressure or cardiac intervals. There were no adverse CNS effects in the rat functional observational battery and no adverse effects on respiratory rate in dogs. Receptor binding studies suggest that Compound 1 has little off-target risk.

[0522] Compound 1 is effective in vitro and in vivo in mouse tumor models and is relatively selective for mutant kinases of interest. Safety pharmacology studies have shown no respiratory or CNS risks and no off-target receptor involvement. Given the unexplained arrhythmia in one high-dose (100 mg / kg) telemetry dog ​​and one high-dose (100 mg / kg) death (day 13) associated with myocardial degeneration in a 4-week dog toxicity study, regular ECG monitoring up to 8 hours after dosing to cover parent and metabolites, as well as cardiac enzyme (troponin) monitoring in Phase 1, along with pharmacokinetics, are recommended.

[0523] The pharmacology and brain exposure profile support a Phase 1 oncology dose escalation study in humans.

[0524] Metabolism and Pharmacokinetics The absorption, distribution, and metabolism of Compound 1 were investigated in the studies outlined in Table 11. [Table 11]

[0525] A sensitive and reproducible liquid chromatography tandem mass spectrometry (LC-MS / MS) assay was developed and validated to support metabolism-pharmacokinetic-toxicokinetic studies with compound 1 and its major active metabolite, compound 2.

[0526] Compound 1 is a moderately high clearance compound with a large volume of distribution in rats. max was generally about 5 hours and for Compound 2 it was generally about 7 hours, and T1 / 2 was generally about 5 hours for Compound 1 and about 9 hours for Compound 1-M38. In rats, there were no sex differences, bioavailability averaged 50% and appeared to be independent of dose. Exposure was generally proportional to dose.

[0527] Total brain exposure of Compound 1 was 20-fold higher than plasma at estimated steady state following continuous intravenous infusion and oral dosing, while brain exposure of Compound 2 was essentially equivalent to plasma. No adverse effects were noted in these studies.

[0528] Compound 1 is a weak inhibitor of human BCRP-mediated rosuvastatin transport, with an apparent IC of 3.02 μM (1471 ng / mL). 50 Compound 1 did not inhibit P-gp-mediated transport of digoxin (IC 50 >30.0 μM). Compound 1 has moderate permeability in Caco-2 cells and is unlikely to be a substrate for efflux transporters. Based on these data, there is generally a low risk of significant drug-drug interactions at therapeutic plasma concentrations via effects on these transporters. Further understanding of DDI risk awaits Phase 2 dose and exposure definition.

[0529] Compound 1 is primarily metabolized by CYP3A4 / 3A5, and weak inhibition of CYP3A4-T, but not CYP3A4-M, was observed with an IC50 of 4.89 μM (2381 ng / mL). There was no CYP induction based on enzyme activity, and based on mRNA, there was CYP3A4 induction at 1 μM, but not at lower concentrations. Metabolism, inhibition, and induction were not observed for other CYPs. Potential DDI interactions exist with drugs that are inhibitors of CYP3A4-T or metabolized by CYP3A4 / 3A5, and human pharmacokinetic (PK) data would better define these DDI risks.

[0530] Compound 1 was highly protein bound to plasma proteins across species (95.6-98.7%), and binding was independent of concentration.

[0531] In in vitro studies, metabolic stability was highest in human hepatocytes, with 22 metabolites detected in human, monkey, dog, rat, and / or mouse hepatocytes. Compound 2 was the major demethylation-active metabolite in all species, and with the exception of a minor metabolite, M48, in human hepatocytes, all human metabolites were expressed in rat and / or dog, toxic species.

[0532] In in vivo studies in rats, dogs, and monkeys, 35 metabolites were identified. The major circulating compound in all species was the parent compound, which was also a major component in rat feces. Compound 2, a demethylated metabolite, was the major active metabolite in plasma and rat feces in all species. M34, a glutathione conjugated and hydrolyzed and acetylated metabolite, was the major metabolite in rat urine. Compound 1 was extensively metabolized during excretion, with 31 metabolites in rat urine and 32 metabolites in rat feces.

[0533] Compound 1 has many metabolites and one major active metabolite in all species evaluated. Potential metabolic interactions exist with drugs that are inhibitors of CYP3A4-T or are metabolized by CYP3A4 / 3A5. The significance of these metabolic risks will become clearer once human PK data are available and targeted effective plasma concentrations for Phase 2 are identified.

[0534] toxicology Compound 1 has been tested in repeated dose toxicity studies in rats and dogs for up to 4 weeks (Table 12). The study design, conducted under GLP, was in full compliance with relevant international guidelines. Dose formulation analytical methods were validated. A GLP toxicology program was completed with Compound 1 lot number A05993-056LB. Phase 1 clinical studies will be conducted with drug substance lot number NB-Compound 1-A-3. All impurities in clinical lots stored at accelerated conditions for 6 months were qualified in the toxicology program. The drug product is pure Compound 1 in capsules. [Table 12]

[0535] Oral rat dose ranging study Male and female Sprague-Dawley rats were administered Compound 1 by oral gavage either once (30, 100, 500, 1000 mg / kg / day) or once daily (30, 100, 300 mg / kg / day) for up to 14 days. Single oral doses of Compound 1 were well tolerated at doses from 30 to 1000 mg / kg. When administered for 14 days, morbidity and mortality associated with a marked reduction in food consumption and body weight (6.9%-F and 20.8%-M) was observed at 300 mg / kg, and this group was terminated on day 9. Lymphocyte depletion was observed in the thymus and spleen, as well as vacuolization of renal tubules at this higher dose. Similar, but much less severe, thymic lesions were noted at 100 mg / kg / day on day 14. No significant toxicity was observed at 30 mg / kg / day. In this study, STD 10 was estimated to be 100 mg / kg / day.

