Patent Application
20230265116
Disclosed herein are novel bifunctional compounds formed by conjugating EGFR inhibitor moieties with E3 ligase ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
Proteolysis targeting chimera (PROTAC) consists of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to the protein of interest (POI) a target meant for degradation (Sakamoto K M et al., Proc. Natl. Acad. Sci. 2001, 98: 8554-9; Sakamoto K. M. et al., Methods Enzymol. 2005; 399:833-847). Rather than inhibiting the target protein's enzymatic activity, recruitment of the E3 ligase to the specific unwanted proteins results in ubiquitination and subsequent degradation of the target protein by the proteasome. The whole process of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice G. L. et al., Cell Rep. 2015, 12, 545-553; Swatek K. N. et al., Cell Res. 2016, 26, 399-422). Proteasomes are protein complexes which degrade unneeded, misfolded or abnormal proteins into small peptides to maintain health and productivity of the cells. Ubiquitin ligases, also called an E3 ubiquitin ligase, directly catalyze the transfer of ubiquitin from the E2 to the target protein for degradation. Although the human genome encodes over 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely applied by small molecule PROTAC technology: cereblon (CRBN), Von Hippel-Lindau (VHL), mouse double minute 2 homologue (MDM2) and cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant Human Ring Finger Protein 114 (RNF114) (Spradlin, J. N. et al. Nat. Chem. Biol. 2019, 15, 747-755) and DDB1 And CUL4 Associated Factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746). For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cullin-4A (CUL4A) to ubiquitinate a number of other proteins followed by the degradation via proteasomes. (Yi-An Chen, et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, function as monovalent promoters of PPIs by binding to the cereblon (CRBN) subunit of the CRL4ACRBN E3 ligase complex and recruiting neosubstrate proteins. (Matyskiela, M. E. et al., Nat Chem Biol 2018, 14, 981-987.) As a consequence, the ability of thalidomide, and its derivatives, to recruit CRBN has been widely applied in proteolysis-targeting chimeras (PROTACs) related studies (Christopher T. et al. ACS Chem. Biol. 2019, 14, 342-347; Honorine L. et al, ACS Cent. Sci. 2016, 2, 927-934). PROTACs have great potential to eliminate protein targets that are “undruggable” by traditional inhibitors or are non-enzymatic proteins. (Chu T T. et al., Cell Chem Biol. 2016; 23:453-461. Qin C. et al., J Med Chem 2018; 61: 6685-6704. Winter G E. et al., Science 2015; 348:1376-1381.) In the recent years, PROTACs as useful modulators promote the selective degradation of a wide range of target proteins have been reported in antitumor studies. (Lu J. et al., Chem Biol. 2015; 22(6):755-763; Ottis P. et al., Chem Biol. 2017; 12(4):892-898; Crews C. M. et al., J Med Chem. 2018; 61(2):403-404; Neklesa T. K. et al., Pharmacol Ther 2017, 174:138-144; Cermakova K. et al., Molecules, 2018.23(8); An S. et al., EBioMedicine, 2018; Lebraud H. et al., Essays Biochem. 2017; 61(5): 517-527; Sun Y. H. et al., Cell Res. 2018; 28:779-81; Toure M. et al., Angew Chem Int Ed Engl. 2016; 55(6):1966-1973; Yonghui Sun et al., Leukemia, volume 33, pages 2105-2110(2019); Shaodong Liu et al., Medicinal Chemistry Research, volume 29, pages 802-808(2020); and has been disclosed or discussed in patent publications, e.g., US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016197032, WO2016197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, and WO2018071606.
Epidermal growth factor receptor (EGFR) that belongs to the ErbB family is a transmembrane receptor tyrosine kinase (RTK), which plays a fundamentally key role in cell proliferation, differentiation, and motility (Y. Yarden, et al., Nat. Rev. Mol. Cell Biol. 2001; 2:127-137). Homo- or heterodimerization of EGFR and other ErbB family members activates cytoplasmic tyrosine kinase domains to initiate intracellular signaling. Overexpression or activating mutations of EGFR are associated the development of many types of cancers, such as pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer (Yewale C., et al. Biomaterials. 2013, 34 (34): 8690-8707). The activating mutations in the EGFR tyrosine kinase domain (L858R mutation and exon-19 deletion) have been identified as oncogenic drivers for NSCLC (Konduri, K., et al. Cancer Discovery 2016, 6 (6), 601-611). The first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib have approved for NSCLC patients with EGFR activation mutations (M. Maemondo, N. Engl. J. Med. 362 (2010) 2380-2388). Although most patients with EGFR mutant NSCLC respond to these therapies, patients typically develop resistance after an average of one year on treatment. There are several mechanisms of acquired resistance to gefitinib and erlotinib, including a secondary threonine 790 to methionine 790 mutation (T790M), is also called “gatekeeper” T790M mutation (Xu Y., et al. Cancer Biol Ther. 2010, 9 (8): 572-582). Therefore, the second-generation EGFR-TKIs afatinib and the third-generation EGFR-TKIs osimertinib (AZD9291) were developed as irreversible EGFR inhibitors that bind to Cys797 for the treatment of patients with T790M mutation. In particular, osimertinib that largely spares WT EGFR has achieved greater clinical response rate in NSCLC patients with EGFR T790M. However, several recent studies have reported a tertiary Cys797 to Ser797 (C797S) point mutation with osimertinib clinical therapy (Thress K S, et al. Nat. Med. 2015, 21 (6): 560-562). There is a need for drugs which can overcome EGFR (C797S) resistance obstacle in non-small cell lung cancer (NSCLC). EGFR-Targeting PROTACs serve as a potential strategy to overcome drug resistance mediated by these mutants, which has been disclosed or discussed in patent publications, e.g. WO2018119441, WO2019149922, WO2019183523, WO2019121562 and US20190106417.
Although, a number of EGFR-targeting PROTACs which were designed to degrade EGFR mutant proteins have been published (Zhang X., et al. Eur. J. Med. Chem. 2020, 192, 112199; Zhang H, et al. Eur. 35 J. Med. Chem. 2020, 189, 112061; Lu X, Med. Res. Rev. 2018, 38(5):1550-1581. He K., et al. Bioorg. Med. Chem. Lett. 2020, 15, 127167). Most of the published molecules are based on first, second, and third generation of EGFR inhibitors. However, there were no data which showed those EGFR-Targeting PROTACs degrading all the main EGFR mutations, Such as Del19, L858R, Del19/T790M, L858R/T790M, Del19/T790M/C797S, L858R/T790M/C797S.
The present application provides novel bifunctional compounds and compositions for the treatment of serious diseases.
One objective of the present invention is to provide compounds and derivatives formed by conjugating EGFR inhibitor moieties with E3 ligase ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
Aspect 1. A compound of Formula (I):
or a N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof
wherein:
R1 is selected from —P(O)R1aR1b, —SO2R1a, —SO2—NR1aR1b or —N(R1a)—SO2R1b;
R1a and R1b are each independently selected from hydrogen, halogen, —C1-C8alkyl or C3-C8cycloalkyl, said —C1-C8alkyl or C3-C8cycloalkyl is optionally substituted with at least one halogen;
R2 and R3 are each independently selected from hydrogen, halogen, —C1-C8alkyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —OR2a, —SO2R2a, —SO2NR2aR2b, —C(O)R2a, —CO2R2a, —C(O)NR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b, or —NR2aSO2R2b; each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R2d, or
R2 and R3 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R2e;
R2e, at each occurrence, is independently hydrogen, halogen, —C1-C8alkyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O), —OR2a, thioxo (═S), —SR2a, —CN, —SO2R2a, —SO2NR2aR2b, —C(O)R2a, —CO2R2a, —C(O)NR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b or —NR2aSO2R2b; each of —C1-C8alkyl, —C1-C8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R2d;
R2a and R2b are each independently selected from hydrogen, —C1-C8alkyl, —C1-C8haloalkyl, —C2-C8alkenyl, —C2-C8alkynyl, C1-C8alkoxy-C1-C8alkyl-, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
R2d, at each occurrence, is independently halogen, —OH, —CN, oxo (═O), —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl;
R4 is selected from hydrogen, halogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R4a, —SO2NR4aR4b, —C(O)R4a, —CO2R4a, —C(O)NR4aR4b, —NR4aR4b, —NR4aCOR4b, —NR4aCO2R4b or —NR4aSO2R4b; each of —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with halogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O), —CN, —OR4c, —SO2R4c, —SO2NR4cR4d, —C(O)R4c, —CO2R4c, —C(O)NR4cR4d, —NR4cR4d, —NR4cCOR4d, —NR4cCO2R4d or —NR4cSO2R4d;
R4a, R4b, R4c and R4d are each independently hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl;
R9, R10, R11 and R12 are each independently selected from hydrogen, halogen, —C1-C8alkyl, —NR9aR9b, —OR9a, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O) or —CN; each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9c; or
two R12 together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R9c;
R9a and R9b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5 to 12-membered heteroaryl is optionally substituted with at least one substituent R9d; or
R9c and R9d are each independently halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl;
Z1, Z2, Z3 and Z4 are each independently selected from —CRZ, or N;
RZ, at each occurrence, is independently selected from hydrogen, halogen, —C1-C8alkyl, —NRZaRZb, —ORZa, —SRZa, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, or CN; each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one RZc;
RZa and RZb are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5 to 12-membered heteroaryl is optionally substituted with at least one substituent RZd;
RZc and RZd are each independently selected from halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl;
L1 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL1a—, —C3-C8cycloalkylene-, *L1—O—C1-C8alkylene-**L1, *L1—C1-C8alkylene-O—**L1, *L1—SO2—C1-C8alkylene-**L1, *L1—C1-C8alkylene-SO2—**L1, *L1—C(O)—C1-C8alkylene-**L1, *L1—C1-C8alkylene-C(O)—**L1, *L1—NRL1a—C1-C8alkylene-**L1, *L1—C1-C8alkylene- NRL1a—**L1, *L1—NRL1aC(O)—**L1, *L1—C(O)NRL1a—**L1, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-, —[O(CRL1aRL1b)m4]m5-,
wherein each of said —C3-C8cycloalkylene-, *L1-O—C1-C8alkylene-**L1, *L1—C1-C8alkylene-O—**L1, *L1-SO2—C1-C8alkylene-**L1, *L1—C1-C8alkylene-SO2—**L1, *L1—C(O)—C1-C8alkylene-**L1, *L1—C1-C8alkylene-C(O)—**L1, *L1—NRL1a—C1-C8alkylene-**L1, *L1—C1-C8alkylene-NRL1a—**L1, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-,
is optionally substituted with at least one RL1c;
wherein *L1 refers to the position attached to the
moiety, and **L1 refers to the position attached to the
moiety;
RL1a and RL1b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL1d;
each of said RL1c and RL1d are independently oxo (═O), halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; or
two RL1c together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, —C1-C8alkyl;
L2 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL2a—, —C3-C8cycloalkylene-, *L2-O—C1-C8alkylene-**L2, *L2—C1-C8alkylene-O—**L2, *L2—SO2—C1-C8alkylene-**L2, *L2—C1-C8alkylene-SO2—**L2, *L C(O)—C1-C8alkylene-**L2, *L2—C1-C8alkylene-C(O)—**L2, *L2-NRL2a—C1-C8alkylene-**L2, *L2—C1-C8alkylene-NRL2a—**L2, *L2-NRL2aC(O)—**L2, *L2—C(O)NRL2a—**L2 C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-, —[O(CRL2aRL2b)m4]m5—,
wherein each of said —C3-C8cycloalkylene-, *L2-O—C1-C8alkylene-**L2, *L2—C1-C8alkylene-O—**L2, *L2—SO2C1-C8alkylene-**L2, *L2—C1-C8alkylene-SO2r**L2, *L2—C(O)—C1-C8alkylene-**L2, *L2—C1-C8alkylene- C(O)—**L2, *L2—NRL2aC1-C8alkylene-**L2, *L2—C1-C8alkylene-NRL2a—**L2, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-,
is optionally substituted with at least one substituent RL2c;
wherein *L2 refers to the position attached to
moiety, and **L2 refers to the position attached to the
RL2a and RL2b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL2d;
each of said RL2c and RL2d is independently selected from oxo (═O), halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; or
two RL2c together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, —C1-C8alkyl;
L3 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL3a—, —C3-C8cycloalkylene-, *L3—O—C1-C8alkylene-**L3, *L3—C1-C8alkylene-O—**L3, *L3—SO2—C1-C8alkylene**L3, *L3—C1-C8alkylene-SO2—**L3, *L3 —C(O)—C1-C8alkylene-**L3, *L3—C1-C8alkylene-C(O)—**L3, *L3—NRL3a—C1-C8alkylene_**L3, *L3—C1-C8alkylene- NRL3a—**L3, *L3—NRL3aC(O)—**L3, *L3—C(O)NRL3a—**L3, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-, —[O(CRL3aRL3b)m4]m5—
wherein each of said —C3-C8cycloalkylene-, *L3—O—C1-C8alkylene-**L3, *L3—C1-C8alkylene-O—**L3, *L3—SO2—C1-C8alkylene-**L3, *L3—C1-C8alkylene-SO2**L3, *L3—C(O)—C1-C8alkylene**L3,*L3—C1-C8alkylene- C(O)—**L3, *L3—NRL3a—C1-C8alkylene-**L3, *L3—C1-C8alkylene-NRL3a_**L3, —C1-C8alkylene-, —C2-C8alkenylene-, —C2-C8alkynylene-,
is optionally substituted with at least one substituent RL3c;
wherein *L3 refers to the position attached to
moiety, and **L3 refers to the position attached to the
RL3a and RL3b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL3d;
each of said RL3c and RL3d is independently selected from oxo (═O), halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; or
two RL3c together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, or —C1-C8alkyl;
is selected from
Ring A is selected from 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, aryl, or heteroaryl;
R13, R14, R15, R16 and R17are each independently selected from hydrogen, halogen, CN, —C1-C8alkyl, —C1-C8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; said each —C1-C8alkyl, —C1-C8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, —C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl-, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
X1, X2, X3, X4 and X8 are each independently selected from —CRa, or N;
X5, X6, X7 and X9 are each independently selected from —NRa—, —O—, —S— and —CRaRb—.
X12 and X13 are each independently selected from —C(O)—. —NRa— and —O—;
L4, L5 and L6 are each independently selected from a single bond, —O—, —NRa—, —(CRaRb)n8-, —O(CRaRb)n8-, —NRa(CRaRb)n8- or —C(O)—;
Q1, Q2, Q3, Q4, Y1, Y2, Y3 and Y4 are each independently selected from CRa or N;
Y5 is selected from NRa, O or S;
Q5 is each independently selected from —O—, —NRa—, —CRaRb—, —S— or —C(O)—;
P1 is a single bond, —O—, —NRa—, —CRaRb—, —S—, —SO— or —SO2—;
at each occurrence, Ra and Rb are each independently selected from hydrogen, hydroxy, halogen, CN, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, halogen, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; or
Ra and Rb together with the carbon atoms to which they are attached, form a 3- to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl;
m1 is 0, 1 or 2;
m2 and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;
m4 and m5 are each independently 0, 1, 2 or 3;
n, n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3; and
n6, n7, n8 and n9 are each independently 0, 1, 2, 3 or 4.
Aspect 2. The compound of Aspect 1, wherein the compound is selected from formula (II), (III), (IV), (V), (VI) or (VII),
R1, R2, R3, R4, R9, R10, R11, R12, R13, R14, Ra, Z1, Z2, Z3, Z4, L1, L2, L3, L4, L5, L6, X1, X2, X8, X9, Y1, Y2, Y3, Y4, Y5, n, n6, n7, m1, m2 and m3 are each independently defined as Aspect 1.
Aspect 3. The compound of Aspects 1-2, wherein R1 is selected from —P(O)R1aR1b or —N(R1a)—SO2R1b, wherein R1a and R1b are each independently selected from hydrogen, halogen, —C1-C8alkyl (preferably —CH3, —C2H5, —C3H7, —C4H9 or —C5H11; more preferably —CH3, —CH2CH3, —CH2CH2CH3,-iso-C3H7, —CH2CH2CH2CH3,-iso-C4H9, -sec-C4H9 or -tert-C4H9) or C3-C8cycloalkyl (preferably cyclopropyl, cyclobutyl or cyclopentyl).
Aspect 4. The compound of any one of Aspects 1-3, wherein R1 is selected from —P(O)(CH3)2, —NH—SO2CH3 or —N(CH3)—SO2CH3.
Aspect 5. The compound of any one of Aspects 1-4, wherein R1 is —P(O)(CH3)2.
Aspect 6. The compound of any one of Aspects 1-5, wherein R2 and R3 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5 to 12-membered heteroaryl, —CN, —OR2a, —SO2R2a, —SO2NR2aR2b, —C(O)R2a, —CO2R2a, —C(O)NR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b, or —NR2aSO2R2b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R2d, or
R2 and R3 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R2e;
R2e, at each occurrence, is independently —H, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 3- to 8-membered heterocyclyl, 5- to 12-membered heteroaryl, oxo (═O), —CN, CF3, CHF2, CH2F, thioxo (═S), —SCF3, —SCHF2, —SCH2F, —SCH2CF3, —SCF2CH3, —SCF2CF3, —SO2R2a, —SO2NR2aR2b, —C(O)R2a, —CO2R2a, —C(O)NR2aR2b, —NR2aR2b, —NR2aCOR2b, —NR2aCO2R2b or —NR2aSO2R2b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 3- to 8-membered heterocyclyl, 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R2a.
R2a and R2b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C1-C8alkoxy-C1-C8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;
R2d, at each occurrence, is independently selected from halogen, —OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.
Aspect 7. The compound of any one of Aspects 1-6, wherein R2 and R3 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated (preferred aromatic) or saturated ring, said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with at least one substituent —H, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n- or iso-), butyl (n-, iso- or t-), pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —CH2OH, —SCH3, —SC2H5, oxo (═O), thioxo (═S), —CF3, —CHF2, —CH2F, —SCF3, —OMe, —OC2H5, —CN, —C(O)CH3,
Aspect 8. The compound of any one of Aspects 1-7, wherein R2 and R3 together with the carbon atoms to which they are attached, form a 6-membered unsaturated (preferred aromatic) ring, said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with one substituent —H, —F, —Cl, —Br, —I, methyl, ethyl or cyclopropyl.
Aspect 9. The compound of any one of Aspects 1-8, wherein R4 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —C2-C8alkenyl, —C2-C8alkynyl or —C1-C8alkoxy; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —C2-C8alkenyl or —C2-C8alkynyl is optionally substituted with —F, —Cl, —Br, —I, oxo (═O), or —CN.
Aspect 10. The compound of any one of Aspects 1-9, wherein R4 is hydrogen, —F, —Cl, —Br, —I, —CH3, —CF3, —CH2F, —CHF2, —C(O)OMe, —C(O)OEt, —C(O)OiPr or —C(O)OtBu.
Aspect 11. The compound of any one of Aspects 1-10, wherein R4 is hydrogen, —F, —Cl, —Br or —I.
Aspect 12. The compound of any one of Aspects 1-11, wherein R9, R10, R11 and R12 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NR9aR9b, —OR9a, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (═O), or —CN; each of -methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9c;
R9a and R9b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9d;
R9c and R9d are each independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl.
Aspect 13. The compound of any one of Aspects 1-12, wherein R9, R10, R11 and R12 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, —NH2, —NHCH3, —OH, —OCH3, —OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2OH, —CH2OMe, oxo (═O), or —CN.
Aspect 14. The compound of any one of Aspects 1-13, wherein R9, R10, R11 and R12 are each independently selected from hydrogen, —CH3, —F, —Cl, —Br or —I.
Aspect 15. The compound of any one of Aspects 1-11, wherein two R12 together with the carbon atoms to which they are attached, form a 3, 4, 5, 6, 7 or 8-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R9c;
R9c is independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl.
Aspect 16. The compound of any one of Aspects 1-11, wherein two R12 together with the carbon atoms to which they are attached, form a 3, 4, 5, 6, 7 or 8-membered ring, preferably form a 3, 4, 5 or 6-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, —NH2, —NHCH3, —OH, —OCH3, —OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Aspect 17. The compound of any one of Aspects 1-5, wherein the
moiety is
Ring B is a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0, 1, 2 or 3 heteroatoms; said heteroatoms are independently selected from N, NR2e, 0 or
said ring is optionally substituted with at least one substituent R2e.
Aspect 18. The compound of any one of Aspects 1-17, wherein the
moiety is selected from
Z5, Z6, Z7 and Z8 are each independently selected from N, CH or CR2e;
Z9 and Z10 are each independently selected from O, S, NH or NR2e.
Aspect 19. The compound of any one of Aspects 1-18, wherein the
moiety is selected from
Aspect 20. The compound of any one of Aspects 1-19, wherein the
moiety is selected from
Aspect 21. The compound of any one of Aspects 1-20, wherein L1 is selected from a single bond, —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), —C(O)—C1-C8alkylene-(preferably —C(O)—CH2—, —C(O)—C2H4—, —C(O)—C3H6—), —C1-C8alkylene-C(O)-(preferably —CH2—C(O)—, —C2H4—C(O)—, —C3H6—C(O)—), —C(O)—, —O—, —N(CH3)—, —NH—,
wherein each of said C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), *L1—C(O)C1-C8alkylene_**L1 (preferably *L1—C(O)—CH2—**L1, *L1—C(O)—C2H4—**L1, *L1—C(O)—C3H6—**L1), *L1—C1-C8alkylene-C(O)—**L1 (preferably *L1—CH2—C(O)—**L1, *L1—C2H4—C(O)—**L1, *L1—C3H6—C(O)—**L), —N(CH3)—, —NH—,
is optionally substituted with at least one RL1c;
each of said RL1c is independently selected from oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; or
two RL1c together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl.
Aspect 22. The compound of any one of Aspects 1-21, wherein L1 is selected from a single bond, —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—, —C(O)—, —O—, —N(CH3)—, —NH—,
Aspect 23. The compound of any one of Aspects 1-22, wherein X1 and X2 are each independently selected from —CRa or N;
Ra is selected from hydrogen, —F, —Cl, —Br, —I, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, each of said methyl, ethyl, methoxy, ethoxy, cyclopropyl, is optionally substituted with at least one substituent —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, (preferably, X1 and X2 are each independently selected from CH, C(F), C(CH3) or N);
m1=1 or 0;
R12 is hydrogen, oxo (═O), methoxymethyl, hydroxymethyl, —CN or —CH3.
Aspect 24. The compound of any one of Aspects 1-23, wherein m1 is 1; preferably,
moiety is
wherein *X refers to the position attached to
moiety, and **X refers to the position attached to the
moiety.
Aspect 25. The compound of any one of Aspects 1-24, wherein m1 is 1; preferably,
wherein *X refers to the position attached to
moiety, and **X refers to the position attached to the
moiety.
Aspect 26. The compound of any one of Aspects 1-25, wherein m1 is 1,
moiety is
wherein *Xrefers to the position attached to
moiety, and **X refers to the position attached to the
moiety.
Aspect 27. The compound of any one of Aspects 1-26, wherein L2 is selected from a single bond, —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), *L2—C(O)—C1-C8alkylene_**L2 (preferably *L2—C(O)—CH2—**L2, *L2—C(O)—C2H4—**L2, *L2—C(O)—C3H6—**L2), *L2—C1-C8alkylene-C(O)—**L2 (preferably *L2—CH2—C(O)—**L2, *L2 C2H4—C(O)—**L2, *L2—C3H6—C(O)—**L2), —C(O)—, —O—, —N(CH3)—, —NH—,
wherein each of said —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), *L2—C(O)—C1-C8alkylene-**L2 (preferably *L2—C(O)—CH2—**L2, *L2—C(O)—C2H4—**L2, *L2—C(O)—C3H6—**L2), *L2—C, —C8alkylene-C(O)—**L2 (preferably *L2—CH2—C(O)—**L2, *L2—C2H4—C(O)—**L2, *L2—C3H6—C(O)—**L2), —N(CH3)—, —NH—,
is optionally substituted with at least one RL2c;
each of said RL2c is independently selected from oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; or two RL2c together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.
Aspect 28. The compound of any one of Aspects 1-27, wherein L2 is selected from a single bond, —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), —C(O)—, —O—, —N(CH3)—, —NH—,
Aspect 29. The compound of any one of Aspects 1-28, wherein L3 is selected from single bond, —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), *L3—C(O)—C1-C8alkylene-**L3 (preferably *L3—C(O)—CH2—**L3*L3—C(O)—C2H4—**L3, *L3—C(O)—C3H6—**L13), *L3—C1-C8alkylene-C(O)—**L3 (preferably *L3—CH2—C(Q)-**L3, *L3-C2H4—C(O)—**L3, *L3—C3H6—C(O)—**L3), —C(O)—, —O—, —N(CH3)—, —NH—,
wherein each of said —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), *L3—C(O)—C1-C8alkylene_**L3 (preferably *L3—C(O)—CH2—**L3, *L3—C(O)—C2H4—**L3, *L3—C(O)—C3H6—**L3, *L3—C1-C8alkylene-C(O)—**L3 (preferably *L3—CH2—C(O)—**L3, *L3—C2H4—C(O)—**L3, *L3—C3H6—C(O)—**L3), —N(CH3)—, —NH—,
is optionally substituted with at least one RL3c;
each of said RL3c is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; or
two RL3c together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl.
Aspect 30. The compound of any one of Aspects 1-29, wherein L3 is selected from a single bond, —C1-C8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), —C(O)—, —O—, —N(CH3)—, —NH—,
Aspect 31. The compound of any one of Aspects 1-30, wherein L2 is a single bond, L3 is a single bond, or L2 and L3 are both single bond.
Aspect 32. The compound of any one of Aspects 1-31, wherein
is selected from
Aspect 33. The compound of any one of Aspects 1-32, wherein R13, R14, R15, R16 and R17 are each independently selected from hydrogen, —F, —Cl, —Br, —I, CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, 15 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; said each methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, C1-C8alkoxy-C1-C8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl.
Aspect 34. The compound of any one of Aspects 1-33, wherein at each occurrence, Ra and Rb are each independently selected from hydrogen, —F, —Cl, —Br, —I, CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; or
Ra and Rb together with the carbon atoms to which they are attached, form a 3, 4, 5, 6, 7 or 8-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl.
Aspect 35. The compound of any one of Aspects 1-34, wherein
is selected from
Ring A is selected from 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclyl, aryl, or heteroaryl;
R14 is independently selected from hydrogen, halogen, —C1-C8alkyl, —C1-C8alkoxy, or CN; said each —C1-C8alkyl, or —C1-C8alkoxy is optionally substituted by one or more halogen or —C1-C8alkyl; preferably R14 is independently selected from H, F, Cl, Br, I, CH3, —OCH3, —OCH2F, —OCHF2, —O CF3, CH2F, CN, CHF2, or CF3;
X8 is independently selected from CH, CD, C(CH3), C(C2H5), C(C3H7), C(F) or N;
L4 is independently selected from a single bond, —O—, —NH—, —CH2—, —CHF—, or —CF2—;
Y1, Y2, and Y3 are each independently selected from CRa or N;
X9 is CH2;
Ra is each independently selected from hydrogen, halogen, —C1-C8alkyl, or —C1-C8alkoxy, each of said —C1-C8alkyl or —C1-C8alkoxy is optionally substituted with at least one or more halogen, hydroxy, —C1-C8alkyl, or —C1-C8alkoxy; and
n6 is independently 0,1 or 2.
Aspect 36. The compound of any one of Aspects 1-35, wherein
is selected from
R14 is independently selected from hydrogen, halogen, —C1-C8alkyl, —C1-C8alkoxy, or CN; said each —C1-C8alkyl, or —C1-C8alkoxy is optionally substituted by one or more halogen; preferably R14 is independently selected from H, F, Cl, Br, I, CH3, —OCH3, —OCH2F, —OCHF2, —O CF3, CH2F, CN, CHF2, or CF3;
X8 is independently selected from CH, CD, C(CH3), C(C2H5), C(C3H7), C(F) or N;
L4 is a single bond;
Y1, Y2, and Y3 are each independently selected from CRa or N;
X9 is CH2;
Ra is each independently selected from hydrogen, halogen, —C1-C8alkyl, or —C1-C8alkoxy, each of said —C1-C8alkyl or —C1-C8alkoxy is optionally substituted with at least one or more halogen; and
n6 is 1.
Aspect 37. The compound of any one of Aspects 1-36, wherein
is selected from
R14 is independently selected from hydrogen, halogen, —C1-C8alkyl, —C1-C8alkoxy, or CN; said each —C1-C8alkyl, or —C1-C8alkoxy is optionally substituted by one or more halogen; preferably R14 is independently selected from H, F, Cl, Br, I, CH3, —OCH3, —OCH2F, —OCHF2, —O CF3, CH2F, CN, CHF2, or CF3;
Y1 and Y3 are each independently selected from CH or N;
Ra is each independently selected from hydrogen, halogen, —C1-C8alkyl, or —C1-C8alkoxy, each of said —C1-C8alkyl or —C1-C8alkoxy is optionally substituted with at least one or more halogen.
Aspect 38. The compound of any one of Aspects 1-35, wherein
is selected from
R14 is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or CN; said each methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy is optionally substituted by one or more F, Cl, Br, I; preferably R14 is independently selected from H, F, Cl, Br, I, CH3, —OCH3, —OCH2F, —OCHF2, —O CF3, CH2F, CN, CHF2, or CF3;
Ra is each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy is optionally substituted with at least one or more F, Cl, Br, I.
Aspect 39. The compound of any one of Aspects 1-38, wherein
is selected from
R14 is independently selected from F, Cl, Br, I, —CH3, —OCH3, —OCH2F, —OCHF2, —O CF3, CH2F, CN, CHF2, or CF3;
Ra is each independently selected from F, Cl, Br, I, —CH3, —OCH3, —OCH2F, —OCHF2, —O CF3, CH2F, CN, CHF2, or CF3.
Aspect 40. The compound of any one of Aspects 1-39, wherein
is
Wherein L5 and L6 are independently selected from a single bond, —O—, —NRa—, —(CRaRb)n8-, —O(CRaRb)n8-, —NRa(CRaRb)n8- or —C(O)—;
X9 is —CRaRb—;
Ra and Rb are each independently selected from hydrogen, hydroxy, F, Cl, Br, I, CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, —C6-C12aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, F, Cl, Br, I, CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; or
Ra and Rb together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;
each R13 is independently selected from hydrogen, halogen, CN, —C1-C8alkyl, or —C1-C8alkoxy;
n6 is 0 or 1; and
n7 is 0, 1 or 2.
Aspect 41. The compound of any one of Aspects 1-40, wherein
is
Wherein L5 and L6 is independently selected from a single bond,
—O—, —NH—, —NMe-, —N(CH2CH3)—, —N(iPr)—, —CH2—, —CHF—, —CF2—, —C(CH3)2— or —C(O)— (preferably L5 is —C(O)— or —CH2—, and L6 is
—O—, —NH—, —NMe-, —N(CH2CH3)—, —N(iPr)—,
—CH2—, —CHF—, —CF2—, —C(CH3)2— or —C(O)—);
X9 is CH2;
each R13 is independently selected from hydrogen, halogen, CN, —C1-C8alkyl, or —C1-C8alkoxy;
n6 is 0 or 1; and
n7 is 0, 1 or 2.
Aspect 42. The compound of any one of Aspects 1-41, wherein
is
Wherein L5 and L6 are each independently selected from
—O—, —NH—, —NMe-, —N(CH2CH3)—, —N(iPr)—, —CH2—, —CHF—, —CF2—, —C(CH3)2— or —C(O)—;
each R13 is independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, —C3H7, —C4H9, —OMe, —OCH2F, —OCHF2, —O CF3, —OEt, —OC3H7 or —OC4H9;
n7 is 0, 1 or 2.
Aspect 43. The compound of any one of Aspects 1-42, wherein
is
Wherein L6 is selected from
—O—, —NMe-, —N(CH2CH3)—, —N(iPr)—, —CH2—, —CHF—, —CF2— or —C(CH3)2—;
Wherein L5 is —C(O)—;
each R13 is independently selected from hydrogen, F, Cl, Br, I, CN, —C1-C8alkyl, or —C1-C8alkoxy;
n7 is 0, 1 or 2.
Aspect 44. The compound of any one of Aspects 1-43, wherein
is
each R13 is independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, —C3H7, —C4H9, —OMe, —OCH2F, —OCHF2, —O CF3, —OEt, —OC3H7 or —OC4H9;
n7 is 0, 1 or 2.
Aspect 45. The compound of any one of Aspects 1-44, wherein
is
Wherein L4 is independently selected from a single bond,
—O—, —NH—, —CH2—, —CHF—, or —CF2—;
X8 is independently selected from CH, C(CH3), C(C2H5), C(C3H7), C(F) or N;
X9 is CH2;
each R13 is independently selected from hydrogen, halogen, CN, —C1-C8alkyl, or —C1-C8alkoxy;
Y1, Y2, Y3 and Y4 are each independently selected from CH, C(CH3), C(F), or N;
Y5 is selected from NH, N(CH3), O or S;
n6 is 0 or 1; and
n7 is 0, 1 or 2.
Aspect 46. The compound of any one of Aspects 1-45, wherein
is selected from
Aspect 47. The compound of any one of Aspects 1-46, wherein Z1, Z2, Z3 and Z4 are each independently —CRz;
RZ, at each occurrence, is independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NRZaRZb, —ORZa, —SRZa, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one RZc;
RZa and RZb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RZd;
RZc and RZb are each independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.
Aspect 48. The compound of any one of Aspects 1-47, wherein Rz is selected from H, —CH3, —C2H5, F, —CH2F, —CHF2, —CF3, —OCH3, —OC2H5, —C3H7, —OCH2F, —OCHF2, —OCH2CF3, —OCF3, —SCF3, —CF3, —CH(OH)CH3,
Aspect 49. The compound of any one of Aspects 1-48 selected from the compound of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 541, 542, 543, 544, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 723, 724, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755 or 756.
One another aspect, the compound of any one of Aspects 1-48 selected from
Aspect 50. A pharmaceutical composition comprising a compound of any one of Aspects 1-49 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.
Aspect 51. A method of treating a disease that can be affected by EGFR modulation, comprises administrating a subject in need thereof an effective amount of a compound of any one of Aspects 1-49 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof.
Aspect 52. The method of Aspect 51, wherein the disease is selected from cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.
Aspect 53. Use of a compound of any one of Aspects 1-49 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof in the preparation of a medicament for treating a disease that can be affected by EGFR modulation.
Aspect 54. The use of Aspect 53, wherein the disease is cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.
The following terms have the indicated meanings throughout the specification: Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
The following terms have the indicated meanings throughout the specification:
As used herein, including the appended claims, the singular forms of words such as “a”, “an”, and “the”, include their corresponding plural references unless the context clearly indicates otherwise.
The term “or” is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.
The term “alkyl” includes a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C1-6 alkyl) include, but not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.
The term “propyl” includes 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”).
The term “butyl” includes 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”).
The term “pentyl” includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.
The term “hexyl” includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl.
The term “alkylene” refers to a divalent alkyl group by removing two hydrogen from alkane. Alkylene includes but not limited to methylene, ethylene, propylene, and so on.
The term “halogen” includes fluoro (F), chloro (Cl), bromo (Br) and iodo (I).
The term “alkenyl” includes a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C═C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C2-6 alkenyl, include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.
The term “alkenylene” refers to a divalent alkenyl group by removing two hydrogen from alkene. Alkenylene includes but not limited to, vinylidene, butenylene, and so on.
The term “alkynyl” includes a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C≡C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.
The term “alkynylene” refers to a divalent alkynyl group by removing two hydrogen from alkyne. Alkynylene includes but not limited to ethynylene and so on.
The term “cycloalkyl” includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.
For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, examples of the saturated monocyclic cycloalkyl group, e.g., C3-8cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C3-6 cycloalkyl), including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.
The term “spiro cycloalkyl” includes a cyclic structure which contains carbon atoms and is formed by at least two rings sharing one atom.
The term “fused cycloalkyl” includes a bicyclic cycloalkyl group as defined herein which is saturated and is formed by two or more rings sharing two adjacent atoms.
The term “bridged cycloalkyl” includes a cyclic structure which contains carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other. The term “7 to 10 membered bridged cycloalkyl” includes a cyclic structure which contains 7 to 12 carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.
Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include but are not limited to bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, as well as benzo 3 to 8 membered cycloalkyl, benzo C40.6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1, 2, 3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8 to 9 membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms within the above examples.
The term “aryl” used alone or in combination with other terms includes a group selected from:
The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.
Specifically, the term “bicyclic fused aryl” includes a bicyclic aryl ring as defined herein. The typical bicyclic fused aryl is naphthalene.
The term “heteroaryl” includes a group selected from:
When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
Specifically, the term “bicyclic fused heteroaryl” includes a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, a bicyclic fused heteroaryl is 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, or 6-membered/7-membered bicyclic. The group can be attached to the remainder of the molecule through either ring.
“Heterocyclyl”, “heterocycle” or “heterocyclic” are interchangeable and include a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.
The term “H” or “hydrogen” disclosed herein includes Hydrogen and the non-radioisotope deuterium.
The term “at least one substituent” disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met. For example, “at least one substituent F” disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents F.
The term “divalent” refers to a linking group capable of forming covalent bonds with two other moieties. For example, “a divalent cycloalkyl group” refers to a cycloalkyl group obtained by removing two hydrogen from the corresponding cycloalkane to form a linking group. the term “divalent aryl group”, “divalent heterocyclyl group” or “divalent heteroaryl group” should be understood in a similar manner.
Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.
When compounds disclosed herein contain a di-substituted cyclic ring system, substituents found on such ring system may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides. For example, the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.
It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art could select and apply the techniques most likely to achieve the desired separation.
“Diastereomers” refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.
A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H, et al. “Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, referred to as tautomers. For example, compounds including carbonyl —CH2C(O)— groups (keto forms) may undergo tautomerism to form hydroxyl —CH═C(OH)— groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.
“Prodrug” refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In some embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
“deuterated analog” refers to a derivative of an active agent that an arbitrary hydrogen is substituted with deuterium. In some embodiments, the deuterated site is on the Warhead moiety. In some embodiments, the deuterated site is on the Linker moiety. In some embodiments, the deuterated site is on the Degron moiety.
“Pharmaceutically acceptable salts” refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base. The term also includes salts of the stereoisomers (such as enantiomers and/or diastereomers), tautomers and prodrugs of the compound of the invention.
In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.
The terms “administration”, “administering”, “treating” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
The term “effective amount” or “therapeutically effective amount” refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The term “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer, tautomer or prodrug thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined herein, a disease or disorder in a subject. In the case of combination therapy, the term “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
The term “disease” refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition”.
Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise”, and variations such as “comprises” and “comprising” are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term “comprising” can be substituted with the term “containing”, “including” or sometimes “having”.
Throughout this specification and the claims which follow, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-8, C1-6, and the like.
Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
General Reaction Scheme for Compound Preparation
The subject compounds and pharmaceutically acceptable salts thereof, can be prepared from (a) commercially available starting materials (b) known starting materials which may be prepared as described in literature procedures (c) new intermediates described in the schemes and experimental procedures herein. In making the compounds of the invention, the order of synthetic steps may be varied to increase the yield of the desired product. Some of the compounds in this invention may be generated by the methods as shown in the following reaction schemes and the description thereof.
The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperature is in degrees Centigrade. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless indicated otherwise. Unless indicated otherwise, the reactions set forth below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.
