Bifunctional degraders of hematopoietic progenitor kinase and therapeutic uses thereof

Abstract

The present disclosure provides bifunctional compounds as HPK1 degraders via ubiquitin proteosome pathway, and method for treating diseases modulated by HPK1.

1 .- 2 . (canceled) 
     
     
         3 . A compound having a structure of Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein, 
         R 3  and R 13  together form ═O; 
         each R 9a , R 9b , R 9c , R 9d , and R 9e  is independently H, halogen, C 1-6  alkyl, or —C(O)N(R 19 ) 2 , wherein R 19  is C 1-6  alkyl; 
         R 4 , R 5  and R 10  are each H; and 
         R 7  is C 1-6  alkyl. 
       
     
     
         4 .- 5 . (canceled) 
     
     
         6 . The compound of  claim 3 , wherein X is piperdinyl. 
     
     
         7 .- 8 . (canceled) 
     
     
         9 . The compound of  claim 3 , wherein the compound has a structure of Formula (Ic): 
       
         
           
           
               
               
           
         
         L is 
       
       
         
           
           
               
               
           
         
       
       wherein,
 t is 0, 1, 2, 3, 4, 5, 6, or 7; 
 q is 0, 1, 2, 3, 4, 5, 6, or 7; 
 L 1  is a direct bond, —C(O)NH—, or —C(O)—; and 
 L 2  is —C(O)NH—, —O—, or —NH—. 
 
     
     
         10 . The compound of  claim 9 , wherein L has one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 3 , wherein the compound has a structure of Formula (Ic): 
       
         
           
           
               
               
           
         
         L is 
       
       
         
           
           
               
               
           
         
       
       wherein,
 w is 1, 2, or 3; 
 v is 1 or 2; 
 p is 1, 2, 3, 4, or 5; 
 Y 1  is a direct bond, —(CH 2 ) p —, or —O—; 
 Y 2  is a direct bond, —(CH 2 ) p —, —C(O)—, or —C(O)—CH 2 —, 
 X 3  and X 4  are independently N or C(R), wherein R is H or C 1-3 alkyl; 
 L 4  is a direct bond, —NH—, —NHC(O)—, or 
 L 4  is 
 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein L has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 3 , wherein L is any one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 3 , wherein the LHM has one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         16 .- 17 . (canceled) 
     
     
         18 . The compound of  claim 3 , wherein the LHM has one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         19 .- 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising the compound of  claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
         35 .- 36 . (canceled) 
     
     
         37 . A method of treating a disease or disorder associated with increased hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 3 . 
     
     
         38 . A method of increasing T-cell activation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 3 . 
     
     
         39 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 3 . 
     
     
         40 . The method of  claim 39 , wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, transitional cell carcinoma, and urothelial cancer 
     
     
         41 . A method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 3 . 
     
     
         42 . The method of  claim 39 , further comprising administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 42 , wherein the one or more additional therapeutic agents is selected from the group consisting of: Inducible T-cell costimulator (ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47 (CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors, STING agonists, C—X—C chemokine receptor type 4 (CXCR-4) inhibitors, B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusion proteins, MKNK1/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 
     
     
         44 . The method of  claim 39 , further comprising administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, wherein the one or more additional therapeutic agents is selected from the group consisting of: rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide, XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile, and ipilimumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 
     
     
         45 . The method of  claim 39 , further comprising administering a therapeutically effective amount of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, wherein the one or more additional therapeutic agents is selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 
     
     
         46 .- 58 . (canceled)