[0536] Oral cavity rat 4-week study Compound 1 (0, 10, 30, and 100 mg / kg / day) was administered by oral gavage once daily for up to 28 days to male and female Sprague-Dawley rats. Morbidity was associated with significant weight loss, necessitating termination of dosing in the high dose group on days 12 / 13. At this time, 5 / sex in the high dose group were necropsied and 5 / sex were initiated into recovery for the remainder of the study.

[0537] On day 28, exposure to Compound 1 and Compound 2 increased with increasing dose from 10 to 30 mg / kg, and exposure as area under the curve (AUC) was generally dose proportional. No obvious sex differences or accumulation were observed (Table 13). [Table 13]

[0538] Major histological findings at mid-course necropsy (100 mg / kg) included generalized lymphodepletion, pulmonary edema / inflammation, and testicular vas deferens degeneration. In this study, all findings except testicular degeneration were reversible (approximately 14 days), and the reversibility period was not sufficient to assess the reversibility of testicular changes. On day 29, only testicular degeneration was observed at 30 and 100 mg / kg. No toxicity was observed at 10 mg / kg. STD 10 was 30 mg / kg.

[0539] Oral dog dose ranging study In a dose-ranging study in dogs, compound 1 was administered by oral gavage either once (30, 100, 600, 1000 mg / kg) or once daily for 14 days (30, 100, 300 mg / kg / day) to male and female beagle dogs. Single oral doses of compound 1 were well tolerated at doses from 30 to 1000 mg / kg. When administered for 14 days, morbidity and mortality associated with mild reductions in food intake and marked reductions in body weight (7.6%-M and 10.6%-F) were observed at 300 mg / kg / day, and thymic lymphocyte depletion, hepatocellular pigmentation, renal tubular vacuolization, and erosions in the fundus stomach were noted in these dogs. Similar, but much milder, thymic and hepatic changes were noted at 100 mg / kg / day on day 15.

[0540] No significant toxicity was observed at 100 mg / kg / day. HNSTD was estimated to be 100 mg / kg / day in this study.

[0541] Oral dog 4-week study Compound 1 (0, 10, 30, and 100 mg / kg / day) was administered by oral gavage once daily to male and female beagle dogs (4 / sex) for up to 28 days. In the high dose group, one male was found dead on day 13, and abnormal clinical observations and weight loss at this dose necessitated discontinuation of dosing in the high dose group on days 18-M and 17-F. The high dose survivor began the recovery period on days 18 / 17 to 29. The cause of death of this high dose male was attributed to myocardial degeneration. This lesion was not observed in any other dog in the study. The increases in alkaline phosphatase, globulins, cholesterol, triglycerides, and fibrinogen, as well as the decrease in reticulocyte counts noted in the high dose group at mid-study, returned to baseline by the end of the study after 11 / 12 days of recovery. Testicular changes at all doses (semi- cular epithelial vacuolization at 10 mg / kg and 30 mg / kg, and degeneration / atrophy at 100 mg / kg) were not reversible in this short-term study, and the period of reversibility was not long enough to assess the reversibility of testicular changes.

[0542] C maxExposure to Compound 1 and Compound 2, as assessed by AUC0-24 and AUC0-24, generally increased with increasing dose on Days 1 and 28. Increases were generally dose-proportional or greater than dose-proportional on Days 1 and 28. No gender differences were observed. No significant accumulation of Compound 1 or Compound 2 was observed. These data are shown in Table 14. [Table 14]

[0543] In females, no significant toxicity was observed at 10 or 30 mg / kg / day. HNSTD was estimated to be 30 mg / kg / day.

[0544] Integrated Nonclinical Efficacy and Safety Summary GBM is the most common primary brain tumor in adults (Ostrom 2018). Many targeted therapies have demonstrated widespread success in other cancer types, but efficacy in GBM is limited, and the prognosis for patients with GBM remains grim (Kurz 2018, Miller and Wen 2016). More than 50% of GBM harbor abnormal EGFR gene variants. Most of these EGFR variants arise via mutations in the extracellular domain (Vivanco 2012). Among them, the most common EGFR variant (v), EGFRvIII (exon 2-7 deletion), has an in-frame extracellular domain truncation (Furnari 2015). It has been shown that EGFR-mutated GBM cells are likely dependent on EGFR signaling (An 2018, Huang 2009). Thus, EGFR is an attractive therapeutic target in GBM.

[0545] Compound 1, a third generation tyrosine kinase inhibitor, is in development for GBM (Wang 2020) where Compound 1 binds covalently to its target. Compound 1 demonstrated mutant kinase binding (Kd<1nM) selectivity for several EGFR single and double mutants with little activity against wild-type EGFR. Compound 2 (the major active metabolite) showed similar selective activity. In oral GBM mouse studies, Compound 1 appeared to be safe and active at 37.5 and 75mg / kg, with IC50-100 in targeted in vitro studies targeting reduction of phosphorylated EGFR and cell viability. 50 was in the range of 0.17 to 3.28 μM.