1H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 n), Mass detector: 6120 SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)
LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 n), Mass detector: G6125C SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)
LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm Gradient method: Flow: 1.2 mL/min Time (min) A (%) B (%)
Preparative HPLC was conducted on a column (150×21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml/min, injection volume 2 m1, at room temperature and UV Detection at 214 nm and 254 nm.
In the following examples, the abbreviations below are used:
A mixture of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (4 g, 16 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (6.4 g, 24 mmol), K2CO3 (4.4 g, 32 mmol) in DMF (50 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (7 g, 90%). [M+H]+=499.0.
Step 2: tert-butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate
A mixture of tert-butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (7 g, 14 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.3 g, 28 mmol), Pd(dppf)Cl2 (1.1 g, 1.4 mmol) and K3PO4 (8.9 g, 42 mmol) in DMF (160 mL) and water (20 mL) was stirred in a flask at 90° C. under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3×1000 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (5 g, 80%). [M+H]+=447.0.
To a stirred solution of tert-butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (5 g, 11.2 mmol) in MeOH (100 mL) and DCM (20.00 mL) was added Pd/C (wet, 10%) (1 g) under nitrogen atmosphere. The resulting mixture was stirred for 16 hrs at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/CH3OH (10: 1, 200 mL). The filtrate was concentrated under reduced pressure to afford the product (4.0 g, 85.3%). [M+H]+=419.1.
A mixture of 5-bromoquinoxalin-6-amine (10 g, 44.8 mmol), dimethylphosphine oxide (10.5 g, 134.5 mmol), Pd(OAc)2 (1.0 g, 4.5 mmol) Xanphos (5.2 g, 9 mmol) and K3PO4 (28 g, 134 mmol) in DMF (250 mL) and water (50 mL) was stirred in a flask at 130° C. under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with DCM (3×1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford the product (6 g, 60%), [M+H]+=222.0.
A mixture of (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (6 g, 27.3 mmol), 5-bromo-2,4-dichloropyrimidine (12.3 g, 54.6 mmol) in THF (200 mL) was stirred in a flask at 0° C. under nitrogen atmosphere, 54 mL KHMDS (1M in THF) was added. The reaction mixture was allowed to warm up to room temperature for 2 hours. The reaction was quenched with water and the mixture was extracted with DCM, washed three times with saturated brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford the product (4 g, 35%). [M+H]+=412.0.
A mixture of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxide (2 g, 4.8 mmol), tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (2.6 g, 6.3 mmol) and MsOH (184 mg, 1.92 mmol) in t-BuOH (20 mL) was stirred in a flask at 90° C. under nitrogen atmosphere for overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the product (2 g, 60%). [M+H]+=694.0.
To a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (The intermediate can be prepared according to the way described in WO2017197046) (25 g, 59.9 mmol) and 4-bromoiodobenzene (20.3 g, 71.9 mmol) in dioxane (250 mL) and H2O (50 mL) were added K2CO3 (16.6 g, 120 mmol) and Pd(dppf)Cl2 (4.4 g, 6.0 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80° C. under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford the product (23 g, 86%); [M+H]+=446.2.
To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (15 g, 33.6 mmol) and ethyl 2-(piperidin-4-yl)acetate (8.6 g, 50.4 mmol) in 2-methyl-THF (150 mL) and H2O (15 mL) were added Cs2CO3 (32.9 g, 100.8 mmol), DavePhos (2.7 g, 6.7 mmol) and Pd2(dba)3 (3.1 g, 3.4 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with water (3×200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (14 g, 78%); [M+H]+=537.3.
To a stirred solution of ethyl 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)acetate (13 g, 24.2 mmol) in THF (130 mL) was added LiAlH4 (1 g, 26.6 mmol) in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water/ice (50 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:2) to afford the product (11 g, 92%); [M+H]+=495.3.
To a stirred solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethan-1-ol (10.5 g, 21.2 mmol) in EtOH (100 mL), EtOAc (100 mL) and DCM (20 mL) was added Pd/C (wet, 10%) (5 g) under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/CH3OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (1:10) to afford the product (5.1 g, 76%). [M+H]+=317.1.
A mixture of 3-[4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl]piperidine-2,6-dione (100 mg, 0.32 mmol) and IBX (132 mg, 0.47 mmol) in DMSO (10 mL) was stirred in a flask at room temperature overnight. The reaction was quenched with water and the mixture was extracted with EtOAc, washed three times with saturated aqueous NaCl and twice with saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum to afford the product (70 mg, 70%). [M+H]+=315.2.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (40 mg, 0.057 mmol) and 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde (21 mg, 0.069 mmol) and NaOAc (14 mg, 0.17 mmol) in chloromethane (4 mL) and EtOH (0.5 mL) was stirred in a flask at room temperature for 2 hour. The mixture was added NaBH3CN (10 mg, 0.17 mmol) and stirred in a flask at room temperature 2 h.
Then the mixture was evaporated in vacuum to afford the crude product, which was purified with HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (15 mg, 27%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.79 (s, 1H), 8.87 (d, J=9.1 Hz, 3H), 8.29 (d, J=12.4 Hz, 2H), 7.91 (s, 1H), 7.38 (s, 1H), 7.03 (d, J=7.8 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.76-3.62 (m, 3H), 3.02 (s, 6H), 2.80-2.53 (m, 12H), 2.44-2.40 (m, 1H), 2.11 (s, 2H), 2.02 (d, J=14.3 Hz, 7H), 1.88 (s, 2H), 1.75 (d, J=11.0 Hz, 2H), 1.48-1.56 (m, 5H), 1.28-1.30 (m, 3H), 0.93-0.95 (m, 3H); [M+H]+=992.5.
2-(4-bromophenyl)ethan-1-ol (20 g, 100 mmol), 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane (38.1 g, 150 mmol), Pd(dppf)Cl2 (7.3 g, 10 mmol), KOAc (19.6 g, 200 mmol) were placed in dioxane (400 mL). The resulting mixture was then heated to reflux for 2 h. The mixture was cooled to room temperature, filtered off the solid and concentrated to afford crude product (28 g, crude), which was used directly without further purification. [M+H]+=249.2.
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol (28 g, crude), Pd(dppf)Cl2 (7.3 g, 10 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (36.9 g, 100 mmol), Cs2CO3 (65.2 g, 200 mmol) were placed in Dioxane/water (300 mL, 10:1). The mixture was stirred at 100° C. overnight. Cooling the reaction to room temperature, filtered off the solid, the filtrate was concentrated and purified with SiO2-gel column (eluted with EtOAc/Hexane=1:2) to give the crude product which was used directly in the next step. [M+H]+=412.2.
2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)ethan-1-ol (the crude from last step) was dissolved in MeOH (500 mL), Pd/C (10%, w/w, 5 g) was added to the solution in one portion. The resulting mixture was stirred under H2 atmosphere (1 atm) for overnight. Filtered off the solid, the filtrate concentrated to give the crude product. The crude was triturated with MTBE (50 mL) to give desire product (13.5 g, 57.9% over 3 steps). [M+H]+=234.1.
2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde was prepared in a manner similar to that in Example 23 Step 11 from 3-(4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione and IBX. [M+H]+=232.19.
The titled compound was synthesized in a manner similar to that in Example 23 step 12 from 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde and (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.83 (s, 1H), 8.87 (d, J=4.2 Hz, 3H), 8.28 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.16 (d, J=19.2 Hz, 4H), 6.81 (s, 1H), 3.77 (s, 4H), 3.00-3.02 (m, 4H), 2.71-2.75 (m, 7H), 2.26-2.40 (m, 12H), 2.02 (m, 7H), 1.85-1.87 (m, 2H), 1.58 (d, J=11.1 Hz, 2H), 0.93 (s, 3H); [M+H]+=909.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 10.72 (s, 1H), 8.85 (s, 3H), 8.26 (d, J=12.7 Hz, 2H), 7.89 (s, 1H), 7.35 (s, 1H), 7.00 (s, 1H), 6.88 (s, 1H), 6.77 (d, J=14.8 Hz, 2H), 3.84 (s, 1H), 3.73 (d, J=13.8 Hz, 6H), 2.98 (s, 2H), 2.51-2.70 (m, 15H), 2.28-2.31 (m, 2H), 2.15-2.18 (s, 2H), 2.00 (d, J=14.3 Hz, 6H), 1.80-1.86 (m, 3H), 1.55-1.58 (m, 2H), 1.21 (s, 1H), 0.90 (s, 3H); [M+H]+=939.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 10.84 (s, 1H), 8.87 (s, 3H), 8.30 (s, 2H), 7.92 (s, 1H), 7.37 (s, 1H), 7.01 (s, 3H), 6.81 (s, 1H), 4.00 (s, 1H), 3.78 (s, 3H), 3.02 (s, 3H), 2.70 (s, 7H), 2.05 (t, J=72.6 Hz, 20H), 1.59 (s, 3H), 1.25 (s, 2H), 0.93 (s, 4H); [M+H]+=923.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 10.88 (s, 1H), 8.85 (s, 3H), 8.26 (d, J=11.9 Hz, 2H), 7.88 (s, 1H), 7.34 (s, 2H), 7.19 (d, J=10.9 Hz, 2H), 6.79 (s, 1H), 4.12 (s, 1H), 3.75 (s, 3H), 2.98 (s, 3H), 2.50-2.80 (m, 13H), 2.30 (m, 4H), 1.90-2.01 (m, 10H), 1.57 (s, 3H), 0.90 (s, 3H); [M+H]+=943.
To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (45.0 g, 193 mmol) in THF (270 mL) was added BH3-THF (1 M, 386 mL) at 0° C. Then the mixture was stirred at 20° C. for 2 hrs. Under cooling with ice, MeOH (250 mL) was dropwise added until there was no foaming in the system and the solvent was distilled off under reduced pressure. To the resulting reside, water (50.0 mL) was added for extraction with EtOAc (1000.0 mL). The combined organic phase was washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. 2-(4-bromo-3-fluorophenyl)ethan-1-ol (38.0 g, 89.8%) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.45 (t, J=7.72 Hz, 1H), 7.00 (dd, J=9.48, 1.76 Hz, 1H), 6.86-6.92 (m, 1H), 3.82 (t, J=6.50 Hz, 2H), 2.80 (t, J=6.50 Hz, 2H), 2.03 (s, 1H); [M+H]+=219.
To a solution of 2-(4-bromo-3-fluorophenyl)ethan-1-ol (38.0 g, 173 mmol) in DCM (210 mL) was added imidazole (17.7 g, 260 mmol) at 20° C. TBSCl (36.6 g, 242 mmol, 29.7 mL) was added to the reaction mixture at 0° C. Then the mixture was stirred at 20° C. for 3 hrs. Then the mixture was adjusted to pH=6 with 5% citric acid (180 mL), and extracted with DCM (150 mL). The organic phase was adjusted to pH=8 with NaHCO3 and then aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuum. (4-bromo-3-fluorophenethoxy)(tert-butyl)dimethylsilane (52.0 g, 156 mmol) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.43 (t, J=7.72 Hz, 1H), 7.00 (dd, J=9.56, 1.87 Hz, 1H), 6.89 (dd, J=8.00, 1.87 Hz, 1H), 3.80 (t, J=6.48 Hz, 2H), 2.78 (t, J=6.48 Hz, 2H), 0.84-0.89 (m, 9H), −0.05-0.01 (m, 6H); [M+H]+=333.
To a solution of (4-bromo-3-fluorophenethoxy)(tert-butyl)dimethylsilane (52.0 g, 156 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65.1 g, 156 mmol) in dioxane (320 mL) was added KOAc (45.9 g, 468 mmol) at 20° C. Pd(dppf)Cl2 (11.4 g, 15.6 mmol) was added to the mixture at 20° C. The suspension was degassed under vacuum and purged with N2 three times. Then the mixture was stirred at 90° C. for 16 hrs. Water (160 mL) was poured into the mixture, extrated with EtOAc (100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography. 2,6-bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)pyridine (32.0 g, 37.8%) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.55 (dd, J=8.04, 0.99 Hz, 1H), 7.43-7.47 (m, 2H), 7.33-7.42 (m, 7H), 7.25-7.33 (m, 3H), 6.98-7.05 (m, 2H), 5.40 (d, J=18.4 Hz, 4H), 3.87 (t, J=6.84 Hz, 1H), 3.84-3.89 (m, 1 H), 2.86 (t, J=6.84 Hz, 2H), 0.88-0.92 (m, 9H), 0.01-0.03 (m, 6H); [M+H]+=544.
To a solution of 2,6-bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)pyridine (32.0 g, 58.8 mmol) in THF (50.0 mL) was added Pd/C (0.800 g, 10.0% purity) under Ar at 20° C. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 50° C. for 16 hrs. The suspension was filtered through a pad of celite and the filter cake was washed with THF (200 mL×3). The combined filtrates were concentrated to dryness to give crude product. The crude product was triturated with petroleum ether (50.0 mL) at 20° C. for 1 hrs. 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-dione (12.0 g, 55.7%) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.06-7.12 (m, 1H) 7.93 (br s, 1H), 6.96-7.04 (m, 2H), 3.91 (dd, J=11.2, 5.04 Hz, 1H), 3.81 (t, J=6.80 Hz, 2 H), 2.82 (t, J=6.80 Hz, 2H), 2.58-2.73 (m, 2H), 2.18-2.34 (m, 2H), 0.87 (s, 9H), 0.00 (s, 6H); [M+H]+=366.
To a solution of 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-dione (12.0 g, 32.8 mmol) in MeOH (60 mL) was added HCl (12 M, 6 mL) at 20° C. Then the mixture was stirred at 20° C. for 3 hrs. Water (60 mL) was poured into the mixture, extracted with EtOAc (40 mL). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuum. The combined crude product was purified by re-crystallization from toluene (32.0 mL) at 100° C. 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (6.50 g, 78.8%) was obtained. 1HNMR (400 MHz, DMSO-d6) δ ppm 10.8 (s, 1H), 7.19 (t, J=7.84 Hz, 1H), 6.99-7.08 (m, 2H), 4.67 (t, J=5.18 Hz, 1H), 3.99 (dd, J=12.6, 4.74 Hz, 1H), 3.55-3.66 (m, 2H), 2.68-2.75 (m, 3H), 2.18 (qd, J=12.8, 3.86 Hz, 1H), 1.93-2.03 (m, 1H); [M+H]+=252.
To a solution of 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (200 mg, 0.8 mmol) in DMSO (10 mL) was added IBX (338 mg, 1.2 mmol). The mixture was stirred in a flask at rt overnight. After being determined the reaction to be completed by LCMS, the mixture was extracted with EA (30 mL * 3). The combined organic phase was dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product (100 mg, crude), which was used for next step without further purification. [M+H]+=250.
The titled compound was synthesized in a manner similar to that in Example 23 step 12 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)acetaldehyde. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 10.85 (s, 1H), 8.86-8.74 (m, 2H), 8.25 (s, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.04 (dd, J=17.1, 10.2 Hz, 2H), 6.79 (s, 1H), 4.15-3.91 (m, 1H), 3.75 (s, 2H), 2.98 (s, 2H), 2.80-2.61 (m, 4H), 2.51-2.60 (m, 4H), 2.41-2.50 (m, 7H), 2.1-2.35 (m, 5H), 2.00 (m, 6H), 1.80-1.84 (m, 2H), 1.55-1.59 (m, 3H), 1.21 (s, 3H), 0.91 (s, 3H); [M+H]+=927.
A mixture of 1-bromo-4-iodobenzene (3.0 g, 10.6 mmol), pent-4-yn-1-ol (0.98 g, 11.7 mmol), CuI (204 mg, 1.06 mmol), Pd(PPh3)2Cl2 (373 mg, 0.53 mmol) and piperidine (1.8 g, 21.2 mmol) in toluene (30 mL) was stirred in a flask at 40° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 2: 1 gradient elution) to give the product (1.5 g, 59%). [M+H]+=239.0.
A mixture of 5-(4-bromophenyl)pent-4-yn-1-ol (1.2 g, 5.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.5 g, 6.0 mmol), Pd(dppf)Cl2 (367 mg, 0.5 mmol) and KOAc (1.5 g, 15.0 mmol) in 1,4-dioxane (30 mL) was stirred in a flask at 80° C. for 1 h. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 4: 1 gradient elution) to give the title product (1.4 g, 97%). [M+H]+=287.2.
A mixture of 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pent-4-yn-1-ol (1.4 g, 4.9 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (1.8 g, 4.9 mmol), Pd(dppf)Cl2 (366 mg, 0.5 mmol) and Cs2CO3 (2.5 g, 7.7 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was stirred in a flask at 80° C. for 2 h. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 2: 1 gradient elution) to give the product (2.0 g, 91%). [M+H]+=450.2.
Under N2, to a solution of 5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pent-4-yn-1-ol (2.0 g, 4.4 mmol) in MeOH (100 mL) was added Pd/C (400 mg, 10%) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 48 h. Reaction was monitored by HPLC. The mixture was filtered through a pad of Celite and washed with MeOH (50 mL). The filtrate was concentrated under vacuum to obtain the product (1.2 g, 97%). [M+H]+=276.2.
To a solution of 3-(4-(5-hydroxypentyl)phenyl)piperidine-2,6-dione (100 mg, 0.36 mmol) in DMSO (3.0 mL) was added IBX (203 mg, 0.72 mmol) in portions at 25° C. The mixture was stirred at 25° C. for 4 h. Water (20.0 mL) was added and the resulting solution was extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (3×20 mL), dried over Na2SO4 and concentrated under vacuum to afford the title product (80 mg, 81%). [M+H]+=274.2.
The titled compound was prepared in a manner similar to that in Example 23 step 12. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.82 (s, 1H), 8.87 (s, 2H), 8.27 (s, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 7.14 (d, J=7.9 Hz, 3H), 6.81 (s, 1H), 3.77 (s, 3H), 2.93-3.00 (m, 4H), 2.77-2.52 (m, 14H), 2.05-2.30 (m, 8H), 2.02 (d, J=14.1 Hz, 6H), 1.84 (s, 2H), 1.58 (s, 4H), 1.44 (s, 2H), 1.30 (s, 2H), 0.92 (s, 3H); [M+H]+=951.
2-(5-bromopyridin-2-yl)ethan-1-ol (19 g, 94.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (26.4 g, 104 mmol), Pd(dppf)Cl2 (6.9 g, 9.45 mmol), KOAc (18.5 g, 189 mmol) were placed in dioxane (300 mL). The resulting mixture was then heated to reflux for 16 h. The mixture was cooled to room temperature, filtered off the solid and concentrated to afford crude product (20 g, crude), which was used directly without further purification. [M+H]+=250.15.
2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-1-ol (20 g, crude), Pd(dppf)Cl2 (4.5 g, 6.18 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (22.9 g, 61.8 mmol), Cs2CO3 (40.2 g, 123.6 mmol) were placed in dioxane/water (300 mL, 10:1). The mixture was stirred at 100° C. for 16 h. Cooling the reaction to room temperature, filtered off the solid, the filtrate was concentrated and purified with SiO2-gel column (eluted with EtOAc/Hexane=1:1) to give the product (19 g, 48.8% for over 2 steps). [M+H]+=413.18.
2-(2′,6′-bis(benzyloxy)-[3,3′-bipyridin]-6-yl)ethan-1-ol (10 g, 24.3 mmol) was dissolved in MeOH (100 mL), Pd/C (10%, 1 g) was added to the solution in one portion. The resulting mixture was stirred under hydrogen atmosphere (1 atm) for 16 h. Filtered off the solid, concentrated to give the crude product. The crude was triturated with MTBE to give the desired product (1.7 g, 30%). [M+H]+=235.1.
Into a flask, was placed 3-(6-(2-hydroxyethyl)pyridin-3-yl)piperidine-2,6-dione (269 mg, 1.15 mmol), DCM (8.00 mL), TEA (174.7 mg, 1.726 mmol), TsCl (328.6 mg, 1.72 mmol). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane and methanol (10:1) to afford the product (150 mg, 34%). [M+H]+=389.2.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (40 mg, 0.057 mmol), 2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)ethyl 4-methylbenzenesulfonate (33 mg, 0.085 mmol), KI (14.2 mg, 0.085 mmol) and DIEA (14.7 mg, 0.114 mmol) in acetonitrile (4 mL) was stirred in a flask at 85° C. for 12 hours. The reaction was quenched with water and the mixture was extracted with DCM, washed with saturated brine. dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, The residue was purified by HPLC chromatography to give the product (2.1 mg, 4%). 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 10.88 (s, 1H), 8.85 (s, 3H), 8.32 (s, 1H), 8.26 (s, 2H), 7.94-7.84 (m, 1H), 7.53 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 6.79 (s, 1H), 3.86 (s, 1H), 3.75 (s, 3H), 2.98 (s, 2H), 2.85 (s, 2H), 2.67 (d, J=11.4 Hz, 5H), 2.50 (m, 3H), 2.10-2.40 (m, 4H), 2.00 (d, J=14.1 Hz, 7H), 1.80-1.85 (m, 3H), 1.55-1.58 (m, 3H), 1.21 (s, 3H), 0.90 (s, 3H); [M+H]+=910.
A solution of 2,6-bis(benzyloxy)-3-bromopyridine (100 g, 0.27 mol) and (4-hydroxyphenyl)boronic acid (48.4 g, 0.35 mol) in dioxane (1.2 L) and water (120 mL) was added Pd(dppf)Cl2 (20 g, 0.027 mol). The mixture was heated to 100° C. for 4 hours. The reaction mixture concentrated and diluted with EA (1.5 L). The organic layer was separated and washed with water (300 mL) and brine (300 mL), and then evaporated to dryness, which was purified by silica gel chromatography (PE:EA=20/1) to give product (72.2 g, 70.6%). [M−H]−=382.
To a solution of 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (72.2 g, 0.189 mol) in methanol (1.5 L) was added Pd/C (50% w/t H2O, 8 g). The mixture was charged with 1 atm H2 and heated to 40° C. for overnight. The mixture was filtered and the filtrate was evaporated to give crude product (35.0 g, 90%). [M−H]−=204.
To a solution of 3-(4-hydroxyphenyl)piperidine-2,6-dione (35 g, 0.17 mol) in DCM (600 mL) was added Ac2O (17.3 g, 0.17 mol) and Et3N (20.2 g, 0.2 mol) at 0° C. The solution was warmed to room temperature overnight. The mixture was diluted with water. The organic layer was separated and washed with water (3*200 mL) and brine (200 mL) and then evaporated to give crude 4-(2,6-dioxopiperidin-3-yl)phenyl acetate which was re-crystallized from EtOAc and PE to give the product (38.3 g, 91.2%). [M−H]−=246.
To the solution of 4-(2,6-dioxopiperidin-3-yl)phenyl acetate (38.3 g, 0.155 mol) in THF (400 mL) was slowly added NaH (60% w/t in mineral oil, 6.2 g, 155 mol) at 0° C. Then SEM-C1 (25.9 g, 0.155 mol) was added at the same temperature. After completion, the mixture was stirred overnight at room temperature and then quenched with water (100 mL). Extracted with EA (2*300 mL), the organic layer was separated, washed with water (3*200 mL) and brine (200 mL), and then evaporated. The crude material was purified by silica gel chromatography (PE/EA=5/1) to give the product (35.2 g, 60%). [M+H]+=378.
To the solution of 4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl acetate (35.2 g, 0.093 mol) in methanol (500 mL) was added AcCl (7.8 g, 0.1 mol) at 0° C. The mixture was stirred overnight at room temperature and then poured into water (200 mL). The mixture was evaporated and extracted with DCM (2*300 mL). The organic solvent was washed with water and brine, and then evaporated. The crude material was purified by silica gel chromatography (PE/EA=3/1) to afford the product (20.6 g, 66%). 1HNMR (400 MHz, CDCl3): 7.04 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 5.28 (s, 2H), 3.81-3.77 (m, 1H), 3.67-3.62 (m, 2H), 2.81-2.71 (m, 2H), 2.23-2.18 (m, 2H), 0.98-0.94 (m, 2H), 0.00 (s, 9H), [M−H]−=334.
3-(4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1.67 g, 5.0 mmol) was dissolved in acetone (4.5 ml). 1,3-Diiodopropane (1.15 ml, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were added and the mixture was stirred at 50° C. for 16 h. The mixture was diluted with diethyl ether, washed with water and dried over MgSO4. The crude material was purified by silica gel chromatography (PE/EA=3/1) to afford the product (0.8 g, 32%). [M+H]+=504.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.072 mmol), 3-(4-(3-iodopropoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (54 mg, 0.11 mmol) and DIEA (28.6 mg, 0.22 mmol) in dichloromethane (3 mL) was stirred in a flask at 85° C. for 16 h. Then the mixture was evaporated in vacuum to afford the 51 mg crude product which was used for next step without further purification. [M+H]+=1071.1.
A mixture of 3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)propoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (51 mg, crude) and trifluoroacetic acid (1 mL) in dichloromethane (2 mL) was stirred in a flask at room temperature overnight. Then the mixture was evaporated in vacuum to afford the crude product, which was dissolved in methanol (2 mL). Ammonium hydroxide (0.5 mL) was added to the resulting solution and stirred for 2 h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to give the product to give the product (2.7 mg). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.81 (s, 1H), 8.86 (d, J=4.3 Hz, 3H), 8.28 (d, J=8.3 Hz, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.81 (s, 1H), 3.99 (s, 2H), 3.77 (s, 4H), 3.00-3.05 (m, 4H), 2.68-2.70 (m, 6H), 2.37-2.39 (m, 8H), 2.15 (s, 2H), 2.02-2.04 (m, 7H), 1.87 (s, 4H), 1.57 (d, J=11.3 Hz, 2H), 0.93 (s, 3H); [M+H]+=939.1.
The titled compound was synthesized in the procedures similar to Example 18.
1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.81 (s, 1H), 8.85 (t, J=10.0 Hz, 3H), 8.27 (t, J=12.2 Hz, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 6.81 (s, 1H), 4.06 (s, 2H), 3.77 (s, 5H), 3.01 (d, J=9.9 Hz, 3H), 2.64 (dd, J=52.0, 22.7 Hz, 10H), 2.31 (s, 2H), 2.17 (d, J=11.5 Hz, 1H), 2.02 (d, J=14.3 Hz, 8H), 1.86 (d, J=10.4 Hz, 2H), 1.57 (d, J=11.3 Hz, 2H), 0.92 (s, 3H); [M+H]+=927.
1-Bromo-4-iodobenzene (2.0 g, 7.1 mmol), piperidin-4-ylmethanol (894.0 mg, 7.8 mmol), CuI (270.0 mg, 1.4 mmol), L-proline (163.0 mg, 1.4 mmol), K3PO4 (3.0 g, 14.2 mmol) were placed in DMSO (20 mL). The resulting mixture was then heated to 80° C. overnight until LC-MS indicated all the starting material was consumed. The mixture was cooled to room temperature, filtered off the solid, diluted with EtOAc (200 mL), and washed with brine for 3 times. The organic layer was dried over Na2SO4, and concentrated to afford crude product (2.8 g, crude), which was used directly without further purification. [M+H]+=270.0.
(1-(4-Bromophenyl)piperidin-4-yl)methanol (2.8 g, crude), Pd(dppf)Cl2 (580.0 mg, 0.79 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.0 g, 7.1 mmol) and Cs2CO3 (4.6 g, 14.2 mmol) were placed in dioxane/water (300 mL, 10:1). The mixture was stirred at 100° C. overnight. The reaction was cooled to room temperature and filtered off the solid. The filtrate was concentrated and purified with SiO2-gel column (eluted with EtOAc/Hexane=1: 1) to give the desired product (3.0 g, 88%, 2 steps). [M+H]+=481.2.
(1-(4-(2,6-Bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol (3.0 g, 6.3 mmol) was dissolved in MeOH (30 mL). Pd/C (10%, w/w, 0.3 g) was added to the solution in one portion. The resulting mixture was stirred under H2 atmosphere (1 atm) overnight. The solid was filtered off and the filtrate was concentrated to give the crude product. The crude was triturated with MTBE to give the desired product (1.2 g, 63.5%). [M+H]+=303.0.
3-(4-(4-(Hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (100.0 mg, 0.33 mmol) was dissolved in DMSO (2 mL). IBX (184.8 mg, 0.66 mmol) was added to the solution in portions at 0° C. and the mixture was stirred at 0° C. for 30 min. Then the mixture was warmed to rt for another 1 h until TLC indicated all the starting material was consumed. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give crude the desired product (100.0 mg, crude) which was used directly without further purification.
The titled compound was synthesized in the procedures similar to that in Example 23 step 12. 1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 10.76 (s, 1H), 8.85 (s, 3H), 8.26 (d, J=11.7 Hz, 2H), 7.89 (s, 1H), 7.35 (s, 1H), 7.00 (s, 2H), 6.87 (s, 2H), 6.79 (s, 1H), 3.68 (d, J=51.3 Hz, 6H), 2.98 (s, 2H), 2.64 (d, J=33.0 Hz, 8H), 2.38-2.20 (m, 5H), 2.13 (s, 3H), 2.00 (d, J=14.3 Hz, 8H), 1.83 (s, 2H), 1.74 (s, 2H), 1.57 (s, 4H), 1.18 (s, 3H), 0.90 (s, 3H); [M+H]+=978.
2,6-bis(benzyloxy)-3-bromopyridine (58.0 g, 156.7 mmol), 4-aminophenylboronic acid pinacol ester (44.6 g, 203.7 mmol), K2CO3 (65.0 g, 470.0 mmol) and Pd(dppf)Cl2 (11.5 g, 15.7 mmol) were added to the reaction flask, the mixture was degassed and purged with nitrogen for three times. Next 1.4-dioxane (1 L) and water (300 mL) were added to the reaction flask, and nitrogen was recharged three times again, the reaction was heated to reflux. After stirring for three hours, the reaction was cooled to room temperature, extracted with EtOAc (500 mL×3), the combined organic phases were washed with water and brine, dried and concentrated. 4-(2,6-bis(benzyloxy)pyridin-3-yl) aniline (57.3 g, 95.6%) was obtained after column separation (petroleum ether: ethyl acetate=10: 1). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.0 Hz, 1H), 7.50-7.27 (m, 12H), 6.72 (d, J=8.5 Hz, 2H), 6.45 (d, J=8.0 Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 3.68 (s, 2H); [M+H]+=383.2.
p-Toluenesulfonic acid monohydrate (106.0 g, 557 mmol) was added to tert-Butanol (800 mL). 4-(2,6-bis(benzyloxy)pyridin-3-yl) aniline (78.5 g, 205 mmol) was dissolved in MeCN (400 mL) and added to the system, and the mixture was stirred at room temperature. NaNO2 (28.3 g, 404 mmol) and KI (85.2 g, 513.1 mmol) in water (400 mL) was added. Then system was stirred at room temperature. After stirred for 1.5 h, the mixture was diluted with water (1.5 L), and pH was adjusted to 10 with 2M sodium hydroxide solution. 2M sodium thiosulfate solution (1 L) was added to the mixture, extracted with DCM (1L×3). The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified with silica gel column (petroleum ether: ethyl acetate=100: 1) to obtain 2,6-bis(benzyloxy)-3-(4-iodophenyl)pyridine (31.2 g, 30.8%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.47-7.28 (m, 12H), 6.48 (d, J=8.1 Hz, 1H), 5.41 (s, 2H), 5.37 (s, 2H); [M+H]+=494.1.
Under the atmosphere of nitrogen, add 2,6-bis(benzyloxy)-3-(4-iodophenyl)pyridine (45.4 g, 92.0 mmol), tert-butyl 2-(piperidin-4-yl)acetate (27.5 g, 138 mmol) and t-BuONa (13.3 g, 138 mmol) to 1.4-dioxane (450 mL). After pumping nitrogen three times, Pd2(dba)3 (4.2 g, 4.6 mmol) and X-phos (4.4 g, 9.2 mmol) were added to the system, and then nitrogen was pumped for three times again, then temperature was raised to reflux. After 1.5h, the reaction was cooled to room temperature, water (250 mL) was added, extracted with DCM (3×250 mL). The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified with silica gel column (petroleum ether: ethyl acetate=20: 1) to obtain tert-butyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)acetate (31.1 g, 60.2%). 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.1 Hz, 1H), 7.50-7.28 (m, 12H), 6.96 (d, J=8.8 Hz, 2H), 6.46 (d, J=8.0 Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 3.73-3.70 (m, 2H), 2.80-2.74 (m, 2H), 2.21 (d, J=7.0 Hz, 2H), 2.00-1.89 (m, 1H), 1.86-1.82 (m, 2H), 1.53-1.35 (m, 11H). [M+H]+=565.3
Tert-butyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)acetate (28.6 g, 50.6 mmol) and Pd/C (7.5 g) were added to DMF (500 mL), the mixture was stirred at 50° C. under hydrogen atmosphere for 16 h, cooled to room temperature, filtered through a pad of Celite and washed with DCM. The filtrate was concentrated to get tert-butyl 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetate (17.4 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.07 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 3.79-3.49 (m, 3H), 2.82-2.54 (m, 4H), 2.27-2.18 (m, 4H), 1.91-1.87 (m, 1H), 1.83-1.80 (m, 2H), 1.50-1.25 (m, 11H). [M+H]+=387.2.
Tert-butyl 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetate (16.2 g, 41.9 mmol) and TFA (95.5 g, 838 mmol) were added to DCM (100 mL). The temperature was raised to 40° C. and stirred for 1.5 h. After cooling to room temperature, the mixture was concentrated, then recrystallized in MTBE (150 mL) to give the product (14.5 g, 77.9%). 1H NMR (400 MHz, MeOD) δ 7.57 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 3.96 (dd, J=11.7, 5.0 Hz, 1H), 3.71-3.68 (m, 2H), 3.61-3.56 (m, 2H), 2.78-2.63 (m, 2H), 2.39-2.38 (m, 2H), 2.27-2.13 (m, 6H), 1.79-1.69 (m, 2H). [M+H]+=331.2.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (40 mg, 0.057 mmol) and 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetic acid trifluoroacetate (37 mg, 0.083 mmol), HATU (26.2 mg, 0.069 mmol) and DIEA (14.7 mg, 0.114 mmol) in DMF (4 mL) was stirred in a flask at room temperature for 2 hours. The reaction was quenched with water and the mixture was extracted with DCM. The organic phase was washed three times with saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC chromatography to give the product (10 mg, 17%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.78 (s, 1H), 8.86 (d, J=5.4 Hz, 3H), 8.28 (d, J=7.6 Hz, 2H), 7.90 (d, J=9.9 Hz, 1H), 7.37 (s, 1H), 7.03 (d, J=7.8 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.48 (s, 4H), 3.02 (d, J=9.2 Hz, 3H), 2.66 (dd, J=26.9, 13.5 Hz, 7H), 2.29 (d, J=6.3 Hz, 7H), 2.02 (d, J=14.2 Hz, 7H), 1.84 (s, 3H), 1.74 (s, 2H), 1.60 (d, J=9.6 Hz, 2H), 1.36-1.19 (m, 3H), 0.93 (s, 3H); [M+H]+=1006.4.
To a solution of 4-nitrophenol (50.0 g, 359 mmol) in DMF (250 mL) was added Cs2CO3 (351 g, 1.08 mol), KI (17.9 g, 108 mmol) and 3-chloropropan-1-ol (35.7 g, 377 mmol), the mixture was stirred at 110° C. for 12 hrs. The mixture was partitioned between ethyl acetate (400 mL×2) and H2O (1500 mL). The combined organic layers were washed with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=1: 0 to 0: 1) to afford the product (70.0 g, 32.9%). [M+H]+=198.
To a solution of 3-(4-nitrophenoxy)propan-1-ol (70.0 g, 355 mmol) in MeOH (350 mL) was added Pd/C (7.00 g, 10.0% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 50° C. for 2 hrs. The suspension was filtered through a pad of celite and the filter cake was washed with MeOH (100 mL×3) to give the product (30.0 g, 50.5%). 1H NMR (CD3OD, 400 MHz) δ 6.63-6.78 (m, 4H), 3.98 (t, J=6.17 Hz, 2H), 3.72 (t, J=6.28 Hz, 2H), 1.93 (quin, J=6.34 Hz, 2H); [M+H]+=168.
To a solution of 3-(4-aminophenoxy)propan-1-ol (25.0 g, 150 mmol), 3-bromopiperidine-2,6-dione (30.1 g, 157 mmol) in DMF (150 mL) was added DIEA (38.7 g, 299 mmol), then the mixture was stirred at 65° C. for 12 hrs. The mixture was partitioned between ethyl acetate (200 mL) and H2O (450 mL). The separated organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography to afford the product (25.2 g, 59.5%). 1H NMR (CD3OD, 400 MHz) δ 6.75-6.82 (m, 2H), 6.67-6.75 (m, 2H), 4.16 (dd, J=11.8, 4.83 Hz, 1H), 3.99 (t, J=6.24 Hz, 2H), 3.73 (t, J=6.36 Hz, 2H), 2.63-2.86 (m, 2H), 2.32 (dtd, J=13.3, 5.01, 5.01, 3.61 Hz, 1H), 1.79-2.02 (m, 3H); [M+H]+=279.
To a solution of 3-((4-(3-hydroxypropoxy)phenyl)amino)piperidine-2,6-dione (1.0 g, 3.6 mmol) in DCM (250 mL) was added DIEA (0.93 g, 7.2 mmol). The resulting reaction mixture was cool down to 0° C., then MsCl (0.62 g, 5.4 mmol) was added. The mixture was stirred at 25° C. for 2 hrs. The resulting mixture was partitioned between ethyl acetate (100 mL×2) and H2O (150 mL). The combined organic layers were washed with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography to afford the product (0.3 g, 23%). [M+H]+=357.
The titled compound was prepared in a manner similar to that in Example 13 step 5.
1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.77 (s, 1H), 8.86 (s, 3H), 8.35 (s, 1H), 8.27 (s, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.71 (s, 2H), 6.63 (s, 2H), 5.42 (s, 1H), 4.19 (s, 1H), 3.88 (s, 2H), 3.77 (s, 3H), 3.00 (s, 6H), 2.69 (d, J=12.1 Hz, 4H), 2.36-2.38 (m, 7H), 2.02-2.06 (m, 8H), 1.84 (m, 5H), 1.58 (m, 2H), 0.92 (s, 3H); [M+H]+=954.3.
2-(4-aminophenyl)ethan-1-ol (13.7 g, 100 mmol), TEA (20.0 g, 200 mmol) and DMAP (1.2 g, 10 mmol) were placed in DCM (150 mL). TBSCl (17.0 g, 110 mmol) was added to the solution in dropwise at 0° C. The resulting mixture was stirred at room temperature for 1h. The mixture was diluted with ice-water, extracted with DCM, the combined organic phases were washed with 0.5 M HCl solution for 3 times and Brine for once. The resulting organic phase was dried over Na2SO4, concentrated to give the desired product (16.9 g, 67.3%), which was used directly without further purification. [M+H]+=252.2
4-(2-((tert-butyldimethylsilyl)oxy)ethyl) aniline (9.4 g, 37.5 mmol), 3-bromopiperidine-2,6-dione (10.8 g, 56 mmol) and DIEA (9.7 g, 75 mmol) were placed in MeCN (200 mL). The mixture was stirred at 80° C. for 8h. Cooling the reaction to room temperature, concentrated and purified with SiO2-gel column to give the desired product (4.8 g, 35.2%). [M+H]+=363.2.
3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)piperidine-2,6-dione (4.8 g, 13.2 mmol) was placed in HCl-dixoane (4M, 30 mL), the mixture was stirred at room temperature for 2h. Concentrated and triturated with MTBE to afford desired product (3.1 g, 95%). [M+H]+=249.1.
