Imidazopyrimidine Derivatives

Abstract

The present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula I, processes for preparing compounds of Formula I, therapeutic methods for treating cancers.

1 - 75 . (canceled) 
     
     
         76 . A method for treating a disease or condition associated with SHP2 modulation comprising administering to a subject an effective amount of a compound having formula (VII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 A is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl, and 4-12 membered heterocyclyl; each A is optionally substituted with one to six R A  independently selected from halo, cyano, hydroxyl, azido, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-4 alkylene-OH, oxo, ═NR a1 , —SR a1 , —OR a1 , —NR a1 R a2 , —COR a2 , —CONR a1 R a2 , —COOR a2 , —N(R a2 )—C(O)R a2 , —N(R a2 )—C(O)OR a2 , —N(R a2 )—C(O)—NR a2 R a2 , —N(R a2 )—SO 2 R a2 , —SO 2 R a2 , —SO 2 OR a2 , —SO 2 NR a1 R a2 , —O—SO 2 —NR a1 R a2 , —O(CO)—N—R a1 R a2 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-4 alkylene-C 3-8 cycloalkyl, —C 1-4 alkylene-(3-8 membered heterocyclyl), —C 1-4 alkylene-C 6-10 aryl, and —C 1-4 alkylene-(5-10 membered heteroaryl); 
 wherein the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-4 alkylene-C 3-8 cycloalkyl, —C 1-4 alkylene-(3-8 membered heterocyclyl), —C 1-4 alkylene-C 6-10 aryl, and —C 1-4 alkylene-(5-10 membered heteroaryl) of R A  are independently optionally substituted with one to three groups selected from halo, cyano, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, and C 1-4 alkylene-OH; 
 wherein the 5-10 membered heteroaryl of A, and R A  contains one to five heteroatoms independently selected from S, N, and O, and optionally comprises one to three C(O) or one S(O) 2 ; 
 L is selected from a bond, —S—, and —O—; 
 Z 1  and Z 2  are independently selected from N and CR 3 ; wherein R 3  is selected from H, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, C 1-4 alkylene-OH, —NR c1 R c2 , —C(O)OR c1 , C 6-10 aryl, and 5-10 membered heteroaryl; wherein each C 6-10 aryl, and 5-10 membered heteroaryl of R 3  is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, —N(R c1 )—SO 2 R c1 , and —SO 2 R c1 ; 
 R 1  is selected from H, halo, —NR c1 R c2 , —C 1-4 alkyl, and C 1-4  haloalkyl; 
 each R 2  is independently selected from halo, cyano, nitro, —O—C 1-6 alkyl, oxo, —NR c1 R c2 , —(SO v )—R c1 , —NR c1 (SO v )R c1 , —C(O)OR c1 , —C(O)—NR c1 R c2 , —S(O 2 )—NR c1 R c2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alklene-OH, —C 1-4 alkylene-NR c1 R 2 , C 3-8 cycloalkyl, 3-6 membered heterocyclyl, —O—C 3-8 cycloalkyl, —O-(3-6 membered heterocyclyl), C 6-10 aryl, and 5-10 membered heteroaryl; 
 each R 22  is independently selected from halo, —NR c1 R c2 , hydroxyl, azido, cyano, oxo, —C(O)OR c1 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, C 1-4 alkylene-NR c1 R c2 , —C 1-4 alkylene-O—C 1-4 alkyl, —C 1-4 alkylene-OH, —COR c1 , —CO—NR c1 R a2 , —C(O)OR c1 , —N(R c1 )—C(O)R c1 , —N(R c1 )—C(O)OR c1 , —N(R c1 )—C(O)—NR c1 R c2 , —N(R c1 )—(SO v )R c1 , —SO 2 R c1 , —SO 2 OR c1 , —SO 2 R c1 R c2  C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; 
 each X 3 , X 4 , X 5 , and X 6  is independently selected from CR xx , and N; wherein R xx  is selected from H, halo, cyano, hydroxyl, azido, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-4 alkylene-OH, —SR a1 , —OR a1 , —NR a1 R a2 , —COR a2 , —CONR a1 R a2 , —COOR a2 , —N(R a2 )—C(O)R a2 , —N(R a2 )—C(O)OR a2 , —N(R a2 )—C(O)—NR a2 R a2 , —N(R a2 )—SO 2 Ra, —SO 2 R a2 , —SO 2 OR a2 , —SO 2 NR a1 R a2 , —O—SO 2 —NR a1 R a2 , —O(CO)—NR a1 R a2 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, —C 1-4 alkylene-C 3-8 cycloalkyl, —C 1-4 alkylene-(3-8 membered heterocyclyl), —C 1-4 alkylene-C 6-10 aryl, and —C 1-4 alkylene-(5-10 membered heteroaryl); 
 R a1  is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylene-OH, C 1-4 alkylene-COOR a2 , —C 1-4 alkylene-C 1-4 alkoxyl, and —C(O)—NH 2 ; 
 R a2  is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylene-OH, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylene-OH, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl of R a2  are independently optionally substituted with one to three groups selected from halo, cyano, hydroxyl, —COOR a3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylene-OH, and C 1-4 alkoxyl; wherein R a3  is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; 
 R c1  and R c2  are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; wherein each of the C 1-6 alkyl and C 1-6 haloalkyl of R c1  and R c2  is optionally substituted with one or two groups selected from C 1-4 alkoxyl, and C 1-4 alklene-OH; 
 v is selected from 0, 1, and 2; 
 m is selected from 0, 1, 2, 3, and 4; and 
 q is selected from 0, 1, 2, 3, and 4. 
 