[0546] There were no adverse effects on blood pressure or cardiac intervals, including QT and QTc. One high-dose telemetry dog ​​had a reversible zygotic arrhythmia 12-24 hours after dosing, with no significant effect on T of either the parent or metabolite. max There was no association with pulmonary embolism, suggesting that it was not caused by Compound 1 or Compound 2. There were no adverse effects on CNS parameters or respiratory rate. Receptor binding studies suggest that Compound 1 has little off-target risk. Given the unexplained arrhythmias in dogs with a single high dose of telemetry, routine ECG monitoring of dogs for up to 8 hours after dosing in Phase 1 is recommended.

[0547] Compound 1 is a moderately high clearance compound with a large volume of distribution in rats. max is generally about 5 hours, for compound 2 is generally about 7 hours, and T 1 / 2 was generally about 5 hours for Compound 1 and about 9 hours for Compound 2. In rats, there were no sex differences, bioavailability averaged 50% and appeared to be dose-independent. Exposure was generally dose-proportional. Compound 1 was highly protein bound to plasma proteins across species, and binding was concentration-independent.

[0548] Compound 1 has many metabolites identified in all species evaluated and one major active metabolite (compound 2). Potential metabolic interactions exist with drugs that are inhibitors of CYP3A4-T or are metabolized by CYP3A4 / 3A5. The significance of these metabolic risks will become clearer once human PK data are available and targeted effective plasma concentrations in humans are identified.

[0549] In a 4-week toxicity study in rats, there was death at 100 mg / kg, and the main histological findings at mid-course necropsy (100 mg / kg) included generalized lymphodepletion, pulmonary edema / inflammation, and testicular vas deferens degeneration. In this study, all findings except testicular degeneration were reversible, and the reversibility period was not sufficient to assess the reversibility of testicular changes. Testicular degeneration was observed at 30 and 100 mg / kg on day 29. No toxicity was observed at 10 mg / kg. STD 10 was 30 mg / kg.

[0550] In a 4-week toxicity study in dogs, there was one death at 100 mg / kg due to myocardial degeneration on day 12, which was the only high-dose dog with myocardial lesions. Testicular changes observed at all doses (vacuolization of the testicular epithelium at 10 and 30 mg / kg, and degeneration / atrophy at 100 mg / kg) were not reversible, and the period of reversibility was not long enough to assess the reversibility of testicular changes. No significant toxicity was observed at 10 or 30 mg / kg / day in females. HNSTD was estimated to be at 30 mg / kg / day.

[0551] Testicular lesions were observed in dogs and rats, no NOEL was established in dogs and 10 mg / kg in rats, and the study was not of sufficient duration to study reversibility. Myocardial lesions leading to reversible junctional arrhythmia in one dog and death in another were observed at 100 mg / kg, and the NOEL for myocardial risk was 30 mg / kg in dogs and 100 mg / kg in rats. These potential risks should be identified in the informed consent document and taken into account in the calculation of the starting dose. In a Phase 1 clinical program, ECG monitoring for up to 8 hours after dosing to cover parent and metabolites, as well as cardiac troponin assessment, are recommended.

[0552] Phase 1 Starting Dose Recommendation Based on pharmacological potency, and nonclinical safety pharmacology, metabolism and pharmacokinetic studies, and dose response, Compound 1 is expected to be a relatively safe and effective compound at therapeutic doses in oncology patients. The toxicology program in dogs (HNSTD = 30 mg / kg) supports a starting dose of up to 300 mg / 60 kg based on oncology dose selection guidance. Rat toxicity data (STD 10 = 30 mg / kg) supports a maximum starting dose of 180 mg / 60 kg based on oncological dose selection guidance.

[0553] Testicular lesions were observed in both rats and dogs at 30 mg / kg and 10 mg / kg, respectively. Myocardial risk was described in dogs at 100 mg / kg but not at 30 mg / kg, with the NOEL for myocardial risk being 30 mg / kg (human equivalent dose [HED] = 15 mg / kg). Based on these data, the starting dose for this oral compound is 1.5 mg / kg or 90 mg / 60 kg. The recommended starting dose for Phase 1 oncology patients is 100 mg QD.

[0554] Main areas of preclinical studies Pharmacologically active in GBM mouse models at oral doses of 37.5 and 75 mg / kg QD · Pharmacologically active in NSCLC mouse models at oral doses of 30 and 50 mg / kg OD Activity was observed at plasma concentrations of 800 ng / mL (1.6 μM) and 1500 ng / mL (3.1 μM) 4 hours after dosing. · Numerous metabolites (22 in human, monkey, dog, rat and / or mouse hepatocytes) and one major active metabolite (compound 2) were identified in all species evaluated, including human hepatocytes. Moderately high clearance with large volume of distribution in rats Oral T max was generally about 5 hours and 7 hours for Compound 1 and Compound 2. T 1 / 2 was generally about 5 hours and 9 hours for Compound 1 and Compound 2. Highly bound to plasma proteins across species and in a concentration-independent manner. The absolute bioavailability in rats was approximately 50%. Total brain exposure of Compound 1 was 20-fold higher than plasma at estimated steady state following continuous intravenous infusion and oral dosing in rats, whereas brain exposure of Compound 2 was essentially equivalent to plasma Potential metabolic interactions exist with drugs that are CYP3A4-T inhibitors or that are metabolized by CYP3A4 / 3A5. Apparent IC of 3.02 μM (1471 ng / mL) 50 Weak inhibitor of rosuvastatin transport through human BCRP with a 100% β-blocking effect No P-gp inhibition Moderately permeable in Caco-2 cells and unlikely to be a substrate for efflux transporters No adverse effects on heart rate, blood pressure, or cardiac intervals, including QT and QTc, in dogs One high-dose telemetry dog ​​had reversible zygotic arrhythmias 12-24 hours after dosing, with no evidence of either parent or metabolite T max There was no association with either compound 1 or compound 2, suggesting that the Testicular degeneration in rats and dogs; studies were not long enough to assess reversibility Myocardial lesions leading to death in one high dose dog on day 12 (100mg / kg) The NOEL for myocardial risk was 30 mg / kg in dogs and 100 mg / kg in rats. No Observed Adverse Effect Level (NOAEL) for 4-week dog toxicity - 10mg / kg 4-week rat toxicity NOAEL-10mg / kg STD 10 was 30 mg / kg in rats. The HNSTD was 30 mg / kg in dogs.