Into a 25-mL flask, 3-((4-(2-hydroxyethyl)phenyl)amino)piperidine-2,6-dione hydrochloride was placed (170.0 mg, 0.6 mmol) was dissolved in pyridine (4.0 mL), TsCl (230.0 mg, 1.2 mmol) was added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (7:1) to afford the product (100 mg, 41.7%). [M+H]+=403.
The titled compound was prepared in a manner similar to that in Example 13 step 5. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 10.77 (s, 1H), 8.85 (d, J=4.4 Hz, 3H), 7.89 (s, 1H), 7.35 (s, 1H), 6.92 (d, J=8.3 Hz, 2H), 6.79 (s, 1H), 6.58 (d, J=8.3 Hz, 2H), 5.64 (d, J=7.6 Hz, 1H), 4.25 (s, 1H), 3.75 (s, 3H), 2.99 (d, J=9.5 Hz, 3H), 2.80-2.62 (m, 4H), 2.50-2.60 (m, 7H), 2.20-2.39 (m, 7H), 2.00 (d, J=14.3 Hz, 8H), 1.83 (s, 4H), 1.48-1.60 (m, 2H), 0.91 (s, 3H); [M+H]+=924.
To a solution of 1-fluoro-4-nitrobenzene (100 g, 710 mmol) and 4-piperidinemethanol (98 g, 85.0 mmol) in DMF (1400 mL) was added K2CO3 (196 g) at 25° C. The mixture reaction was stirred at 80° C. for 15 h. The reaction was cooled to room temperature, poured into ice-water (6000 mL) and stirred for 20 mins. The solid was filtered and washed with water (500 mL×2), dried to give the product (140 g, 83.8%). 1H NMR (400 MHz, DMSO) δH 8.03 (d, J=9.4 Hz, 2H), 7.01-6.98 (m, 2H), 4.54 (t, J=5.3 Hz, 1H), 4.07-4.04 (m, 2H), 3.29-3.26 (m, 2H), 3.00-2.93 (m, 2H), 1.76-1.67 (m, 3H), 1.21-1.11 (m, 2H); [M+H]+=237.2.
Under N2, to a solution of (1-(4-nitrophenyl)piperidin-4-yl)methanol (140 g, 592 mmol) in MeOH (1680 mL) was added 10% Pd/C (28 g) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 15 h. The mixture was filtered through a pad of Celite and washed with MeOH (140.0 mL). The filtrate was concentrated under vacuum to obtain the product (113 g, 92.0%). 1H NMR (400 MHz, DMSO) δH 6.77-6.61 (m, 2H), 6.54-6.38 (m, 2H), 4.53 (brs, 2H), 4.45 (t, J=5.3 Hz, 1H), 3.32-3.27 (m, 2H), 2.46-2.41 (m, 2H), 1.76-1.62 (m, 2H), 1.50-1.31 (m, 1H), 1.27-1.08 (m, 2H); [M+H]+=207.2.
To a solution of (1-(4-aminophenyl)piperidin-4-yl)methanol (25 g, 121 mmol) in PhMe (183 mL) was added acrylic acid (13 g, 180 mmol) at 25° C. The mixture was stirred at 90° C. for 15 h. The reaction was cooled to 25° C., then AcOH (183 mL) and urea (36.4 g, 606 mmol) were added. The mixture was stirred at 110° C. for 24 h. The reaction was cooled to 25° C. and concentrated under vacuum. The residue was dissolved with EtOAc (500 mL) and then adjusted to pH=7 with sat. NaHCO3. The resulting solution was extracted with 2×200 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, and the residue was purified on silica gel to give the product (17.5 g, 42%). 1H NMR (400 MHz, DMSO) δH 10.32 (s, 1H), 7.20 (d, J=8.9 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 3.98 (d, J=6.2 Hz, 2H), 3.80-3.66 (m, 4H), 2.74-2.72 (m, 4H), 2.09 (s, 3H), 1.80 (d, J=13.8 Hz, 4H), 1.37 (dd, J=12.1, 2.8 Hz, 3H); [M+H]+=346.2.
(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate (35.0 g, 101 mmol) was added into 2N HCl (260.0 mL) at 25° C. The mixture was stirred at 100° C. for 15 h. Reaction was monitored by HPLC. The reaction was cooled to 10° C. and then adjusted to pH=7 with sat. NaHCO3. The solid was collected by filtrated, washed by water (50.0 mL), and dried to obtain the product (16.9 g, 55%). 1H NMR (400 MHz, DMSO) δH 10.26 (s, 1H), 7.13 (d, J=8.9 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 4.49 (s, 1H), 3.78-3.61 (m, 4H), 3.30-3.28 (m, 2H), 2.70-2.66 (m, 4H), 1.75-1.72 (m, 2H), 1.52-1.49 (m, 1H), 1.28-1.18 (m, 2H); [M+H]+=304.2.
To a solution of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (15.0 g, 49 mmol) in DMSO (120 mL) was added IBX (32.7 g, 117 mmol) in portions at 25° C. The mixture was stirred at 25° C. for 15 h. Water (300 mL) was added to the reaction at 25° C. The solid was filtered and washed with water (100 mL), EtOAc (100 mL). The resulting solution was extracted with 4×200 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford a crude residue. The crude product was purified by column chromatography to afford the product (3.1 g, 22.1%). 1H NMR (300 MHz, DMSO) δH 10.26 (s, 1H), 9.63 (s, 1H), 7.15-7.10 (m, 2H), 6.95-6.89 (m, 2H), 3.71-3.51 (m, 4H), 2.86-2.57 (m, 4H), 1.94-1.91 (m, 1H), 1.77-1.73 (m, 1H), 1.64-1.51 (m, 2H), 1.38-1.30 (m, 1H).
The titled compound was prepared in a manner similar to that in Example 23 step 12.
1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.26 (s, 1H), 8.86 (d, J=8.0 Hz, 3H), 8.27 (s, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.76 (s, 1H), 3.77 (s, 3H), 3.69 (s, 4H), 3.09 (s, 2H), 2.68 (d, J=10.0 Hz, 6H), 2.30 (m, 5H), 2.10 (s, 3H), 2.02 (d, J=14.3 Hz, 6H), 1.80 (s, 4H), 1.63 (d, J=9.9 Hz, 3H), 1.22 (d, J=11.9 Hz, 2H); [M+H]+=910.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.26 (s, 1H), 8.86 (d, J=4.5 Hz, 3H), 8.27 (s, 2H), 7.91 (s, 1H), 7.12 (s, 2H), 6.93 (s, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.68 (d, J=6.4 Hz, 4H), 3.00 (s, 3H), 2.69 (d, J=7.3 Hz, 8H), 2.28-2.35 (m, 10H), 2.02 (d, J=14.4 Hz, 6H), 1.85 (s, 2H), 1.75 (d, J=11.9 Hz, 2H), 1.57 (d, J=9.7 Hz, 2H), 1.41 (s, 3H), 1.25 (d, J=9.8 Hz, 3H), 0.92 (s, 3H); [M+H]+=993.5.
Into a 25-mL flask, was placed tert-butyl 3-(3-hydroxypropyl) azetidine-1-carboxylate (950 mg, 4.413 mmol), DCM (4.0 mL), TFA (2.0 mL, 2.693 mmol). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum to afford 1.4 g crude product. [M+H]+=116.
Into a 50-mL flask, was placed 3-(azetidin-3-yl)propan-1-ol (1.40 g, crude), DMSO (10 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.21 g, 4.38 mmol), DIEA (2.83 g, 21.9 mmol). The resulting solution was stirred for 1 hour at 80° C. The reaction mixture was cooled to room temperature. The resulting solution was diluted with EA. The resulting solution was extracted with H2O and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (8:1) to afford the product (550 mg, 33.6% for two steps). [M+H]+=372.
Into a 25-mL flask, was placed 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-hydroxypropyl)azetidin-1-yl)isoindoline-1,3-dione (480 mg, 1.29 mmol), DCM (10 mL), TEA (262 mg, 2.59 mmol), TsCl (493 mg, 2.59 mmol). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (7:1) to afford the product (400 mg, 58.89%).[M+H]+=526.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (40 mg, 0.057 mmol), 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propyl 4-methylbenzenesulfonate (37 mg, 0.069 mmol), KI (11.6 mg, 0.069 mmol) and DIEA (14.7 mg, 0.114 mmol) in acetonitrile (4 mL) was stirred in a flask at 75° C. for 12 hours. The reaction was quenched with water and the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, The residue was purified by HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (10 mg, 17%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.08 (s, 1H), 8.86 (d, J=6.5 Hz, 3H), 8.28 (d, J=7.4 Hz, 2H), 7.91 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 5.06 (d, J=7.5 Hz, 1H), 4.13 (d, J=8.4 Hz, 2H), 3.77 (s, 3H), 3.66 (s, 2H), 3.02 (d, J=10.0 Hz, 3H), 2.85-2.89 (m, 2H), 2.80-2.56 (m, 8H), 2.90-2.33 (m, 3H), 2.02 (d, J=14.1 Hz, 8H), 1.87 (s, 2H), 1.60-1.65 (m, 4H), 1.46 (s, 2H), 1.23 (s, 3H), 0.92 (s, 3H); [M+H]+=1047.5.
To a solution of tert-butyl 3-formylazetidine-1-carboxylate (700 mg, 3.78 mmol) in DCM (20 mL) was added Ethyl (triphenylphosphoranylidene)acetate (1.44 g, 4.158 mmol) at 0° C., Then the mixture was stirred at 25° C. overnight. The reaction was quenched with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜20: 1 gradient elution) to give the product (640 mg, 66%). [M+Na]+=278.1.
Under N2, to a solution of tert-butyl(E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (640 mg, 2.51 mmol) in MeOH (10 mL) was added 10% Pd/C (150 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 15 h. The mixture was filtered through a pad of Celite and washed with MeOH (15 mL). The filtrate was concentrated under vacuum to obtain the product (580 mg, 90%). [M+Na]+=280.1.
To a solution of tert-butyl 3-(3-ethoxy-3-oxopropyl)azetidine-1-carboxylate (580 mg, 2.26 mmol) in THF (10 mL) and H2O (2 mL) was added lithium hydroxide hydrate (190 mg, 4.52 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 12 h. The reaction was quenched with HCl (1 N) at 0° C. until pH=5 and extracted with DCM (2×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum to afford the crude product (430 mg, 83%), which was used for next step without further purification. [M+Na]+=252.2.
A solution of 3-(1-(tert-butoxycarbonyl)azetidin-3-yl)propanoic acid (430 mg, 1.894 mmol) in DCM (10 mL) was added TFA (1 mL). The mixture was stirred in a flask at room temperature for 3 h. The mixture was evaporated in vacuum to afford the crude product (220 mg, 51%), which was used for next step without further purification. [M+H]+=130.1.
Into a 100-mL flask, was placed 3-(azetidin-3-yl)propanoic acid trifluoroacetate (220 mg, 0.969 mmol), DMSO (6 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (295 mg, 1.066 mmol), DIEA (625 mg, 4.845 mmol). The resulting solution was stirred for 3 hours at 80° C. The reaction mixture was cooled to room temperature and HCl (1 N) was added until pH ˜ 6. Water was added to the mixture and extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜85: 15 gradient elution) to give the product (65 mg, 17%). [M+H]+=386.1.
To a solution of 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propanoic acid (40 mg, 0.104 mmol), HATU (44 mg, 0.114 mmol) and DIEA (67 mg, 0.52 mmol) in DMF (5 mL) was added (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (72 mg, 0.104 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction was directly purified with pre-HPLC (0.1% FA in water: acetonitrile=90:10˜ 60:40 gradient elution) to give the product (22 mg, 20%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.06 (s, 1H), 8.86 (d, J=6.3 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=10.4 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.62 (d, J=8.3 Hz, 1H), 5.09-5.01 (m, 1H), 4.12 (t, J=8.0 Hz, 2H), 3.77 (s, 3H), 3.69 (s, 2H), 3.46 (s, 4H), 3.01 (s, 3H), 2.75 (dd, J=43.6, 31.7 Hz, 5H), 2.59 (s, 3H), 2.49-2.43 (m, 3H), 2.35 (s, 3H), 2.02 (d, J=14.4 Hz, 7H), 1.86 (d, J=6.7 Hz, 4H), 1.62 (s, 2H), 0.92 (s, 3H); [M+H]+=1061.8.
The titled compound was synthesized in the procedures similar to Example 56. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.07 (s, 1H), 8.86 (d, J=4.3 Hz, 3H), 8.27 (s, 2H), 7.92 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 6.90 (s, 1H), 6.81 (s, 2H), 5.05 (s, 1H), 3.77 (s, 3H), 3.53 (d, J=20.9 Hz, 2H), 3.41 (s, 1H), 3.30-3.27 (m, 1H), 3.14 (s, 1H), 3.01 (s, 3H), 2.89 (s, 2H), 2.70 (d, J=14.9 Hz, 3H), 2.60 (m, 7H), 2.37 (s, 5H), 2.13 (s, 1H), 2.02 (d, J=14.3 Hz, 7H), 1.87 (s, 2H), 1.76 (s, 1H), 1.61 (s, 2H), 0.93 (s, 3H);[M+H]+=1033.8.
Into a 100-mL flask, was placed azetidin-3-ylmethanol hydrochloride (500 mg, 4.05 mmol), DMSO (8 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.23 g, 4.45 mmol), DIEA (2.61 g, 20.25 mmol). The resulting solution was stirred for 3 hours at 80° C. The reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 90: 10 gradient elution) to give the product (600 mg, 43%). [M+H]+=344.1.
To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (300 mg, 0.875 mmol) in DCM (10 mL) was added TEA (353 mg, 3.498 mmol). The reaction mixture was cool down to 0° C., then MsCl (152 mg, 1.313 mmol) was added. The mixture was stirred at 25° C. for 3 hrs. The reaction was quenched with water and extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜20: 1 gradient elution) to give the product (180 mg, 49%). [M+H]+=422.3.
The titled compound was synthesized in the procedures similar to Example 56 step 4.
1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.07 (s, 1H), 8.87 (d, J=4.3 Hz, 3H), 8.27 (s, 2H), 7.92 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 6.80 (d, J=13.3 Hz, 2H), 6.65 (d, J=8.3 Hz, 1H), 5.06 (d, J=12.3 Hz, 1H), 4.13 (s, 2H), 3.77 (s, 3H), 3.69 (s, 2H), 3.00 (s, 4H), 2.88 (s, 2H), 2.69 (d, J=13.4 Hz, 3H), 2.57 (m, 7H), 2.43 (s, 3H), 2.33 (s, 2H), 2.02 (d, J=14.3 Hz, 7H), 1.85 (s, 2H), 1.58 (d, J=10.5 Hz, 2H), 0.93 (s, 3H);[M+H]+=1019.8.
Into a 50-mL flask, was placed 3-(piperazin-1-yl)propan-1-ol (1.0 g, 6.9 mmol), DMSO (10 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (2.09 g, 7.59 mmol), DIEA (2.67 g, 20.7 mmol). The resulting solution was stirred for 1 h at 80° C. The reaction mixture was cooled to room temperature. The resulting solution was diluted with EA. The resulting solution was extracted with H2O and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (8:1) to afford the product (620 mg, 20%). [M+H]+=401.27.
Into a 25-mL flask, was placed 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-hydroxypropyl)piperazin-1-yl)isoindoline-1,3-dione (620 mg, 1.55 mmol), DCM (12 mL), TEA (469.6 mg, 4.65 mmol), TsCl (354 mg, 1.86 mmol). The resulting solution was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (7:1) to afford the product (410 mg, 47.7%). [M+H]+=555.28.
The titled compound was prepared in a manner similar to that in Example 56 step 4. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.09 (s, 1H), 8.87 (d, J=4.6 Hz, 3H), 8.40-8.21 (m, 3H), 7.91 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.36 (d, J=10.2 Hz, 2H), 7.27 (s, 1H), 6.81 (s, 1H), 5.06 (s, 1H), 3.77 (s, 3H), 3.44 (s, 4H), 2.95-3.00 (m, 7H), 2.79-2.56 (m, 5H), 2.33-2.35 (s, 12H), 2.02 (d, J=14.6 Hz, 7H), 1.85-1.87 (m, 3H), 1.62-1.66 (m, 4H), 0.93 (s, 3H); [M+H]+=1076.
A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (300 mg, 0.88 mmol) (The intermediate can be prepared according to the method described in US 20180125821), tert-butyl acrylate (337 mg, 2.63 mmol) and DIEA (226 mg, 1.76 mmol) in MeCN (8 mL) was stirred in a flask at 80° C. overnight. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to give the product (280 mg, 68%). [M+H]+=471.2.
A solution of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoate (280 mg, 0.59 mmol) in HCl/1,4-dioxane (4M, 8 mL) was stirred in a flask at room temperature overnight. The mixture was evaporated in vacuum to afford the crude product (245 mg, 99%), which was used for next step without further purification. [M+H]+=415.2.
The titled compound was prepared in a manner similar to that in Example 24 step 6.
1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.09 (s, 1H), 8.86 (d, J=6.4 Hz, 3H), 8.28 (d, J=8.4 Hz, 2H), 8.20 (s, 1H), 7.91 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.35 (s, 2H), 7.27 (d, J=8.5 Hz, 1H), 6.81 (s, 1H), 5.07 (d, J=7.8 Hz, 1H), 3.77 (s, 3H), 3.44 (m, 8H), 2.94 (m, 7H), 2.44-2.54 (m, 12H), 2.42-2.36 (m, 1H), 2.02 (d, J=14.2 Hz, 7H), 1.80-1.83 (m, 2H), 1.60-1.62 (m, 2H), 1.23 (s, 1H), 0.92 (t, 3H); [M+H]+=1090.4.
A solution of tert-butyl 5-bromopentanoate (2.00 g, 8.434 mmol), benzyl piperazine-1-carboxylate (1.86 g, 8.434 mmol) and DIEA (2.18 g, 16.868 mmol) in acetonitrile (20 mL) was stirred for 1 h at 85° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (2.52 g) which was used in the next step directly without further purification. [M+H]+=377.2.
A solution of benzyl 4-(5-(tert-butoxy)-5-oxopentyl)piperazine-1-carboxylate (2.50 g, crude), AcOH (20 mL) and Pd/C (1.20 g, 10% wt) in MeOH (20 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the crude product (1.53 g) which was used in the next step directly without further purification. [M+H]+=243.2.
A solution of tert-butyl 5-(piperazin-1-yl)pentanoate (600 mg, crude), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (684 mg, 2.48 mmol) and DIEA (1.60 g, 12.4 mmol) in DMSO (6 mL) was stirred for 1 h at 80° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (1.12 g) which was used in the next step directly without further purification [M+H]+=499.3.
A solution of tert-butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentanoate (800 mg, crude) and TFA (8 mL) in DCM (8 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water. The resulting mixture was concentrated under vacuum to afford the crude product (715 mg) which was used in the next step directly without further purification. [M+H]+=443.2.
The titled compound was prepared in a manner similar to that in Example 24 step 6.
1H NMR (400 MHz, CD3OD) δ 8.92 (s, 2H), 8.24-8.26 (m, 2H), 7.77 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J=7.4 Hz, 1H), 7.30 (s, 1H), 6.91 (s, 1H), 5.09 (s, 1H), 4.79 (s, 2H), 4.29 (s, 1H), 4.21 (d, J=12.6 Hz, 2H), 3.85 (s, 3H), 3.74 (d, J=10.2 Hz, 4H), 3.65-3.56 (m, 1H), 3.48-3.50 (m, 2H), 3.15 (d, J=13.7 Hz, 3H), 2.90 (d, J=13.3 Hz, 3H), 2.74 (d, J=13.9 Hz, 3H), 2.65-2.67 (m, 9H), 2.34 (s, 3H), 2.16 (d, J=14.4 Hz, 7H), 2.03 (s, 2H), 1.89 (s, 2H), 1.76 (s, 2H), 1.04-1.06 (m, 3H); [M+H]+=1118.
To a stirred solution of benzyl 4-formylpiperidine-1-carboxylate (1.01 g, 4.044 mmol), tert-butyl piperidine-4-carboxylate hydrochloride (897 mg, 4.044 mmol), AcONa (3.31 g, 40.4 mmol,) and DCM (20 mL) was added STAB (5.14 g, 24.263 mmol) in portions at 0° C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (1.20 g) which was used in the next step directly without further purification. [M+H]+=417.3.
A suspension of benzyl 4-((4-(tert-butoxycarbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.20 g, crude), AcOH (20 mL) and Pd/C (1.20 g, 10% wt) in MeOH (20 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the crude product (900 mg) which was used in the next step directly without further purification. [M+H]+=283.2.
A solution of tert-butyl 1-(piperidin-4-ylmethyl)piperidine-4-carboxylate (500 mg, crude) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (489 mg, 1.770 mmol), DIEA (1.14 g, 8.852 mmol) in DMSO (6 mL) was stirred for 1 h at 80° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (830 mg) which was used in the next step directly without further purification. [M+H]+=539.3.
A solution of tert-butyl 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) piperidin-4-yl)methyl)piperidine-4-carboxylate (810.00 mg, crude) and TFA (8 mL) in DCM (8 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water. The resulting mixture was concentrated under vacuum to afford the crude product (725 mg) which was used in the next step directly without further purification. [M+H]+=483.2.
The titled compound was prepared in a manner similar to that in Example 24 step 6.
1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.09 (s, 1H), 8.86 (s, 2H), 8.36-8.11 (m, 3H), 7.88 (s, 1H), 7.64 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 6.81 (s, 1H), 5.06 (s, 1H), 4.03 (s, 2H), 3.77 (s, 3H), 3.47 (s, 4H), 3.11-2.77 (m, 9H), 2.77-2.58 (m, 4H), 2.33 (m, 6H), 2.12 (s, 2H), 2.02 (d, J=14.3 Hz, 6H), 1.95-1.71 (m, 7H), 1.58 (s, 6H), 1.14 (m, 2H), 0.92 (s, 3H); [M+H]+=1158.
A mixture of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (The synthesis of this intermediate is described in WO2020051564) (300 mg, 0.91 mmol), tert-butyl 2-bromoacetate (890 mg, 4.6 mmol) and TEA (185 mg, 1.82 mmol) in THF (10 mL) was stirred in a flask at 60° C. for 3 hours. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to give the title product (280 mg, 69%). [M+H]+=443.2.
A solution of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetate (280 mg, 0.63 mmol) in HCl/1,4-dioxane (10 mL) was stirred in a flask at room temperature overnight. The mixture was evaporated in vacuum to afford the crude product (240 mg, 98%), which was used for next step without further purification. [M+H]+=387.2.
To a solution of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetic acid (23 mg, 0.06 mmol), HATU (23 mg, 0.06 mmol) and DIEA (20 mg, 0.15 mmol) in DMF (2 mL) was added (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (35 mg, 0.05 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was directly purified with pre-HPLC to give the product (9 mg, 14%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.71 (s, 1H), 8.85 (d, J=12.0 Hz, 3H), 8.28 (d, J=11.7 Hz, 2H), 7.90 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J=9.4 Hz, 1H), 7.01 (s, 1H), 6.80 (s, 1H), 5.30 (s, 2H), 4.58-4.53 (m, 1H), 3.76 (s, 3H), 3.58 (s, 2H), 3.47 (s, 2H), 3.22 (s, 3H), 3.00 (s, 4H), 2.40-2.57 (m, 12H), 2.36 (d, J=21.9 Hz, 3H), 2.02 (d, J=14.3 Hz, 8H), 1.84 (s, 2H), 1.61 (s, 2H), 1.23 (s, 1H), 0.92 (s, 3H); [M+H]+=1062.
The titled compound was synthesized in the procedures similar to Example 13. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.90 (s, 1H), 8.86 (s, 3H), 8.36 (s, 1H), 8.27 (s, 2H), 7.94 (s, 1H), 7.56 (s, 1H), 7.35 (s, 2H), 6.75 (s, 1H), 3.91 (d, J=12.0 Hz, 1H), 3.77 (s, 3H), 3.07 (s, 3H), 2.85-2.88 (m, 4H), 2.66 (s, 3H), 2.53 (s, 2H), 2.32 (s, 3H), 2.18-2.26 (m, 1H), 2.09 (s, 3H), 2.03 (d, J=13.8 Hz, 6H), 1.79 (m, 2H), 1.61 (m, 2H); [M+H]+=841.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.83 (s, 1H), 8.86 (d, J=9.0 Hz, 3H), 8.27 (s, 2H), 7.91 (s, 1H), 7.35 (s, 1H), 7.21 (s, 2H), 7.15 (s, 2H), 6.75 (s, 1H), 3.77 (s, 4H), 3.08 (s, 2H), 2.71 (d, J=28.8 Hz, 8H), 2.36 (s, 4H), 2.19 (s, 1H), 2.09 (s, 3H), 2.03 (d, J=14.2 Hz, 7H), 1.80 (s, 2H), 1.65 (s, 2H), 1.24 (s, 2H); [M+H]+=840.
The titled compound was synthesized in the procedures similar to Example 18. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.81 (s, 1H), 8.86 (d, J=8.6 Hz, 3H), 8.27 (s, 2H), 7.93 (d, J=7.8 Hz, 1H), 7.35 (s, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 6.76 (s, 1H), 4.05 (s, 2H), 3.77 (s, 4H), 3.11 (d, J=9.7 Hz, 2H), 2.86 (s, 2H), 2.66 (d, J=10.3 Hz, 3H), 2.52 (s, 1H), 2.48-2.42 (m, 1H), 2.34 (s, 3H), 2.16 (d, J=9.6 Hz, 1H), 2.10 (s, 3H), 2.02 (d, J=14.3 Hz, 7H), 1.83 (d, J=12.4 Hz, 2H), 1.64 (d, J=10.9 Hz, 2H); [M+H]+=856.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.79 (s, 1H), 8.87 (d, J=10.2 Hz, 3H), 8.28 (s, 2H), 7.94 (s, 1H), 7.37 (s, 1H), 7.03 (s, 2H), 6.92 (s, 2H), 6.76 (s, 1H), 3.78 (s, 6H), 3.13-3.28 (m, 6H), 2.51-2.70 (m, 6H), 2.11 (s, 4H), 2.03-2.05 (m, 8H), 1.62-1.88 (m, 6H), 1.18-1.26 (m, 3H); [M+H]+=909.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.78 (s, 1H), 8.87 (s, 3H), 8.27 (s, 2H), 7.94 (s, 1H), 7.03 (d, J=7.4 Hz, 2H), 6.90 (s, 2H), 6.76 (s, 1H), 3.77 (m, 8H), 3.09 (m, 2H), 2.67 (m, 6H), 2.24 (s, 3H), 2.10 (s, 3H), 2.03 (d, J=14.2 Hz, 6H), 1.79 (m, 3H), 1.64 (m, 2H), 1.41 (m, 3H), 1.24 (s, 6H); [M+H]+=923.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.26 (s, 1H), 8.87 (d, J=7.8 Hz, 3H), 8.27 (s, 2H), 7.94 (s, 1H), 7.35 (s, 1H), 7.13 (d, J=8.0 Hz, 2H), 6.93 (d, J=7.3 Hz, 2H), 6.76 (s, 1H), 3.77 (s, 3H), 3.69 (s, 4H), 3.09 (s, 3H), 2.66 (d, J=12.3 Hz, 6H), 2.52 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 2.03 (d, J=14.2 Hz, 6H), 1.76-1.79 (m, 4H), 1.55-1.64 (m, 2H), 1.38-1.50 (m, 3H), 1.19-1.30 (m, 2H); [M+H]+=924.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 10.37 (s, 1H), 8.84 (dd, J=8.4, 1.9 Hz, 3H), 8.25 (d, J=4.8 Hz, 2H), 7.90 (d, J=8.6 Hz, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 6.74 (s, 3H), 3.75 (s, 5H), 3.60 (t, J=6.7 Hz, 2H), 3.07 (d, J=11.2 Hz, 2H), 2.67 (t, J=6.7 Hz, 6H), 2.27 (d, J=24.6 Hz, 6H), 2.07 (s, 3H), 2.00 (d, J=14.4 Hz, 6H), 1.76 (s, 4H), 1.61 (s, 3H), 1.16 (d, J=11.3 Hz, 2H); [M+H]+=928.
A mixture of 1,2-difluoro-4-nitrobenzene (90.0 g, 566.0 mmol), piperidin-4-ylmethanol (90.0 g, 782.6 mmol), and TEA (90.0 g, 891.1 mmol) in MeOH (1 L) was stirred at 60° C. for 12 hours. The reaction mixture was cooled down to rt and concentrated. The residue was treated with water (500 mL) and filtered. The filtered cake was slurried with EA (50 mL) and dried to afford example 82-compound 2 (130 g, yield: 90%). [M+H]+=255.1.
To a solution of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol (130 g, 511.8 mmol) in EtOH (1.5 L) was added Pd/C (15 g) at rt. The reaction mixture was stirred at 50° C. for 16 hours under H2 (1 atm). The reaction mixture was cooled to rt, filtered and concentrated to afford the product (90 g, yield: 78%). [M+H]+=225.1.
A mixture of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (40.0 g, 178 mmol) and acrylic acid (40.0 g, 555 mmol) in toluene (500 mL) was stirred at 100° C. for 3 hours. The reaction mixture was cooled down to rt and filtered. The filtered cake was dried to afford the product (55 g, crude). [M+H]+=297.2.
A mixture of 3-((3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino) propanoic acid (55.0 g, crude) and urea (50.0 g, 833.3 mmol) in AcOH (600 mL) was stirred at 120° C. for 12 hours. The reaction mixture was cooled to rt and concentrated. The residue was poured into water (200 mL) and extracted with DCM (100 mL) for three times. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by chromatography on silica gel column (DCM/MeOH=20/1) to afford the product (55 g, yield: 81%). [M+H]+=364.2.
A solution of (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidin-4-yl)methyl acetate (50.0 g, 137.7 mmol) in MeOH (600 mL) was added AcCl (12.0 g, 152.8 mmol) at rt. The reaction mixture was stirred at rt for 12 hours. Then the reaction mixture was filtered. The filtered cake was dissolved in water (50 mL) and adjusted pH=7 with aq Na2CO3. The mixture was filtered and the filtered cake was triturated with DCM (20 mL) and dried to afford product (26.084 g, yield: 59%). 1H NMR (DMSO-d6, 400 MHz): δ 10.36 (s, 1H), 7.17-7.14 (m, 1H), 7.07-7.00 (m, 2H), 4.48 (t, J=4.8 Hz, 1H), 3.73 (t, J=5.2 Hz, 2H), 3.33-3.29 (m, 4H), 2.70-2.60 (m, 4H), 1.77-1.74 (m, 2H), 1.50-1.46 (m, 1H), 1.34-1.27 (m, 2H). [M+H]+=322.2.
Step 6: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidine-4-carbaldehyde
The titled compound was synthesized in a manner similar to that in Example 79 step 7 from 1-(3-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione and IBX. [M+H]+=320.2
The titled compound was synthesized in a manner similar to that in Example 79 step 8 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidine-4-carbaldehyde and (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.36 (s, 1H), 8.86 (d, J=4.6 Hz, 3H), 8.26 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.6 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=13.3 Hz, 1H), 7.05 (s, 2H), 6.76 (s, 1H), 3.83-3.67 (m, 5H), 3.35 (s, 2H), 3.09 (s, 2H), 2.68 (d, J=6.3 Hz, 7H), 2.34 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H), 2.03 (d, J=14.4 Hz, 6H), 1.83 (d, J=11.6 Hz, 4H), 1.63 (d, J=12.2 Hz, 3H), 1.28 (d, J=11.3 Hz, 2H); [M+H]+=928.
To a solution of 4-fluoro-2-methyl-1-nitrobenzene (31 g, 200 mmol) and 4-piperidinemethanol (28 g, 240 mmol) in DMF (200 mL) was added K2CO3 (55 g, 400 mmol) at 25° C. The mixture reaction was stirred at 80° C. for 15 h. The reaction was cooled to room temperature, the mixture was poured into ice-water (2000 mL) and stirred for 20 mins. The solid was filtered and washed with water (100 mL×2), dried to give the product (50 g, 100%). [M+H]+=251.2.
Under N2, to a solution of (1-(3-methyl-4-nitrophenyl)piperidin-4-yl)methanol (50 g, 200 mmol) in MeOH (500 mL) was added 10% Pd/C (5 g) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 15 h. The mixture was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to obtain the product (41 g, 93.0%). [M+H]+=221.2.
To a solution of (1-(4-amino-3-methylphenyl)piperidin-4-yl)methanol (41 g, 186 mmol) in toluene (200 mL) was added acrylic acid (41 g, 0.57 mol) at 25° C. The mixture was stirred at 80° C. for 2 h. The reaction was cooled to 25° C., then HOAc (200 mL) and urea (90 g, 1.5 mol) were added. The mixture was stirred at 110° C. for 24 h. The reaction was cooled to 25° C. and concentrated under vacuum. To the residue was added Na2CO3 (aqueous, saturated, 300 m1) and EtOAc(300 m1). The solid was filtered and dried to give the product (24 g, 36%). [M+H]+=360.2.
(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl acetate(24 g, 67 mmol) was added into 4N HCl (250 mL) at 25° C. The mixture was stirred at 100° C. for 30 min. The reaction was cooled to 10° C. and then adjusted to pH=7 with sat. NaHCO3. The solid was collected by filtrated, washed by water (50.0 mL), and dried to obtain the product (13 g, 61%). [M+H]+=318.2.
To a solution of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (10 g, 31 mmol) in DMSO (50 mL) was added IBX (18 g, 63 mmol) in portions at 25° C. The mixture was stirred at 25° C. for 15 h. Water (300 mL) was added to the reaction at 25° C. The solid was filtered and washed with water (100 mL) and then EtOAc (100.0 mL). The resulting solution was extracted with 4×200 mL of EtOAc. The combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford a crude residue. The crude product was purified by column chromatography to afford the product (5 g, 50%). [M+H]+=316.
The titled compound was synthesized in a manner similar to that in Example 79 step 8. 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 10.24 (s, 1H), 8.84 (dd, J=8.0, 1.9 Hz, 3H), 8.25 (d, J=4.5 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H), 7.32 (s, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.84-6.64 (m, 3H), 3.75 (s, 3H), 3.68 (d, J=9.4 Hz, 3H), 3.50-3.39 (m, 1H), 3.06 (s, 2H), 2.65 (dd, J=13.1, 9.2 Hz, 5H), 2.45-2.38 (m, 1H), 2.34-2.19 (m, 7H), 2.09 (d, J=7.8 Hz, 5H), 2.00 (d, J=14.4 Hz, 6H), 1.78 (s, 4H), 1.58-1.64 (m, 3H), 1.10-1.20 (m, 2H); [M+H]+=924.
A mixture of 1-fluoro-2-methyl-4-nitrobenzene (100.0 g, 645.2 mmol), piperidin-4-ylmethanol (111.3 g, 967.8 mmol) and DIEA (166.0 g, 1286.8 mmol) in THF (1.5 L) and DMF (50 mL) was stirred at 50° C. overnight. The reaction mixture was cooled down to rt, poured into water (1 L) and extracted with EA (500 mL) for three times. The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The residue was slurried with Et2O (100 mL) and dried to afford the product (75 g, yield: 46%). [M+H]+=251.1.
To a solution of (1-(2-methyl-4-nitrophenyl)piperidin-4-yl)methanol (75.0 g, 297.6 mmol) in EtOH (750 mL) was added Pd/C (7.5 g) at rt. The reaction mixture was stirred at 60° C. overnight under H2 (1 atm). The reaction mixture was cooled to rt, filtered and concentrated to afford the product (65 g, yield: 99%). [M+H]+=221.2.
A mixture of (1-(4-amino-2-methylphenyl)piperidin-4-yl)methanol (22.0 g, 99.1 mmol) and acrylic acid (22.0 g, 3055.6 mmol) in toluene (300 mL) was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled down to rt and filtered. The filtered cake was dried to afford the product (27.8 g, yield: 96%). [M+H]+=293.2.
A mixture of 3-((4-(4-(hydroxymethyl)piperidin-1-yl)-3-methylphenyl)amino)propanoic acid (27.8 g, 95.1 mmol) and urea (18.0 g, 300.0 mmol) in AcOH (500 mL) was stirred at 120° C. overnight. The reaction mixture was cooled to rt and concentrated. The residue was poured into water (200 mL) and extracted with DCM (100 mL) for three times. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by chromatography on silica gel column (DCM/MeOH=20/1) to afford the product (19.1 g, yield: 56%). [M+H]+=360.2.
To a solution of (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-4-yl)methyl acetate (19.1 g, 53.2 mmol) in MeOH (500 mL) was added AcCl (8.4 g, 106.4 mmol) at rt. The reaction mixture was stirred at rt overnight. Then the reaction mixture was filtered. The filtered cake was dissolved in water (50 mL) and adjusted pH=7 with sat. Na2CO3. The mixture was filtered and the filtered cake was slurried with acetonitrile (20 mL) and dried to afford the product (10.96 g, yield: 65%). 1H NMR (DMSO-d6, 400 MHz): δ 10.28 (s, 1H), 7.10-6.99 (m, 3H), 4.48 (t, J=4.8 Hz, 1H), 3.71 (t, J=5.2 Hz, 2H), 3.33-3.31 (m, 2H), 3.04 (d, J=11.2 Hz, 2H), 2.67 (t, J=5.2 Hz, 2H), 2.59-2.53 (m, 2H), 2.22 (s, 3H), 1.77-1.74 (m, 2H), 1.52-1.44 (m, 1H), 1.34-1.24 (m, 2H). [M+H]+=318.1.
The titled compound was synthesized in a manner similar to that in Example 79 step 7 from 1-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione and IBX. [M+H]+=316.2.
The titled compound was synthesized in a manner similar to that in Example 79 step 8. 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.29 (s, 1H), 8.85 (dd, J=6.8, 2.0 Hz, 3H), 8.25 (s, 2H), 7.92 (s, 1H), 7.33 (s, 1H), 7.15-6.92 (m, 3H), 6.75 (s, 1H), 3.76 (s, 3H), 3.69 (t, J=6.7 Hz, 2H), 3.02 (m, 4H), 2.66 (m, 6H), 2.32 (s, 3H), 2.23 (m, 6H), 2.09 (s, 3H), 2.01 (d, J=14.4 Hz, 6H), 1.80 (m, 4H), 1.62 (m, 3H), 1.27 (m, 3H); [M+H]+=926.
To a solution of 4-aminophenol (250 g, 2.29 mol) and acrylic acid (363 g, 5.04 mol) in the water (1.25 L) was stirred at 80˜85° C. for 16 hrs. The mixture was cooled to 20-25° C. The reaction mixture was filtered and the filter cake was washed with H2O (2.00 L). The filter cake was concentrated in vacuum to afford the product (552 g, 95.1% yield). 1H NMR (400 MHz, DMSO) δH 12.18 (br s, 2H), 8.67 (br s, 1H), 6.48-6.88 (m, 4H), 3.38 (s, 5H), 2.36 (t, J=7.06 Hz, 4H).