     
     
         77 . The method of  claim 76 , wherein the disease or condition is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias (JMML), neuroblastoma, melanoma, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, squamous-cell carcinoma of the head and neck, anaplastic large-cell lymphoma and glioblastoma. 
     
     
         78 . The method of  claim 76 , wherein L is —S—. 
     
     
         79 . The method of  claim 76 , wherein R A  is independently selected from F, Cl, —CH 3 , —CF 3 , and —NH 2 . 
     
     
         80 . The method of  claim 76 , wherein R 1  is selected from H, halo, and C 1-4 alkyl. 
     
     
         81 . The method of  claim 76 , wherein R 1  is selected from Cl and —CH 3 . 
     
     
         82 . The method of  claim 76 , wherein Z 1  and Z 2  are CH. 
     
     
         83 . The method of  claim 76 , wherein q is 1 or 2. 
     
     
         84 . The method of  claim 76 , wherein X 3 , X 4 , X 5 , and X 6  are each CH. 
     
     
         85 . The method of  claim 76 , wherein each R 22  is selected from CH 3 , CH 2 NH 2 , NH 2 , and OH. 
     
     
         86 . The method of  claim 76 , wherein the compound having formula (VII) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         87 . The method of  claim 76 , wherein the compound having formula (VII) has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         88 . The method of  claim 76 , further comprising administration of one or more additional therapeutic agents. 
     
     
         89 . The method of  claim 88 , wherein the method comprises administration of one, two, three, or four additional therapeutic agents. 
     
     
         90 . The method of  claim 88 , wherein the one or more additional therapeutic agents comprise agents that are therapeutic for a hepatitis B virus (HBV) infection, human immunodeficiency virus (HIV) infection, cancer, or a hyper-proliferative disease. 
     
     
         91 . The method of  claim 88  wherein the one or more additional therapeutic agents comprise PD1 inhibitors and/or PDL1 inhibitors. 
     
     
         92 . The method of  claim 88 , wherein the one or more additional therapeutic agents are selected from the group consisting of adefovir (HepseraR), tenofovir disoproxil fumarate+emtricitabine (TruvadaR), tenofovir disoproxil fumarate (VireadR), entecavir (BaracludeR), lamivudine (Epivir-HBVR), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (TyzekaR), ClevudineR, emtricitabine (EmtrivaR), peginterferon alfa-2b (PEG-IntronR), MultiferonR, interferon alpha 1b (HapgenR), interferon alpha-2b (Intron AR), pegylated interferon alpha-2a (PegasysR), interferon alfa-n1 (HumoferonR), ribavirin, interferon beta-1a (AvonexR), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 
     
     
         93 . The method of  claim 88 , wherein the one or more additional therapeutic agents are selected from the group consisting of 4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 
     
     
         94 . The method of  claim 88 , wherein the one or more additional therapeutic agents are selected from the group consisting of nivolumab, lambrolizumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, and avelumab, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. 
     
     
         95 . The method of  claim 88 , wherein the one or more additional therapeutic agents are selected from the group consisting of rituxan, doxorubicin, gemcitabine, 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, PI3K II, 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. 
     
     
         96 . The method of  claim 88 , wherein the one or more additional therapeutic agents are 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.