Bicyclic heteroaryl compounds and uses thereof

Abstract

The present disclosure is directed to modulators of SOS1 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.

1 . A compound having the structure of Formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein: 
         R 1  is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6-membered aryl, and optionally substituted 5-6 membered heteroaryl; 
         R 2  is selected from the group consisting of H, C 1-6  alkyl, halogen, —NHR 2a , —OR 2a , cyclopropyl, and —CN; wherein C 1-6  alkyl is optionally substituted with halogen, —NHR 2a , —OR 2a , or 5-6 membered heterocyclyl, and further wherein R 2a  is selected from the group consisting of H, C 1-6  alkyl, 3-6 membered heterocyclyl, and C 1-6  haloalkyl; 
         R 3  is selected from the group consisting of H, C 1-3  alkyl, —OR 3a , cyclopropyl, and 3-6 membered heterocyclyl, wherein each of C 1-3  alkyl, cyclopropyl, and 3-6 membered heterocyclyl is optionally substituted with R 3a , and further wherein R 3a  is selected from the group consisting of C 1-3  alkyl, halogen, —OH, or —CN; 
         L 4  is selected from the group consisting of bond, —C(O)—, —C(O)O—, —C(O)NH(CH 2 ) o —, —NH—, —S—, —S(O) 2 —, 
       
       
         
           
           
               
               
           
         
       
       —(CH 2 ) p —, and —O—; wherein o is 0, 1, or 2; and wherein p is a number from 1 to 6; and
 R 4  is selected from the group consisting of H, C 1-6  alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C 1-6  alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with C 1-6  alkyl, —R 4a , —OR 4a , —O—C 1-6  alkyl-R 4a , ═O, halogen, —C(O)R 4a , —C(OO)R 4a , —C(O)NR 4b R 4c , —NR 4b C(O)R 4c , —CN, ═NR 4a , —NR 4b R 4c , —SO 2 R 4a , 3-6 membered cycloalkyl optionally substituted with R 4a , 3-7 membered heterocyclyl optionally substituted with R 4a , 6-10 membered aryl optionally substituted with R 4a , or 5-10 membered heteroaryl optionally substituted with R 4a ;
 wherein R 4a  is H, C 1-6  alkyl, C 1-6  haloalkyl, —C(O)R 4b , —C(O)NR 4b R 4c , ═O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with —OR 4b , —CN, ═N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, —(CH 2 )OCH 3 , or —(CH 2 )OH, wherein r is 1, 2, or 3; 
 wherein each R 4b  is independently H, C 1-6  alkyl; and 
 wherein each R 4c  is independently H or C 1-6  alkyl. 
 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 1  is optionally substituted 6-membered aryl. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 1  is optionally substituted 5-6 membered heteroaryl. 
     
     
         4 . The compound of  claim 1 , having the structure of Formula (II), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2 , R 3 , L 4 , and R 4  are as defined in  claim 1 ; 
         R 5 , R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, —OH, halogen, —NO 2 , —CN, —NR 11 R 12 , —SR 10 , —S(O) 2 NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —S(O)NR 11 R 12 , —S(O)R 10 , —NR 10 S(O)NR 11 R 12 , —NR 10 S(O)R 11 , —C(O)R 10 , —CO 2 R 10 , 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —OH, C 1-6  alkyl optionally substituted with —R 10 , halogen, —NO 2 , oxo, —CN, —R 10 , —OR 10 , —NR 11 R 12 , —SR 10 , —S(O) 2 NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —S(O)NR 11 R 12 , —S(O)R 10 , —NR 10 S(O)NR 11 R 12 , —NR 10 S(O)R 11 , 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R 10 , 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9  forms an optionally substituted 3-14 membered fused ring; 
         R 10 , R 11 , and R 12  are at each occurrence independently selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, —OR 13 , —SR 13 , halogen, —NR 13 R 14 , —NO 2 , and —CN; and 
         R 13  and R 14  are at each occurrence independently selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —SH, —NH 2 , —NO 2 , or —CN. 
       
     
     
         5 . The compound of  claim 1 , having the structure of Formula (III), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2 , R 3 , L 4 , and R 4  are as defined in  claim 1 ; 
         R 5 , R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, —OH, halogen, —NO 2 , —CN, —NR 11 R 12 , —SR 10 , —S(O) 2 NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —S(O)NR 11 R 12 , —S(O)R 10 , —NR 10 S(O)NR 11 R 12 , —NR 10 S(O)R 11 , —C(O)R 10 , —CO 2 R 10 , 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —OH, C 1-6  alkyl optionally substituted with —RO, halogen, —NO 2 , oxo, —CN, —R 10 , —OR 10 , —NR 11 R 12 , —SR 10 , —S(O) 2 NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —S(O)NR 11 R 12 , —S(O)R 10 , —NR 10 S(O)NR 11 R 12 , —NR 10 S(O)R 11 , 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R 10 , 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9  forms an optionally substituted 3-14 membered fused ring; 
         R 10 , R 11 , and R 12  are at each occurrence independently selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, —OR 13 , —SR 13 , halogen, —NR 13 R 14 , —NO 2 , and —CN; and 
         R 13  and R 14  are at each occurrence independently selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —SH, —NH 2 , —NO 2 , or —CN. 
       