To a solution of 3,3′-((4-hydroxyphenyl)azanediyl)dipropionic acid (300 g, 1.18 mol) in the AcOH (1.50 L) was added urea (106 g, 1.76 mol) at 20˜30° C. After addition, the mixture was stirred at 120˜130° C. for 12 hrs. 10.0% HCl (1.00 L) was added to the reactor at 120˜130° C. After addition, the mixture was stirred at 120˜130° C. for 1 hr. The reaction mixture was cooled to 20° C., filtered and the filter cake was rinsed with petroleum ether (2.00 L) to afford the crude product (185 g). 1H NMR (400 MHz, DMSO) δH 10.3 (s, 1H), 9.45 (s, 1H), 7.00-7.26 (m, 2H), 6.67-6.86 (m, 2H), 3.67 (t, J=6.72 Hz, 2H), 2.67 (t, J=6.72 Hz, 2H).
To a solution of 1-(4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (80.0 g, crude) and imidazole (52.8 g, 0.770 mol) in the DCM (400 mL) was added TBSCl (64.3 g, 0.420 mol) at 10˜15° C. Then the mixture was stirred at 25° C. for 12 hrs. The reaction mixture was partitioned between DCM (400 mL) and water (500 mL). The aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL) and dried with anhydrous Na2SO4. The solvent was removed to afford the product (120 g, 96.1% yield). 1H NMR (400 MHz, DMSO) δH 10.31 (s, 1H), 7.07-7.40 (m, 2H), 6.67-6.95 (m, 2H), 3.72 (t, J=6.73 Hz, 2H), 2.68 (t, J=6.73 Hz, 2H), 0.95 (s, 9H), 0.20 (s, 6H).
To a solution of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (85.0 g, 0.265 mol) and DIEA (137 g, 1.06 mol) in the ACN (425 mL) was added SEMCl (88.4 g, 0.530 mol) at 25° C. The mixture was stirred at 85° C. for 12 hrs. TLC indicated starting material was consumed. The reaction mixture was cooled to 25° C. and put into water (500 mL). The mixture was filtered and concentrated in reduced pressure at 45° C. The residue was purified by activated carbon, then purified by silica gel to give product (81.8 g, 68.6% yield). 1H NMR (400 MHz, DMSO) δH 7.03-7.21 (m, 2H), 6.85 (d, J=8.60 Hz, 2H), 5.29 (s, 2H), 3.78 (t, J=6.62 Hz, 2H), 3.61-3.72 (m, 2H), 2.89 (t, J=6.62 Hz, 2H), 0.98 (s, 9H), 0.72-0.93 (m, 1H), 0.20 (s, 5H), 0.04-0.04 (m, 10H).
To a solution of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (81.8 g, 0.182 mol) and NH4F (13.5 g, 0.364 mol) in the MeOH (620 mL) was stirred at 20° C. for 1 hr. TLC indicated starting material was consumed. The resulting solution was filtered and the filtrate was concentrated to afford the crude residue. The crude product was triturated with petroleum ether: ethyl acetate=10: 1 (200 mL) at 15° C. for 45 mins to afford the product (41.9 g, 68.6% yield). 1H NMR (400 MHz, CDCl3) δH 6.96-7.15 (m, 2H), 6.63-6.84 (m, 2H), 5.31 (s, 2H), 5.93 (s, 1H), 3.76 (t, J=6.80 Hz, 2H), 3.66-3.73 (m, 2H), 2.90 (t, J=6.58 Hz, 2 H), 0.87-1.16 (m, 2H), 0.02 (s, 9H).
To a solution of PPh3 (56.1 g, 214 mmol), 1-(4-hydroxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (41.9 g, 125 mmol), 3-iodopropan-1-ol (53.1 g, 285 mmol, 27.3 mL) in THF (250 mL) was added DIAD (43.2 g, 214 mmol), the reaction was stirred at 15° C. for 3 hrs. TLC showed the staring material was consumed completely and the product was formed. The mixture was concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with Petroleum ether in Ethyl acetate=100˜0% to give the product (25.0 g, 39.7% yield). [M+Na]+=527.
The titled compound was prepared in a manner similar to that in Example 18 step 7. [M+H]+=1001.
The titled compound was prepared in a manner similar to that in Example 18 step 8.
1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.32 (s, 1H), 8.86 (d, J=9.4 Hz, 3H), 8.27 (s, 2H), 7.94 (s, 1H), 7.34 (s, 1H), 7.23 (d, J=8.7 Hz, 2H), 6.95 (d, J=8.6 Hz, 2H), 6.75 (s, 1H), 4.03 (s, 2H), 3.77 (s, 3H), 3.71 (s, 2H), 3.07 (s, 2H), 2.65 (d, J=29.3 Hz, 6H), 2.26 (s, 3H), 2.09 (s, 3H), 2.02 (d, J=14.3 Hz, 6H), 1.86 (s, 2H), 1.77 (s, 2H), 1.63 (s, 2H), 1.24 (s, 1H); [M+H]+=871.
The titled compound was synthesized in the procedures similar to Example 1. 1HNMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.84 (s, 1H), 8.86 (s, 3H), 8.28 (d, J=12.1 Hz, 2H), 7.95 (s, 1H), 7.34 (s, 1H), 7.23 (s, 2H), 7.16 (s, 2H), 6.80 (s, 1H), 3.79 (s, 4H), 2.90 (s, 5H), 2.79 (s, 3H), 2.65 (d, J=16.2 Hz, 8H), 2.17 (s, 1H), 2.11 (s, 3H), 2.02 (d, J=14.1 Hz, 6H); [M+H]+=812.
The titled compound was synthesized in the procedures similar to Example 13. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.91 (s, 1H), 8.87 (s, 3H), 8.37 (s, 1H), 8.28 (d, J=9.4 Hz, 2H), 7.94 (d, J=8.5 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.40-7.20 (m, 2H), 6.80 (s, 1H), 3.92 (d, J=12.0 Hz, 1H), 3.78 (s, 3H), 2.92 (d, J=19.0 Hz, 6H), 2.82-2.55 (m, 8H), 2.37-2.19 (m, 1H), 2.11 (s, 3H), 2.03 (d, J=13.7 Hz, 7H); [M+H]+=813.
The titled compound was synthesized in the procedures similar to Example 22. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.79 (s, 1H), 8.86 (d, J=5.2 Hz, 3H), 8.27 (s, 2H), 7.94 (d, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.04 (d, J=7.9 Hz, 2H), 6.90 (d, J=7.5 Hz, 2H), 6.81 (s, 1H), 3.79 (s, 3H), 3.68 (d, J=13.6 Hz, 3H), 2.90 (s, 4H), 2.72-2.55 (m, 5H), 2.45 (s, 2H), 2.26 (s, 2H), 2.19-1.95 (m, 11H), 1.83 (d, J=11.7 Hz, 2H), 1.71 (s, 1H), 1.24 (d, J=8.7 Hz, 2H); [M+H]+=881.
The titled compound was synthesized in the procedures similar to Example 22.1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.78 (s, 1H), 8.86 (s, 3H), 8.23 (s, 2H), 7.95 (s, 1H), 7.32 (s, 1H), 7.04 (d, J=7.1 Hz, 2H), 6.91 (s, 2H), 6.69 (s, 1H), 6.50 (s, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.18 (s, 4H), 3.04-2.87 (m, 1H), 2.66 (s, 6H), 2.47-2.40 (m, 1H), 2.24 (m, 2H), 2.12 (m, 1H), 2.02 (d, J=14.1 Hz, 7H), 1.89-1.68 (m, 3H), 1.19-1.25 (m, 2H); [M+H]+=867.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.78 (s, 1H), 8.86 (d, J=6.6 Hz, 3H), 8.27 (s, 2H), 7.94 (s, 1H), 7.35 (s, 1H), 7.02 (s, 2H), 6.89 (d, J=7.7 Hz, 2H), 6.79 (s, 1H), 3.60-3.88 (m, 6H), 2.84-2.90 (m, 4H), 2.63 (t, J=12.2 Hz, 3H), 2.40-2.45 (m, 4H), 2.02-2.15 (m, 12H), 1.78 (d, J=10.5 Hz, 3H), 1.46 (s, 3H), 1.26-1.30 (m, 3H); [M+H]+=895.
The titled compound was synthesized in the procedures similar to Example 18. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.81 (s, 1H), 8.86 (d, J=8.0 Hz, 3H), 8.28 (d, J=10.1 Hz, 2H), 7.93 (d, J=8.7 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 6.80 (s, 1H), 4.13 (s, 2H), 3.78 (s, 4H), 2.90 (s, 4H), 2.79 (s, 2H), 2.68 (s, 5H), 2.40-2.50 (m,2 H)2.17 (d, J=11.5 Hz, 1H), 2.10 (s, 3H), 2.02 (d, J=14.3 Hz, 6H); [M+H]+=828.
Hydroquinone (10.6 g, 96.1 mmol) was dissolved in DMF (100 mL). The solution was added (3-bromopropoxy)(tert-butyl)dimethylsilane (23.0 g, 91 mmol) and Cs2CO3 (45.0 g, 138.1 mmol). The mixture was stirred at 50° C. for 2h. The mixture was diluted with water (100 mL), extracted with EA (150 mL×2). The combined organic lays were washed with water (50 mL×3) and brine (50 mL×2), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography to obtain the product (8.5 g, 31.3%). 1H NMR (400 MHz, CDCl3) δH 6.80-6.74 (m, 4H), 4.50 (s, 1H), 4.00 (t, J=6.4 Hz, 2H), 3.79 (t, J=6.4 Hz, 2H), 1.96 (t, J=6.0 Hz, 2H), 0.89 (s, 9H).
Br2 (25.4 g, 158 mmol) was added to a solution of piperidine-2,6-dione (15.0 g, 132 mmol) in CHCl3 (30 mL), the mixture is stirred for 4 h at 110° C. After cooling, the mixture was added water (200 mL), extracted with EA (200 mL×2). The combined organic lays were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (7.9 g, 31%). [M+H]+=192.
4-(3-((Tert-butyldimethylsilyl)oxy)propoxy)phenol (22.1 g, 78.1 mmol) was dissolved in THF (100 mL). The solution was added NaH (4.7 g, 60%, 117.2 mmol) at 0° C., the resulting mixture was stirred for 1h. Then the mixture was dropped into a solution of 3-bromopiperidine-2,6-dione (15.0 g, 78.1 mmol) in THF (100 mL). The mixture was stirred at 60° C. for 2 h, then added saturated aqueous solution of NH4Cl (100 mL) at 0° C., extracted with EA (100 mL×4). The combined organic phases were washed with water (50 mL×2) and brine (50 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (14.5 g, 47%). 1H NMR (400 MHz, CDCl3) δH 7.85 (s, 1H), 6.99-6.96 (m, 2H), 6.85-6.83 (m, 2H), 4.71-4.74 (dd, J1=12.0, 3.3 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H), 3.79 (t, J=6.0 Hz, 2H), 2.90-2.98 (m, 1H), 2.69-2.61 (m, 1H), 2.30-2.04 (m, 2H), 1.97-1.93 (m, 2H), 0.89 (s, 9H); [M+H]+=394.2.
3-(4-(3-((Tert-butyldimethylsilyl)oxy)propoxy)phenoxy)piperidine-2,6-dione (19.0 g, 48.3 mmol) was dissolved in THF (200 mL), was added TBAF (1M in THF) (72.5 mL, 72.5 mmol), the mixture was stirred at 25° C. for 5 h. The mixture was added water (100 mL), extracted with EA (150 mL×2). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography) to give the product (5.3 g, 39.3%). 1H NMR (400 MHz, DMSO) δH 10.89 (s, 1H), 6.94 (d, J=9.1 Hz, 2H), 6.84 (d, J=9.1 Hz, 2H), 5.02 (dd, J=10.5, 4.9 Hz, 1H), 4.51 (t, J=5.1 Hz, 1H), 3.97 (t, J=6.4 Hz, 2H), 3.56-3.52 (m, 2H), 2.76-2.54 (m, 2H), 2.23-2.02 (m, 2H), 1.88-1.79 (m, 2H). [M+H]+=280.2.
The titled compound was prepared in a manner similar to that in Example 23 step 11. [M+H]+=278.
The titled compound was prepared in a manner similar to that in Example 23 step 12. 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.92 (s, 1H), 8.87 (d, J=11.4 Hz, 3H), 8.29 (d, J=7.7 Hz, 2H), 7.95 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 6.97 (d, J=8.0 Hz, 2H), 6.89 (d, J=7.3 Hz, 2H), 6.78 (s, 1H), 5.05 (s, 1H), 4.02 (s, 2H), 3.80 (s, 3H), 2.99 (s, 5H), 2.45-2.70 (m, 4H), 1.85-2.25 (m, 15H), 1.23 (s, 1H); [M+H]+=858. Example 93: 3-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperazin-1-yl)ethyl)phenoxy)piperidine-2,6-dione
The titled compound was synthesized in the procedures similar to Example 18. 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.94 (s, 1H), 8.87 (d, J=8.3 Hz, 2H), 8.29 (d, J=11.5 Hz, 2H), 8.11 (d, J=17.5 Hz, 1H), 7.95 (s, 1H), 7.37 (s, 1H), 7.18 (s, 2H), 6.97 (s, 2H), 6.79 (s, 1H), 6.54 (s, 1H), 5.16 (s, 1H), 3.79 (s, 3H), 2.75 (dd, J=79.7, 43.5 Hz, 14H), 2.11 (s, 5H), 2.03 (d, J=14.3 Hz, 6H), 1.58 (d, J=13.2 Hz, 1H); [M+H]+=828.
The titled compound was synthesized in the procedures similar to Example 55. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.27 (s, 1H), 8.86 (d, J=7.9 Hz, 3H), 8.26 (t, J=13.1 Hz, 2H), 7.92 (s, 1H), 7.35 (s, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.93 (d, J=7.5 Hz, 2H), 6.80 (s, 1H), 3.78 (s, 3H), 3.69 (s, 4H), 2.89 (s, 4H), 2.66-2.88 (m, 4H), 2.38-2.42 (m, 5H), 2.10 (s, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.79 (d, J=13.0 Hz, 2H), 1.46 (s, 3H), 1.29 (s, 3H); [M+H]+=896.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.26 (s, 1H), 8.86 (d, J=5.7 Hz, 3H), 8.27 (s, 2H), 7.95 (s, 1H), 7.36 (s, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.94 (d, J=7.6 Hz, 2H), 6.81 (s, 1H), 3.79 (s, 3H), 3.70 (s, 4H), 2.90 (s, 4H), 2.68 (s, 5H), 2.54 (s, 3H), 2.27 (s, 2H), 2.10 (s, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.83 (m, 2H), 1.73 (s, 1H), 1.24 (m, 3H); [M+H]+=882.
The titled compound was synthesized in the procedures similar to Example 82. 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 10.36 (s, 1H), 8.84 (s, 3H), 8.25 (s, 2H), 7.92 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 6.78 (s, 3H), 3.76 (s, 4H), 3.60 (s, 1H), 2.87 (s, 4H), 2.67 (s, 4H), 2.23 (s, 4H), 2.11-1.91 (m, 10H), 1.77 (s, 5H), 1.20 (s, 3H); [M+H]+=900.
The titled compound was synthesized in the procedures similar to Example 82. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.35 (s, 1H), 8.86 (d, J=5.4 Hz, 3H), 8.27 (s, 2H), 7.94 (d, J=10.0 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=12.7 Hz, 1H), 7.06 (s, 2H), 6.81 (s, 1H), 3.79 (s, 3H), 3.74 (s, 2H), 3.34 (s, 2H), 2.90 (s, 4H), 2.68 (d, J=5.4 Hz, 4H), 2.52 (s, 4H), 2.28 (s, 2H), 2.10 (s, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.85 (d, J=11.0 Hz, 2H), 1.71 (s, 1H), 1.32 (d, J=10.7 Hz, 2H); [M+H]+=900.
The titled compound was synthesized in the procedures similar to Example 84. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.28 (s, 1H), 8.86 (d, J=5.8 Hz, 3H), 8.27 (s, 2H), 7.94 (d, J=9.0 Hz, 1H), 7.36 (s, 1H), 7.11 (s, 2H), 7.02 (d, J=8.5 Hz, 1H), 6.80 (s, 1H), 3.79 (s, 3H), 3.71 (s, 2H), 3.06 (d, J=10.8 Hz, 2H), 2.90 (s, 4H), 2.73-2.55 (m, 7H), 2.29 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.86 (d, J=12.0 Hz, 2H), 1.70 (s, 1H), 1.31 (d, J=11.1 Hz, 2H); [M+H]+=896.
The titled compound was synthesized in the procedures similar to Example 82. 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 10.34 (s, 1H), 8.95 (s, 3H), 8.35 (s, 2H), 8.01 (s, 1H), 7.44 (s, 1H), 7.12 (s, 1H), 6.90 (s, 3H), 3.87 (s, 2H), 3.77 (s, 3H), 2.98 (s, 4H), 2.60-2.80 (m, 7H), 2.34 (s, 2H), 2.25-2.05 (m, 12H), 1.70-1.95 (m, 5H), 1.32 (s, 3H); [M+H]+=896.
A mixture of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (500 mg, 2.70 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (782 mg, 3.24 mmol) and K2CO3 (932 mg, 6.75 mmol) in DMF (10 mL) was stirred in a flask at 80° C. overnight. The reaction was cooled to room temperature, quenched with water and extracted with DCM (2×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜20: 1 gradient elution) to give the product (350 mg, 32%). [M+H]+=407.3.
Under N2, to a solution of tert-butyl 3-(4-(5-methoxy-2-methyl-4-nitrophenyl)piperazin-1-yl)azetidine-1-carboxylate (350 mg, 0.861 mmol) in MeOH (15 mL) was added 10% Pd/C (100 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 12 h. Reaction was monitored by LCMS. The mixture was filtered through a pad of Celite and washed with MeOH (15 mL). The filtrate was concentrated under vacuum to obtain the product (300 mg, 93%). [M+H]+*=377.4.
A mixture of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (100 mg, 0.242 mmol), tert-butyl 3-(4-(4-amino-5-methoxy-2-methylphenyl)piperazin-1-yl)azetidine-1-carboxylate (119 mg, 0.315 mmol) and MsOH (93 mg, 0.968 mmol) in t-BuOH (10 mL) was stirred in a flask at 100° C. overnight under N2. The mixture was evaporated in vacuum. The residue was diluted with DCM (10 mL) and washed with H2O (2×20 mL) and brine(2×10 mL), dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product which was used for next step without further purification (110 mg, 61%). [M+H]+=652.5.
To a solution of 5-((4-(2,6-dioxopiperidin-3-yl)phenyl)carbamoyl)pyrazine-2-carboxylic acid (30.6 mg, 0.086 mmol), HATU (36 mg, 0.095 mmol) and DIEA (33 mg, 0.258 mmol) in DMF (3 mL) was added (6-((2-((4-(4-(azetidin-3-yl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide methanesulfonate (64 mg, 0.086 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction was directly purified with pre-HPLC to give the title product (6 mg, 7%). 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 10.93 (s, 1H), 10.86 (s, 1H), 9.26 (d, J=36.9 Hz, 1H), 8.87 (d, J=6.7 Hz, 3H), 8.29 (d, J=15.8 Hz, 2H), 7.93 (d, J=8.4 Hz, 1H), 7.86 (d, J=7.2 Hz, 2H), 7.36 (s, 1H), 7.24 (d, J=7.0 Hz, 2H), 6.80 (s, 1H), 4.69 (s, 1H), 4.49 (s, 1H), 4.23 (s, 1H), 4.04 (s, 1H), 3.85 (d, J=8.0 Hz, 1H), 3.79 (s, 3H), 2.93 (s, 5H), 2.69 (s, 2H), 2.53 (s, 3H), 2.23 (d, J=11.6 Hz, 1H), 2.11 (s, 3H), 2.03 (d, J=14.4 Hz, 8H).[M+H]+=988.5.
A mixture of 4-bromo-2-methoxy-1-nitrobenzene (500 mg, 2.16 mmol), tert-butly 4-vinylpiperidine-1-carboxylate (455 mg, 2.16 mmol), TEA (1.09 g, 10.79 mmol) and dichlorobis(tri-O— tolylphosphine)palladium(II) (C:40691-33-6) (170 mg, 0.216 mmol) in DMF (5 mL) was stirred at 130° C. for 1.5 h under N2. The reaction was quenched with water and the mixture was washed with saturated brine, then extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified by Prep-TLC with (EA:PE=1:2) to give the product (180 mg, 23.0%). [M+H]+=363.
Step 2: Tert-butyl-4-(4-amino-3-methoxyphenethyl)piperidine-1-carboxylate
A mixture of tert-butyl(E)-4-(3-methoxy-4-nitrostyryl)piperidine-1-carboxylate (180 mg, 0.50 mmol), 10% Pd/C (180 mg), AcOH (0.02 m1) in MeOH (3 m1) was stirred overnight under H2 at RT. The solid was filtered out and the filtrate was concentrated under reduced pressure to give the product (160 mg, 96.4%). [M+H]+=335.
The titled compound was prepared in a manner similar to that in Example 23 step 6. [M+H]+=610.
The titled compound was synthesized in a manner similar to that in Example 79 step 8 from (2-((5-chloro-2-((2-methoxy-4-(2-(piperidin-4-yl)ethyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide and 2-(4-(2,6-dioxopiperidin-3-yl)phenyl) acetaldehyde. 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.86 (d, J=9.5 Hz, 3H), 8.45-8.25 (m, 2H), 7.98 (s, 1H), 7.52 (s, 1H), 7.14 (d, J=15.2 Hz, 4H), 6.94 (s, 1H), 6.74 (s, 1H), 3.80 (s, 4H), 2.85-3.00 (m, 4H), 2.58-2.70 (m, 6H), 2.16 (s, 1H), 2.02 (d, J=14.3 Hz, 6H), 1.87 (s, 2H), 1.72 (s, 2H), 1.54 (s, 2H), 1.24 (m, 4H); [M+H]+=825.
The titled compound was synthesized in the procedures similar to Example 103. 1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.99 (s, 1H), 8.86 (s, 3H), 8.40 (s, 1H), 8.27 (s, 2H), 7.93 (s, 2H), 7.49-7.27 (m, 5H), 6.78 (s, 1H), 5.12 (s, 1H), 4.92 (s, 1H), 4.53 (s, 1H), 4.43 (s, 1H), 4.29 (s, 1H), 3.79 (s, 3H), 3.62 (s, 2H), 2.92 (s, 5H), 2.62 (d, J=44.6 Hz, 4H), 2.45 (s, 6H), 2.13-1.88 (m, 10H), 1.74 (s, 3H), 1.38 (s, 3H), 0.96 (s, 9H); [M+H]+=1109.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (90 mg, 0.13 mmol) and tert-butyl 3-(2-bromoethoxy)propanoate (50 mg, 0.20 mmol) in DMF(2 mL) was added K2CO3(37 mg, 0.26 mmol). The resulting mixture was heated at 90° C. for 1 hour. The crude solution was purified with flash C18 column chromatography to give the title product (50 mg, 45%). [M+H]+=866.
A solution of tert-butyl 3-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethoxy)propanoate (50 mg, 0.057 mmol) in HCl/1,4-dioxane (3 mL) was stirred in a round bottom flask at room temperature overnight. The mixture was evaporated in vacuum to afford the crude product (40 mg, 87%), which was used for next step without further purification. [M+H]+=810.
To a solution of 3-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethoxy)propanoic acid (40 mg, 0.049 mmol), HATU (22 mg, 0.05 mmol) and DIEA (24 mg, 0.15 mmol) in DMF(2 mL) was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (26 mg, 0.05 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was directly purified with pre-HPLC to give the title product (10 mg, 16.6%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.98 (s, 1H), 8.86 (d, J=7.7 Hz, 3H), 8.59 (s, 1H), 8.29 (d, J=10.1 Hz, 2H), 7.97 (s, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.40 (d, J=9.5 Hz, 5H), 6.81 (s, 1H), 5.16 (s, 1H), 4.57 (d, J=9.2 Hz, 1H), 4.43 (s, 2H), 4.36 (s, 1H), 4.22 (d, J=10.9 Hz, 1H), 3.77 (s, 3H), 3.64 (m, 7H), 3.02 (m, 4H), 2.71 (m, 4H), 2.50-2.54 (m, 5H), 2.40-2.48 (m, 7H), 2.02 (d, J=14.4 Hz, 8H), 1.91 (s, 3H), 1.63 (s, 2H), 0.95 (m, 13H); [M+H]+=1222.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 10.83 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=5.9 Hz, 2H), 7.53 (dd, J=14.1, 7.5 Hz, 1H), 7.42-7.29 (m, 2H), 7.13 (dt, J=13.5, 7.5 Hz, 5H), 6.63 (s, 1H), 6.47 (d, J=8.5 Hz, 1H), 3.84-3.68 (m, 6H), 3.09-2.89 (m, 1H), 2.75-2.60 (m, 6H), 2.54 (s, 5H), 2.45-2.30 (m, 5H), 2.17 (d, J=8.5 Hz, 1H), 2.03 (s, 1H), 1.86 (d, J=11.9 Hz, 2H), 1.76 (d, J=13.5 Hz, 6H), 1.53 (d, J=10.4 Hz, 2H); [M+H]+=785.4.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.79 (s, 1H), 8.49 (s, 1H), 8.08 (d, J=10.7 Hz, 2H), 7.54 (s, 1H), 7.46-7.29 (m, 2H), 7.11 (s, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.89 (d, J=7.8 Hz, 2H), 6.64 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.77 (s, 3H), 3.68 (d, J=14.3 Hz, 3H), 3.15 (s, 4H), 2.72-2.52 (m, 8H), 2.24 (d, J=6.9 Hz, 2H), 2.12 (s, 1H), 2.01 (s, 1H), 1.79 (t, J=18.0 Hz, 9H), 1.23 (d, J=10.9 Hz, 2H); [M+H]+=771.3.
The titled compound was synthesized in the procedures similar to Example 23. 1H NMR (400 MHz, DMSO) δH 11.19 (s, 1H), 10.78 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=5.1 Hz, 2H), 7.58-7.47 (m, 1H), 7.42-7.28 (m, 2H), 7.10 (d, J=7.1 Hz, 1H), 7.03 (d, J=8.2 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 6.47 (d, J=8.6 Hz, 1H), 3.74 (d, J=15.4 Hz, 6H), 3.64 (d, J=11.5 Hz, 2H), 3.12-2.88 (m, 1H), 2.72-2.52 (m, 10H), 2.43 (s, 6H), 2.11 (s, 1H), 2.01 (s, 1H), 1.88 (d, J=11.3 Hz, 2H), 1.76 (d, J=13.3 Hz, 8H), 1.54 (d, J=10.2 Hz, 2H), 1.42 (s, 3H), 1.24 (d, J=7.5 Hz, 2H); [M+H]+=868.4.
The titled compound was synthesized in the procedures similar to Example 24. 1H NMR (400 MHz, DMSO) δH 11.19 (s, 1H), 10.78 (s, 1H), 8.48 (s, 1H), 8.08 (d, J=6.3 Hz, 2H), 7.53 (dd, J=13.8, 7.7 Hz, 1H), 7.43-7.29 (m, 2H), 7.10 (d, J=7.3 Hz, 1H), 7.03 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.64 (s, 1H), 6.48 (d, J=8.1 Hz, 1H), 3.83-3.60 (m, 9H), 3.47 (s, 3H), 2.70-2.61 (m, 7H), 2.43 (s, 2H), 2.28 (s, 3H), 2.12 (d, J=9.4 Hz, 1H), 2.01 (s, 1H), 1.88 (s, 3H), 1.76 (d, J=13.5 Hz, 9H), 1.59 (s, 2H), 1.34-1.22 (m, 2H); [M+H]+=882.4.
The titled compound was synthesized in the procedures similar to Example 48. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 10.78 (s, 1H), 8.48 (s, 1H), 8.07 (s, 2H), 7.53 (dd, J=14.2, 7.5 Hz, 1H), 7.36 (s, 2H), 7.09 (s, 1H), 6.93 (d, J=7.9 Hz, 2H), 6.66-6.55 (m, 3H), 6.47 (d, J=8.1 Hz, 1H), 5.64 (s, 1H), 4.26 (s, 1H), 3.73 (d, J=18.8 Hz, 5H), 3.04-2.94 (m, 1H), 2.68 (d, J=11.5 Hz, 4H), 2.56 (d, J=16.7 Hz, 5H), 2.42 (d, J=6.4 Hz, 5H), 2.33 (s, 2H), 2.09 (s, 1H), 1.86 (d, J=10.8 Hz, 3H), 1.76 (d, J=13.4 Hz, 6H), 1.54 (s, 2H); [M+H]+=800.4.
The titled compound was synthesized in the procedures similar to Example 92. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 10.91 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=7.0 Hz, 2H), 7.53 (dd, J=13.9, 7.6 Hz, 1H), 7.42-7.28 (m, 2H), 7.09 (t, J=7.3 Hz, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 6.63 (s, 1H), 6.47 (d, J=8.6 Hz, 1H), 5.07-4.99 (m, 1H), 3.94 (s, 2H), 3.73 (d, J=19.4 Hz, 5H), 2.71-2.60 (m, 4H), 2.52 (s, 4H), 2.45-2.32 (m, 7H), 2.22-2.05 (m, 2H), 1.84 (s, 4H), 1.76 (d, J=13.5 Hz, 6H), 1.53 (d, J=11.0 Hz, 2H); [M+H]+=831.4.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 10.27 (s, 1H), 8.49 (s, 1H), 8.07 (s, 2H), 7.52 (d, J=13.2 Hz, 1H), 7.43-7.28 (m, 2H), 7.13 (d, J=8.2 Hz, 3H), 6.92 (d, J=7.6 Hz, 2H), 6.63 (s, 1H), 6.47 (d, J=8.1 Hz, 1H), 3.80-3.63 (m, 10H), 2.72-2.54 (m, 9H), 2.37 (s, 5H), 2.15 (s, 2H), 1.86 (d, J=10.5 Hz, 2H), 1.77 (d, J=13.1 Hz, 8H), 1.66 (s, 1H), 1.53 (d, J=11.4 Hz, 2H), 1.19 (d, J=10.7 Hz, 2H); [M+H]+=855.4.
To a solution of 2-(4-(bromomethyl)phenyl)acetic acid (50.0 g, 218 mmol) in THF (250 mL) was added dropwise BH3−THF (1M, 261 mL) at 0° C. The mixture was stirred at 15° C. for 5 hrs. TLC (Petroleum ether: Ethyl acetate=1: 1) showed the reaction was completed. The mixture was added sat. K2CO3 (200 mL), the THF of the biphasic mixture was removed in vacuo and the resulting aqueous phase was extracted with EtOAc (250 mL×2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum to provide the product (46.0 g, 213 mmol, 97.9%). 1H NMR (400 MHz, CDCl3) δH 7.36 (d, J=8.16 Hz, 2H), 7.22 (d, J=8.16 Hz, 2H), 4.50 (s, 2H), 3.87 (q, J=6.18 Hz, 2H), 2.88 (t, J=6.62 Hz, 2H), 1.39 (t, J=5.96 Hz, 1H).
To a solution of 2-(4-(bromomethyl)phenyl)ethan-1-ol (46.0 g, 213 mmol) in DCM (230 mL) was added imidazole (15.2 g, 224 mmol) and TBSCl (33.8 g, 224 mmol) at 0° C. The mixture was stirred at 15° C. for 2 hrs. The mixture was filtered and the filtrate was concentrated in vacuum to provide the product (68.0 g, 96.5%). [M+H]+=329.
To a solution of (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (29.0 g, 88.0 mmol) in DMF (150 mL) was added Cs2CO3 (43.0 g, 132 mmol) and 1H-pyrimidine-2,4-dione (10.8 g, 96.8 mmol) at 15° C. The mixture was stirred at 15° C. for 12 hrs. The mixture was poured into water (1500 mL) and was added EtOAc (400 mL). Then the mixture was partitioned between EtOAc and water. And the aqueous phase was extracted with EtOAc (300 mL×2). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=10: 1 to 1: 2) to afford the product (23.0 g, 72.5%). 1H NMR (400 MHz, CDCl3) δH 8.08 (s, 2H), 7.32 (s, 1H), 7.25-7.29 (m, 2H), 7.18 (d, J=7.96 Hz, 1H), 5.72 (dd, J=7.96, 2.20 Hz, 1H), 4.94 (s, 2H), 3.85 (t, J=6.92 Hz, 2H), 2.87 (t, J=6.86 Hz, 2H), 0.91 (s, 9H), 0.02 (s, 6H).
To a solution of 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)pyrimidine-2,4(1H,3H)-dione (16.0 g, 44.3 mmol) in MeOH (160 mL) was added Pd/C (2.00 g, 10.0% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50.0 Psi) at 50° C. for 5 hrs. The mixture was filtered, the filtrate was concentrated under reduced pressure to provide the product (13.0 g, 80.8% yield). 1H NMR (400 MHz, CDCl3)6H 7.43 (br s, 1H), 7.33 (s, 2H), 4.65 (s, 2 H), 3.86 (t, J=6.84 Hz, 2H), 3.37 (t, J=6.84 Hz, 2H), 2.88 (t, J=6.84 Hz, 2H), 2.67 (t, J=6.74 Hz, 2H), 0.03 (s, 6H), 0.92 (s, 9H).
To a solution of 1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione (10.0 g, 27.5 mmol) in MeOH (50.0 mL) was added NH4F (4.09 g, 110 mmol). The mixture was stirred at 25° C. for 8 hrs. Evaporate the solution on a water bath under reduced pressure using a rotary evaporator. Then was added H2O (100 mL) and EtOAc (80 mL), the reaction mixture was partitioned between EtOAc and water. And the resulting aqueous phase was extracted with EtOAc (40 mL×2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with EtOAc (50 mL) at 15° C. for 2 hrs to afford the product (4.84 g, 70.9% yield). 1H NMR (400 MHz, CDCl3) δH 7.46-7.52 (m, 1H), 7.27 (d, J=2.22 Hz, 1H), 7.25 (s, 3 H), 4.60 (d, J=1.76 Hz, 2H), 3.85-3.92 (m, 2H), 3.34 (td, J=6.78, 2.09 Hz, 2H), 2.86-2.92 (m, 2H), 2.64 (td, J=6.78, 1.87 Hz, 2H), 1.41 (td, J=5.73, 1.76 Hz, 1H); [M+H]+=249.
The titled compound was synthesized in a manner similar to that in Example 79 step 7 from 1-(4-(2-hydroxyethyl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione and IBX. [M+H]+=247.1.
The titled compound was synthesized in a manner similar to that in Example 79 step 8 from (2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (The synthesis of this intermediate is described in WO 2019196812) and 2-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)acetaldehyde. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 10.20 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=7.5 Hz, 2H), 7.53 (dd, J=14.3, 7.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.19 (s, 4H), 7.09 (s, 1H), 6.63 (s, 1H), 6.47 (d, J=8.4 Hz, 1H), 4.47 (s, 2H), 3.73 (d, J=18.3 Hz, 5H), 3.26 (t, J=6.5 Hz, 2H), 2.74-2.62 (m, 4H), 2.54 (s, 5H), 2.48-2.30 (m, 8H), 1.86 (d, J=11.5 Hz, 2H), 1.76 (d, J=13.6 Hz, 6H), 1.52 (d, J=11.5 Hz, 2H); [M+H]+=800.4.
To a solution of 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoic acid (17 mg, 0.04 mmol), HATU (15 mg, 0.04 mmol) and DIEA (13 mg, 0.1 mmol) in DMF (2 mL) was added (2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (20 mg, 0.033 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was directly purified with pre-HPLC to give the title product (5 mg, 15%). 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 11.09 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=5.5 Hz, 2H), 7.67 (s, 1H), 7.52 (d, J=13.7 Hz, 1H), 7.35 (s, 4H), 7.09 (s, 1H), 6.63 (s, 1H), 6.47 (d, J=8.5 Hz, 1H), 5.07 (d, J=7.3 Hz, 1H), 3.76 (s, 5H), 3.44 (s, 8H), 2.88 (s, 1H), 2.72-2.52 (m, 12H), 2.39 (s, 5H), 2.01 (s, 1H), 1.83 (s, 2H), 1.76 (d, J=13.5 Hz, 6H), 1.54 (d, J=10.9 Hz, 2H); [M+H]+=966.4.
The titled compound was synthesized in the procedures similar to Example 63. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 11.09 (s, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 8.07 (d, J=6.9 Hz, 2H), 7.65 (d, J=8.3 Hz, 1H), 7.58-7.48 (m, 1H), 7.33 (d, J=23.7 Hz, 3H), 7.23 (d, J=8.6 Hz, 1H), 7.09 (s, 1H), 6.63 (s, 1H), 6.47 (d, J=8.0 Hz, 1H), 5.07 (d, J=7.6 Hz, 1H), 4.04 (d, J=12.6 Hz, 2H), 3.74 (d, J=13.8 Hz, 5H), 3.46 (s, 4H), 3.02-2.79 (m, 6H), 2.66 (s, 5H), 2.39 (s, 3H), 2.11 (s, 2H), 2.02 (s, 1H), 1.95-1.73 (m, 14H), 1.56 (s, 6H), 1.12 (d, J=11.1 Hz, 2H); [M+H]+=1034.5.
The titled compound was synthesized in the procedures similar to Example 62. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 11.09 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=6.7 Hz, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.53 (dd, J=13.8, 7.5 Hz, 1H), 7.34 (s, 3H), 7.26 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 6.62 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 5.07 (d, J=7.9 Hz, 1H), 3.73 (d, J=17.2 Hz, 5H), 3.44 (s, 8H), 2.86 (d, J=12.0 Hz, 1H), 2.70-2.55 (m, 4H), 2.39 (s, 8H), 2.35 (d, J=20.2 Hz, 5H), 2.01 (s, 1H), 1.83 (d, J=11.6 Hz, 2H), 1.76 (d, J=13.6 Hz, 6H), 1.51 (s, 6H); [M+H]+=994.5.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δH 11.19 (s, 1H), 10.27 (s, 1H), 8.50 (s, 1H), 8.08 (d, J=10.6 Hz, 2H), 7.54 (s, 1H), 7.38 (d, J=20.9 Hz, 2H), 7.14 (d, J=8.5 Hz, 3H), 6.94 (d, J=7.5 Hz, 2H), 6.66 (s, 1H), 6.49 (s, 1H), 3.77 (s, 3H), 3.69 (s, 4H), 3.16 (s, 4H), 2.72-2.53 (m, 9H), 2.33-2.18 (m, 1H), 1.87-1.73 (m, 9H), 1.26 (s, 2H); [M+H]+=772.3.
A mixture of 4-bromoaniline (1.0 g, 5.81 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.67 g, 6.39 mmol), Pd(dppf)Cl2 (425 mg, 0.581 mmol) and Cs2CO3 (4.72 g, 14.53 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred in a flask at 100° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 0: 100 gradient elution) to give the product (1.2 g, 55%). [M+H]+=383.4.
Under N2, to a solution of 4-(2,6-bis(benzyloxy)pyridin-3-yl) aniline (1.2 g, 3.14 mmol) in MeOH (20 mL) and DCM (20 mL) was added 10% Pd/C (600 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 24 h. Reaction was monitored by LCMS. The mixture was filtered through a pad of Celite and washed with MeOH (20 mL) and DCM (30 mL). The filtrate was concentrated under vacuum to obtain the product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give the product (350 mg, 55%). [M+H]+=205.0.
To a solution of pyrazine-2,5-dicarboxylic acid (150 mg, 0.892 mmol), HATU (373 mg, 0.981 mmol) and DIEA (345 mg, 2.676 mmol) in DMF (6 mL) was added 3-(4-aminophenyl)piperidine-2,6-dione (182 mg, 0.892 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched with water and extracted with DCM (2×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give the product (155 mg, 49%). [M+H]+=355.1.
