The disclosure relates to substituted fused heteroaromatic tricyclic compounds and the use thereof. Specifically, the disclosure provides compounds of the following Formula I: ##STR00001##
or a pharmaceutically acceptable salt or prodrug thereof, wherein A.sub.1-A.sub.3, B.sub.1-B.sub.3, D.sub.1-D.sub.4 and R.sub.1-R.sub.2 are defined herein. Compounds having Formula I are ATM kinase inhibitors. Therefore, compounds of the disclosure may be used to treat clinical conditions caused by DDR functional defects, such as cancer.

The disclosure relates to substituted fused heteroaromatic tricyclic compounds and the use thereof. Specifically, the disclosure provides compounds of the following Formula I: ##STR00001##
or a pharmaceutically acceptable salt or prodrug thereof, wherein A.sub.1-A.sub.3, B.sub.1-B.sub.3, D.sub.1-D.sub.4 and R.sub.1-R.sub.2 are defined herein. Compounds having Formula I are ATM kinase inhibitors. Therefore, compounds of the disclosure may be used to treat clinical conditions caused by DDR functional defects, such as cancer.

It is intended to provide a novel method for treating a cancer using an FGFR inhibitor that exhibits a remarkably excellent antitumor effect and has fewer side effects. The present invention provides a combination preparation for the treatment of a malignant tumor comprising a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, and one or more additional compound(s) having an antitumor effect or pharmaceutically acceptable salt(s) thereof, and a pharmaceutical composition comprising both the active ingredients. The present invention also provides an antitumor effect enhancer, an antitumor agent, a kit for malignant tumor treatment, etc. comprising a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof.

Methods of treating cancer are provided. In some instances, the method comprises applying alternating electric fields to the abdomen of the subject at a frequency of 100 to 500 kHz, administering a checkpoint inhibitor to the subject, and administering systemic cancer therapy to the subject. In some instances, the cancer is pancreatic ductal adenocarcinoma.

Methods of treating cancer are provided. In some instances, the method comprises applying alternating electric fields to the abdomen of the subject at a frequency of 100 to 500 kHz, administering a checkpoint inhibitor to the subject, and administering systemic cancer therapy to the subject. In some instances, the cancer is pancreatic ductal adenocarcinoma.

The present application discloses an acid labile lipophilic molecular conjugate of cancer chemotherapeutic agents and methods for reducing or substantially eliminating the side effects of chemotherapy associated with the administration of a cancer chemotherapeutic agent to a patient in need thereof.

The present application discloses an acid labile lipophilic molecular conjugate of cancer chemotherapeutic agents and methods for reducing or substantially eliminating the side effects of chemotherapy associated with the administration of a cancer chemotherapeutic agent to a patient in need thereof.

The present invention relates to therapeutic immunoconjugates comprising SN-38 attached to an antibody or antigen-binding antibody fragment. The antibody may bind to EGP-1 (TROP-2), CEACAM5, CEACAM6, CD74, CD19, CD20, CD22, CSAp, HLA-DR, AFP or MUC5ac and the immunoconjugate may be administered at a dosage of between 4 mg/kg and 24 mg/kg, preferably 4, 6, 8, 9, 10, 12, 16 or 18 mg/kg. When administered at specified dosages and schedules, the immunoconjugate can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy.

The present invention relates to therapeutic immunoconjugates comprising SN-38 attached to an antibody or antigen-binding antibody fragment. The antibody may bind to EGP-1 (TROP-2), CEACAM5, CEACAM6, CD74, CD19, CD20, CD22, CSAp, HLA-DR, AFP or MUC5ac and the immunoconjugate may be administered at a dosage of between 4 mg/kg and 24 mg/kg, preferably 4, 6, 8, 9, 10, 12, 16 or 18 mg/kg. When administered at specified dosages and schedules, the immunoconjugate can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy.

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.