     
     
         6 . The compound of  claim 1 , having the structure of Formula (IV-a), (IV-b), or (IV-c), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2 , R 3 , L 4 , and R 4  are as defined in  claim 1 ; 
         R 5 , R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, —OH, halogen, —NO 2 , —CN, —NR 11 R 12 , —SR 10 , —S(O) 2 NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —S(O)NR 11 R 12 , —S(O)R 10 , —NR 10 S(O)NR 11 R 12 , —NR 10 S(O)R 11 , —C(O)R 10 , —CO 2 R 10 , 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —OH, C 1-6  alkyl optionally substituted with —R 10 , halogen, —NO 2 , oxo, —CN, —R 10 , —OR 10 , —NR 11 R 12 , —SR 10 , —S(O) 2 NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —S(O)NR 11 R 12 , —S(O)R 10 , —NR 10 S(O)NR 11 R 12 , —NR 10 S(O)R 11 , 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R 10 , 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9  forms an optionally substituted 3-14 membered fused ring; 
         R 10 , R 11 , and R 12  are at each occurrence independently selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, —OR 13 , —SR 13 , halogen, —NR 13 R 14 , —NO 2 , and —CN; and 
         R 13  and R 14  are at each occurrence independently selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C 1-6  alkyl, C 2-6  alkenyl, 4-8 membered cycloalkenyl, C 2-6  alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —SH, —NH 2 , —NO 2 , or —CN. 
       
     
     
         7 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of R 5 , R 6 , R 7 , R 8 , and R 9  is C 1-6  alkyl substituted with halogen. 
     
     
         8 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of R 5 , R 6 , R 7 , R 8 , and R 9  is C 1-6  alkyl substituted with halogen and —OH. 
     
     
         9 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of R 5 , R 6 , R 7 , R 8 , and R 9  is halogen, and one to three of R 5 , R 6 , R 7 , R 8 , and R 9  is C 1-6  alkyl substituted with halogen. 
     
     
         10 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of R 5 , R 6 , R 7 , R 8 , and R 9  is —NH 2 . 
     
     
         11 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one of R 5 , R 6 , R 7 , R 8 , and R 9  is —NH 2 ; and one of R 5 , R 6 , R 7 , R 8 , and R 9  is C 1-6  alkyl substituted with halogen. 
     
     
         12 . The compound of  claim 4 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9  forms a 3-14 membered fused ring, wherein the fused ring is substituted with halogen. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is H. 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is C 1-6  alkyl. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is C 1-6  alkyl substituted with 5-6 membered heterocyclyl. 
     
     
         16 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is C 1-6  alkyl substituted with —NHR 2a , wherein R 2a  is C 1-6  alkyl or 3-6 membered heterocyclyl. 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is C 1-6  alkyl substituted with —OR 2a , wherein R 2a  is C 1-6  alkyl. 
     
     
         18 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is —NHR 2a , wherein R 2a  is C 1-6  alkyl. 
     
     
         19 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 2  is —OR 2a , wherein R 2a  is C 1-6  alkyl. 
     
     
         20 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 3  is C 1-3  alkyl. 
     
     
         21 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 3  is C 1-3  alkyl substituted with —OH. 
     
     
         22 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 3  is H. 
     
     
         23 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 3  is cyclopropyl. 
     
     
         24 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 3  is 3-6 membered heterocyclyl. 
     
     
         25 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L 4  is selected from the group consisting of bond, —C(O)—, —C(O)O—, —C(O)NH(CH 2 ) o —, —NH—, —S—, —S(O) 2 —, 
       
         
           
           
               
               
           
         
       
       —(CH 2 ) p —, and —O—; wherein o is 0, 1, or 2; and wherein p is a number from 1 to 6. 
     
     
         26 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L 4  is a bond. 
     
     
         27 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L 4  is —C(O)—. 
     
     
         28 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L 4  is —(CH 2 ) p —. 
     
     
         29 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 4  is selected from the group consisting of H, C 1-6  alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
 wherein each C 1-6  alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with C 1-6  alkyl —OR 4a , ═O, halogen, —C(O)R 4a , —C(OO)R 4a , —C(O)NR 4b R 4c , —CN, —NR 4b R 4c ,3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.   
     
     
         30 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 4  is 3-14 membered heterocyclyl. 
     
     
         31 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 4  is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl. 
     
     
         32 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 4  is 3-14 membered heterocyclyl substituted with C 1-6  alkyl. 
     
     
         33 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 4  is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl. 
     
     
         34 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R 4  is 3-14 membered heterocyclyl substituted with ═O. 
     
     
         35 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 1. 
     
     
         36 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 2. 
     
     
         37 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 3. 
     
     
         38 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 4. 
     
     
         39 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 5. 
     
     
         40 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Table A. 
     
     
         41 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         42 . A method of inhibiting SOS1 in a subject, comprising administering to the subject a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof. 
     
     
         43 . A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof. 
     
     
         44 . A method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof. 
     
     
         45 . A method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof. 
     
     
         46 . The method of  claim 44 , wherein the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas. 
     
     
         47 . The method of  claim 44 , wherein the disease is a RASopathy. 
     
     
         48 . The method of  claim 47 , wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, and Hereditary gingival fibromatosis. 
     
     
         49 . The method of  claim 45 , wherein the cancer comprises a Ras MUT  or an NF1 LOF  mutation.