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (500 mg, 2.92 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (706 mg, 2.92 mmol) and K2CO3 (800 mg, 5.79 mmol) in DMF (10 mL) was stirred in a flask at 80° C. overnight. The reaction was cooled to room temperature, the mixture was poured into water (50 mL) and stirred for 10 mins. The solid was filtered and washed with water (20 mL×2), dried to give the product (1.0 g, 87%). [M+H]+=393.3.
Under N2, to a solution of tert-butyl 3-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)azetidine-1-carboxylate (1.0 g, 2.55 mmol) in MeOH (20 mL) was added 10% Pd/C (200 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 12 h. Reaction was monitored by LCMS. The mixture was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to obtain the product (0.9 g, 98%). [M+H]+=363.4.
A mixture of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg, 0.633 mmol), tert-butyl 3-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)azetidine-1-carboxylate (230 mg, 0.633 mmol), Pd2(dba)3 (60 mg, 0.063 mmol), BINAP (80 mg, 0.126 mmol) and K3PO4 (403 mg, 1.90 mmol) in toluene (10 mL) was stirred in a flask at 100° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to give the product (160 mg, 39%). [M+H]+=642.6.
A solution of tert-butyl 3-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)azetidine-1-carboxylate (160 mg, 0.249 mmol) in HC/1,4-dioxane (6 mL) was stirred in a flask at room temperature for 2 h. The mixture was evaporated in vacuum to afford the crude product (140 mg, 97%), which was used for next step without further purification. [M+H]+=542.5.
To a solution of 5-((4-(2,6-dioxopiperidin-3-yl)phenyl)carbamoyl)pyrazine-2-carboxylic acid (30.6 mg, 0.086 mmol), HATU (36 mg, 0.095 mmol) and DIEA (33 mg, 0.258 mmol) in DMF (3 mL) was added (2-((2-((4-(4-(azetidin-3-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide hydrochloride (50 mg, 0.086 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction was directly purified with pre-HPLC to give the title product (6 mg, 8%). 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.92 (s, 1H), 10.86 (s, 1H), 9.26 (d, J=36.5 Hz, 1H), 8.48 (s, 1H), 8.09 (d, J=17.0 Hz, 2H), 7.86 (d, J=7.1 Hz, 2H), 7.52 (d, J=13.7 Hz, 1H), 7.43-7.30 (m, 2H), 7.24 (d, J=7.2 Hz, 2H), 7.10 (s, 1H), 6.66 (s, 1H), 6.49 (d, J=8.0 Hz, 1H), 4.69 (s, 1H), 4.49 (s, 1H), 4.23 (s, 1H), 4.05 (s, 1H), 3.85 (d, J=8.0 Hz, 1H), 3.77 (s, 3H), 3.30-3.25 (m, 2H), 3.19 (s, 4H), 2.68 (s, 1H), 2.54 (s, 4H), 2.21 (s, 1H), 2.06 (s, 1H), 1.76 (d, J=13.5 Hz, 6H); [M+H]+=878.5.
To a solution of (S)-3-((tert-butoxycarbonyl)amino)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (The synthesis of this intermediate is described in J. Med. Chem., 2019, 62(2), 941-964) (366 mg, 1.05 mmol), HATU (441 mg, 1.16 mmol) and DIEA (406 mg, 3.15 mmol) in DMF (6 mL) was added (2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (600 mg, 1.05 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give the product (340 mg, 36%). [M+H]+=914.7.
A solution of tert-butyl tert-butyl (S)-(3-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate (340 mg, 0.377 mmol) in HCl/1,4-dioxane (6 mL) was stirred in a flask at room temperature for 2 h. The mixture was evaporated in vacuum to afford the crude product (300 mg, 95%), which was used for next step without further purification. [M+H]+=814.7.
To a solution of (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid (This intermediate can be prepared according to way described in WO2020010204) (7.1 mg, 0.024 mmol), HATU (10 mg, 0.026 mmol) and DIEA (10 mg, 0.078 mmol) in DMF (2 mL) was added (S)-3-amino-1-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-3-(4-(4-methylthiazol-5-yl)phenyl)propan-1-one hydrochloride (20 mg, 0.024 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction was directly purified with pre-HPLC to give the title product (2.7 mg, 10%). 1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 8.98 (d, J=3.2 Hz, 1H), 8.45 (s, 2H), 8.07 (s, 1H), 8.05 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.39-7.33 (m, 4H), 7.07 (s, 1H), 6.57 (s, 1H), 6.42 (s, 1H), 6.20 (s, 1H), 5.19 (s, 1H), 5.08 (d, J=3.9 Hz, 1H), 4.31 (s, 1H), 4.27-4.24 (m, 1H), 3.74 (s, 4H), 3.64-3.60 (m, 1H), 2.83-2.79 (m, 2H), 2.55 (d, J=13.4 Hz, 6H), 2.46 (s, 4H), 2.32-2.30 (m, 1H), 2.26-2.23 (m, 2H), 2.18 (s, 3H), 2.16 (s, 1H), 1.74 (d, J=13.6 Hz, 12H), 1.47-1.39 (m, 3H), 0.95 (d, J=6.3 Hz, 4H), 0.80-0.77 (m, 1H), 0.75 (d, J=6.7 Hz, 3H); [M+H]+=1092.7.
The titled compound was synthesized in the procedures similar to Example 56. 1H NMR (400 MHz, DMSO) δH 11.18 (s, 1H), 11.07 (s, 1H), 8.48 (s, 1H), 8.07 (s, 2H), 7.63 (s, 1H), 7.57-7.47 (m, 1H), 7.42-7.29 (m, 2H), 7.09 (s, 1H), 6.76 (s, 1H), 6.63 (s, 2H), 6.47 (d, J=8.5 Hz, 1H), 5.05 (d, J=7.4 Hz, 1H), 4.13 (s, 2H), 3.74 (d, J=15.0 Hz, 5H), 3.65 (s, 2H), 2.93-2.52 (m, 9H), 2.31 (d, J=17.5 Hz, 7H), 2.02 (s, 1H), 1.87 (s, 2H), 1.76 (d, J=13.4 Hz, 6H), 1.65-1.42 (m, 7H); [M+H]+=923.4.
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (500 mg, 2.92 mmol), tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate (940 mg, 3.49 mmol) and K2CO3 (800 mg, 5.79 mmol) in DMF (10 mL) was stirred in a flask at 80° C. overnight. The reaction was cooled to room temperature, the mixture was poured into water (50 mL) and stirred for 10 mins. The solid was filtered and washed with water (20 mL×2), dried to give the product (1.2 g, 98%). [M+H]+=421.3.
Under N2, to a solution of tert-butyl 4-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylate (1.2 g, 2.85 mmol) in MeOH (30 mL) was added 10% Pd/C (200 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 2 h. Reaction was monitored by HPLC. The mixture was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to obtain the product (1.1 g, 98%). [M+H]+=391.3.
A mixture of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (150 mg, 0.43 mmol) (The synthesis of this intermediate is described in J. Med. Chem., 2016, 59(16), 7478-7496), tert-butyl 4-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)piperidine-1-carboxylate (169 mg, 0.43 mmol), Pd2(dba)3 (40 mg, 0.043 mmol), BINAP (54 mg, 0.086 mmol) and K3PO4 (276 mg, 1.29 mmol) in toluene (10 mL) was stirred in a flask at 100° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to give the product (160 mg, 53%). [M+H]+=701.3.
A solution of tert-butyl 4-(4-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)piperidine-1-carboxylate (160 mg, 0.23 mmol) in HCl/1,4-dioxane (10 mL) was stirred in a flask at room temperature for 2 h. The mixture was evaporated in vacuum to afford the crude product (135 mg, 98%), which was used for next step without further purification. [M+H]+=601.3.
A mixture of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (25 mg, 0.04 mmol), 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde (11 mg, 0.048 mmol) and NaOAc (10 mg, 0.12 mmol) in DCM (3 mL) and MeOH (0.5 mL) was stirred in a flask at room temperature for 1 hour. The mixture was added NaBH3CN (7 mg, 0.12 mmol) and stirred in a flask at room temperature for 2h. The reaction was quenched with water (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with pre-HPLC. Before lyophilization, the solution was treated with 1N HCl (0.2 mL) to get the product as HCl salt (9 mg, 22%). 1H NMR (400 MHz, DMSO) δH 11.40 (s, 1H), 10.85 (s, 1H), 10.68 (s, 1H), 8.86-8.66 (m, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.63 (d, J=7.1 Hz, 1H), 7.42-7.14 (m, 7H), 6.73 (s, 1H), 6.54 (s, 1H), 3.89 (s, 3H), 3.79 (s, 4H), 3.64 (s, 2H), 3.51 (s, 1H), 3.34-3.16 (m, 9H), 3.10-2.95 (m, 8H), 2.67 (s, 1H), 2.54 (s, 1H), 2.47-2.42 (m, 2H), 2.20 (d, J=12.6 Hz, 3H), 2.03 (s, 1H); [M+H]+=816.3.
To a solution of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (30 mg, 0.05 mmol) and 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde (23 mg, 0.1 mmol) in DCM (5 mL) was added AcONa (8.2 mg, 0.1 mmol). The resulting mixture was stirred for 30 min at room temperature, then NaBH3CN (6.2 mg, 0.1 mmol) was added. The resulting mixture was stirred for 2 h at room temperature. The crude solution was purified with Prep-HPLC column chromatography to give the title product (10 mg, 24%). 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.28 (s, 2H), 8.21 (s, 1H), 8.10 (s, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.25 (s, 1H), 7.15 (dd, J=26.3, 7.7 Hz, 5H), 6.62 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.81 (d, J=7.0 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 1H), 3.18 (s, 3H), 3.10 (s, 3H), 2.76-2.59 (m, 6H), 2.51 (s, 6H), 2.48-2.40 (m, 4H), 2.33 (s, 2H), 2.17 (d, J=11.1 Hz, 1H), 2.03 (s, 1H), 1.86 (d, J=10.2 Hz, 2H), 1.53 (d, J=10.6 Hz, 2H); [M+H]+=816.3.
The titled compound was synthesized in the procedures similar to Example 119. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.28 (s, 4H), 8.10 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.02 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.2 Hz, 2H), 6.62 (s, 1H), 6.45 (d, J=8.9 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 2H), 3.63 (d, J=11.8 Hz, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.61 (dd, J=24.3, 12.4 Hz, 8H), 2.47-2.24 (m, 8H), 2.18-2.07 (m, 1H), 1.99-1.95 (m, 1H), 1.85 (d, J=11.5 Hz, 2H), 1.74 (d, J=11.7 Hz, 2H), 1.52-1.48 (m, 2H), 1.39 (s, 3H), 1.23 (d, J=9.0 Hz, 2H); [M+H]+=899.4.
The titled compound was synthesized in the procedures similar to Example 24. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.30 (d, J=13.2 Hz, 3H), 8.11 (d, J=9.5 Hz, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 7.25 (s, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.03 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 6.62 (s, 1H), 6.46 (d, J=8.6 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 2H), 3.64 (d, J=12.1 Hz, 2H), 3.46 (s, 6H), 3.18 (s, 3H), 3.10 (s, 3H), 2.65-2.62 (m, 5H), 2.41-2.36 (m, 5H), 2.28 (d, J=6.3 Hz, 2H), 2.17-2.07 (m, 1H), 2.01 (dd, J=9.9, 7.0 Hz, 1H), 1.85 (d, J=10.9 Hz, 3H), 1.74 (d, J=11.9 Hz, 2H), 1.55 (d, J=12.6 Hz, 2H), 1.28 (d, J=11.1 Hz, 2H); [M+H]+=913.4.
Tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (17 g, 44 mmol), Pd(dppf)Cl2 (3.2 g, 4.4 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (16.2 g, 44.0 mmol), Cs2CO3 (28.7 g, 88 mmol) were placed in dioxane/water (300 mL, 10:1). The mixture was stirred at 100° C. for overnight until LC-MS indicated all the starting material was consumed. The resulting solution was filtered and the filtrate was concentrated to afford the crude residue which was purified by SiO2-gel column (eluted with EtOAc/Hexane=1:1) to give the desire product (5 g, 21%). [M+H]+=551.3.
Tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-1-carboxylate (5 g, 9.1 mmol) was dissolved in MeOH (50 mL), Pd/C (10%, w/w, 0.5 g) was added to the solution in one portion. The resulting mixture was stirred under H2 atmosphere for overnight until LC-MS indicated all the starting material was consumed. The resulting solution was filtered and the filtrate was concentrated to give the desire product (1.9 g, 56.1%). [M+H]+=373.
Tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate (1.9 g, 5.1 mmol) was placed in HCl-dixoane (4M, 20 mL), the mixture was stirred at room temperature for 2h until LC-MS indicated all the starting material was consumed. The resulting solution was concentrated to afford the crude residue which was triturated with MTBE (5 mL) to afford desire product (1.38 g, 88%). [M+H]+=273.2.
A mixture of 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (228 mg, 0.74 mmol), tert-butyl acrylate (189 mg, 1.48 mmol) and DIEA (189 mg, 1.48 mmol) in MeCN (8 mL) was stirred in a flask at 80° C. overnight. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to give the product (178 mg, 60%); [M+H]+=401.2.
A solution of tert-butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)propanoate (178 mg, 0.45 mmol) in HCl/1,4-dioxane (8 mL) was stirred in a flask at room temperature overnight. The mixture was evaporated in vacuum to afford the crude product (150 mg, 97%), which was used for next step without further purification. [M+H]+ 345.4.
To a solution of 3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)propanoic acid (20 mg, 0.06 mmol), HATU (46 mg, 0.12 mmol) and DIEA (15 mg, 0.12 mmol) in DMF (2 mL) was added N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (36 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was directly purified with pre-HPLC to give the title product (10 mg, 18%); 1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 8.28 (s, 2H), 8.11 (d, J=7.9 Hz, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.24-7.08 (m, 5H), 6.63 (s, 1H), 6.46 (d, J=8.4 Hz, 1H), 3.94-3.68 (m, 6H), 3.46 (s, 6H), 3.18 (s, 3H), 3.10 (s, 3H), 2.98 (d, J=11.0 Hz, 2H), 2.67 (t, J=11.3 Hz, 3H), 2.54 (s, 4H), 2.46 (s, 5H), 2.16 (d, J=11.5 Hz, 1H), 2.03 (t, J=11.1 Hz, 3H), 1.85 (d, J=10.5 Hz, 2H), 1.73 (d, J=11.5 Hz, 2H), 1.59-1.43 (m, 4H); [M+H]+=927.4.
2-(4-aminophenyl)ethan-1-ol (13.7 g, 100 mmol), acrylic acid (7.9 g, 110 mmol) were placed in Toluene (150 mL). The mixture was stirred at 90° C. for 4h until LC-MS indicated all the starting material was consumed. Cooling the reaction to room temperature, Urea (30 g, 500 mmol) and AcOH (150 mL) was added to the mixture. The resulting mixture was stirred at 110° C. for 24h until all the intermediate was consumed. The reaction was cooled to room temperature, concentrated under vacuo to remove excess solvents. The resulting mixture was diluted with EtOAc, adjust pH to 7 with saturated NaHCO3 (aq.) solution, extracted with EtOAc. The combined organic phases were dried over Na2SO4, concentrated and purified with SiO2-gel column (eluted with EtOAc/Hexane=1:1) to give the desired product (5.9 g, 21.4%). [M+H]+=277.1
4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl acetate (5.9 g, 21.4 mmol) was dissolved in HCl (aq., 2 M, 50 mL). The solution was stirred at 100° C. for 1h until LC-MS indicated all the starting material was consumed. Concentrated to remove solvent, diluted with EtOAc, adjust pH to 7 with saturated NaHCO3 (aq.) solution, extracted with EtOAc, the combined organic phase was washed with Brine, dried over Na2SO4, concentrated to give the desire product (3.1 g, 61.9%). [M+H]+=235.1.
The titled compound was prepared in a manner similar to that in Example 79 step 7. [M+H]+=233.
The titled compound was prepared in a manner similar to that in Example 79 step 8. 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.28 (s, 2H), 8.21-8.06 (m, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.24 (s, 4H), 7.16 (t, J=7.6 Hz, 1H), 6.63 (s, 1H), 6.46 (d, J=9.1 Hz, 1H), 3.76 (s, 7H), 3.18 (s, 3H), 3.10 (s, 3H), 2.65-2.60 (m, 17H), 1.90 (d, J=10.4 Hz, 2H), 1.56 (d, J=11.1 Hz, 2H); [M+H]+=817.3.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δH 10.38 (s, 1H), 8.28 (s, 2H), 8.11 (d, J=7.7 Hz, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J=7.3 Hz, 2H), 6.77 (dd, J=20.3, 11.8 Hz, 2H), 6.62 (s, 1H), 6.45 (d, J=8.7 Hz, 1H), 3.73 (d, J=17.9 Hz, 7H), 3.61 (s, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.72-2.62 (m, 7H), 2.52 (s, 2H), 2.45-2.25 (m, 6H), 1.84 (s, 2H), 1.73 (d, J=13.7 Hz, 2H), 1.60-1.33 (m, 6H), 1.21 (d, J=18.0 Hz, 3H); [M+H]+=918.4.
The titled compound was synthesized in the procedures similar to Example 48. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.26 (d, J=11.2 Hz, 3H), 8.11 (d, J=7.5 Hz, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 7.16 (t, J=7.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 6.67-6.55 (m, 3H), 6.45 (d, J=8.6 Hz, 1H), 5.65 (d, J=6.9 Hz, 1H), 4.27 (s, 1H), 3.75 (s, 3H), 3.71 (s, 1H), 3.18 (s, 3H), 3.10 (s, 3H), 2.79-2.62 (m, 3H), 2.56 (d, J=18.7 Hz, 7H), 2.46-2.27 (m, 7H), 2.09 (s, 1H), 1.86 (d, J=11.5 Hz, 3H), 1.52 (d, J=11.2 Hz, 2H); [M+H]+=831.3.
The titled compound was synthesized in the procedures similar to Example 92. 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.28 (s, 2H), 8.11 (d, J=8.3 Hz, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 6.94 (d, J=9.0 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 6.62 (s, 1H), 6.45 (d, J=8.6 Hz, 1H), 5.04 (dd, J=10.4, 4.8 Hz, 1H), 3.94 (s, 2H), 3.73 (d, J=19.2 Hz, 5H), 3.18 (s, 3H), 3.10 (s, 3H), 2.65-2.57 (m, 8H), 2.36-2.26 (m, 7H), 2.13-2.02 (m, 2H), 1.84 (s, 4H), 1.53 (d, J=11.3 Hz, 2H); [M+H]+=862.2.
The titled compound was synthesized in the procedures similar to Example 62. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 8.28 (s, 2H), 8.15 (s, 1H), 8.11 (d, J=7.4 Hz, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.36 (d, J=10.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 7.15 (t, J=7.3 Hz, 1H), 6.62 (s, 1H), 6.45 (d, J=8.8 Hz, 1H), 5.11-4.98 (m, 1H), 3.75 (s, 3H), 3.71 (s, 2H), 3.44 (s, 8H), 3.18 (s, 3H), 3.10 (s, 3H), 2.93-2.81 (m, 1H), 2.70-2.51 (m, 11H), 2.41-2.30 (m, 5H), 2.05-1.96 (m, 1H), 1.84 (d, J=11.3 Hz, 2H), 1.59-1.44 (m, 6H); [M+H]+=1025.4.
The titled compound was synthesized in the procedures similar to Example 63. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 8.28 (s, 2H), 8.12 (s, 1H), 8.10 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.23 (s, 2H), 7.17 (d, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.46 (d, J=8.7 Hz, 1H), 5.06 (dd, J=13.1, 5.5 Hz, 1H), 4.04 (d, J=12.8 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 2H), 3.45 (s, 4H), 3.18 (s, 3H), 3.10 (s, 3H), 3.03-2.92 (m, 3H), 2.85 (s, 3H), 2.74-2.53 (m, 6H), 2.42-2.30 (m, 2H), 2.11 (d, J=4.7 Hz, 2H), 2.02 (s, 1H), 1.84-1.76 (m, 8H), 1.56 (s, 6H), 1.12 (d, J=11.9 Hz, 2H); [M+H]+=1065.4.
The titled compound was synthesized in the procedures similar to Example 68. 1H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.28 (s, 2H), 8.11 (d, J=6.9 Hz, 2H), 7.55-7.50 (m, 2H), 7.36 (d, J=8.2 Hz, 1H), 7.25 (s, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.00 (s, 1H), 6.61 (s, 1H), 6.45 (d, J=8.2 Hz, 1H), 5.30 (s, 2H), 4.60-4.52 (m, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 3.56 (s, 2H), 3.46 (s, 2H), 3.29 (s, 5H), 3.21 (s, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.69-2.54 (m, 10H), 2.43-2.31 (m, 2H), 2.08-1.92 (m, 2H), 1.84 (d, J=11.5 Hz, 2H), 1.55 (d, J=10.7 Hz, 2H); [M+H]+=969.4.
A mixture of 1-bromo-4-iodobenzene (3.0 g, 10.6 mmol), pent-4-yn-1-ol (0.98 g, 11.7 mmol), CuI (204 mg, 1.06 mmol), Pd(PPh3)2Cl2 (373 mg, 0.53 mmol) and piperidine (1.8 g, 21.2 mmol) in toluene (30 mL) was stirred in a flask at 40° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 2: 1 gradient elution) to give the product (1.5 g, 59%). [M+H]+=239.0.
A mixture of 5-(4-bromophenyl)pent-4-yn-1-ol (1.2 g, 5.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.5 g, 6.0 mmol), Pd(dppf)Cl2 (367 mg, 0.5 mmol) and KOAc (1.5 g, 15.0 mmol) in 1,4-dioxane (30 mL) was stirred in a flask at 80° C. for 1 h. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 4: 1 gradient elution) to give the title product (1.4 g, 97%). [M+H]+=287.2.
A mixture of 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pent-4-yn-1-ol (1.4 g, 4.9 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (1.8 g, 4.9 mmol), Pd(dppf)Cl2 (366 mg, 0.5 mmol) and Cs2CO3 (2.5 g, 7.5 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was stirred in a flask at 80° C. for 2 h. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 2: 1 gradient elution) to give the product (2.0 g, 91%). [M+H]+=450.2.
Under N2, to a solution of 5-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pent-4-yn-1-ol (2.0 g, 4.4 mmol) in MeOH (100 mL) was added 10% Pd/C (400 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 48 h. Reaction was monitored by HPLC. The mixture was filtered through a pad of Celite and washed with MeOH (50 mL). The filtrate was concentrated under vacuum to obtain the product (1.2 g, 97%). [M+H]+=276.2.
To a solution of 3-(4-(5-hydroxypentyl)phenyl)piperidine-2,6-dione (100 mg, 0.36 mmol) in DMSO (3.0 mL) was added IBX (203 mg, 0.72 mmol) in portions at 25° C. The mixture was stirred at 25° C. for 4 h. Reaction was monitored by HPLC. Water (20.0 mL) was added and the resulting solution was extracted with EtOAc (2×30.0 mL). The combined organic layer was washed with brine (3×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the title product (80 mg, 81%). [M+H]+=274.2.
A mixture of N-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (50 mg, 0.09 mmol), 5-(4-(2,6-dioxopiperidin-3-yl)phenyl)pentanal (24 mg, 0.09 mmol) and NaOAc (22 mg, 0.27 mmol) in DCM (5 mL) and MeOH (1 mL) was stirred in a flask at room temperature for 1 hour. The mixture was added NaBH3CN (16 mg, 0.27 mmol) and stirred in a flask at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with DCM (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with pre-HPLC to give the product (12 mg, 16%). 1H NMR (400 MHz, DMSO) δH 10.80 (s, 1H), 8.36-8.17 (m, 3H), 8.16-7.95 (m, 2H), 7.56 (d, J=5.8 Hz, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 7.17-7.01 (m, 5H), 6.60 (s, 1H), 6.42 (s, 1H), 3.81-3.57 (m, 6H), 3.15 (d, J=6.0 Hz, 3H), 3.07 (d, J=6.0 Hz, 3H), 2.75-2.51 (m, 8H), 2.44-2.37 (m, 1H), 2.20-1.85 (m, 4H), 1.61-1.24 (m, 8H); [M+H]+=789.4.
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.0 g, 5.8 mmol), tert-butyl piperidin-4-ylcarbamate (1.23 g, 6.1 mmol) and K2CO3 (1.6 g, 11.6 mmol) in DMF (15 mL) was stirred in a flask at 60° C. overnight. The reaction was cooled to room temperature, the mixture was poured into water (50 mL) and stirred for 10 mins. The solid was filtered and washed with water (20 mL×2), dried to give the product (2.0 g, 98%). [M+H]+=352.2.
Under N2, to a solution of tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate (2.0 g, 5.7 mmol) in MeOH (50 mL) was added 10% Pd/C (400 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 2 h. The mixture was filtered through a pad of Celite and washed with MeOH (50 mL). The filtrate was concentrated under vacuum to obtain the product (1.8 g, 98%). [M+H]+=322.2.
A mixture of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (410 mg, 1.2 mmol), tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)carbamate (381 mg, 1.2 mmol), Pd2(dba)3 (108 mg, 0.12 mmol), BINAP (147 mg, 0.24 mmol) and K3PO4 (753 mg, 3.75 mmol) in toluene (20 mL) was stirred in a flask at 100° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to give the product (450 mg, 60%). [M+H]+=632.2.
A solution of tert-butyl (1-(4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)carbamate (450 mg, 0.71 mmol) in HCl/1,4-dioxane (15 mL) was stirred in a flask at room temperature for 2 h. The mixture was evaporated in vacuum to afford the crude product (375 mg, 98%), which was used for next step without further purification. [M+H]+=532.2.
A mixture of 1-bromo-4-iodobenzene (3.0 g, 10.6 mmol), hept-6-yn-1-ol (1.3 g, 11.7 mmol), CuI (204 mg, 1.06 mmol), Pd(PPh3)2Cl2 (373 mg, 0.53 mmol) and piperidine (1.8 g, 21.2 mmol) in toluene (20 mL) was stirred in a flask at 40° C. overnight under N2. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 2: 1 gradient elution) to give the product (2.4 g, 85%). [M+H]+=267.1.
A mixture of 7-(4-bromophenyl)hept-6-yn-1-ol (2.4 g, 9.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.7 g, 10.8 mmol), Pd(dppf)Cl2 (650 mg, 0.9 mmol) and KOAc (2.6 g, 27.0 mmol) in 1,4-dioxane (50 mL) was stirred in a flask at 80° C. for 1 h. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 4: 1 gradient elution) to give the title product (2.8 g, 99%). [M+H]+=315.2.
A mixture of 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)hept-6-yn-1-ol (2.8 g, 8.9 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (3.3 g, 8.9 mmol), Pd(dppf)Cl2 (658 mg, 0.89 mmol) and Cs2CO3 (4.4 g, 13.5 mmol) in 1,4-dioxane (75 mL) and H2O (15 mL) was stirred in a flask at 80° C. for 2 h. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 0˜ 2: 1 gradient elution) to give the product (3.2 g, 75%). [M+H]+=478.3.
Under N2, to a solution of 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)hept-6-yn-1-ol (3.2 g, 6.7 mmol) in MeOH (150 mL) was added 10% Pd/C (500 mg) at 25° C. And then the mixture was exchanged with H2 two times and stirred under H2 atmosphere at 25° C. for 48 h. Reaction was monitored by HPLC. The mixture was filtered through a pad of Celite and washed with MeOH (100 mL). The filtrate was concentrated under vacuum to obtain the product (2.0 g, 98%). [M+H]+=304.2.
To a solution of 3-(4-(7-hydroxyheptyl)phenyl)piperidine-2,6-dione (52 mg, 0.17 mmol) in DMSO (2.0 mL) was added IBX (96 mg, 0.34 mmol) in portions at 25° C. The mixture was stirred at 25° C. for 4 h.
Reaction was monitored by HPLC. Water (20.0 mL) was added to the reaction at 25° C. The resulting solution was extracted with 2×30.0 mL of EtOAc. The combined organic layer was washed with brine (3×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the title product (50 mg, 97%). [M+H]+=302.2.
A mixture of N-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (47 mg, 0.09 mmol), 7-(4-(2,6-dioxopiperidin-3-yl)phenyl)heptanal (25 mg, 0.08 mmol) and NaOAc (20 mg, 0.24 mmol) in DCM (5 mL) and MeOH (1 mL) was stirred in a flask at room temperature for 1 hour. The mixture was added NaBH3CN (15 mg, 0.24 mmol) and stirred in a flask at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with pre-HPLC to give the product (24 mg, 35%). 1H NMR (400 MHz, DMSO) δH 10.84 (s, 1H), 8.36 (s, 1H), 8.29 (s, 2H), 8.12 (d, J=7.2 Hz, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.27 (s, 1H), 7.14 (dd, J=14.7, 7.7 Hz, 5H), 6.64 (s, 1H), 6.47 (d, J=8.3 Hz, 1H), 3.85-3.64 (m, 6H), 3.19 (s, 3H), 3.11 (s, 3H), 2.85-2.53 (m, 8H), 2.46 (s, 1H), 2.18 (d, J=11.3 Hz, 1H), 2.09-1.91 (m, 3H), 1.54 (d, J=31.4 Hz, 6H), 1.32 (s, 6H); [M+H]+=817.4.
The titled compound was synthesized in the procedures similar to Example 119. 1H NMR (400 MHz, DMSO) δH 10.83 (s, 1H), 8.28 (s, 2H), 8.12 (d, J=13.0 Hz, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.28-7.08 (m, 6H), 6.64 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.85-3.74 (m, 4H), 3.18 (s, 7H), 3.10 (s, 3H), 2.79 (s, 2H), 2.70-2.58 (m, 7H), 2.47-2.43 (m, 1H), 2.17 (s, 1H), 2.04 (s, 1H); [M+H]+=733.3.
The titled compound was synthesized in the procedures similar to Example 119. 1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.34 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.19 (s, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.49 (d, J=15.3 Hz, 1H), 7.39 (t, J=7.3 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.14-7.08 (m, 5H), 6.45 (t, J=9.3 Hz, 1H), 3.88 (s, 4H), 3.81 (d, J=9.0 Hz, 1H), 3.32 (s, 4H), 3.19 (s, 3H), 3.10 (s, 3H), 2.71-2.52 (m, 6H), 2.24-2.12 (m, 1H), 2.02 (dd, J=14.0, 7.8 Hz, 1H); [M+H]+=733.2.
The titled compound was synthesized in the procedures similar to Example 47. 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.34 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.19 (s, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.5 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.45 (t, J=9.4 Hz, 1H), 5.43 (s, 1H), 4.20 (s, 1H), 3.87 (d, J=16.3 Hz, 7H), 3.19 (s, 3H), 3.10 (s, 3H), 2.71 (d, J=11.7 Hz, 1H), 2.57-2.49 (m, 5H), 2.09 (s, 1H), 1.84 (d, J=8.6 Hz, 1H), 1.67 (s, 2H); [M+H]+=778.3.
The titled compound was synthesized in the procedures similar to Example 48. 1H NMR (400 MHz, DMSO)1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 9.33 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.48 (d, J=15.2 Hz, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.15 (s, 1H), 6.91 (d, J=7.8 Hz, 2H), 6.59 (d, J=7.4 Hz, 2H), 6.44 (t, J=9.2 Hz, 1H), 5.66 (d, J=7.6 Hz, 1H), 4.27 (s, 1H), 3.87 (s, 4H), 3.29 (s, 5H), 3.19 (s, 3H), 3.10 (s, 3H), 2.72 (d, J=11.5 Hz, 2H), 2.40 (s, 2H), 2.08 (s, 1H), 1.87 (s, 1H); [M+H]+=748.2.
The titled compound was synthesized in the procedures similar to Example 63. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.36 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.65 (t, J=8.2 Hz, 2H), 7.53 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.26 (t, J=8.0 Hz, 2H), 7.15 (d, J=7.8 Hz, 1H), 6.47 (t, J=9.4 Hz, 1H), 5.07 (dd, J=12.8, 5.2 Hz, 1H), 4.34 (s, 2H), 4.08-3.94 (m, 8H), 3.19 (s, 3H), 3.10 (s, 3H), 3.02-2.82 (m, 4H), 2.57 (d, J=24.7 Hz, 4H), 2.50-2.23 (m, 4H), 1.99-1.76 (m, 2H), 1.75-1.62 (m, 6H), 1.17 (d, J=10.2 Hz, 2H); [M+H]+=982.4.
The titled compound was synthesized in the procedures similar to Example 119. 1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 8.00 (d, J=6.1 Hz, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 7.34 (d, J=6.7 Hz, 1H), 7.15-7.10 (m, 7H), 6.59 (s, 1H), 6.37 (d, J=7.9 Hz, 1H), 3.81 (d, J=7.5 Hz, 1H), 3.75 (s, 3H), 3.69 (d, J=10.5 Hz, 2H), 2.93 (s, 3H), 2.66-2.53 (m, 7H), 2.33 (s, 6H), 2.17 (d, J=9.8 Hz, 2H), 2.03 (s, 2H), 1.86 (d, J=10.4 Hz, 3H), 1.52 (d, J=11.0 Hz, 3H); [M+H]+=802.4.
The titled compound was synthesized in the procedures similar to Example 79. 1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.38-7.30 (m, 3H), 7.28-7.01 (m, 5H), 6.92 (d, J=7.9 Hz, 2H), 6.59 (s, 1H), 6.37 (d, J=7.9 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 7H), 2.95 (s, 3H), 2.63-2.50 (m, 15H), 1.88 (d, J=10.0 Hz, 2H), 1.74 (d, J=11.4 Hz, 2H), 1.54 (d, J=10.6 Hz, 2H), 1.44 (s, 3H), 1.25 (d, J=9.0 Hz, 2H); [M+H]+=886.5.
The titled compound was synthesized in the procedures similar to Example 48. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 8.06 (s, 2H), 7.89 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.32 (s, 1H), 7.09 (s, 2H), 6.93 (d, J=7.6 Hz, 2H), 6.60 (s, 3H), 6.39 (d, J=8.5 Hz, 1H), 5.65 (d, J=6.6 Hz, 1H), 4.27 (s, 1H), 3.75 (s, 3H), 3.69 (d, J=10.2 Hz, 2H), 2.89 (s, 3H), 2.66 (d, J=11.0 Hz, 8H), 2.33 (s, 6H), 2.09 (s, 2H), 1.86 (d, J=10.4 Hz, 4H), 1.52 (d, J=10.0 Hz, 3H); [M+H]+=817.4.
The titled compound was synthesized in the procedures similar to Example 62. 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.75 (s, 1H), 8.22 (s, 2H), 8.02 (s, 1H), 7.86 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.24 (s, 2H), 6.98 (s, 2H), 6.57 (s, 1H), 6.37 (s, 1H), 5.03 (s, 1H), 3.73 (s, 3H), 3.67 (d, J=11.4 Hz, 2H), 3.41 (s, 9H), 2.81 (s, 3H), 2.71-2.53 (m, 6H), 2.30 (s, 10H), 1.99 (s, 2H), 1.79 (s, 2H), 1.49 (s, 6H); [M+H]+=1011.6.
The titled compound was synthesized in the procedures similar to Example 63. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.41 (d, J=9.5 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.24 (s, 1H), 7.15 (s, 2H), 6.59 (s, 1H), 6.39 (s, 1H), 5.05 (s, 1H), 4.04 (d, J=11.3 Hz, 2H), 3.75 (s, 3H), 3.70 (d, J=11.9 Hz, 2H), 3.46 (s, 4H), 2.91-2.80 (m, 9H), 2.70-2.57 (m, 4H), 2.45-2.33 (m, 3H), 2.13 (s, 2H), 1.93 (s, 4H), 1.78 (d, J=12.9 Hz, 6H), 1.58 (s, 6H), 1.14 (s, 2H); [M+H]+=1051.7.
The titled compound was synthesized in the procedures similar to Example 47. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.14 (s, 2H), 6.71 (s, 2H), 6.63 (s, 3H), 6.39 (s, 1H), 5.43 (s, 1H), 4.21 (s, 1H), 3.88 (s, 2H), 3.76 (s, 3H), 3.68 (s, 2H), 2.92 (s, 3H), 2.63 (d, J=15.6 Hz, 8H), 2.41 (s, 7H), 2.10 (s, 1H), 1.84 (s, 5H), 1.54 (s, 2H); [M+H]+=847.4.
A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (171 mg, 0.384 mmol), 4-(3-methoxy-4-nitrobenzylidene)piperidine (100 mg, 0.403 mmol), Pd2(dba)3 (35 mg, 0.0384 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (44 mg, 0.0768 mmol), Cs2CO3 (250 mg, 0.768 mmol) in 1,4-dioxane (5.0 mL) was stirred in a microwave vial at 100° C. under atmosphere of N2 for 16 h. After being cooled to room temperature, the mixture was filtrated through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was purified by prep TLC with PE/EA (1:1) as eluent to obtain crude product. It was further purified by prep TLC with pure DCM as eluent to give the target product (98 mg, 42%). [M+H]+=614.3.
A mixture 2,6-bis(benzyloxy)-3-(4-(4-(3-methoxy-4-nitrobenzylidene)piperidin-1-yl)phenyl)pyridine (98 mg, 0.160 mmol), 10% Pd/C (98 mg, 100 wt %) in EtOH/DCM/AcOH (2 mL/1 mL/30 μl) was stirred in a round flask at room temperature under hydrogen atmosphere for 16 h. The mixture was filtrated through a pad of celite, the filtrate was concentrated in vacuum to afford the crude product as colorless oil (65 mg, crude). [M+H]+=408.3.
A mixture 3-(4-(4-(4-amino-3-methoxybenzyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (65 mg, 0.160 mmol), (2-((2,5-dichloropyrimidin-4-yl)amino)ph-enyl)dimethylphosphine oxide (51 mg, 0.160 mmol), TFA (120 uL, 1.60 mmol) in n-BuOH (2.0 mL) was stirred in a macrowave vial at 80° C. under nitrogen atmosphere for 16 h. After being cooled to room temperature, n-hexane (2.0 mL) was added, the precipitate was collected as crude product. It was further purified by prep HPLC to afford the product (10.5 mg, 9.6%). 1H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 10.79 (s, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.65-7.52 (m, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.18-7.14 (m, 5H), 6.92 (s, 1H), 6.76 (d, J=8.1 Hz), 3.80 (s, 3H), 3.62 (d, J=11.9 Hz), 2.18-1.97 (m, 7H), 1.78-1.74 (m, 10H), 1.49 (s, 3H); [M+H]+=687.3.
A solution of 1,3-difluoro-2-nitrobenzene (50.0 g, 314.4 mmol) in NMP (300 mL) were cooled to −20° C. under N2 atmosphere. Then a mixture of ethyl 2-chloroacetate (65.5 g, 534.7 mmol) and t-BuOK (121.0 g, 1.08 mol) in NMP (50 mL) was added slowly at −10° C. to −20° C. over 2 h. After being stirred for 2 h, the reaction was quenched by pouring into 1M HCl (200 mL) and ice-water. The mixture was extracted with EA (300 mL×3). The combined organic layer was washed by brine, dried with Na2SO4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA=200/1 to 100/1) to provide product (13.7 g, 18%). 1H NMR (400 MHz, CDCl3) δH 7.06 (d, J=8.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.65 (s, 2H), 1.28 (t, J=7.2 Hz, 3H).