[0555] Dosage and Administration Compound 1 will be administered orally as a single daily dose (although alternative frequency or intermittent schedules may be pursued in response to emerging safety, tolerability, or PK data). Dosing should be administered on an empty stomach (i.e., at least 1 hour before or 2 hours after a meal) at approximately the same time each day. The initial daily dose in initial human studies will be 100 mg.

[0556] The dog toxicity program (HNSTD = 30 mg / kg) supports a starting dose of up to 300 mg / 60 kg based on oncology dose selection guidance. 10 = 30 mg / kg) supports a maximum starting dose of 180 mg / 60 kg based on oncological dose selection guidance.

[0557] Testicular lesions were observed in both rats and dogs at 30 mg / kg and 10 mg / kg, respectively. Myocardial risk was described in dogs at 100 mg / kg but not at 30 mg / kg, with the NOEL for myocardial risk being 30 mg / kg ([HED]=15 mg / kg). Based on these data, the starting dose is 1.5 mg / kg or 90 mg / 60 kg.

[0558] The recommended starting dose for Phase 1 oncology patients is 100 mg QD.

[0559] Example 14 Drug delivery across the blood-brain barrier (BBB) ​​is a major obstacle that all EGFR-targeted agents for brain cancer must face. Despite evidence that EGFR signaling is required for the survival of EGFR-mutant GBM cells, numerous EGFR-TKIs have been unsuccessfully evaluated for the treatment of GBM (Westphal, M., et al. CNS Drugs 31, 2017, 723-735). Many of these inhibitors are unable to cross the BBB or are substrates for drug efflux pumps, often with a relatively small therapeutic window.

[0560] To determine the brain penetration of compound 1, a comparative evaluation of the brain exposure of compound 1 and gefitinib was performed 7 hours after a single oral dose of compound 11 (30 mg / kg) or gefitinib (50 mg / kg) in rats. The results showed that the brain / plasma (B / P) ratio of compound 11 was 28.3 and the B / P ratio of gefitinib was 0.22 (Tables 3 and 4). A more detailed comparative evaluation of the brain exposure of compound 11 and gefitinib after continuous intravenous infusion to a presumed steady state in rats was performed. Both compounds were infused to a total dose of 3 mg / kg over a period of 5 hours. The results showed that the B / P ratio of compound 11 was 20.3 and that of gefitinib was 0.55, consistent with the data from oral administration of the drugs. Notably, the plasma concentration of compound 11 was much lower than that of gefitinib at all time points in both oral and intravenous administration (Tables 3 and 4). These data support compound 11 as an ideal compound for treating GBM because it is preferentially present in the brain at high concentrations without any apparent adverse effects in these pilot studies.

[0561] Compound 11 is a weak inhibitor of human breast cancer resistance protein (BCRP)-mediated rosuvastatin transport with an apparent IC50 value of 3.02 μM. Compound 11 did not inhibit P-glycoprotein (P-gp)-mediated transport of digoxin (IC50>30.0 μM). Compound 11 also showed moderate permeability in Caco-2 cells. Based on these data, compound 11 is unlikely to be a substrate for efflux transporters and, in general, there is a low risk of significant drug-drug interactions at therapeutic plasma concentrations via effects on these transporters.

[0562] Surprisingly, compound 11 distributes and accumulates in the brain at levels approximately 20 times higher than plasma levels.Unlike other EGFR-TKIs that are subject to efflux transporters, compound 11 is not a substrate for P-gp or BCRP-mediated drug transport function, but is instead a moderate inhibitor of BCRP.Furthermore, compound 11 exhibits a relatively high clearance rate to maintain a relatively low plasma level.

[0563] Recent studies have shown that EGFR is important for embryonic and early postnatal brain development, but adult mice with brain-specific deletion of EGFR appear normal (Robson, JP, et al. The FEBS Journal 285, 2018, 3175-3196), suggesting that EGFR inhibition in the CNS does not result in dose-limiting toxicity. Thus, the distinct pharmacological properties of compound 11, particularly its high brain / plasma ratio, potentially provide a "tissue-based" therapeutic window to allow for effective inhibition of EGFR in tumors, while relatively sparing the receptor systemically. Preclinical data have shown that compound 11 provides a sufficiently wide therapeutic window to effectively inhibit EGFRvIII intracranially without significant extracranial toxicity.

