Bifunctional molecules for degradation of egfr and methods of use

Abstract

The present application provides bifunctional compounds of Formula (I): which act as protein degradation inducing moieties for EGFR and/or a mutant thereof. The present application also describes methods for the targeted degradation of EGFR and/or a mutant thereof through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to EGFR and/or a mutant thereof which can be utilized in the treatment of disorders modulated by EGFR or a mutant thereof.

1 . A bifunctional compound of the Formula I: 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein: 
         the Linker is of Formula L0: 
       
       
         
           
           
               
               
           
         
         wherein the Linker is covalently bonded to the Degron via the 
       
       
         
           
           
               
               
           
         
          next to Q, and covalently bonded to 
       
       
         
           
           
               
               
           
         
          via the 
       
       
         
           
           
               
               
           
         
          next to Z; 
         the Degron is Formula D1c: 
       
       
         
           
           
               
               
           
         
         A is phenyl or pyridinyl; 
         X is CH, C(C 1 -C 3 ) alkyl, or N; 
         R 1  is H or (C 1 -C 3 ) alkyl; 
         R 2  is (C 6 -C 10 ) aryl, or heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R 4 ; 
         each R 4  is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , OH, CN, C(O)R 6 , C(O)OR 6 , C(O)NR 6 R 7 , NR 6 R 7 , (C 3 -C 7 ) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C 6 -C 10 ) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R 5 ; 
         each R 5  is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , OH, and CN; 
         each R 6  is independently H or (C 1 -C 3 ) alkyl; 
         each R 7  is independently H or (C 1 -C 3 ) alkyl; 
         R 3  is (C 1 -C 3 ) alkyl or 
       
       
         
           
           
               
               
           
         
         X 2  is N or CR 8 ; 
         R 8  is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , OH, or CN; 
         each R 9  is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , OH, and CN; 
         n is 0 or 1; 
         p is 0, 1, 2, or 3; 
         p1 is an integer selected from 0 to 12; 
         p2 is an integer selected from 0 to 12; 
         p3 is an integer selected from 0 to 6; 
         each W is independently absent, CH 2 , or O; 
         Z is absent, CH 2 , O, or C(O)(CH 2 ) 0-3 ; 
         Q is absent or heterocycle; 
         each R 14  is independently C 1 -C 3  alkyl; 
         each R 16  is independently halogen, OH, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; 
         q is 0, 1, or 2; and 
         v is 0, 1, 2, or 3. 
       
     
     
         2 . (canceled) 
     
     
         3 . The bifunctional compound of  claim 1 , wherein X is N. 
     
     
         4 . The bifunctional compound of  claim 1 , wherein A is phenyl. 
     
     
         5 . The bifunctional compound of  claim 1 , wherein n is 0. 
     
     
         6 . The bifunctional compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The bifunctional compound of  claim 1 , wherein X 2  is CH. 
     
     
         8 . The bifunctional compound of  claim 1 , wherein R 1  is H. 
     
     
         9 . (canceled) 
     
     
         10 . The bifunctional compound of  claim 1 , wherein R 2  is thiazole. 
     
     
         11 - 14 . (canceled) 
     
     
         15 . The bifunctional compound of  claim 1 , wherein the compound is of Formula: 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The bifunctional compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         17 . (canceled) 
     
     
         18 . The bifunctional compound of  claim 1 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         19 . (canceled) 
     
     
         20 . The bifunctional compound of  claim 1 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         21 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound of  claim 1 , or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         32 - 36 . (canceled) 
     
     
         37 . A method of treating cancer or a proliferation disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         38 . (canceled) 
     
     
         39 . The method of  claim 37 , wherein the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas 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, leukemias, lymphomas, myelomas, or solid tumors. 
     
     
         40 . The method of  claim 37 , wherein the disease is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, systemic lupus erythematosus (SLE), skin-related conditions, psoriasis, eczema, burns, dermatitis, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, as well as complications associated with hypertension and/or heart failure such as vascular organ damage, restenosis, cardiomyopathy, stroke including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia including stroke and brain ischemia, and ischemia resulting from cardiac/coronary bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, herpes virus, myalgias due to infection, influenza, autoimmune disease, graft vs. host reaction and allograft rejections, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, colorectal cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, bladder cancer, cervical cancer, squamous cell and/or basal cell cancers, renal cell carcinoma, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis, metastasis, central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy, or B-Cell Lymphoma. 
     
     
         41 - 42 . (canceled) 
     
     
         43 . The bifunctional compound of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.