To a solution of ethyl 2-(3,5-difluoro-4-nitrophenyl)acetate (13.7 g, 56 mmol) in MeOH (150 mL) was added 10% Pd/C (1.5 g) at r.t. The mixture was stirred at r.t under H2 atmosphere for 5 h. Filtrated on vacuum to remove Pd/C and concentrated in vacuum to provide the product (12.2 g), which was used in next step without further purification. 1H NMR (400 MHz, DMSO_d6) δH 6.82 (d, J=8.0 Hz, 2H), 5.69 (s, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.52 (s, 2H), 1.17 (t, J=7.2 Hz, 3H). [M+H]+=216.4.
A solution of ethyl 2-(4-amino-3,5-difluorophenyl)acetate (12.2 g, 56 mmol) in MeCN (150 mL) was cooled to 0° C. under N2 atmosphere and CuI (21.2 g, 112 mmol) was added. After stirring for 10 min, tert-butylnitrite (11.5 g, 112 mmol) was added dropwise over 30 min. Then the mixture was stirred at r.t for overnight. The reaction was quenched by pouring into water and extracted with EA (300 mL×3). All organic layers were combined and washed by brine, dried with Na2SO4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA=500/1 to 100/1) to provide the product (8.8 g, 48%). [M+H]+=326.5.
To a solution of ethyl 2-(3,5-difluoro-4-iodophenyl)acetate (8.8 g, 27.0 mmol) in a mixed solvent of 1,4-dioxane/H2O (100 mL/20 mL) were added K2CO3 (9.3 g, 67.4 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (14.6 g, 35.0 mol) and Pd(dppf)Cl2 (2.9 g, 4.0 mmol) under N2 atmosphere. The resulting solution was stirred for 6 h at 100° C. The mixture was diluted with water (300 mL) and extracted with EA (300 mL×3). All organic layers were combined and washed with brine (300 mL), dried over Na2SO4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA=200/1) to give the product (8.2 g, 62%). 1H NMR (400 MHz, CDCl3) δH 7.49 (d, J=8.0 Hz, 1H), 7.40-7.24 (m, 10H), 6.90 (d, J=8.0 Hz, 2H), 6.47 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.61 (s, 2H), 1.28 (t, J=7.2 Hz, 3H).
A solution of ethyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)acetate (8.2 g, 16.7 mol) in THF (100 mL) was cooled to 0° C. under N2 atmosphere and 1.5 M DIBAL-H (45 mL, 67.5 mol) in THF was added dropwise over 30 min. Then the mixture was stirred at r.t for 2 h. The reaction was quenched by pouring into water and extracted with EA (300 mL×3). All organic layers were combined and washed by brine, dried with Na2SO4. The solution was concentrated in vacuum and the residue was purified by column chromatography (PE/EA=10/1 to 3/1) to provide the product (6.6 g, 88%). 1H NMR (400 MHz, CDCl3) δH7.49 (d, J=8.0 Hz, 1H), 7.42-7.25 (m, 9H), 6.84 (d, J=8.0 Hz, 2H), 6.47 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 3.90 (m, 2H), 2.87 (t, J=6.4 Hz, 2H). [M+H]+=448.3.
To a solution of 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)ethanol (6.6 g, 14.7 mmol) in DCM (150 mL) was added TFA (50 mL). After stirred overnight, the mixture was concentrated in vacuo. The residue was dissolved in MeOH (200 mL) and 10% Pd/C (1.0 g) was added. The resulted mixture was stirred for 2 days at r.t under H2 atmosphere. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by reversed flash C18 chromatography (ACN/water=0% to 30%) to give the title compound (2.1 g, 53%). [M+H]+=270.1.
The titled compound (430 mg, 34%) was synthesized in a manner similar to that in Example 5 step 6 from 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione and IBX. [M+H]+=268.1.
To a solution of 7-bromo-3-chloroisoquinoline (2.5 g, 13.8 mmol) and diphenylmethanimine (3.35 g, 13.8 mmol) in dioxane (100 mL) was added Cs2CO3 (9 g, 27.6 mmol) at 20° C. Pd2(dba)3 (1.26 g, 1.4 mmol) and BINAP (1.72 g, 2.8 mmol) was added to the mixture at 20° C. The suspension was degassed under vacuum and purged with N2 three times. Then the mixture was stirred at 100° C. for 14 hrs. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1). N-(3-chloroisoquinolin-7-yl)-1,1-diphenylmethanimine (3.3 g, 69.8%) was obtained. [M+H]+=343.1.
To a solution of N-(3-chloroisoquinolin-7-yl)-1,1-diphenylmethanimine (3 g, 8.7 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.2 g, 17.5 mmol) in dioxane (100 mL) was added K2CO3 (2.42 g, 17.5 mmol) at 20° C. Pd(dppf)Cl2 (642 mg, 0.88 mmol) was added to the mixture at 20° C. The suspension was degassed under vacuum and purged with N, three times. Then the mixture was stirred at 100° C. for 12 hrs. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (PE/EA=10/1 to 1/1). N-(3-methylisoquinolin-7-yl)-1,1-diphenylmethanimine (1.9 g, 67.3%) was obtained. [M+H]+=323.2.
To a solution of N-(3-methylisoquinolin-7-yl)-1,1-diphenylmethanimine (1.9 g, 5.9 mmol) in THF (50 mL) was added HCl (aq. 12 N, 5 mL) at 20° C. Then the mixture was stirred at 20° C. for 1 hrs. Then the mixture was adjusted to pH=8 with NaHCO3, and extracted with DCM (150 mL). The organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuum. 3-methylisoquinolin-7-amine (630 mg, 67.8%) was obtained. [M+H]+=159.2.
To a solution of 3-methylisoquinolin-7-amine (630 mg, 4 mmol) in HOAc (10 mL) was added ICl (775 mg, 4.8 mmol) at 20° C. Then the mixture was stirred at 20° C. for 1 hrs. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 solution and extracted with DCM (150 mL). The organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuum. 8-iodo-3-methylisoquinolin-7-amine (900 mg, 79.6%) was obtained. [M+H]+=285.3.
To a solution of 8-iodo-3-methylisoquinolin-7-amine (0.9 g, 3.2 mmol) and dimethylphosphine oxide (370 mg, 4.8 mmol) in dioxane (90 mL) was added K3PO4 (1.34 g, 6.3 mmol) at 20° C. And then Pd(OAc)2 (71 mg, 0.3 mmol) and Xantphos (366 mg, 0.6 mmol) were added to the mixture at 20° C. The suspension was degassed under vacuum and purged with N2 three times. Then the mixture was stirred at 100° C. for 14 hrs. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1). (7-amino-3-methylisoquinolin-8-yl)dimethylphosphine oxide (700 mg, 94%) was obtained. [M+H]+=235.2.
To a solution of (7-amino-3-methylisoquinolin-8-yl)dimethylphosphine oxide (400 mg, 1.7 mmol) in DMF (10 mL) was added 5-bromo-2,4-dichloropyrimidine (158 mg, 2.6 mmol) at 0° C. And then LiHMDS (1 N, 1.88 mL, 314 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at 20° C. for 3 hrs. Water (100 mL) was poured into the mixture, which was further extracted with EtOAc (100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1). (7-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-methylisoquinolin-8-yl)dimethylphosphine oxide (180 mg, 24.8%) was obtained. [M+H]+=425.1.
To a solution of (7-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-methylisoquinolin-8-yl)dimethylphosphine oxide (180 mg, 0.4 mmol) in n-BuOH (10 mL) was added tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (This intermediate was prepared according to the same manner in Example 23 step 3) (177 mg, 0.4 mmol) at 20° C. 4-methylbenzenesulfonic acid (218 mg, 1.3 mmol) was added to the reaction mixture at 20° C. Then the mixture was stirred at 100° C. for 13 hrs. Water (100 mL) was poured into the mixture. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 solution and extracted with DCM (150 mL). The organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1). (7-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-methylisoquinolin-8-yl)dimethylphosphine oxide (120 mg, 40.1%) was obtained. [M+H]+=707.2.
To a solution of (7-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-methylisoquinolin-8-yl)dimethylphosphine oxide (30 mg, 0.04 mmol) in DCM (5 mL) was added 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (11 mg, 0.04 mmol) at 20° C. The mixture was stirred at 20° C. for 1 hrs and STAB (18 mg, 0.08 mmol) was added. Then the mixture was stirred at 20° C. for 12 hrs. Water (10 mL) was poured into the mixture. Then the mixture was extracted with DCM (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford the product (7.2 mg, 17.6%). 1H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 10.96 (s, 1H), 9.51 (s, 1H), 8.26 (d, J=19.8 Hz, 2H), 7.99-7.81 (m, 2H), 7.67 (s, 1H), 7.47 (d, J=11.3 Hz, 1H), 7.09 (dd, J=20.7, 9.1 Hz, 2H), 6.73 (s, 1H), 4.20 (d, J=7.4 Hz, 1H), 3.77 (s, 3H), 3.52 (s, 2H), 3.17-2.89 (m, 7H), 2.79 (s, 3H), 2.72-2.54 (m, 9H), 2.36 (s, 2H), 2.21 (d, J=73.4 Hz, 4H), 2.05 (d, J=13.3 Hz, 7H), 1.79 (s, 2H), 0.74 (s, 3H). [M+H]+=958.2.
The titled compound (3.1 g, 85%) was prepared in a manner similar to that in Example 200 step 11 from quinolin-6-amine. [M+H]+=271.0
The titled compound (2.4 g, 95%) was prepared in a manner similar to that in Example 200 step 12 from 5-iodoquinolin-6-amine. [M+H]+=221.2
The titled compound (1.2 g, 75%) was prepared in a manner similar to that in Example 208 step 6 from (6-aminoquinolin-5-yl)dimethylphosphine oxide and 5-bromo-2,4-dichloropyrimidine. [M+H]+=411.0
To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (500 mg, 1.22 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (510 mg, 1.22 mmol) in t-BuOH (30 mL) was added MsOH (468 mg, 4.88 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. The resulting solution was concentrated and basified with sat. aq. NaHCO3 solution, then extracted with DCM (2×80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜5: 1 gradient elution) to give the desired product (270 mg, 32%). [M+H]+=693.5.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (30 mg, 0.04 mmol) in DCM (6 mL) was added 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (22 mg, 0.08 mmol) at room temperature. After stirring at room temperature for 1h, NaBH(OAc)3 (26 mg, 0.12 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL) and extracted with DCM (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give an impure product, which was further purified with pre-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to give the desired product (15 mg, 37%). 1H NMR (400 MHz, DMSO) δH 11.97 (s, 1H), 10.95 (s, 1H), 8.86 (d, J=3.1 Hz, 1H), 8.64 (d, J=8.8 Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.02-7.92 (m, 2H), 7.55 (dd, J=8.7, 4.1 Hz, 1H), 7.41 (s, 1H), 7.03 (d, J=10.1 Hz, 2H), 6.75 (s, 1H), 4.20 (dd, J=12.8, 4.9 Hz, 1H), 3.77 (s, 3H), 2.95 (d, J=11.0 Hz, 2H), 2.85-2.73 (m, 3H), 2.65 (t, J=10.9 Hz, 2H), 2.54 (d, J=7.5 Hz, 7H), 2.48-2.26 (m, 7H), 2.18-2.08 (m, 1H), 2.02 (d, J=13.3 Hz, 7H), 1.84 (d, J=11.2 Hz, 2H), 1.55 (d, J=8.9 Hz, 2H), 0.76 (s, 3H); [M+H]+=944.5.
A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (15 g, 40.65 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (12.6 g, 49.61 mmol), Pd(dppf)Cl2 (3.32 g, 4.07 mmol), KOAc (12 g, 122.45 mmol) in dioxane (200 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH and DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford the product (9.00 g, 53%). m/z[M+H]+=418.3.
A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.00 g, 21.56 mmol) and 5-bromo-1,3-difluoro-2-iodobenzene (6.88 g, 21.57 mmol), K2CO3 (10.43 g, 75.48 mmol), Pd(dppf)Cl2 (789 mg, 1.078 mmol) in dioxane (90 mL) and H2O (30 mL) was stirred for 16h at 100° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford the product (4 g, 38%). [M+H]+=482.4.
A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (4.00 g, 8.29 mmol), ethyl 2-(piperidin-4-yl)acetate (2.13 g, 12.43 mmol), Cs2CO3 (8.11 g, 24.89 mmol), DavePhos (652.7 mg, 1.659 mmol), Pd2(dba)3 (759.4 mg, 0.829 mmol) in 2-methyl-THF (50 mL) and H2O (5 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (2 g, 42%). [M+1]+=573.1.
To a stirred mixture of ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetate (2.00 g, 3.49 mmol) in THF (50 mL) was added LiBH4 (1.52 g, 69.77 mmol) in portions at room temperature overnight. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (1.8 g, 97%) [M+1]+=531.2.
To a stirred mixture of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)ethan-1-ol (1.80 g, 3.39 mmol) and Pd/C (1 g, 10% wt) in EtOH (20 mL) and DCM (20 mL) were added AcOH (20 mL) at rt and stirred at 40° C. under hydrogen atmosphere overnight. The resulting mixture was filtered, the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to afford the product (1.2 g, 100%). [M+1]+=353.3.
The titled compound (1.4 g, 92%) was prepared in a manner similar to that in Example 291 step 6 from 3-(2,6-difluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione and IBX. [M+H]+=351.2.
The titled compound was synthesized in the procedures similar to Example 200. 1H NMR (400 MHz, DMSO)6H 11.96 (s, 1H), 10.86 (s, 1H), 8.85 (d, J=4.0 Hz, 1H), 8.63 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 8.03-7.90 (m, 2H), 7.54 (dd, J=8.7, 4.0 Hz, 1H), 7.40 (s, 1H), 6.74 (s, 1H), 6.60 (d, J=12.8 Hz, 2H), 4.06-4.02 (m, 1H), 3.76 (s, 5H), 2.94 (d, J=10.4 Hz, 2H), 2.79-2.64 (m, 10H), 2.31 (s, 7H), 2.14-1.98 (m, 10H), 1.83 (d, J=10.3 Hz, 2H), 1.70 (t, J=14.9 Hz, 2H), 1.59-1.43 (m, 3H), 1.38 (d, J=6.8 Hz, 2H), 1.17 (d, J=13.6 Hz, 2H), 0.75 (s, 3H); [M+H]+=1027.7.
A mixture of 1,2-difluoro-4-nitrobenzene (1.20 g, 5.0 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (0.80 g, 5.0 mmol), K2CO3 (1.38 g, 10.0 mmol) in ACN (80 mL) was stirred in a round bottom flask at 80° C. for 18 hours. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 1˜ 1: 100 gradient elution) to give the title product (0.86 g, 45%). [M+H]+=380.8.
To a solution of tert-butyl 3-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)azetidine-1-carboxylate (0.86 g, 2.26 mmol) in MeOH (40 mL) was added Pd/C (86 mg) and stirred at 25° C. for 18 hours under one balloon H2. The mixture was filtered and evaporated in vacuum to afford the crude product (0.60 g, 80%). [M+H]+=350.8.
A mixture of tert-butyl 3-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)azetidine-1-carboxylate (0.62 g, 1.77 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (0.44 g, 1.07 mmol) in isopropanol (30 mL) and MsOH (1 mL) was stirred in a round bottom flask at 100° C. for 18 hours. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with C18 column chromatography (0.5% FA in water: ACN=90: 10˜ 55: 45 gradient elution) to give the title product (0.27 g, 40%). [M+H]+=625.8.
A mixture of (6-((2-((4-(4-(azetidin-3-yl)piperazin-1-yl)-3-fluorophenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (30 mg, 0.05 mmol) in DCM (5 mL) and MeOH (1 mL) was added 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde (this material was obtained through the similar method of example 22) (30 mg, 0.10 mmol) then stirred in a round bottom flask at room temperature for 1 hour. The mixture was added NaBH(OAc)3 (106 mg, 0.50 mmol) and stirred in a round bottom flask at room temperature 18 hours. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with Pre-TLC (DCM: MeOH=10:1) to give the product (12 mg, 25%). 1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 10.81 (s, 1H), 9.58 (s, 1H), 9.02-8.81 (m, 3H), 8.37 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.63 (d, J=15.0 Hz, 1H), 7.29-7.21 (m, 1H), 7.10-7.02 (m, 1H), 7.00-6.93 (m, 1H), 6.71 (d, J=11.0 Hz, 2H), 3.94-3.80 (m, 2H), 3.75-3.67 (m, 2H), 3.04-2.87 (m, 6H), 2.76-2.59 (m, 4H), 2.48-2.42 (m, 4H), 2.24-2.10 (m, 2H), 1.99-1.91 (m, 2H), 1.75-1.67 (m, 2H), 1.57-1.42 (m, 2H), 1.40-1.33 (m, 2H), 1.29-1.11 (m, 7H), 0.92-0.73 (m, 3H). [M+H]+=942.2.
A mixture of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.00 g, 5.4 mmol), tert-butyl piperazine-1-carboxylate (1.08 g, 5.8 mmol) and DIPEA (1.40 g, 10.8 mmol) in DMSO (20 mL) was stirred in a round bottom flask at 100° C. for 60 hours. The mixture was added brine (100 mL), extracted with EA (100 mL×3). The organics were evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 1˜ 1:1 gradient elution) to give product (1.25 g, 66%). [M+H]+=351.9.
To a solution of tert-butyl 4-(5-methoxy-2-methyl-4-nitrophenyl)piperazine-1-carboxylate (1.25 g, 3.6 mmol) in DCM (100 mL) was added 4N HCl in dioxane (10 mL) and stirred at 25° C. for 2 hours. The mixture was filtered, the filter cake was washed with DCM and dried in vacuum to afford the product (1.14 g, 90%). [M+H]+=251.8.
A mixture of 1-(5-methoxy-2-methyl-4-nitrophenyl)piperazine (575 mg, 2.0 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (342 mg, 2 mmol) in dichloromethane (40 mL) and EtOH (5 mL) was added Ti(iPrO)4 (2.84 g, 10.0 mmol) stirred in a round bottom flask at room temperature for 2 hours. The mixture was added NaBH(OAc)3 (2.12 g, 10.0 mmol) and stirred at 50° C. for 18 hours. Then the mixture was washed with water (50 mL×3), then evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 1˜ 85: 15 gradient elution) to give product (1.20 g, crude). [M+H]+=406.8.
A mixture of tert-butyl 3-(4-(5-methoxy-2-methyl-4-nitrophenyl)piperazin-1-yl)azetidine-1-carboxylate (1.02 g, 2 mmol) in MeOH (20 mL) was added Pd/C (200 mg) stirred in a round bottom flask at room temperature under one balloon H2 for 18 hours. The mixture was filtered and washed with MeOH, then evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 1˜ 85: 15 gradient elution) to give product (0.44 g, 58%). [M+H]1=376.8.
A mixture of tert-butyl 3-(4-(4-amino-5-methoxy-2-methylphenyl)piperazin-1-yl)azetidine-1-carboxylate (0.44 g, 1.17 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (0.21 g, 0.50 mmol) in isopropanol (20 mL) and MsOH (0.196 g, 2.0 mmol) was stirred in a round bottom flask at 100° C. for 36 hours. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with C18 column chromatography (0.5% FA in water: ACN=90: 10˜ 55: 45 gradient elution) to give the title product (90 mg, 6%). [M+H]+=651.8.
A mixture of (6-((2-((4-(4-(azetidin-3-yl)piperazin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol) in dichloromethane (10 mL) and MeOH (1 mL) was added 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde (35 mg, 0.10 mmol) then stirred in a round bottom flask at room temperature for 1 hour. The mixture was added NaBH(OAc)3 (106 mg, 0.50 mmol) and stirred in a round bottom flask at room temperature 18 hours. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with Pre-TLC (DCM: MeOH=7:1) to give the product (3.5 mg, 5%). 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.86 (s, 1H), 8.97-8.76 (m, 3H), 8.30-8.25 (m, 2H), 8.24-8.20 (m, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 6.79 (s, 1H), 6.60 (d, J=13.0 Hz, 2H), 4.04 (dd, J=12.5, 5.0 Hz, 1H), 3.78 (s, 3H), 3.76-3.69 (m, 2H), 3.42 (t, J=6.0 Hz, 3H), 2.97-2.91 (m, 1H), 2.90-2.83 (m, 4H), 2.82-2.74 (m, 3H), 2.74-2.65 (m, 2H), 2.46-2.33 (m, 3H), 2.12-2.06 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.99-1.92 (m, 1H), 1.77-1.65 (m, 2H), 1.54-1.41 (m, 1H), 1.29-1.07 (m, 4H). [M+H]+=985.8.
To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (45.0 g, 193 mmol) in THF (270 mL) was added BH3-THF (1 M, 386 mL) at 0° C. Then the mixture was stirred at 20° C. for 2 hrs. Under cooling with ice, MeOH (250 mL) was dropwise added until there was no foaming in the system and the solvent was distilled off under reduced pressure. To the resulting reside, water (50.0 mL) was added for extraction with EtOAc (1000.0 mL). The combined organic phase was washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. 2-(4-bromo-3-fluorophenyl)ethan-1-ol (38.0 g, 89.8%) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.45 (t, J=7.72 Hz, 1H), 7.00 (dd, J=9.48, 1.76 Hz, 1H), 6.86-6.92 (m, 1H), 3.82 (t, J=6.50 Hz, 2H), 2.80 (t, J=6.50 Hz, 2H), 2.03 (s, 1H); [M+H]+=219.3.
To a solution of 2-(4-bromo-3-fluorophenyl)ethan-1-ol (38.0 g, 173 mmol) in DCM (210 mL) was added imidazole (17.7 g, 260 mmol) at 20° C. TBSCl (36.6 g, 242 mmol, 29.7 mL) was added to the reaction mixture at 0° C. Then the mixture was stirred at 20° C. for 3 hrs. Then the mixture was adjusted to pH=6 with 5% citric acid (180 mL), and extracted with DCM (150 mL). The organic phase was adjusted to pH=8 with NaHCO3 and then aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuum. (4-bromo-3-fluorophenethoxy)(tert-butyl)dimethylsilane (52.0 g, 156 mmol) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.43 (t, J=7.72 Hz, 1H), 7.00 (dd, J=9.56, 1.87 Hz, 1H), 6.89 (dd, J=8.00, 1.87 Hz, 1H), 3.80 (t, J=6.48 Hz, 2H), 2.78 (t, J=6.48 Hz, 2H), 0.84-0.89 (m, 9H),−0.05-0.01 (m, 6H); [M+H]+=333.1.
To a solution of (4-bromo-3-fluorophenethoxy)(tert-butyl)dimethylsilane (52.0 g, 156 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65.1 g, 156 mmol) in dioxane (320 mL) was added KOAc (45.9 g, 468 mmol) at 20° C. Pd(dppf)Cl2 (11.4 g, 15.6 mmol) was added to the mixture at 20° C. The suspension was degassed under vacuum and purged with N2 three times. Then the mixture was stirred at 90° C. for 16 hrs. Water (160 mL) was poured into the mixture, extrated with EtOAc (100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography. 2,6-bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)pyridine (32.0 g, 37.8%) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.55 (dd, J=8.04, 0.99 Hz, 1H), 7.43-7.47 (m, 2H), 7.33-7.42 (m, 7H), 7.25-7.33 (m, 3H), 6.98-7.05 (m, 2H), 5.40 (d, J=18.4 Hz, 4H), 3.87 (t, J=6.84 Hz, 1H), 3.84-3.89 (m, 1 H), 2.86 (t, J=6.84 Hz, 2H), 0.88-0.92 (m, 9H), 0.01-0.03 (m, 6H); [M+H]+=544.2.
To a solution of 2,6-bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)pyridine (32.0 g, 58.8 mmol) in THF (50.0 mL) was added Pd/C (0.800 g, 10.0% purity) under Ar at 20° C. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 50° C. for 16 hrs. The suspension was filtered through a pad of celite and the filter cake was washed with THF (200 mL×3). The combined filtrates were concentrated to dryness to give crude product. The crude product was triturated with petroleum ether (50.0 mL) at 20° C. for 1 hrs. 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-dione (12.0 g, 55.7%) was obtained. 1HNMR (400 MHz, CDCl3-d) δ ppm 7.06-7.12 (m, 1H) 7.93 (br s, 1H), 6.96-7.04 (m, 2H), 3.91 (dd, J=11.2, 5.04 Hz, 1H), 3.81 (t, J=6.80 Hz, 2 H), 2.82 (t, J=6.80 Hz, 2H), 2.58-2.73 (m, 2H), 2.18-2.34 (m, 2H), 0.87 (s, 9H), 0.00 (s, 6H); [M+H]+=366.2.
To a solution of 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-dione (12.0 g, 32.8 mmol) in MeOH (60 mL) was added HCl (12 M, 6 mL) at 20° C. Then the mixture was stirred at 20° C. for 3 hrs. Water (60 mL) was poured into the mixture, extrated with EtOAc (40 mL). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuum. The combined crude product was purified by re-crystallization from toluene (32.0 mL) at 100° C. 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (6.50 g, 78.8%) was obtained. 1HNMR (400 MHz, DMSO-d6) δ ppm 10.8 (s, 1H), 7.19 (t, J=7.84 Hz, 1H), 6.99-7.08 (m, 2H), 4.67 (t, J=5.18 Hz, 1H), 3.99 (dd, J=12.6, 4.74 Hz, 1H), 3.55-3.66 (m, 2H), 2.68-2.75 (m, 3H), 2.18 (qd, J=12.8, 3.86 Hz, 1H), 1.93-2.03 (m, 1H); [M+H]+=252.2.
To a solution of 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (200 mg, 0.8 mmol) in DMSO (10 mL) was added IBX (338 mg, 1.2 mmol). The mixture was stirred in a flask at rt overnight. After being determined the reaction to be completed by LCMS, the mixture was extracted with EA (30 mL * 3). The combined organic phase was dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product (100 mg, crude), which was used for next step without further purification. [M+H]+=250.3.
To a solution of 1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-one (600 mg, 2.17 mmol), tert-butyl(S)-2-(hydroxymethyl)piperazine-1-carboxylate (511.7 mg, 2.39 mmol) in DCE (10 mL) was added Ti(iPrO)4 (27.88 mg 0.216 mmol). Then the mixture was stirred at 60° C. for 12 h and water (10 mL) was poured into the mixture. The reaction mixture was filtered and extracted with EtOAc (10 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography to afford product (700 mg, 67.6%). [M+H]+=477.2
To a solution of tert-butyl(S)-2-(hydroxymethyl)-4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (600 mg, 1.26 mmol), in DCM (10 mL), MeOH (10 mL) was added Pd—C under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at rt for 12 h. Then the mixture was stirred at 60° C. for another 12 h. The reaction mixture was filtered and extracted with DCM (3×30 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=10/1 to 5/1) to afford product (500 mg, 88.5%). [M+H]+=449.1.
To a solution of tert-butyl(S)-4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (300 mg, 0.589 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (267.9 mg, 0.648 mmol) in n-BuOH(10 mL) was added TsOH (336.12 mg 1.767 mmol). Then the mixture was stirred at 100° C. for 12 h. Water (30 mL) was poured into the mixture. The reaction mixture was filtered and extracted with DCM (2×50 mL). The combined organic phase was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography to afford product (230 mg, 47.5%). [M+H]+=724.2.
The titled compound (11 mg, 26%) was prepared in a manner similar to that in Example 204 step 6 from (S)-(6-((5-bromo-2-((5-ethyl-4-(4-(3-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.86 (s, 1H), 8.85 (t, J=16.5 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.06 (d, J=21.3 Hz, 2H), 6.81 (s, 1H), 4.00 (d, J=17.4 Hz, 1H), 3.77 (s, 3H), 3.64 (s, 1H), 3.41 (s, 2H), 3.01 (s, 2H), 2.88 (d, J=6.4 Hz, 3H), 2.63 (s, 8H), 2.38 (d, J=42.8 Hz, 6H), 2.19 (s, 2H), 2.02 (d, J=14.4 Hz, 7H), 1.85 (s, 2H), 1.59 (d, J=11.6 Hz, 2H), 0.94 (s, 3H). [M+H]+=957.6.
The titled compound was synthesized in a manner similar to that in Example 200. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.86 (s, 1H), 8.85 (t, J=15.3 Hz, 3H), 8.29 (d, J=13.8 Hz, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.04 (d, J=11.2 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 3.86 (dd, J=12.0, 4.8 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J=10.7 Hz, 2H), 2.73-2.68 (m, 7H), 2.56 (s, 3H), 2.52 (s, 1H), 2.48 (s, 5H), 2.6-2.32 (m, 2H), 2.25-2.21 (m, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.87 (d, J=10.0 Hz, 2H), 1.58 (d, J=9.3 Hz, 2H), 0.92 (t, J=7.2 Hz, 3H); [M+H]+=927.6.
The titled compound was synthesized in a manner similar to that in Example 200. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.94 (s, 1H), 8.86 (d, J=20.7, 10.3 Hz, 3H), 8.28 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.14 (t, J=7.1 Hz, 1H), 7.06 (t, J=7.0 Hz, 1H), 6.81 (s, 1H), 4.10 (dd, J=12.7, 4.9 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J=11.1 Hz, 2H), 2.83-2.64 (m, 6H), 2.55 (dd, J=16.4, 5.5 Hz, 6H), 2.47 (d, J=7.2 Hz, 5H), 2.34 (d, J=21.6 Hz, 2H), 2.23 (dd, J=12.9, 4.0 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.86 (d, J=11.5 Hz, 2H), 1.62-1.54 (m, 2H), 0.93 (t, J=6.6 Hz, 3H); [M+H]+=945.6.
The titled compound was synthesized in a manner similar to that in Example 200.
1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.96 (s, 1H), 8.86 (dt, J=22.8, 11.4 Hz, 3H), 8.28 (d, J=9.1 Hz, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.81 (s, 1H), 4.20 (dd, J=12.8, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J=11.5 Hz, 2H), 2.76 (m, 6H), 2.54 (d, J=1.8 Hz, 6H), 2.48 (s, 5H), 2.36 (s, 2H), 2.13 (d, J=9.6 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.87 (d, J=11.4 Hz, 2H), 1.58 (d, J=8.8 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=945.6.
The titled compound was synthesized in a manner similar to that in Example 200.
1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.93 (s, 1H), 8.86 (d, J=4.5 Hz, 2H), 8.84-8.79 (m, 1H), 8.27 (s, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 7.23 (s, 2H), 6.81 (s, 1H), 3.99 (d, J=9.2 Hz, 2H), 3.77 (s, 7H), 3.00 (s, 2H), 2.70 (t, J=11.0 Hz, 5H), 2.52 (s, 5H), 2.48-2.45 (m, 1H), 2.31 (s, 6H), 2.02 (d, J=14.4 Hz, 8H), 1.84 (s, 2H), 1.74 (d, J=12.1 Hz, 2H), 1.58 (s, 2H), 1.40 (s, 2H), 1.23 (s, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=1017.4.
To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1 g, 2.07 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (495 mg, 3 mmol) and Cs2CO3 (1.95 g, 6 mmol) in 10 mL DMSO, Pd2(dba)3 (183 mg, 0.2 mmol) and Xantphos (231 mg, 0.4 mmol) was added under N2 atmosphere. The mixture was stirred at 90° C. for 16 hours under N2 atmosphere. After LCMS showed the reaction was completed. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL×2). The organic phase was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica column chromatography (PE:EA=10:1) to afford product (740 mg, 67.4% yield). [M+H]+=530.8.
To a solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate (740 mg, 1.4 mmol) in 10 mL THF, LiOH H2O (84 mg, 2 mmol) in 2 mL water was added. The mixture was stirred at 25° C. for 2 hours. After LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was adjust pH<5 with 1 N HCl and extracted with 50 mL EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated in vacuum to afford product (700 mg, 96.9% yield). [M+H]+=516.8.
To a solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (700 mg, 1.35 mmol) in 5 mL DCM and 30 mL MeOH, 350 mg Pd/C was added. The mixture was stirred at 30° C. for 16 hours under H2 atmosphere. After LCMS showed the reaction was completed and the mixture was filtered. The organic phase was concentrated in vacuum to afford product (350 mg, 76.7% yield). [M+H]+=338.8.
To a solution of 2-methylquinolin-6-amine (5 g, 31.62 mmol) in AcOH(50 mL) was added dropwise a solution of ICl (8.85 g, 37.95 mmol) in AcOH(10 mL) was stirred at 5° C.˜10° C. Then the mixture was stirred at rt for 1h. The reaction solution was concentrated to dryness and the mixture was diluted with water (200 mL), neutralized with solid K2CO3. The mixture was extracted with DCM (3×150 mL). The combined organic phase was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH=20:1) to afford product (7.1 g, 79.06%). [M+H]+=285.2.
To a solution of 5-iodo-2-methylquinolin-6-amine (7.1 g, 24.99 mmol) and dimethylphosphine oxide (2.93 g, 37.49 mmol) in dioxane (100 mL) was added Pd(OAc)2 (0.55 g, 2.45 mmol), Xantphos (2.89 g, 4.99 mmol), K3PO4 (10.61 g, 49.98 mmol) under N2 atmosphere. The mixture was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 balloon at 100° C. for 6 h. The reaction mixture was extracted with DCM (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH=15:1) to afford the product (4.5 g, 76.9%). [M+H]+=235.2.
A solution of (6-amino-2-methylquinolin-5-yl)dimethylphosphine oxide (4.5 g, 19.21 mmol), 5-bromo-2,4-dichloropyrimidine (13.13 g, 57.64 mmol) and DIEA (7.45 g, 57.64 mmol) in n-BuOH (100 mL) was stirred at 120° C. for 12 h. The reaction solution was concentrated to dryness, then the crude product was purified by re-crystallization from EA:PE=5:1 (50 mL). The mixture was filtered and the filter cake was washed with DCM (3×50 mL). The combined organic phase was washed with brine (2×100 mL), dried over Na2SO4 and concentrated in vacuum to afford product (5.5 g, 67.3%). [M+H]+=425.2.
A solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (5.5 g, 12.91 mmol), TsOH (6.67 g, 38.73 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (5.67 g, 13.56 mmol) in n-BuOH (80 mL) was stirred at 100° C. for 12 h. The reaction mixture was adjusted to pH=8 with 1M NaOH, and then extracted with DCM (3×80 mL). The combined organic phase was washed with brine (2×100 mL), dried over Na2SO4 and concentrated in vacuum, The residue was purified by column chromatograph (DCM:MeOH=8:1) to afford the product (5.2 g, 57.01%). [M+H]+=707.3.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol), (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (24 mg, 0.07 mmol) and DIEA (26 mg, 0.2 mmol) in 10 mL DCM, 50% w.t. T3P in EtOAc solution (64 mg, 0.1 mmol) was added. The mixture was stirred at 25° C. for 16 hours. After LCMS showed the reaction was completed. The mixture was quenched with 10 mL water. The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford the desired product (21.69 mg, 30.1% yield). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.84 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (d, J=7.1 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.46-7.33 (m, 2H), 6.74 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.02 (dd, J=12.6, 5.1 Hz, 1H), 3.76 (s, 3H), 3.59-3.42 (m, 6H), 3.36-3.22 (m, 4H), 2.95 (d, J=10.7 Hz, 2H), 2.83-2.73 (m, 1H), 2.70-2.62 (m, 5H), 2.56 (d, J=15.8 Hz, 2H), 2.45-2.35 (m, 3H), 2.30 (d, J=7.1 Hz, 2H), 2.21-2.03 (m, 3H), 2.03-1.91 (m, 7H), 1.84 (d, J=10.2 Hz, 2H), 1.65-1.50 (m, 2H), 0.92-0.63 (m, 3H). [M+H]+=1027.6.
The titled compound was prepared in a manner similar to that in Example 57. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 11.08 (s, 1H), 8.85 (t, J=9.5 Hz, 3H), 8.28 (d, J=6.1 Hz, 2H), 7.90 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.38 (s, 1H), 6.83 (d, J=11.6 Hz, 2H), 6.71 (d, J=8.3 Hz, 1H), 5.07 (d, J=12.8 Hz, 1H), 4.23 (d, J=8.4 Hz, 2H), 4.14 (s, 2H), 3.92 (s, 2H), 3.77 (s, 4H), 3.52 (s, 3H), 3.03 (d, J=10.2 Hz, 3H), 2.87 (d, J=13.4 Hz, 2H), 2.72 (t, J=10.5 Hz, 3H), 2.57 (s, 2H), 2.37 (d, J=34.2 Hz, 2H), 2.02 (d, J=14.4 Hz, 8H), 1.85 (s, 2H), 1.61 (d, J=9.8 Hz, 2H), 0.93 (s, 3H). [M+H]+=1035.9
The titled compound was prepared in a manner similar to that in Example 57. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.08 (s, 1H), 8.87 (d, J=4.8 Hz, 3H), 8.27 (t, J=11.6 Hz, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 6.98-6.79 (m, 3H), 5.06 (d, J=8.0 Hz, 1H), 3.77 (s, 3H), 3.69-3.48 (m, 10H), 3.02 (s, 3H), 2.96-2.81 (m, 2H), 2.72 (t, J=10.7 Hz, 2H), 2.60 (s, 4H), 2.42 (s, 1H), 2.24 (s, 1H), 2.14 (s, 1H), 2.04 (t, J=14.1 Hz, 8H), 1.86 (s, 2H), 1.62 (d, J=10.0 Hz, 2H), 0.93 (s, 3H). [M+H]+=1049.8
The titled compound was prepared in a manner similar to that in Example 57. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.08 (s, 1H), 8.87 (d, J=4.4 Hz, 3H), 8.28 (d, J=6.9 Hz, 2H), 7.89 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 6.94 (s, 1H), 6.82 (s, 2H), 5.07 (s, 1H), 3.77 (s, 3H), 3.55 (d, J=32.6 Hz, 10H), 3.02 (s, 3H), 2.88 (s, 2H), 2.70 (d, J=21.8 Hz, 3H), 2.60 (s, 3H), 2.45-2.37 (m, 1H), 2.23 (s, 1H), 2.14 (s, 1H), 2.02 (d, J=14.2 Hz, 7H), 1.86 (s, 2H), 1.63 (s, 2H), 0.93 (s, 3H). [M+H]+=1049.8
The titled compound was prepared in a manner similar to that in Example 57. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 11.08 (s, 1H), 8.86 (s, 3H), 8.27 (s, 2H), 7.91 (s, 1H), 7.66 (s, 1H), 7.43-7.23 (m, 3H), 6.81 (s, 1H), 5.06 (s, 1H), 4.07 (d, J=10.2 Hz, 2H), 3.77 (s, 3H), 3.56 (s, 2H), 3.46 (s, 4H), 3.12-2.95 (m, 8H), 2.92-2.83 (m, 2H), 2.72 (s, 2H), 2.32 (s, 2H), 2.02 (d, J=14.1 Hz, 8H), 1.85 (s, 2H), 1.66 (d, J=28.9 Hz, 6H), 0.93 (s, 3H). [M+H]+=1061.3.
The titled compound was synthesized in the procedures similar to Example 237. 1H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 10.95 (s, 1H), 8.84 (t, J=13.9 Hz, 3H), 8.24 (d, J=22.1 Hz, 3H), 7.91 (d, J=8.6 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.06 (s, 2H), 6.80 (s, 1H), 5.02 (d, J=7.9 Hz, 1H), 4.32 (s, 1H), 4.21 (d, J=17.1 Hz, 1H), 3.86 (d, J=12.6 Hz, 6H), 3.02 (d, J=10.3 Hz, 3H), 2.89 (s, 2H), 2.83 (d, J=12.6 Hz, 2H), 2.69 (d, J=11.9 Hz, 3H), 2.63 (s, 4H), 2.42 (s, 2H), 2.06 (d, J=7.7 Hz, 9H), 2.01 (s, 3H), 1.88 (s, 2H), 1.75 (d, J=12.4 Hz, 2H), 1.58 (d, J=10.9 Hz, 2H), 1.43 (s, 2H), 1.23 (s, 3H), 0.91 (s, 3H). [M+H]+=1050.1.