[0564] Example 15: Preparation of salts of N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(methylamino)ethyl))amino)phenyl)acrylamide (salts of compound 12) [ka] Step 1. Synthesis of tert-butyl (2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl)(methyl)carbamate (compound b) To a solution of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-amine (compound a, 17.2 g, 1.0 equiv.) in ACN (260 mL), tert-butyl methyl(2-(methylamino)ethyl)carbamate (12.7 g, 1.5 equiv.) and DIPEA (11.7 g, 2.0 equiv.) were added at 20° C., and the resulting mixture was stirred at 80° C. for 24 h. The reaction mixture was cooled to 38° C., HO (200 mL) was added, and the mixture was stirred for an additional 30 min. The resulting mixture was filtered through Celite, and the filter cake was rinsed with HO and then with ACN. The filter cake was dried under vacuum at 40-45 °C (tank temperature) to give crude compound b (23.0 g, 93% yield, 97.9% purity as determined by HPLC) as a red solid. t =5.329 minutes. MSm / z:225.2[(M-Boc) / 2+l].

[0565] Steps 2 and 3. Synthesis of tert-butyl (2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-acrylamido-5-methoxyphenyl)(methyl))amino)ethyl)(methyl)carbamate (compound d) To a solution of compound b (16 g, 1.0 equiv.) in THF (160 mL), Pd / C (0.8 g, 5 wt%) was added and the resulting mixture was evacuated to ≦-80 KPa and then expanded with hydrogen to 3× atm. The hydrogenation reaction was maintained at 25±5° C. for 42 h. The reaction mixture was filtered through Celite and the filter cake was washed with THF. The filtrate was cooled to 0-5° C. and 3-chloropropanoyl chloride was added while keeping the reaction mixture at 0-5° C. After 15 min, a yellow solid precipitated. LC-MA analysis showed that the intermediate, tert-butyl(2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-amino-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)carbamate (compound c), had disappeared in 1 h and was complete. To the reaction mixture, a solution of NaOH (4.7 g, 4.0 equiv.) in water (128 mL) was added at 20-25 °C and stirred for 21 h. The organic phase was separated and concentrated under reduced pressure at a temperature below 40 °C. Ethyl acetate was added to the concentrated organic phase and washed with water. The organic layer was collected and concentrated under reduced pressure at a temperature below 40 °C. Purification by chromatography (silica gel 200-300 mesh, PE:EA=3:1) afforded compound d (10 g, 60% yield, 94.6% purity as determined by HPLC) as a pale yellow solid. R t =4.221 minutes. MSm / z:573.2[M+1]+.

[0566] Step 4. Synthesis of N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(methylamino)ethyl))amino)phenyl)acrylamide bis(2,2,2-trifluoroacetate) (compound 2·2TFA) To a solution of compound d (3.0 g, 1.0 equiv) in DCM (45 mL) at 20-25 °C was added TFA (11.1 g, 18.6 equiv). After 18 h, the reaction mixture was concentrated under vacuum at 40 °C to dryness. The concentrated residue was dissolved in EA, and then saturated sodium bicarbonate solution was added until the PH was 7-8. The resulting mixture was filtered through Celite, and the filter cake was rinsed with H2O and then ACN. The filter cake was dried under vacuum at 40-45 °C (tank temperature) to give compound 2·2TFA (2.0 g, 80.6% yield, 97.8% purity as determined by HPLC) as a red solid. R t =13.299 minutes. MSm / z:473.2[M+1]+. 1 H NMR (300MHz, DMSO-d6) δ9.31 (s, 1H), 8.92 (s, 1H), 8.73 (d, J=4.0Hz, 1H), 8.63-8.53 (m, 3H) ), 8.52-8.40(m, 2H), 8.20(s, 1H), 8.13(dd, J=7.8, 1.6Hz, 1H), 7.33(dd, J=7.8, 4.8Hz, 1H ), 7.00(s, 1H), 6.83-6.67(m, 2H), 6.36(dd, J=16.9, 2.1Hz, 1H), 5.81(dd, J=10.1, 2.1Hz, 1H), 3.90(s, 3H), 3.22(t, J=5.7Hz, 2H), 3.14(d, J=5.7Hz, 2H), 2.64(s, 3H), 2.60(s, 3H).

[0567] Example 16: Cell viability assay of AZD9291 and Compound 1 Cell viability assays of the known EGFR inhibitor AZD9291 and compound 1 described herein were performed according to the procedures described in General Biological Assay A, Cell Viability Assay. The CellTiter-Glo (Promega) assay kit (https: / / www.promega.com / resources / protocols / technical-bulletins / 0 / celltiter-glo-luminescentcell-viability-assay-protocol / ) was used here. NCI-H1975 cells (EGFR L858R / T790M mutation) and PC-9 cells (EGFR exon 19 deletion) were used in the cell viability assay.

[0568] AZD9291 was obtained from a commercial source. Compound 2 was synthesized as described in Example 15. Compound 1 was synthesized according to the method disclosed in Gray et al., U.S. Patent Application Publication No. 2017 / 0362204(A1).

[0569] NCI-H1975 cells (EGFR L858R / T790M mutation) were incubated for 72 hours with AZD9291 and Compound 1, respectively. AZD9291 had an IC 50 Compound 1 showed an IC of 34.39 nM. 50 showed.