A mixture of methyl 2-cyano-4-fluorobenzoate (10.00 g, 55.87 mmol) and 2-(methylamino)ethan-1-ol (4.61 g, 61.45 mmol), DIEA (23.78 g, 184.35 mmol) in DMSO (100 mL) was stirred for 3 h at 60° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (10 g, 76.51%). m/z[M+H]+=235.1.
To a stirred mixture of methyl 2-cyano-4-((2-hydroxyethyl)(methyl)amino)benzoate (10.0 g, 42.74 mmol) and oxophosphinic acid sodium hydride (44.44 g, 427.35 mmol, 60%) in pyridine (100.00 mL), AcOH (40.00 mL) and H2O (40.00 mL) was added Raney-Ni (10.00 g) in portions and stirred at 70° C. under nitrogen atmosphere for 3 days. The reaction was quenched with 1 M HCl at room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with citric acid, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford the product (5 g, 49.4%). [M+H]+=238.1.
A mixture of 3-aminopiperidine-2,6-dione (5.82 g, 42.19 mmol) and DIEA (13.71 g, 105.49 mmol) in DMF (50.00 mL) was stirred for 5 h at room temperature. The mixture was acidified to pH=6 with AcOH (7.6 g, 126.58 mmol). To the above mixture was added methyl 2-formyl-4-((2-hydroxyethyl)(methyl)amino)benzoate (5.0 g, 21.1 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature. To the above mixture was added NaBH3CN (5.23 g, 84.39 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (8:1) to afford the product (2.61 g, 39.0%). [M+H]+=318.3.
The titled compound (150 mg, 76%) was prepared in a manner similar to that in Example 207 step 4 from 3-(5-((2-hydroxyethyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and MsCl. [M+H]+=395.1.
The titled compound (12 mg, 26%) was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)(methyl)amino)ethyl methanesulfonate. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.94 (s, 1H), 8.86 (d, J=4.9 Hz, 3H), 8.28 (s, 1H), 7.91 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 6.81 (s, 3H), 6.60 (s, 1H), 5.03 (d, J=8.5 Hz, 1H), 4.32 (d, J=16.7 Hz, 1H), 4.19 (d, J=16.8 Hz, 1H), 3.77 (s, 3H), 3.55 (s, 5H), 2.95 (d, J=43.9 Hz, 10H), 2.76-2.66 (m, 3H), 2.60 (s, 1H), 2.33 (s, 4H), 2.02 (d, J=14.4 Hz, 8H), 1.85 (s, 2H), 1.57 (d, J=9.0 Hz, 2H), 1.24 (s, 1H), 0.92 (s, 3H). [M+H]+=993.9.
A solution of methyl 3-hydroxybenzoate (40.00 g, 262.90 mmol) in THF (1.00 L) was stirred at room temperature. To the mixture was added hexamethylenetetramine (44.17 g, 315.48 mmol) in portions at room temperature. The resulting mixture was stirred for additional 4 h at 80° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with ice water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford the product (20 g, 42%). [M+H]+=181.2.
A mixture of methyl 2-formyl-3-hydroxybenzoate (20.00 g, 111.01 mmol) and [(2-bromoethoxy)methyl]benzene (71.63 g, 333.03 mmol), K2CO3 (30.69 g, 222.02 mmol), KI (9.21 g, 55.50 mmol) in DMF (300 mL) was stirred overnight at 70° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2:1) to afford the product (10 g, 29%). [M+H]+=315.2.
A mixture of 3-aminopiperidine-2,6-dione hydrochloride (6.26 g, 38.17 mmol) and DIEA (8.22 g, 63.62 mmol) in DCE (100 mL) and DMF (5 mL) was stirred for 2 h at room temperature. The mixture was acidified to pH=6 with AcOH. To the above mixture was added methyl 3-(2-(benzyloxy)ethoxy)-2-formylbenzoate (10.00 g, 31.81 mmol). The resulting mixture was stirred overnight at room temperature. To the above mixture was added NaBH3CN (6.00 g, 95.43 mmol) in portions at room temperature. The resulting mixture was stirred for additional 5 h at room temperature. The reaction was quenched by the addition of water. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (5:1) to afford crude product. The residue was purified by reverse phase flash chromatography with the following conditions: mobile phase, MeCN/H2O (0 to 50% in 30 min elution gradient) to afford the product (4.1 g, 33%). [M+H]+=395.2.
A mixture of 3-(4-(2-(benzyloxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4.10 g, 10.39 mmol), Pd/C (2.00 g, 10% wt), AcOH (4 mL), THF (30 mL) and DCM (30 mL) was stirred for 16 h at 40° C. under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH and DCM. The filtrate was concentrated under reduced pressure to afford the product (2.13 g, 67%). [M+1]+=305.2.
The titled compound (120 mg, 56%) was prepared in a manner similar to that in Example 207 step 4 from 3-(4-(2-hydroxyethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and MsCl. [M+H]+=383.1.
The titled compound (15 mg, 26%) was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl methanesulfonate. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.97 (s, 1H), 8.86 (d, J=5.2 Hz, 3H), 8.26 (d, J=5.7 Hz, 2H), 7.90 (d, J=9.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.42-7.23 (m, 3H), 6.80 (s, 1H), 5.11 (d, J=9.3 Hz, 1H), 4.38 (d, J=17.3 Hz, 1H), 4.25 (d, J=7.0 Hz, 3H), 3.77 (s, 3H), 2.95 (d, J=33.8 Hz, 5H), 2.70 (d, J=22.0 Hz, 5H), 2.57 (d, J=27.9 Hz, 8H), 2.31 (s, 2H), 2.02 (d, J=14.3 Hz, 6H), 1.84 (s, 2H), 1.57 (d, J=12.1 Hz, 2H), 0.92 (s, 3H). [M+H]+=982.9.
The titled compound was synthesized in the procedures similar to Example 59. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 11.09 (s, 1H), 8.85 (t, J=15.8 Hz, 3H), 8.29 (d, J=13.6 Hz, 2H), 7.89 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 6.73 (dd, J=72.3, 8.7 Hz, 3H), 5.06 (dd, J=12.7, 5.5 Hz, 1H), 4.13 (t, J=8.0 Hz, 2H), 3.77 (s, 3H), 3.72-3.62 (m, 2H), 3.01 (d, J=10.4 Hz, 3H), 2.87 (d, J=12.6 Hz, 4H), 2.77 (d, J=8.3 Hz, 2H), 2.73-2.61 (m, 5H), 2.27 (s, 2H), 2.09-2.00 (m, 10H), 1.83-1.82 (m, 2H), 1.57 (d, J=9.2 Hz, 2H), 1.09-1.00 (m, 6H), 0.95-0.89 (m, 3H). [M+H]+=1047.4
The titled compound was synthesized in the procedures similar to Example 237. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.94 (s, 1H), 8.87 (d, J=4.5 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.50 (d, J=10.6 Hz, 2H), 5.03 (dd, J=12.9, 5.3 Hz, 1H), 4.28-4.38 (m, 1H), 4.19 (s, 1H), 4.02-4.05 (m, 2H), 3.77 (s, 3H), 3.56 (s, 2H), 2.91-3.10 (m, 6H), 2.71-2.80 (m, 3H), 2.58-2.61 (m, 6H), 2.42-2.45 (m, 6H), 2.02 (d, J=14.4 Hz, 6H), 1.97-1.90 (m, 1H), 1.85 (s, 2H), 1.58 (d, J=9.4 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H); [M+H]+=1005.5.
The titled compound was synthesized in the procedures similar to Example 200. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.92 (s, 1H), 8.87 (d, J=6.2 Hz, 2H), 8.85-8.78 (m, 1H), 8.28 (d, J=5.8 Hz, 2H), 7.91 (s, 1H), 7.42 (d, J=6.9 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J=10.9 Hz, 1H), 6.81 (s, 1H), 4.05 (dd, J=12.7, 4.7 Hz, 1H), 3.77 (s, 3H), 3.30 (s, 3H), 3.02 (d, J=10.9 Hz, 2H), 2.85 (s, 2H), 2.72 (d, J=12.0 Hz, 3H), 2.64 (s, 1H), 2.58-2.52 (m, 4H), 2.49-2.45 (m, 5H), 2.36 (s, 1H), 2.24 (d, J=9.5 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.88 (s, 2H), 1.61 (s, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=961.4.
The titled compound was synthesized in the procedures similar to Example 200. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.91 (s, 1H), 8.86 (d, J=5.4 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.48 (d, J=7.0 Hz, 1H), 7.38 (s, 1H), 7.22 (d, J=10.6 Hz, 1H), 6.81 (s, 1H), 4.18 (dd, J=12.5, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J=10.8 Hz, 2H), 2.76-2.71 (m, 6H), 2.56 (s, 7H), 2.48 (s, 5H), 2.35-2.30 (m, 2H), 2.02 (d, J=14.4 Hz, 6H), 1.99-1.94 (m, 1H), 1.86 (d, J=11.1 Hz, 2H), 1.58 (d, J=9.4 Hz, 2H), 0.93 (t, J=6.7 Hz, 3H); [M+H]+=961.6.
The titled compound was synthesized in the procedures similar to Example 207. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.74 (s, 1H), 8.87 (d, J=5.6 Hz, 3H), 8.27 (s, 2H), 7.92 (s, 1H), 7.39 (s, 1H), 6.99 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 6.49 (s, 2H), 3.77 (s, 3H), 3.67 (s, 1H), 3.34 (s, 3H), 3.24-3.17 (m, 1H), 3.02 (s, 6H), 2.72 (s, 3H), 2.53 (s, 6H), 2.33 (s, 6H), 2.02 (d, J=14.5 Hz, 9H), 1.93-1.82 (m, 1H), 1.79-1.52 (m, 3H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=964.4.
A mixture of 3-(4-bromophenyl)cyclopentan-1-one (2.39 g, 10.0 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.17 g, 10.0 mmol), Cs2CO3 (6.50 g, 20.0 mmol) and Pd(DPPF)Cl2 (0.73 g, 1.0 mmol) in dioxane (80 mL) and water (20 mL) was stirred in a round bottom flask at 95° C. for 18 hours. The mixture was evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EA=100: 1˜ 50: 50 gradient elution) to give the title product (4.02 g, 81%). [M+H]+=449.8.
To a solution of 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclopentan-1-one (4.02 g, 8.95 mmol) in DCM (100 mL) and MeOH (100 mL) was added Pd/C (400 mg) and stirred at 25° C. for 18 hours under one balloon H2. The mixture was filtered and evaporated in vacuum to afford the crude product (2.20 g, 90%). [M+H]+=271.8.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (36 mg, 0.05 mmol) in DCM (6 mL) and EtOH (1 mL) was added 3-(4-(3-oxocyclopentyl)phenyl)piperidine-2,6-dione (27 mg, 0.10 mmol) then stirred in a round bottom flask at room temperature for 1 hour. The mixture was added NaBH(OAc)3 (106 mg, 0.50 mmol) and stirred in a round bottom flask at room temperature 18 hours. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with Pre-TLC (DCM: MeOH=7:1) to give the product (5.0 mg, 10%). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.83 (s, 1H), 9.04-8.69 (m, 2H), 8.39-8.20 (m, 2H), 8.01-7.86 (m, 1H), 7.45-7.35 (m, 1H), 7.30-7.21 (m, 2H), 7.16 (s, 2H), 6.81 (s, 1H), 3.93-3.70 (m, 4H), 3.60-3.43 (m, 1H), 3.31-3.26 (m, 3H), 3.05 (s, 8H), 2.82-2.59 (m, 5H), 2.47-2.36 (m, 3H), 2.26-2.11 (m, 3H), 2.07-1.97 (m, 8H), 1.94-1.76 (m, 3H), 1.71-1.47 (m, 3H), 1.34-1.17 (m, 2H), 0.98-0.83 (m, 3H). [M+H]+=949.8.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.76 (s, 1H), 8.85 (dt, J=18.6, 9.3 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.8 Hz, 1H), 7.38 (s, 1H), 7.02 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 6.42 (d, J=8.4 Hz, 2H), 4.01 (t, J=5.6 Hz, 2H), 3.89-3.80 (m, 3H), 3.77 (s, 3H), 3.73-3.67 (m, 1H), 3.49 (s, 2H), 3.02 (d, J=11.1 Hz, 2H), 2.77-2.54 (m, 7H), 2.48-2.36 (m, 3H), 2.17-1.94 (m, 12H), 1.85-1.90 (m, 2H), 1.67-1.53 (m, 2H), 0.93-0.98 (m, 3H); [M+H]+=964.5.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.94 (s, 1H), 8.89-8.75 (m, 3H), 8.27 (s, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.00 (d, J=10.0 Hz, 2H), 6.81 (s, 1H), 4.19 (dd, J=12.5, 5.0 Hz, 1H), 3.77 (s, 3H), 3.05-2.97 (m, J=11.5 Hz, 2H), 2.85-2.77 (m, 1H), 2.74-2.67 (m, 2H), 2.63-2.59 (m, 2H), 2.59-2.52 (m, 4H), 2.48-2.34 (m, 7H), 2.32-2.25 (m, 3H), 2.16-2.08 (m, 1H), 2.04-1.97 (m, 7H), 1.89-1.83 (m, 2H), 1.78-1.70 (m, 2H), 1.62-1.52 (m, 2H), 0.96-0.87 (m, 3H). [M+H]+=959.50.
To a mixture of benzo[d]thiazol-5-amine (15 g, 100 mmol), NaHCO3 (16.8 g, 200 mmol) in CH2Cl2 250 mL was added ICl (17.8 g, 110 mmol) portionwise at 5° C. for 30 minutes. The mixture was stirred at 20° C. for 2 hours. The mixture was quenched by saturated brine 100 mL and saturated Na2S2O3 aqueous solution 50 mL, and then extracted with DCM (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel column (MeOH in DCM, 0% to 2%) to afford the product (22.8 g, 82.6%). [M+H]+=277.2.
A mixture of 4-iodobenzo[d]thiazol-5-amine (22.8 g, 82.5 mmol), dimethylphosphine oxide (9.67 g, 123.8 mmol), Pd(OAc)2 (1.85 g, 8.25 mmol), Xantphos (9.55 g, 16.52 mmol), K3PO4 (43.8 g, 206 mmol) in DMF (150 mL) was stirred at 120° C. overnight. The solvent was removed by rotary concentration. The residue was diluted with water 100 mL and extracted with EtOAc (3×200 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel column (MeOH in DCM, 0% to 6%) to afford the product (15.6 g, 83.5%). [M+H]+=227.2.
A mixture of (5-aminobenzo[d]thiazol-4-yl)dimethylphosphine oxide (1.13 g, 5 mmol), 5-bromo-2,4-dichloropyrimidine (1.37 g, 6 mmol), Et3N (1.52 g, 15 mmol) in n-BuOH 100 mL was stirred at 80° C. for 24 hours. The solvent was removed by rotary concentration. The residue was purified with silica gel column (MeOH in DCM, 0% to 5%) to afford product (1.8 g, 86.3%). [M+H]+=416.9.
A mixture of (5-((5-bromo-2-chloropyrimidin-4-yl)amino)benzo[d]thiazol-4-yl)dimethylphosphine oxide (0.48 g, 1.15 mmol), tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (0.53 g, 1.26 mmol) and TsOH (0.39 g, 2.3 mmol) in dioxane 100 mL was stirred at 95° C. for 60 hours. The mixture was concentrated and diluted with 1N aqueous NaOH (50 mL), extracted with DCM (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel column (MeOH in DCM, 0% to 5%) to afford product (238 mg, 25.9%). [M+H]+=799.4.
To a solution of tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)benzo[d]thiazol-5-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate in EtOH (30 mL) was added a solution of HCl (4N, 10 mL) in dioxane. The resulting solution was stirred at rt for 2 hours. The mixture was concentrated to dryness and 1N NaOH aqueous (10 mL) was added. The mixture was extracted with DCM (3×50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford product (180 mg, 86.4%). [M+H]+=699.4.
A solution of (5-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d]thiazol-4-yl)dimethylphosphine oxide (100 mg, 0.143 mmol), 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (57 mg, 0.214 mmol) and HOAc (1.7 mg, 0.0286 mmol) in DCM/EtOH (30/30 mL) was stirred at 20° C. for 3 hours. Then NaBH(OAc)3 (60.6 mg, 0.286 mmol) was added to the mixture at 20° C. The solution was stirred at 20° C. for 9 hrs. The reaction was quenched by aqueous Na2CO3 (10 mL), extracted with DCM (3×100 mL). The combined organic phase dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by Prep. HPLC (ACN in water with 0.1% of FA, 0% to 90%). 3-(4-(2-(4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)benzo[d]thiazol-5-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione (86.9 mg, 64.0%) was obtained. 1H NMR (500 MHz, DMSO) δ 11.90 (s, 1H), 10.95 (s, 1H), 9.50 (s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.11 (d, 2H), 7.45 (s, 1H), 7.03 (d, 2H), 6.77 (s, 1H), 4.20 (dd, 1H), 3.77 (s, 3H), 3.01-2.99 (m, 2H), 2.83-2.70 (m, 3H), 2.69-2.64 (m, 2H), 2.60-2.54 (m, 7H), 2.45-2.40 (m, 7H), 2.34-2.30 (m, 1H), 2.14-2.11 (m, 1H), 2.04 (s, 3H), 1.98 (s, 3H), 1.87-1.85 (m, 2H), 1.56 (dd, 2H), 0.92 (t, 3H); [M+H]+=950.4.
To a solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (8.34 g, 20 mmol), 5-bromo-2-iodobenzonitrile (6.75 g, 22 mmol) and K2CO3 (5.52 g, 40 mmol) in 50 mL dioxane and 5 mL water, Pd(dppf)Cl2 (731 mg, 1 mmol) was added under N2 protected. The mixture was stirred at 90° C. for 16 hours under N2 atmosphere. The mixture was concentrated in vacuum. The residue was washed with water (100 mL) and extracted by EtOAc (100 mL×3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica solumn chromatography (PE:EA=20:1) to afford product (8.5 g, 90.4% yield). [M+H]+=471.6.
To a solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromobenzonitrile (3.1 g, 6.85 mmol), azetidin-3-ylmethanol hydrochloride (984 mg, 8 mmol) and K3PO4 (3.4 g, 16 mmol) in 20 mL DMSO, CuI (190 mg, 1 mmol) and L-Proline (230 mg, 2 mmol) was added under N2 protected. The mixture was stirred at 100° C. for 16 hours under N2 atmosphere. The mixture was diluted with EtOAc (150 mL) and washed with brine (100 mL×2). The organic phase was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica column chromatography (PE:EA=5:1) to afford product (2.1 g, 64.3% yield). [M+H]+=477.6.
To a solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)benzonitrile (500 mg, 1.05 mmol) in EtOAc (50 mL), 500 mg Pd/C was added. The mixture was stirred at 50° C. for 2 days under H2 atmosphere. The mixture was filtered through celite. Pd/C was washed with 50 mL solvent (DCM:MeOH=1:10) twice. The combined organic phase was concentrated in vacuum to afford product (100 mg, 32.2% yield). [M+H]+=299.6.
To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)benzonitrile (100 mg, 0.33 mmol) and Et3N (100 mg, 1 mmol) in 10 mL DCM, MsCl (40 mg, 0.35 mmol) was slowly added at 0° C. The mixture was stirred at 25° C. for 2 hours. After LCMS shown the reaction was completed. The mixture was quenched with 10 mL water. The organic phase was separated and concentrated in vacuum. The residue was purified by prep-TLC (DCM:MeOH=20:1) to afford product (44 mg, 35.3% yield). [M+H]+=377.6.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol), (1-(3-cyano-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)methyl methanesulfonate (26 mg, 0.07 mmol), KI (33 mg, 0.2 mmol) and DIEA (39 mg, 0.3 mmol) in 5 mL ACN. The mixture was stirred at 80° C. for 16 hours. After LCMS shown the reaction was completed. The mixture was concentrated in vacuum. The residue was dissolved in DCM and filtered. The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford product (7.06 mg, 10.2% yield). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.90 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.22 (d, J=8.6 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 6.74 (s, 1H), 6.69 (dd, J=8.6, 2.4 Hz, 1H), 4.01-3.93 (m, 3H), 3.75 (s, 3H), 3.54-3.46 (m, 2H), 2.94 (d, J=10.9 Hz, 3H), 2.85-2.74 (m, 1H), 2.69-2.61 (m, 5H), 2.59-2.51 (m, 7H), 2.38 (ddd, J=9.0, 5.9, 5.4 Hz, 2H), 2.33-2.22 (m, 4H), 2.04-1.93 (m, 7H), 1.83 (d, J=10.1 Hz, 2H), 1.60-1.48 (m, 2H), 0.82-0.72 (m, 3H). [M+H]+=988.6.
To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1 g, 2.07 mmol), methyl (1r,3r)-3-aminocyclobutane-1-carboxylate hydrochloride (495 mg, 3 mmol) and Cs2CO3 (1.95 g, 6 mmol) in 10 mL DMSO, Pd2(dba)3 (183 mg, 0.2 mmol) and Xantphos (231 mg, 0.4 mmol) was added under N2 protected. The mixture was stirred at 80° C. for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL×2). The organic phase was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica column chromatography (PE:EA=20:1) to afford product (351 mg, 32% yield). [M+H]+=530.8.
To a solution of methyl (1r,3r)-3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)cyclobutane-1-carboxylate (351 mg, 0.66 mmol) in 10 mL THF, LiOH H2O (84 mg, 2 mmol) in 2 mL water was added. The mixture was stirred at 25° C. for 2 hours. After LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was adjust pH<5 with 1 N HCl and extracted with 50 mL EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated in vacuum to afford product (320 mg, 94% yield). [M+H]+=516.8.
To a solution of (1r,3r)-3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)cyclobutane-1-carboxylic acid (320 mg, 0.62 mmol) in 5 mL DCM and 30 mL MeOH, 160 mg Pd/C was added. The mixture was stirred at 30° C. for 16 hours under H2 atmosphere. The mixture was filtered through celite. Pd/C was washed with 50 mL solvent (DCM:MeOH=1:10) twice and filtered. The organic phase was concentrated in vacuum to afford (1r,3r)-3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutane-1-carboxylic acid (153 mg, 73% yield). [M+H]+=338.8.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol), (1r,3r)-3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutane-1-carboxylic acid (24 mg, 0.07 mmol) and DIEA (26 mg, 0.2 mmol) in 10 mL DCM, 50% w.t. T3P in EtOAc solution (64 mg, 0.1 mmol) was added. The mixture was stirred at 25° C. for 16 hours. The mixture was quenched with water (10 mL). The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 50: 50 gradient elution) to afford product (8.2 mg, 11.4% yield). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.83 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 8.30 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.46-7.30 (m, 2H), 6.73 (s, 1H), 6.58 (dd, J=39.3, 6.3 Hz, 1H), 6.13 (dd, J=25.1, 11.7 Hz, 2H), 3.98 (dd, J=12.5, 4.4 Hz, 1H), 3.81-3.70 (m, 4H), 3.52-3.43 (m, 2H), 3.40 (s, 2H), 3.04 (dt, J=17.7, 8.9 Hz, 1H), 2.94 (d, J=10.2 Hz, 2H), 2.82-2.72 (m, 1H), 2.66 (d, J=16.8 Hz, 5H), 2.60-2.52 (m, 3H), 2.48-2.46 (m, 4H), 2.40-2.26 (m, 3H), 2.12-1.89 (m, 10H), 1.81 (d, J=11.1 Hz, 2H), 1.56 (dd, J=21.3, 11.6 Hz, 2H), 0.90-0.62 (m, 3H). [M+H]+=1027.6.
Into a 1000-mL round-bottom flask, were placed 5-bromo-N1-methylbenzene-1,2-diamine (10.0 g, 50.0 mmol), CH3CN (200 mL), 1,1′-Carbonyldiimidazole (9.4 g, 58.0 mmol). The resulting solution was stirred for 5 h at 70° C. The filtrate was concentrated after filtration. This resulted in 10.0 g (88.6%) of 6-bromo-1-methyl-3H-1,3-benzodiazol-2-one. 1HNMR (500 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 7.31 (t, J=1.5 Hz, 1H), 7.11 (ddd, J=8.2 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 3.27 (s, 3H). [M+H]+=227.2.
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 6-bromo-1-methyl-3H-1,3-benzodiazol-2-one (10.0 g, 44.0 mmol), THF (100 mL), t-BuOK (4.9 g, 44.0 mmol), the resulting solution was stirred for 0.5 h at 0° C. and then was added 3-bromo-1-((4-methoxyphenyl)methyl)piperidine-2,6-dione (13.7 g, 44.0 mmol). The resulting solution was allowed to react, with stirring, for an additional 3 days at rt. The resulting solution was diluted with (200 mL) of EtOAc. The resulting mixture was washed with (3×200 m1) of H2O. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-50%) to give the product (2.2 g, 11% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.48 (d, J=1.9 Hz, 1H), 7.27-7.14 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.97-6.81 (m, 2H), 4.89-4.71 (m, 2H), 3.74 (s, 3H), 3.36 (s, 3H), 3.15-2.97 (m, 1H), 2.89-2.78 (m, 1H), 2.72 (td, J=13.1 Hz, 1H), 2.13-1.97 (m, 1H). [M+H]+=458.1.
Into a 50-mL vial purged and maintained with an inert atmosphere of nitrogen, were placed 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (800.0 mg, 1.7 mmol), dioxane (20 mL), tert-butyl piperidine-4-carboxylate (485.1 mg, 2.6 mmol), Cs2CO3 (1.1 g, 3.5 mmol), Ruphos-G3 (225.2 mg, 0.3 mmol). The resulting solution was stirred for 15 h at 100° C. The resulting solution was diluted with EtOAc (50 mL). The resulting mixture was washed with water (3×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-25%) to give the product (400 mg, 41% yield). [M+H]+=563.2.
Into a 10-mL vial purged and maintained with an inert atmosphere of nitrogen, were placed tert-butyl 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxylate (300.0 mg, 0.53 mmol), Toluene (2 mL), CH3SO3H (1 mL). The resulting solution was stirred for 2 h at 100° C. The resulting solution was diluted with EtOAc (10 mL). The solids were collected by filtration. The solids were washed with EtOAc (3×20 mL). The solids were dried in vacuum. The product 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxylic acid (190 mg, 92.22%) was obtained. [M+H]+=387.2.
A mixture of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxylic acid (28.5 mg, 0.073 mmol), HATU (23.7 mg, 0.062 mmol) and DIEA (21.9 mg, 0.17 mmol) in DMF (4 mL) was stirred at rt for 10 min. Then, (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (40 mg, 0.056 mmol) was added to the mixture. The resulting mixture was stirred at rt for 16 h. The mixture was diluted with water (50 mL), extracted with EA (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 70: 30 gradient elution) to afford the product (9.60 mg, 15.7%). 1H NMR (500 MHz, DMSO) δH 11.76 (s, 1H), 11.06 (s, 1H), 8.56 (d, J=10.0 Hz, 1H), 8.34-8.26 (m, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=10.0 Hz, 1H), 7.42 (d, J=10.0 Hz, 1H), 7.38 (s, 1H), 6.92 (d, J=5.0 Hz, 1H), 6.85-6.83 (m, 1H), 6.74 (s, 1H), 6.66-6.62 (m, 1H), 5.32-5.26 (m, 1H), 3.76 (s, 3H), 3.65-3.59 (m, 2H), 3.57-3.51 (m, 2H), 3.50-3.45 (m, 2H), 2.99-2.84 (m, 3H), 2.79-2.52 (m, 16H), 2.44-2.25 (m, 4H), 2.01-1.96 (m, 7H), 1.88-1.78 (m, 2H), 1.75-1.68 (m, 4H), 1.63-1.52 (m, 2H), 0.82-0.71 (m, 3H). [M+H]+=1075.4.
To a solution of 5-bromo-1H-indazole (2.0 g, 10.2 mmol) and 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (This intermediate was prepared according to the same manner described in WO2020113233A1) (5.8 g, 15.3 mmol) in THF(50 mL) was added t-BuOK (15 mL, 15.3 mmol) at 0° C.
Then the mixture was stirred at 30° C. for 2 hrs. The reaction was quenched with water and the mixture was extracted with DCM (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH(15: 1) to afford the example 211-compound 1 (1.2 g, 28%). [M+H]+=428.2 and example 211-compound 2 (1.3 g, 30%) [M+H]+=428.1
A mixture of 3-(5-bromo-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1.2 g, 2.8 mmol) in toluene (10 mL) and MsOH (5 mL) was stirred in a round bottom flask at 100° C. under nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by purified by silica gel column chromatography, eluted with DCM/MeOH (15: 1) to afford the product (480 mg, 56%), [M+H]+=308.2.
A mixture of 3-(5-bromo-1H-indazol-1-yl)piperidine-2,6-dione (70 mg, 0.23 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91 mg, 0.46 mmol), Pd(dppf)Cl2 (15 mg, 0.023 mmol) and CsF (100 mg, 0.69 mmol) in DMF (5 mL) was stirred in a round bottom flask at 90° C. under nitrogen atmosphere for 2 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (15: 1) to afford the product (50 mg, 72%), [M+H]+=300.0.
A mixture of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.17 mmol) in HCOOH (2 mL) was stirred in a round bottom flask at 25° C. under nitrogen atmosphere for 30 min. The reaction mixture was concentrated under reduced pressure to afford crude product which was directly used for the next step. [M+H]+=272.2.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (40 mg, 0.057 mmol) and 2-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)acetaldehyde (20 mg, 0.069 mmol) and NaOAc (14 mg, 0.17 mmol) in DCM (4 mL) and EtOH (0.5 mL) was stirred in a round bottom flask at room temperature for 2 hour. The mixture was added NaBH3CN (10 mg, 0.17 mmol) and stirred in a round bottom flask at room temperature 2 h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified by HPLC chromatography with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to give the product (15 mg, 27%). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 11.09 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.45-7.36 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 6.74 (s, 1H), 5.81 (dd, J=11.7, 5.0 Hz, 1H), 3.76 (s, 3H), 2.98-2.90 (m, 2H), 2.89-2.82 (m, 3H), 2.78-2.53 (m, 14H), 2.33-2.40 (m, 5H), 1.98 (d, J=13.3 Hz, 7H), 1.92-1.81 (m, 2H), 1.62-1.50 (m, 2H), 0.81-0.69 (m, 3H); [M+H]+=962.5.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.65 (d, J=25.5 Hz, 1H), 10.86 (s, 1H), 8.88 (d, J=8.5 Hz, 1H), 8.84 (dd, J=9.7, 1.8 Hz, 2H), 8.27 (d, J=9.5 Hz, 1H), 8.23 (s, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.08 (d, J=11.8 Hz, 1H), 7.03 (t, J=8.8 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.49 (dd, J=8.7, 2.3 Hz, 1H), 4.00 (dd, J=12.5, 4.9 Hz, 1H), 3.83-3.72 (m, 5H), 3.31-3.22 (m, 4H), 2.78-2.67 (m, 5H), 2.54 (m, 4H), 2.36 (m, 4H), 2.24-2.13 (m, 1H), 2.07-1.95 (m, 7H), 1.86 (d, J=10.4 Hz, 2H), 1.52 (m, 2H). [M+H]+=899.3
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 10.86 (s, 1H), 8.89 (s, 1H), 8.85 (dd, J=9.4, 1.7 Hz, 2H), 8.36 (s, 1H), 8.27 (s, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 6.66 (t, J=7.5 Hz, 1H), 6.60 (d, J=12.8 Hz, 2H), 6.48 (dd, J=8.7, 2.2 Hz, 1H), 4.04 (dd, J=12.6, 4.9 Hz, 1H), 3.81-3.70 (m, 7H), 3.26-3.20 (m, 4H), 2.83-2.62 (m, 6H), 2.52 (s, 2H), 2.39-2.25 (m, 6H), 2.13-1.91 (m, 9H), 1.85 (d, J=11.3 Hz, 2H), 1.71 (d, J=11.4 Hz, 2H), 1.50 (t, J=11.2 Hz, 2H), 1.41-1.34 (m, 2H), 1.17 (d, J=12.5 Hz, 1H). [M+H]+=1000.3
The titled compound (840 mg, 86%) was prepared in a manner similar to that in Example 216 step 3 from 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=435.3
The titled compound (720 mg, 88%) was prepared in a manner similar to that in Example 216 step 4 from tert-butyl 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate and Pd/C. [M+H]+=405.3
The titled compound (420 mg, 67%) was prepared in a manner similar to that in Example 216 step 5 from tert-butyl 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylate and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. [M+H]+=680.2.
The titled compound (50 mg, 36%) was prepared in a manner similar to that in Example 204 step 6 from (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 10.86 (s, 1H), 8.86 (dd, J=8.3, 1.9 Hz, 3H), 8.26 (d, J=9.0 Hz, 2H), 7.93 (d, J=9.6 Hz, 1H), 7.36 (s, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.08 (d, J=11.7 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.75 (s, 1H), 4.00 (dd, J=12.5, 4.9 Hz, 1H), 3.77 (s, 3H), 3.10 (d, J=11.2 Hz, 2H), 2.79-2.71 (m, 3H), 2.67 (m, 3H), 2.55 (m, 8H), 2.38-2.32 (m, 1H), 2.19 (dt, J=12.9, 8.7 Hz, 1H), 2.08 (d, J=9.6 Hz, 5H), 2.05-1.97 (m, 7H), 1.88 (d, J=11.0 Hz, 2H), 1.59 (m, 2H). [M+H]+=913.3.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 10.86 (s, 1H), 8.86 (dd, J=8.6, 1.8 Hz, 3H), 8.27 (s, 1H), 8.25 (s, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.36 (s, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.59 (s, 1H), 4.04 (dd, J=12.5, 5.0 Hz, 1H), 3.77 (s, 3H), 3.74 (d, J=12.6 Hz, 2H), 3.31-3.29 (m, 4H), 3.09 (d, J=11.0 Hz, 2H), 2.73 (m, 5H), 2.54 (s, 2H), 2.43-2.27 (m, 6H), 2.13-2.06 (m, 4H), 2.02 (s, 6H), 1.99-1.92 (m, 1H), 1.87 (d, J=11.3 Hz, 2H), 1.73 (t, J=11.7 Hz, 2H), 1.58 (m, 2H), 1.48 (s, 1H), 1.42-1.34 (m, 2H), 1.24-1.13 (m, 2H). [M+H]+=1014.4
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (3.5 g, 17.4 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.0 g, 11.6 mmol) and CuI (2.2 g, 11.6 mmol) in DMSO (40 mL) was stirred at 60° C. for 16 hrs. The mixture was extracted with EtOAc (100.0 mL). The combined organic phase was washed with brine (100.0 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (PE/EA=10/1 to 1/1) to afford product (4.2 g, 87.3%). [M+H]+=416.2
To a solution of tert-butyl 4-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-oxopiperazine-1-carboxylate (4.2 g, 10.1 mmol) and Pd/C (2.1 g) in DCM (30 mL) and MeOH (30 mL) was stirred at 35° C. for overnight. The mixture was filtered and concentrated in vacuum to afford product (2.6 g, 92.3%). [M+H]+=284.2
To a solution of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1 g, 5.4 mmol), tert-butyl 3-oxo-4-(piperidin-4-yl)piperazine-1-carboxylate (1.8 g, 6.5 mmol) and K2CO3 (1.5 g, 10.8 mmol) in DMF (40 mL) was stirred at 80° C. for overnight. The mixture was extracted with EtOAc (100.0 mL). The combined organic phase was washed with brine (100.0 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (PE/EA=10/1 to 1/1) to afford product (1.3 g, 53.7%). [M+H]+=449.2
To a solution of tert-butyl 4-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate (1.3 g, 2.9 mmol) and Pd/C (400 mg) in DCM (20 mL) and MeOH (20 mL) was stirred at 35° C. for 16 hrs under hydrogen atmosphere. The mixture was filtered and concentrated in vacuum to afford product (1.0 g, 82.3%). [M+H]+=419.2.
The titled compound (50 mg, 36%) was prepared in a manner similar to that in Example 203 step 3 from tert-butyl 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. [M+H]+=694.2
The titled compound (11 mg, 26%) was prepared in a manner similar to that in Example 204 step 6 from 1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-2-one and 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 10.86 (s, 1H), 8.86 (dd, J=7.1, 1.8 Hz, 3H), 8.27 (s, 2H), 7.94 (d, J=9.6 Hz, 1H), 7.36 (s, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 4.39 (d, J=12.0 Hz, 1H), 4.04 (dd, J=12.4, 4.8 Hz, 1H), 3.79 (s, 3H), 3.74 (d, J=12.6 Hz, 2H), 3.28-3.20 (m, 4H), 3.11 (d, J=10.9 Hz, 2H), 3.01 (s, 2H), 2.75 (m, 4H), 2.63 (d, J=1.6 Hz, 2H), 2.54 (s, 1H), 2.38 (dd, J=13.2, 4.4 Hz, 2H), 2.09 (m, 4H), 2.02 (s, 6H), 1.97-1.83 (m, 3H), 1.73 (d, J=11.6 Hz, 2H), 1.62 (d, J=10.9 Hz, 2H), 1.50 (s, 1H), 1.44-1.36 (m, 2H), 1.24-1.13 (m, 2H). [M+H]+=1028.3
The titled compound (62 mg, 32%) was prepared in a manner similar to that in Example 203 step 3 from tert-butyl 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylate and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide. [M+H]+=693.2.
The titled compound (11 mg, 22%) was prepared in a manner similar to that in Example 204 step 6 from (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.91 (s, 1H), 10.86 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.38 (d, J=5.9 Hz, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 6.68 (s, 1H), 6.62 (s, 1H), 6.59 (s, 1H), 4.04 (dd, J=12.5, 5.0 Hz, 1H), 3.74 (m, 5H), 3.21 (m, 4H), 3.02 (d, J=10.9 Hz, 2H), 2.80-2.53 (m, 11H), 2.34 (m, 6H), 2.08 (dt, J=13.6, 9.6 Hz, 1H), 1.99 (s, 6H), 1.92 (s, 3H), 1.84 (d, J=10.8 Hz, 2H), 1.71 (d, J=11.7 Hz, 2H), 1.53 (m, 3H), 1.45-1.34 (m, 2H), 1.25-1.11 (m, 2H). [M+H]+=1027.4
The titled compound was prepared in a manner similar to that in Example 217. 1H NMR (500 MHz, DMSO) δ 11.99 (s, 1H), 10.86 (s, 1H), 8.45 (t, J=11.1 Hz, 2H), 8.17 (s, 1H), 7.99 (s, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.26 (s, 1H), 6.62 (s, 1H), 6.59 (s, 2H), 6.26 (d, J=8.2 Hz, 1H), 4.04 (dd, J=12.6, 5.0 Hz, 1H), 3.74 (m, 5H), 3.66 (d, J=12.0 Hz, 2H), 3.28-3.25 (m, 2H), 2.82-2.60 (m, 9H), 2.54 (s, 2H), 2.32 (m, 7H), 2.08 (dt, J=13.6, 9.8 Hz, 1H), 1.97 (m, 7H), 1.83 (d, J=11.4 Hz, 2H), 1.71 (d, J=12.2 Hz, 2H), 1.49 (m, 3H), 1.42-1.33 (m, 2H), 1.17 (q, J=11.4 Hz, 2H). [M+H]+=1013.4.