[0570] PC-9 cells (EGFR exon 19 deletion) were incubated with AZD9291 and Compound 1. AZD9291 had an IC of 18.12 nM. 50 Compound 1 showed an IC of 62.78 nM. 50 showed.

[0571] In cell viability assays, compound 1 demonstrated excellent potency in inhibiting both EGFR with L858R / T790M mutations and EGFR with exon 19 deletions.

[0572] Example 17: In vitro EGFR / ERK phosphorylation assay of AZD9291 and Compound 1 EGFR / ERK phosphorylation assays were performed according to known procedures. NCI-H1975 cells (EGFR L858R / T790M mutation) and PC-9 cells (EGFR exon 19 deletion) were used in the phosphorylation assays.

[0573] NCI-H1975 cells (EGFR L858R / T790M mutation) were treated for 6 hours with each of AZD9291 and Compound 1. The EGFR signaling pathway was determined by Western blot analysis.

[0574] PC-9 cells (EGFR exon 19 deletion) were treated for 6 hours with each of AZD9291 and Compound 1. The EGFR signaling pathway was determined by Western blot analysis.

[0575] Example 18: Toxicokinetic analysis of the EGFR inhibitor Compound 1 Thirty-two beagle dogs (conventional and naive) were divided into four groups. Each group consisted of four males and four females. Beagle dogs in group 1 were administered vehicle, and beagle dogs in groups 2-4 were administered 10 mg / kg, 30 mg / kg, and 100 mg / kg of Compound 1 by oral gavage once daily for 28 consecutive days (Table 15). The 8-hour T 1 / 2 and 4-hour T max was measured for Compound 1 on Day 1. For Groups 2 to 4, the C max (ng / mL) and AUC last (time*ng / mL) was obtained (Table 15). [Table 15]

[0576] Compound 1 and its active / major metabolite, Compound 2, were evaluated in multiple in vitro and in vivo pharmacology studies to assess target responses in lung and brain models. Kinase selectivity was also investigated.

[0577] Compound 1 and / or compound 2 (active / major metabolites) were evaluated for off-target activity in a large panel of receptors and ion channels, including the human ether-a-go-go-related gene (hERG) assay. Compound 1 was comprehensively evaluated in GLP safety pharmacology studies, including studies of cardiovascular, respiratory, and central nervous system function.

[0578] Pharmacokinetic / toxicokinetic (mouse / rat / dog), comparative protein binding, P450 inhibition and induction, transporter profiling, comparative in vitro metabolism and in vivo metabolism (rat) studies were performed with Compound 1. CNS exposure was assessed by oral and intravenous administration. Rats and dogs are metabolically and pharmacologically relevant species for the nonclinical development program.

[0579] The toxicity of Compound 1 and its major metabolite, Compound 2, via metabolism, was evaluated in dose-ranging and 4-week oral GLP studies in rats and dogs. All GLP studies were performed using the tosylate salt.

[0580] Pharmacology and Activity Profile A comparative activity profiling study, shown in Figure 11, was performed and showed that compound 1 was superior or competitive to osimertinib. (See also Ni, J. et al. 2021 "Targeting EGFR in glioblastoma with a novel brain-penetrant small molecule EGFR-TKI" bioRxiv preprint doi: https: / / doi.org / 10.1101 / 2021.01.09.426030).

[0581] Compound 1 and its active metabolite, Compound 2, were evaluated in multiple in vitro and in vivo studies to assess on-target and off-target pharmacology.

[0582] Compound 1 and Compound 2 (major metabolites) were evaluated on a panel of 468 human kinases and disease-associated mutant variants. Compound 1 and Compound 2 bound to several non-mutated kinases at less than 1% of control. The data suggest that Compound 1 and its major metabolites do not exhibit significant non-selective kinase binding to wild-type proteins. Targeted non-mutated kinases included in Compound 1: MAST1, PAK4, PDGFRB, and ULK3 and Compound 2: ERBB2, JAK3 (JH1 domain catalytic), MKNK2, MTOR, OSR1, and TNK1. Although there is some variability between Compound 1 and Compound 2, it was clear that both compounds were highly effective at binding to a large panel of mutant kinases. Binding constants (Kd) of less than 100 nM were observed for ALK, EGFR, and FLT3 mutants. The binding constant to wild-type EGFR was 4.9 nM. Binding constants of less than 1 nM were evident for compound 1 with EGFR (E746A-740del, L858R-T790M, and T790M) double and single mutants, and compound 2 showed similar activity with EGFR (L858R-T790M, T790M) double and single mutants.

[0583] Safety pharmacology studies have demonstrated no cardiopulmonary or CNS risks.

[0584] There were no adverse CNS effects in the rat functional observational battery and no adverse effects on respiratory rate in dogs. Receptor binding studies suggest that compound 1 poses little off-target risk.

[0585] Metabolism and Pharmacokinetics A sensitive and reproducible LC-MS / MS assay was developed and validated to support metabolism-pharmacokinetic-toxicokinetic studies with compound 1 and its major active metabolite, compound 2.

[0586] Compound 1 is a moderately high clearance compound with a large volume of distribution in rats. maxis generally about 5 hours, for compound 2 is generally about 7 hours, and T 1 / 2 was generally about 5 hours for Compound 1 and about 9 hours for Compound 2. In rats, there were no sex differences, bioavailability averaged 50% and appeared to be independent of dose. Exposure was generally proportional to dose.

[0587] Total brain exposure of Compound 1 was found to be approximately 20-fold higher than plasma at estimated steady state with continuous intravenous infusion and oral dosing, while brain exposure of Compound 2 was essentially equivalent to plasma. No adverse effects were noted in these studies.

[0588] Compound 1 is primarily metabolized by CYP3A4 / 3A5, and weak inhibition of CYP3A4-T, but not CYP3A4-M, was observed with an IC50 of 4.89 μM (2381 ng / mL). There was no CYP induction based on enzyme activity, and based on mRNA, there was CYP3A4 induction at 1 μM, but not at lower concentrations. No metabolism, inhibition, or induction was observed for other CYPs. Potential DDI interactions exist with drugs that are inhibitors of CYP3A4-T or metabolized by CYP3A4 / 3A5, and human PK data would better define these DDI risks.

[0589] Compound 1 was highly protein bound to plasma proteins across species (95.6-98.7%), and binding was independent of concentration.

[0590] In in vitro studies, metabolic stability was highest in human hepatocytes, with 22 metabolites detected in human, monkey, dog, rat, and / or mouse hepatocytes. Compound 2 was the major demethylation-active metabolite in all species, with the exception of a few metabolites.

[0591] In in vivo studies in rats, dogs, and monkeys, 35 metabolites were identified. The major circulating compound in all species was the parent compound, which was also a major component in rat feces. The demethylated metabolite, compound 2, was the major active metabolite in plasma and rat feces in all species. Compound 1 was extensively metabolized during excretion, with 31 metabolites in rat urine and 32 metabolites in rat feces.

[0592] Brain and plasma exposure studies A comparative evaluation of brain and plasma exposure of Compound 1, Compound 2, and gefitinib was performed. [Table 16] [Table 17] [Table 18]

[0593] Incorporation by Reference All U.S. patents and U.S. and PCT published patent applications cited herein are hereby incorporated by reference.

[0594] Equivalent The foregoing written specification is believed to be sufficient to enable one skilled in the art to practice the invention. The invention is not limited in scope by the examples provided, as the examples are intended to be merely illustrative of one aspect of the invention, and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention other than those shown and described herein will become apparent to those skilled in the art from the above description. These modifications are within the scope of the appended claims. The advantages and objectives of the invention are not necessarily encompassed in each embodiment of the invention.

Claims

1. A pharmaceutical composition for treating glioblastoma multiforme, astrocytoma, congenital tumor of the brain, ependymoma, germ cell tumor, glioma, gliomatosis, gliosarcoma, medulloblastoma, meningioma, meningiosarcoma, oligodendroglioma, pinealoma, retinoblastoma, schwannoma, or spinal neurofibroma, wherein the composition comprises a compound of formula I: 【Chemical 101】 or a pharmaceutically acceptable salt thereof, and the composition is for administration to a human subject in an amount of at least 100 mg / day of the compound or its pharmaceutically acceptable salt, characterized in that wherein Z １ , Z ２ , and Z ３ are each independently N or CR ８ , and at least two of Z １ , Z ２ , and Z ３ are N R ８ is H, (C １ -C ４ ), alkyl, (C １ -C ４ ), haloalkyl, or halogen, and R １ is H, (C １ -C ４ )alkyl, (C １ -C ４ )haloalkyl, NH ２ , NH(C １ -C ４ )alkyl, N((C １ -C ４ )alkyl) ２ , or halogen, R ２ is H or (C １ -C ６ )alkyl, R ３ is (C １ -C ４ ) alkoxy, (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, or halogen, R ４ is NR ９ R １０ or is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more R １１ groups R ９ is H or (C １ -C ４ ) alkyl, R １０ is (C １ -C ４ ) alkyl, (C １ -C ４ ) alkyl-NH(C １ -C ４ ) alkyl, or (C １ C ４ ) alkyl-N((C １ -C ４ ) alkyl) ２ or Alternatively, R ９ and R １０ together with the nitrogen atom to which they are attached optionally contain one or two additional heteroatoms selected from N, O, and S and form a 5- to 7-membered heterocyclic ring optionally substituted with one or more R １１ groups, Each R １１ is independently (C １ -C ４ )alkyl, (C １ -C ４ )haloalkyl, (C １ -C ４ )alkoxy, or halogen, R ５ is NR １２ C(O)R １３ or C(O)NR １２ R １３ and R １２ is H or (C １ -C ６ ) alkyl, R １３ is (C １ -C ６ )alkyl or (C ２ -C ６ )alkenyl, and the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH ２ ; R ６ and R ７ together with the nitrogen atom to which they are attached form a substituent of the following formula, 【Chemical 102】 wherein X ３ is N, and X １ , X ２ , X ４ , X ５ , and X ６ are each independently CH or CR １５ and Each R １５ is independently (C １ -C ６ )alkyl, (C １ -C ６ )haloalkyl, (C １ -C ６ )alkoxy, OH, NH ２ , NH(C １ -C ６ )alkyl, N((C １ -C ６ )alkyl) ２ , or halogen, a pharmaceutical composition.

2. The composition according to claim 1, wherein the subject does not lose more than 10% of its body weight within one month after administration.

3. The composition according to claim 1, characterized in that the composition is for daily administration to the subject for at least one month, and the subject does not lose more than 10% of its body weight within one month of daily administration.

4. The composition according to claim 1, characterized in that the composition is for administration to the subject in an amount of the compound or its pharmaceutically acceptable salt of 100 mg / day to 1000 mg / day, 100 mg / day to 800 mg / day, 100 mg / day to 500 mg / day, or 200 mg / day to 500 mg / day.

5. The composition according to any one of claims 1 to 4, wherein the subject does not show skin lesions within one month after administration, or the subject does not show skin lesions within two months after administration.

6. The composition according to any one of claims 1 to 4, characterized in that the composition is for treating glioblastoma multiforme.

7. The composition according to claim 6, wherein the glioblastoma multiforme is characterized by an increase in the level of EGFR and / or mutant EGFR.

8. The composition according to claim 7, wherein the compound of formula I is characterized by a binding affinity for EGFR and / or mutant EGFR in the subject of 10 nM or less, such as 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.15 nM or less, 0.12 nM or less, 0.11 nM or less, or 0.10 nM or less.

9. The composition according to any one of claims 1 to 4, characterized in that the composition is for treating astrocytoma.

10. Z １ and Z ２ are each N, and Z ３ is CR ８ The composition according to any one of claims 1 to 4, wherein

11. R １ is H or NH ２ The composition according to any one of claims 1 to 4.

12. R ２ The composition according to any one of claims 1 to 4, wherein R is H.

13. R ３ is (C １ -C ４ ) alkoxy, the composition according to any one of claims 1 to 4.

14. R ４ is NR ９ R １０ The composition according to any one of claims 1 to 4, wherein

15. R ５ is NR １２ C(O)R １３ The composition according to any one of claims 1 to 4, wherein

16. R １５ is selected from (C １ -C ６ )alkyl and (C １ -C ６ )haloalkyl, the composition according to any one of claims 1 to 4.

17. R １５ is methyl and CF ３ The composition according to any one of claims 1 to 4, selected from.

18. R ８ The composition according to any one of claims 1 to 4, wherein R is H or halogen.

19. R ９ is (C １ -C ４ ) alkyl, the composition according to any one of claims 1 to 4.

20. R １０ is (C １ -C ４ )alkyl-NH(C １ -C ４ )alkyl or (C １ -C ４ )alkyl-N((C １ -C ４ )alkyl) ２ The composition according to any one of claims 1 to 4.

21. R ４ is NR ９ R １０ and R ９ and R １０ together with the nitrogen atom to which they are attached optionally contain one or two additional heteroatoms selected from N, O, and S and form a 5- to 7-membered heterocyclic ring optionally substituted with one or more R １１ The composition according to any one of claims 1 to 4.

22. R １１ is (C １ -C ４ ) alkyl, R １２ is H, R １３ is (C ２ -C ６ ) alkenyl, the composition according to any one of claims 1 to 4.

23. R １１ is (C １ -C ４ ) alkyl, R １２ is (C １ -C ６ ) alkyl, R １３ is (C ２ -C ６ ) alkenyl, the composition according to any one of claims 1 to 4.

24. The compound of formula I is a compound of formula Ia: 【Chemical 103】 or a pharmaceutically acceptable salt thereof, wherein X １ 、 X ２ 、 X ４ 、 X ５ 、 and X ６ are each independently CR １５ and R ９１ is (C １ -C ４ ) alkyl, and R １０１ is (C １ -C ４ )alkyl-NH(C １ -C ４ )alkyl or (C １ -C ４ )alkyl-N((C １ -C ４ )alkyl) ２ or Alternatively, R ９１ and R １０１ together with the nitrogen atom to which they are attached optionally contain one or two additional heteroatoms selected from N, O, and S and form a 5- to 7-membered heterocyclic ring optionally substituted with one or more R １１ The composition according to any one of claims 1 to 4.

25. The compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide, and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharmaceutically acceptable salt thereof, and the composition according to any one of claims 1 to 4.

26. The compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof, and the composition according to any one of claims 1 to 4.

27. The composition according to any one of claims 1 to 4, characterized in that the composition is for once-daily, twice-daily, or three-times-daily administration.

28. The composition according to any one of claims 1 to 4, characterized in that the composition is for systemic administration, oral administration, or intravenous administration.

29. A pharmaceutical composition for (i) treating a brain tumor or a related disease or condition, (ii) inhibiting the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a brain tumor, or (iii) treating a brain disease or condition mediated by epidermal growth factor receptor (EGFR), wherein the composition comprises a compound having the formula of Compound 1: 【Chemical Formula 104】 Or a pharmaceutically acceptable salt thereof.

30. A compound having the structural formula of Compound 2: 【Chemical 108】 Or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition for treating a disease or condition mediated by epidermal growth factor receptor (EGFR), wherein the pharmaceutical composition comprises a compound having the formula of Compound 2: 【Chemical 112】 Or a pharmaceutically acceptable salt thereof.

32. The composition according to claim 31, wherein the disease or condition is cancer.

33. A pharmaceutical composition for (i) treating a brain tumor or a related disease or condition, (ii) inhibiting the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a brain tumor, or (iii) treating a brain disease or condition mediated by epidermal growth factor receptor (EGFR), wherein the pharmaceutical composition comprises a compound having the formula of Compound 2: 【Chemical 113】 Or a pharmaceutically acceptable salt thereof.

34. The composition according to claim 29 or 33, wherein the brain tumor includes a primary tumor.

35. The composition according to claim 29 or 33, wherein the brain tumor includes a metastatic tumor.

36. The composition according to claim 29 or 33, wherein the brain tumor is glioblastoma.

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