The titled compound was prepared in a manner similar to that in Example 207. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.74 (s, 1H), 8.86 (d, J=4.0 Hz, 2H), 8.81 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.6 Hz, 1H), 7.38 (s, 1H), 6.99 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 6.48 (d, J=8.6 Hz, 2H), 3.77 (s, 3H), 3.68 (dd, J=10.4, 4.9 Hz, 1H), 3.35 (m, 1H), 3.28-3.24 (m, 2H), 3.20 (d, J=7.8 Hz, 1H), 3.02 (d, J=10.8 Hz, 2H), 2.98-2.92 (m, 1H), 2.71 (t, J=10.9 Hz, 2H), 2.63 (m, 1H), 2.58 (m, 5H), 2.46 (m, 3H), 2.42 (m, 2H), 2.33 (d, J=6.8 Hz, 3H), 2.07 (d, J=6.7 Hz, 2H), 2.02 (d, J=14.4 Hz, 8H), 1.87 (d, J=11.7 Hz, 2H), 1.70 (s, 1H), 1.59 (d, J=8.8 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=964.7.
The titled compound was prepared in a manner similar to that in Example 207. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.74 (s, 1H), 8.86 (d, J=4.3 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.81 (s, 1H), 6.48 (d, J=8.4 Hz, 2H), 3.77 (s, 3H), 3.68 (dd, J=10.2, 4.9 Hz, 1H), 3.20 (d, J=7.5 Hz, 4H), 3.02 (d, J=10.4 Hz, 3H), 2.96 (d, J=6.8 Hz, 2H), 2.71 (t, J=11.5 Hz, 3H), 2.59 (s, 5H), 2.48-2.42 (m, 4H), 2.35 (s, 2H), 2.08 (s, 2H), 2.02 (d, J=14.3 Hz, 8H), 1.88 (d, J=10.7 Hz, 2H), 1.71 (d, J=7.2 Hz, 1H), 1.59 (d, J=8.9 Hz, 2H), 0.93 (t, J=7.0 Hz, 3H); [M+H]+=964.8.
The titled compound was prepared in a manner similar to that in Example 57. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 11.08 (s, 1H), 8.86 (dd, J=8.9, 1.9 Hz, 3H), 8.28 (d, J=10.0 Hz, 2H), 7.91 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 6.82-6.74 (m, 2H), 6.63 (dd, J=8.4, 2.0 Hz, 1H), 5.05 (dd, J=12.7, 5.4 Hz, 1H), 4.18 (t, J=8.2 Hz, 2H), 3.77 (s, 3H), 3.71-3.66 (m, 2H), 3.45 (s, 4H), 3.02 (d, J=11.8 Hz, 3H), 2.87 (d, J=11.7 Hz, 1H), 2.79 (d, J=7.7 Hz, 2H), 2.71 (t, J=11.2 Hz, 2H), 2.60 (s, 1H), 2.57-2.52 (m, 3H), 2.48 (s, 3H), 2.36 (s, 2H), 2.02 (d, J=14.4 Hz, 7H), 1.85 (d, J=10.8 Hz, 2H), 1.60 (d, J=8.6 Hz, 2H), 0.92 (t, J=7.2 Hz, 3H); [M+H]+=1047.4.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.75 (s, 1H), 8.87 (d, J=4.8 Hz, 3H), 8.28 (d, J=5.9 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.51 (d, J=8.5 Hz, 2H), 3.77 (s, 3H), 3.69 (d, J=6.0 Hz, 1H), 3.58 (s, 3H), 3.48 (d, J=22.9 Hz, 7H), 3.29-3.24 (m, 4H), 3.03 (d, J=10.2 Hz, 2H), 2.72 (t, J=11.0 Hz, 2H), 2.58 (s, 3H), 2.43 (s, 2H), 2.12 (d, J=8.2 Hz, 2H), 2.02 (d, J=14.3 Hz, 7H), 1.87 (d, J=10.0 Hz, 2H), 1.61 (d, J=9.3 Hz, 2H), 0.94 (d, J=7.0 Hz, 3H); [M+H]+=978.8.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.75 (s, 1H), 8.87 (d, J=4.6 Hz, 3H), 8.28 (d, J=5.5 Hz, 2H), 7.90 (d, J=9.1 Hz, 1H), 7.38 (s, 1H), 7.00 (d, J=8.3 Hz, 2H), 6.82 (s, 1H), 6.51 (d, J=8.5 Hz, 2H), 3.77 (s, 3H), 3.69 (dd, J=10.8, 5.1 Hz, 1H), 3.58 (s, 2H), 3.46 (dd, J=19.8, 11.6 Hz, 5H), 3.25 (d, J=7.2 Hz, 4H), 3.03 (d, J=9.9 Hz, 2H), 2.72 (t, J=11.1 Hz, 2H), 2.60 (d, J=14.8 Hz, 3H), 2.48 (s, 2H), 2.43 (s, 2H), 2.13 (dd, J=14.9, 6.9 Hz, 2H), 2.02 (d, J=14.4 Hz, 8H), 1.87 (d, J=9.8 Hz, 2H), 1.61 (d, J=8.6 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=978.8.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.81 (s, 1H), 8.85 (dd, J=16.2, 14.6 Hz, 3H), 8.31 (s, 1H), 8.28 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.45 (d, J=7.8 Hz, 2H), 6.39 (s, 1H), 3.77 (s, 3H), 3.76-3.73 (m, 1H), 3.59-3.50 (m, 6H), 3.44 (s, 3H), 3.29-3.22 (m, 3H), 3.04 (d, J=10.0 Hz, 2H), 2.73 (t, J=11.0 Hz, 2H), 2.67-2.60 (m, 2H), 2.48 (s, 2H), 2.45 (d, J=4.6 Hz, 1H), 2.19-2.15 (m, 2H), 2.10 (s, 1H), 2.03 (t, J=10.8 Hz, 8H), 1.88 (s, 2H), 1.63 (s, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=978.3.
A mixture of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (500 mg, 1.12 mmol), azetidin-3-ylmethanol hydrochloride (206 mg, 1.68 mmol), CuI (21 mg, 0.112 mmol), L-Proline (26 mg, 0.224 mmol) and K3PO4 (712 mg, 3.36 mmol) in DMSO (8 mL) was stirred in a round bottom flask at 120° C. under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (3×40 mL) and brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0˜5%) to afford the product (305 mg, 60.2%). [M+H]+=453.1.
To a stirred solution of (1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azetidin-3-yl)methanol (300 mg, 0.664 mmol) in MeOH (5 mL) and DCM (5 mL) was added Pd/C (wet, 10%) (150 mg). The resulting mixture was stirred for 16 hrs at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/CH3OH (10: 1, 20 mL). The filtrate was concentrated under reduced pressure to afford the product (155 mg, 85.6%). [M+H]+=275.1.
The titled compound (83 mg, 43.2%) was prepared in a manner similar to that in Example 207 step 4 from 3-(3-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione and methanesulfonyl chloride. [M+H]+=353.2
The titled compound (9.3 mg, 13.7%) was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and (1-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)methyl methanesulfonate. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.80 (s, 1H), 8.87 (d, J=5.9 Hz, 2H), 8.82 (s, 1H), 8.28 (d, J=4.4 Hz, 2H), 7.90 (d, J=9.2 Hz, 1H), 7.38 (s, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.81 (s, 1H), 6.50 (d, J=7.8 Hz, 1H), 6.31 (d, J=8.1 Hz, 1H), 6.25 (s, 1H), 3.90 (d, J=3.2 Hz, 2H), 3.78-3.71 (m, 4H), 3.42 (d, J=5.7 Hz, 2H), 3.01 (d, J=10.7 Hz, 2H), 2.91 (s, 1H), 2.71 (t. J=11.2 Hz, 2H), 2.63-2.58 (m, 2H), 2.56-2.53 (m, 4H), 2.48-2.45 (m, 3H), 2.44-2.41 (m, 4H), 2.32-2.30 (m, 2H), 2.16-2.13 (m, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.86 (d, J=11.6 Hz, 2H), 1.57 (d, J=9.3 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=950.5.
To a stirred mixture of methyl 2-cyano-5-fluorobenzoate (10.0 g, 55.82 mmol) and 3-azetidinecarboxylic acid (6.8 g, 66.98 mmol) in DMSO (100.00 mL) was added DIEA (14.4 g, 111.638 mmol) and stirred overnight at 60° C. The resulting mixture was extracted with EtOAc (500 mL). The combined organic layers were washed with citric acid (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (11.0 g, 75.7%). [M+H]+=261.2.
To a stirred mixture of 1-(4-cyano-3-(methoxycarbonyl)phenyl)azetidine-3-carboxylic acid (6.0 g, 23.055 mmol) in AcOH (60 mL) and H2O (30 mL) was added Raney-Ni (6.0 g, 70.032 mmol) in portions and stirred overnight at room temperature under air atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM and MeOH (300 mL). The filtrate was concentrated under reduced pressure. The filtrate was extracted with EtOAc (300 mL). The combined organic layers were washed with citric acid (1M in water, 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (9:1) to afford the product (5.0 g, 82.3%) [M+H]+=264.3.
A mixture of 3-aminopiperidine-2,6-dione hydrochloride (9.4 g, 56.980 mmol) and DIEA (9.8 g, 75.974 mmol) in DMF (60 mL) was stirred for 5 h at room temperature. The mixture was acidified to pH<7 with AcOH (11.4 g, 189.934 mmol) followed by the addition of 1-(4-formyl-3-(methoxycarbonyl)phenyl)azetidine-3-carboxylic acid (5.0 g, 18.993 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. To the mixture was added NaBH3CN (3.6 g, 56.980 mmol) in portions at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (5:1 v/v, 0.2 v % AcOH) to afford crude product, which was purified by trituration with CH2Cl2 (40 mL). 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidine-3-carboxylic acid (2.1 g, 32.7%) was obtained. [M+H]+=344.2.
The titled compound (11 mg, 26%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.97 (s, 1H), 8.88-8.85 (m, 2H), 8.82 (s, 1H), 8.28 (d, J=8.8 Hz, 2H), 7.90 (d, J=9.5 Hz, 1H), 7.42-7.36 (m, 2H), 6.82 (s, 1H), 6.73 (d, J=7.6 Hz, 2H), 5.09 (dd, J=13.3, 5.1 Hz, 1H), 4.32 (d, J=16.6 Hz, 1H), 4.20 (d, J=16.5 Hz, 1H), 4.08 (s, 2H), 3.93 (s, 2H), 3.87-3.82 (m, 1H), 3.77 (s, 3H), 3.50-3.45 (m, 2H), 3.36-3.31 (m, 2H), 3.30 (s, 1H), 3.03 (d, J=11.3 Hz, 2H), 2.91-2.87 (m, 1H), 2.72 (t, J=11.3 Hz, 2H), 2.62-2.58 (m, 1H), 2.55-2.52 (m, 3H), 2.48-2.46 (m, 2H), 2.38 (m, 2H), 2.02 (d, J=14.4 Hz, 7H), 1.86-1.82 (m, 2H), 1.61-1.58 (m, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=1019.5.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.80 (s, 1H), 8.87 (dd, J=7.9, 1.9 Hz, 2H), 8.81 (s, 1H), 8.28 (d, J=8.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.06 (t, J=8.3 Hz, 1H), 6.81 (s, 1H), 6.25 (dd, J=15.3, 7.2 Hz, 2H), 4.02 (s, 2H), 3.88 (m, 5H), 3.77 (s, 3H), 3.50 (s, 2H), 3.30 (s, 1H), 3.02 (d, J=10.8 Hz, 2H), 2.72-2.68 (m, 3H), 2.54-2.53 (m, 2H), 2.52-2.50 (m, 1H), 2.48-2.43 (m, 3H), 2.41-2.38 (m, 1H), 2.13-2.09 (m, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.95-1.91 (m, 1H), 1.85 (d, J=9.8 Hz, 2H), 1.61 (d, J=8.8 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=982.5.
A mixture of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (500 mg, 1.12 mmol), methyl azetidine-3-carboxylate hydrochloride (254 mg, 1.68 mmol), CuI (21 mg, 0.112 mmol), L-Proline (26 mg, 0.224 mmol) and K3PO4 (712 mg, 3.36 mmol) in DMSO (8 mL) was stirred in a round bottom flask at 120° C. under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (3×40 mL) and brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0˜5%) to afford the product (210 mg, 39.2%). [M+H]+=481.1.
To a solution of methyl 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azetidine-3-carboxylate (200 mg, 0.417 mmol) in THF (5 mL) and H2O (1 mL) was added lithium hydroxide hydrate (26 mg, 0.625 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 12 h. The reaction was quenched with HCl (1 N) at 0° C. until PH=5 and extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product (155 mg, 79.9%), which was used for next step without further purification. [M+H]+=467.2.
To a stirred solution of 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azetidine-3-carboxylic acid (150 mg, 0.322 mmol) in MeOH (3 mL) and DCM (3 mL) was added Pd/C (wet, 10%) (100 mg). The resulting mixture was stirred for 16 hrs at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/CH3OH (10: 1, 10 mL). The filtrate was concentrated under reduced pressure to afford the product (68 mg, 73.9%). [M+H]+=289.1.
The titled compound (7.4 mg, 27.6%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 1-(3-(2,6-dioxopiperidin-3-yl)phenyl)azetidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.80 (s, 1H), 8.87 (dd, J=8.0, 1.8 Hz, 2H), 8.82 (s, 1H), 8.28 (d, J=8.4 Hz, 2H), 7.89 (s, 1H), 7.37 (s, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.81 (s, 1H), 6.54 (d, J=7.6 Hz, 1H), 6.36 (d, J=8.2 Hz, 1H), 6.31 (s, 1H), 4.01 (s, 2H), 3.84 (m, 3H), 3.77 (s, 3H), 3.76-3.73 (m, 1H), 3.49 (s, 1H), 3.31 (s, 3H), 3.02 (d, J=10.3 Hz, 2H), 2.72 (t, J=11.0 Hz, 2H), 2.68-2.59 (m, 2H), 2.54 (s, 2H), 2.48-2.42 (m, 2H), 2.45-2.41 (m, 1H), 2.38-2.35 (m, 1H), 2.18 (d, J=8.9 Hz, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.85 (d, J=10.8 Hz, 2H), 1.60 (d, J=10.8 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=964.5.
The titled compound was prepared in a manner similar to that in Example 207. 1H NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 11.18 (s, 1H), 9.29 (dd, J=7.3, 1.8 Hz, 2H), 9.24 (s, 1H), 8.70 (d, J=6.4 Hz, 2H), 8.33 (d, J=9.4 Hz, 1H), 7.80 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.24 (s, 1H), 6.80 (d, J=8.5 Hz, 2H), 4.33 (t, J=7.4 Hz, 2H), 4.19 (s, 3H), 4.12 (dd, J=10.9, 4.9 Hz, 1H), 3.87-3.83 (m, 4H), 3.44 (d, J=10.8 Hz, 2H), 3.32-3.31 (m, 1H), 3.13 (t, J=11.0 Hz, 2H), 3.07-3.01 (m, 2H), 2.98 (d, J=7.3 Hz, 4H), 2.88-2.85 (m, 3H), 2.82-2.79 (m, 2H), 2.73 (s, 1H), 2.54-2.51 (m, 1H), 2.43 (t, J=13.4 Hz, 8H), 2.28 (d, J=11.1 Hz, 2H), 1.99 (d, J=9.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H); [M+H]+=950.7.
The titled compound was prepared in a manner similar to that in Example 59. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 11.06 (s, 1H), 8.87 (dd, J=7.4, 1.9 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.1 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 6.90 (d, J=1.8 Hz, 1H), 6.83-6.80 (m, 2H), 5.05 (dd, J=12.9, 5.4 Hz, 1H), 3.77 (s, 3H), 3.57-3.53 (m, 1H), 3.50 (s, 1H), 3.40 (dd, J=18.0, 7.8 Hz, 2H), 3.30-3.27 (m, 1H), 3.16-3.12 (m, 1H), 3.02 (d, J=10.7 Hz, 2H), 2.92-2.85-2.81 (m, 1H), 2.71 (t, J=10.9 Hz, 2H), 2.64-2.54 (m, 8H), 2.47 (d, J=7.4 Hz, 2H), 2.35 (d, J=7.2 Hz, 3H), 2.15-2.11 (m, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.87 (d, J=11.3 Hz, 2H), 1.78-1.74 (m, 1H), 1.58 (dd, J=20.3, 11.1 Hz, 2H), 0.93 (t, J=7.1 Hz, 3H); [M+H]+=1033.7.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.90 (s, 1H), 8.86 (dd, J=7.2, 1.9 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.6 Hz, 1H), 7.38 (s, 1H), 7.23 (dd, J=10.5, 6.2 Hz, 1H), 7.16 (dd, J=10.1, 6.1 Hz, 1H), 6.81 (s, 1H), 4.03 (dd, J=12.8, 4.7 Hz, 1H), 3.77 (s, 3H), 3.39 (s, 2H), 3.01 (d, J=10.9 Hz, 2H), 2.78-2.68 (m, 6H), 2.58-2.53 (m, 7H), 2.47 (d, J=7.1 Hz, 2H), 2.36-2.32 (m, 1H), 2.25-2.21 (m, 1H), 2.00 (dd, J=17.6, 9.8 Hz, 8H), 1.86 (d, J=11.3 Hz, 2H), 1.58 (dd, J=20.5, 11.0 Hz, 2H), 0.93 (t, J=7.0 Hz, 3H); [M+H]+=945.6.
The titled compound was prepared in a manner similar to that in Example 237. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.93 (s, 1H), 8.86 (dd, J=7.5, 1.8 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.62 (d, J=10.1 Hz, 2H), 5.03 (dd, J=13.2, 5.1 Hz, 1H), 4.30 (dd, J=16.7, 3.5 Hz, 1H), 4.18 (dd, J=16.7, 2.9 Hz, 1H), 3.77 (s, 3H), 3.46-3.42 (m, 3H), 3.08-3.00 (m, 3H), 2.91-2.87 (m, 1H), 2.71 (t, J=11.0 Hz, 2H), 2.60-2.56 (m, 7H), 2.47 (d, J=7.3 Hz, 2H), 2.41-2.28 (m, 6H), 2.11 (dd, J=11.9, 5.0 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.98-1.93 (m, 1H), 1.87 (d, J=10.6 Hz, 2H), 1.73 (dd, J=12.1, 7.6 Hz, 1H), 1.58 (dd, J=19.9, 11.2 Hz, 2H), 0.93 (t, J=7.0 Hz, 3H); [M+H]+=1019.7.
The titled compound was prepared in a manner similar to that in Example 59. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 11.06 (s, 1H), 8.87 (dd, J=7.7, 1.8 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.91 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 6.90 (s, 1H), 6.82 (d, J=4.1 Hz, 2H), 5.05 (dd, J=12.9, 5.4 Hz, 1H), 3.77 (s, 3H), 3.56-3.53 (m, 3H), 3.40 (d, J=9.7 Hz, 3H), 3.30 (s, 2H), 3.16-3.12 (m, 1H), 3.02 (d, J=10.8 Hz, 2H), 2.88 (t, J=13.1 Hz, 1H), 2.71 (t, J=11.0 Hz, 2H), 2.65-2.56 (m, 6H), 2.54 (d, J=2.9 Hz, 1H), 2.47 (d, J=7.3 Hz, 1H), 2.36 (s, 2H), 2.13 (d, J=6.2 Hz, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.88 (d, J=9.3 Hz, 2H), 1.76 (dd, J=12.1, 7.5 Hz, 1H), 1.59 (d, J=9.8 Hz, 2H), 0.93 (t, J=6.9 Hz, 3H); [M+H]+=1033.6.
To a solution of (1r,3r)-tert-butyl 3-aminocyclobutanecarboxylate (45.0 g, 263 mmol) in ACN (270 mL) was added TEA (39.9 g, 394 mmol, 54.9 mL) at 0° C. Boc2O (63.1 g, 289 mmol, 66.4 mL) was added to the reaction mixture at 0° C. Then the mixture was stirred at 25° C. for 3 hrs. TLC (Petroleum ether/Ethyl aetate=5/1) showed the reaction was completed. The reaction mixture was quenched by addition H2O (50.0 mL) at 20° C., and then diluted with H2O (400 mL) and extracted with EA (400 mL×3). The combined organic layers were washed with sat. NaCl aq. (400 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 0/1) to obtain the product (70.0 g, 97%). [M−55]+=216.3.
To a solution of NaH (2.65 g, 66.3 mmol, 60%) in DMF (90.0 mL) was added tert-butyl (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate (15.0 g, 55.3 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 hr. Mel (11.8 g, 82.9 mmol, 5.16 mL) was added to the reaction mixture at 0° C. Then the mixture was stirred at 25° C. for 3 hrs. TLC showed (Petroleum ether/Ethyl aetate=5/1) showed the reaction was completed. The reaction mixture was quenched by adding H2O (20.0 mL) at 0° C., and then diluted with H2O (100 mL) which was extracted with EA (150 mL×2). The combined organic layers were washed with sat. aq. NaCl solution (100 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 0/1). tert-butyl (1r,3r)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1-carboxylate (26.0 g, 91.1 mmol, 82.4%) was obtained. [M-55]+=230.1.
To a solution of tert-butyl (1r,3r)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1-carboxylate (8.00 g, 28.0 mmol) in DCM (56.0 mL) was added TFA (12.3 g, 108 mmol, 8.00 mL) at 0° C. The mixture was stirred at 25° C. for 3 hrs. TLC showed (Dichloromethane: Methanol=10/1) the reaction was completed. The reaction mixture was quenched by adding sat. aq. NaHCO3 solution (100 mL) at 0° C., and then diluted with DCM (150 mL×5) which was washed with sat. aq. Na2CO3 solution (50.0 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the product (6 g, 89%). [M−55]+=184.2.
To a solution of 4-fluorophthalic acid (10.0 g, 54.3 mmol) in Ac2O (50 mL) was stirred at 80° C. for 3 hrs. LCMS showed the starting material was consumed completely. The reaction mixture was poured into ice water (40.0 mL), then extracted with EtOAc (30.0 mL×2), the combined organic layer was washed with brine (30.0 mL), dried over Na2SO4, filtered and filtrate was concentrated under vacuum. 5-fluoroisobenzofuran-1,3-dione (8.50 g, 94.2% yield) was obtained and used into the next step without further purification. [M+H]+=167.2.
To a solution of 5-fluoroisobenzofuran-1,3-dione (8.50 g, 51.1 mmol) in HOAc (42.5 mL) was added NaOAc (4.62 g, 56.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (8.42 g, 51.1 mmol, 1.00 eq, HCl) at 25° C. The mixture was stirred at 120° C. for 12 hrs. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to remove most acetic acid. The residue was poured into water (100 mL) and stirred for 10 minutes. The mixture was filtered, the filtered cake was washed with water (100 mL×2) and dried to give the crude product. 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (13.5 g, 48.8 mmol, 95.5% yield) was obtained. [M+H]+=277.
To a solution of tert-butyl (1r,3r)-3-(methylamino)cyclobutane-1-carboxylate (3.50 g, 18.9 mmol) in DMF (30.0 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.61 g, 9.45 mmol) and DIPEA (4.88 g, 37.7 mmol, 6.58 mL) at 25° C. The mixture was stirred at 100° C. for 16 hrs. The reaction mixture was quenched by adding H2O (50.0 mL) at 0° C., and then diluted with EA (100 mL×3) which is extracted with sat. aq. NaCl solution (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250 mm*100 mm*10 um; mobile phase: [water (0.1% TFA)-ACN]; B %: 40%-70%, 25 min). tert-butyl (1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclobutane-1-carboxylate (3.00 g, 6.80 mmol) was obtained [M+H]+=442.2.
To a solution of (1r,3r)-tert-butyl 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclobutanecarboxylate (2.80 g, 6.34 mmol) in HCl/dioxane (4.00 M, 28.0 mL) stirred at 25° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to remove HCl/dioxane. And then the residual dioxane was removed by freeze-drying. (1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclobutanecarboxylic acid (2.32 g) was obtained. [M+H]+=386.2
The titled compound (12 mg, 26%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and (1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(methyl)amino)cyclobutene-1-carboxylic acid. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 11.07 (s, 1H), 8.86 (dd, J=8.1, 1.4 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.9 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.14-7.07 (m, 1H), 7.05-7.00 (m, 1H), 6.81 (d, J=2.4 Hz, 1H), 5.06 (dd, J=12.9, 5.4 Hz, 1H), 4.39-4.32 (m, 1H), 3.77 (d, J=1.0 Hz, 3H), 3.55-3.41 (m, 3H), 3.35 (s, 1H), 3.28 (d, J=14.8 Hz, 1H), 3.05-3.01 (m, 6H), 2.93-2.85 (m, 1H), 2.71 (t, J=10.4 Hz, 2H), 2.61-2.57 (m, 7H), 2.48-2.43 (m, 2H), 2.43-2.36 (m, 1H), 2.29 (d, J=9.6 Hz, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.85 (s, 2H), 1.60 (d, J=11.6 Hz, 2H), 0.92 (t, J=6.8 Hz, 3H); [M+H]+=1061.6.
To a stirred mixture of methyl 2-cyano-4-fluorobenzoate (10.0 g, 55.819 mmol) and (S)-pyrrolidin-3-ylmethanol (6.8 g, 66.983 mmol) in DMSO (80 mL) was added DIEA (14.4 g, 111.638 mmol) and stirred overnight at 60° C. The resulting mixture was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. methyl (S)-2-cyano-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate (10.0 g, 98.3%) was obtained. [M+H]+=261.
To a stirred mixture of methyl (S)-2-cyano-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate (10.0 g, 38.418 mmol) in AcOH (100 mL) and H2O (50 mL) was added Raney-Ni (10.0 g, 116.720 mmol) in portions and stirred overnight at 40° C. under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM and MeOH (300 mL). The filtrate was concentrated under reduced pressure. The filtrate was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (9:1) to afford product (5.0 g, 49.4%). [M+H]+=264.
A mixture of 3-aminopiperidine-2,6-dione hydrochloride (4.7 g, 28.485 mmol) and DIEA (4.9 g, 37.980 mmol) in DMF (50 mL) was stirred for 5 h at room temperature. The mixture was acidified to pH<7 with AcOH (5.7 g, 94.950 mmol) followed by the addition of methyl (S)-2-formyl-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate (5.0 g, 18.990 mmol) in DCE (10.00 mL) and DMF (2 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. To the above mixture was added NaBH3CN (3.6 g, 56.970 mmol) in portions at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (5:1) to afford crude product, which was purified by trituration with DCM (40 mL) to afford the product (2.1 g, 33.2%). [M+H]+=344.0.
The titled compound (120 mg, 44%) was prepared in a manner similar to that in Example 207 step 4 from 3-(5-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and MsCl. [M+H]+=422.2.
The titled compound (11 mg, 24%) was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and ((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl methanesulfonate. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.93 (s, 1H), 8.86 (dd, J=7.7, 1.9 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.62 (d, J=9.9 Hz, 2H), 5.03 (dd, J=13.3, 5.1 Hz, 1H), 4.30 (dd, J=16.8, 3.6 Hz, 1H), 4.18 (dd, J=16.8, 2.8 Hz, 1H), 3.77 (s, 3H), 3.45 (t, J=8.0 Hz, 1H), 3.39 (s, 2H), 3.30-3.27 (m, 2H), 3.06-3.01 (m, 3H), 2.93-2.86 (m, 1H), 2.71 (t, J=10.9 Hz, 2H), 2.59-2.52 (m, 6H), 2.48 (s, 2H), 2.40-2.31 (m, 5H), 2.11 (d, J=6.6 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.98-1.92 (m, 1H), 1.87 (d, J=10.4 Hz, 2H), 1.73 (dd, J=12.2, 7.8 Hz, 1H), 1.59 (dd, J=20.1, 11.4 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=1019.6.
The titled compound was prepared in a manner similar to that in Example 207. 1H NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 10.88 (s, 1H), 8.80 (dd, J=7.6, 1.8 Hz, 2H), 8.75 (s, 1H), 8.20 (s, 2H), 7.83 (d, J=9.5 Hz, 1H), 7.31 (s, 1H), 7.20 (s, 1H), 7.10 (d, J=11.1 Hz, 1H), 6.74 (s, 1H), 4.27 (dd, J=12.4, 5.4 Hz, 1H), 3.70 (s, 3H), 3.30 (s, 3H), 2.95 (d, J=11.1 Hz, 2H), 2.77-2.60 (m, 6H), 2.50-2.46 (m, 8H), 2.42-2.37 (m, 2H), 2.28 (d, J=17.7 Hz, 1H), 1.95 (d, J=14.4 Hz, 6H), 1.90 (s, 1H), 1.80 (d, J=10.7 Hz, 2H), 1.51 (dd, J=20.1, 11.2 Hz, 2H), 0.86 (t, J=7.0 Hz, 3H); [M+H]+=961.5.
The titled compound was prepared in a manner similar to that in Example 237. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.96 (s, 1H), 8.86 (dt, J=20.8, 10.4 Hz, 3H), 8.27 (s, 2H), 7.92 (s, 1H), 7.37 (d, J=7.7 Hz, 2H), 6.81 (s, 1H), 6.70-6.67 (m, 2H), 5.08 (dd, J=13.2, 5.1 Hz, 1H), 4.31 (d, J=16.6 Hz, 1H), 4.19 (d, J=16.5 Hz, 1H), 3.98 (t, J=7.5 Hz, 2H), 3.77 (s, 3H), 3.51-3.48 (m, 3H), 3.01 (d, J=10.5 Hz, 2H), 2.95-2.87 (m, 2H), 2.71 (t, J=11.2 Hz, 2H), 2.62 (d, J=17.2 Hz, 2H), 2.58 (d, J=7.2 Hz, 4H), 2.47 (d, J=7.5 Hz, 2H), 2.43-2.31 (m, 5H), 2.00 (dd, J=21.5, 9.8 Hz, 8H), 1.87 (d, J=11.1 Hz, 2H), 1.58 (d, J=8.9 Hz, 2H), 0.93 (t, J=7.1 Hz, 3H); [M+H]+=1005.6.
The titled compound was prepared in a manner similar to that in Example 227. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.93 (s, 1H), 8.86 (dt, J=17.8, 8.9 Hz, 3H), 8.28 (d, J=3.3 Hz, 2H), 7.90 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 6.82 (s, 1H), 6.65 (d, J=8.9 Hz, 2H), 5.04 (dd, J=13.3, 5.1 Hz, 1H), 4.31 (dd, J=16.8, 3.3 Hz, 1H), 4.19 (dd, J=17.0, 2.6 Hz, 1H), 3.77 (s, 3H), 3.61-3.54 (m, 4H), 3.51 (s, 1H), 3.45-3.37 (m, 4H), 3.04 (d, J=9.2 Hz, 2H), 2.93-2.87 (m, 1H), 2.73 (t, J=11.3 Hz, 2H), 2.60 (t, J=17.0 Hz, 4H), 2.48 (d, J=7.7 Hz, 2H), 2.42-2.31 (m, 2H), 2.22 (d, J=6.9 Hz, 1H), 2.13 (s, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.98-1.93 (m, 1H), 1.88 (s, 2H), 1.63 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); [M+H]+=1033.6.
The titled compound was prepared in a manner similar to that in Example 227. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.93 (s, 1H), 8.85 (t, J=11.9 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.2 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 6.82 (s, 1H), 6.65 (d, J=9.1 Hz, 2H), 5.04 (dd, J=13.3, 5.0 Hz, 1H), 4.31 (dd, J=17.0, 3.5 Hz, 1H), 4.20 (d, J=17.0 Hz, 1H), 3.77 (s, 3H), 3.58-3.53 (m, 6H), 3.45 (s, 3H), 3.03 (d, J=9.6 Hz, 2H), 2.90 (t, J=12.8 Hz, 1H), 2.73 (t, J=11.0 Hz, 2H), 2.60 (t, J=17.7 Hz, 4H), 2.54 (s, 1H), 2.47 (s, 1H), 2.40 (s, 1H), 2.38-2.33 (m, 1H), 2.21 (s, 1H), 2.13 (s, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.99-1.93 (m, 1H), 1.86 (s, 2H), 1.63 (s, 2H), 0.92 (t, J=7.6 Hz, 3H); [M+H]+=1033.7.
The titled compound was prepared in a manner similar to that in Example 237. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.92 (s, 1H), 8.85 (dt, J=19.6, 9.8 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.61 (d, J=7.5 Hz, 2H), 5.03 (dd, J=13.3, 5.2 Hz, 1H), 4.30 (d, J=16.4 Hz, 1H), 4.18 (d, J=16.5 Hz, 1H), 3.77 (s, 3H), 3.51 (t, J=7.4 Hz, 1H), 3.40-3.36 (m, 4H), 3.01 (d, J=10.5 Hz, 2H), 2.97-2.93 (m, 1H), 2.88 (d, J=12.3 Hz, 1H), 2.70 (t, J=11.1 Hz, 2H), 2.62-2.54 (m, 5H), 2.47 (d, J=7.5 Hz, 1H), 2.38-2.28 (m, 6H), 2.16 (s, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.97-1.92 (m, 1H), 1.86 (d, J=10.6 Hz, 2H), 1.72-1.49 (m, 6H), 0.92 (t, J=7.1 Hz, 3H); [M+H]+=1033.7.
The titled compound was prepared in a manner similar to that in Example 207. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.76 (s, 1H), 8.85 (dt, J=22.0, 11.0 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.00 (d, J=8.6 Hz, 2H), 6.81 (s, 1H), 6.72 (t, J=6.9 Hz, 2H), 3.83-3.79 (m, 1H), 3.77 (s, 3H), 3.70 (dd, J=10.9, 4.9 Hz, 1H), 3.01 (d, J=10.7 Hz, 2H), 2.74 (s, 2H), 2.70 (t, J=11.2 Hz, 2H), 2.64-2.60 (m, 1H), 2.53 (s, 3H), 2.47-2.42 (m, 5H), 2.41-2.34 (m, 6H), 2.31 (s, 1H), 2.15-2.11 (m, 3H), 2.01 (dd, J=16.1, 9.5 Hz, 8H), 1.85 (d, J=10.4 Hz, 2H), 1.65 (d, J=10.3 Hz, 2H), 1.57 (d, J=11.5 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H); [M+H]+=978.7.
To a solution of methyl 2-cyano-4-fluorobenzoate (5.00 g, 27.9 mmol) and azetidine-3-carboxylic acid (4.99 g, 36.3 mmol) in DMSO (35.0 mL). The DIPEA (9.02 g, 69.8 mmol) was added to the reaction mixture. The reaction mixture was warmed to 100° C. for 0.5 hr and then stirred at 100° C. for 3 hrs. The reaction mixture was diluted with ACN (35.0 mL) and stirred for 15 min, then filtered to get filtrate and adjusted the filtrate pH=8 by sat.aq.NaHCO3 solution (40.0 mL). The mixture was extracted with EtOAc (50.0 mL). Water phase was adjusted pH=3 by 6N HCl (50.0 mL), extracted with EtOAc (50.0 mL×2). The combine organic phase was washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to obtain product (6.00 g, crude). [M−H]−=259.1.
To a solution of Raney-Ni (2.00 g, 11.7 mmol) in HCOOH (20.0 mL) at 25° C.,1-(3-cyano-4-(methoxycarbonyl)phenyl)azetidine-3-carboxylic acid in HCOOH (20.0 mL) was added to the reaction mixture at 25° C. Then the mixture was stirred at 25° C. for 15 min. The reaction mixture was diluted with solvent H2O (20.0 mL) and extracted with EtOAc (40.0 mL×2). The combined organic phase was washed with brine (40.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to obtain product (5.50 g, crude). [M−H]−=262.1.
To a solution of 1-(3-formyl-4-(methoxycarbonyl)phenyl)azetidine-3-carboxylic acid (5.50 g, 20.9 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3.44 g, 20.9 mmol) in DMF (35.0 mL) was added DIPEA (8.10 g, 62.7 mmol) at 25° C. The mixture was stirred at 25° C. for 1 hr. Then CH3COOH (4.39 g, 73.1 mmol) and NaBH3CN (2.63 g, 41.8 mmol) was added to the reaction mixture at 25° C. The mixture was stirred at 25° C. for 1 hr. The mixture was adjust pH=8 by DIPEA. The mixture was stirred at 25° C. for 1 hr. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue and purified by prep-HPLC ([water (0.225% FA)-ACN]; B %: 3%-35%, 20 min) to obtain the product (1.70 g, 4.95 mmol, 23.7% yield). [M+H]+=344.1.
The titled compound (11 mg, 26%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO) δ 12.58 (s, 1H), 10.87 (s, 1H), 8.79 (dt, J=18.9, 9.5 Hz, 3H), 8.21 (s, 2H), 7.83 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.31 (s, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 6.45 (dd, J=8.3, 1.7 Hz, 1H), 4.97 (dd, J=13.3, 5.0 Hz, 1H), 4.25 (d, J=16.9 Hz, 1H), 4.12 (d, J=16.9 Hz, 1H), 4.06 (t, J=7.9 Hz, 2H), 3.94 (t, J=6.2 Hz, 2H), 3.85-3.79 (m, 1H), 3.71 (s, 3H), 3.44 (s, 2H), 2.96 (d, J=10.6 Hz, 2H), 2.87-2.79 (m, 1H), 2.65 (t, J=11.0 Hz, 2H), 2.51-2.46 (m, 5H), 2.41 (s, 2H), 2.38-2.25 (m, 3H), 1.98-1.87 (m, 8H), 1.79 (d, J=10.7 Hz, 2H), 1.54 (dd, J=20.3, 11.1 Hz, 2H), 0.86 (t, J=7.1 Hz, 3H); [M+H]+=1019.7.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.76 (s, 1H), 8.86 (d, J=6.9 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.3 Hz, 1H), 7.37 (s, 1H), 7.04-7.00 (m, 2H), 6.81 (s, 1H), 6.74 (d, J=8.6 Hz, 2H), 3.98-3.92 (m, 1H), 3.77 (s, 3H), 3.70 (dd, J=10.9, 5.0 Hz, 1H), 3.53-3.39 (m, 4H), 3.02 (d, J=9.6 Hz, 3H), 2.77 (d, J=15.9 Hz, 3H), 2.71 (s, 2H), 2.66-2.59 (m, 2H), 2.53 (d, J=8.6 Hz, 1H), 2.48-2.43 (m, 6H), 2.37 (d, J=9.7 Hz, 1H), 2.31 (d, J=9.2 Hz, 1H), 2.19-2.16 (m, 1H), 2.14-2.11 (m, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.83 (s, 2H), 1.59 (d, J=11.5 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=992.7.
To a solution of 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.50 g, 5.19 mmol) in MeOH (40 mL) was added Pd/C (wt % 100 mg) and stirred at 25° C. for 18 hours under H2 atmosphere. The mixture was filtered and evaporated in vacuum to afford the product (0.90 g, 69%). [M+H]+=260.1.
A mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.65 g, 2.5 mmol), 2-bromoethan-1-ol (0.62 g, 5 mmol) and DIPEA (0.97 g, 7.5 mmol) in DMSO (15 mL) was stirred in a round bottom flask at 120° C. for 48 hours. The mixture was added brine (100 mL), extracted with DCM (100 mL×3). The organics were evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH=100: 1˜ 10:1 gradient elution) to give product (0.3 g, 40%). [M+H]+=304.1.
The titled compound (210 mg, 56%) was synthesized in a manner similar to that in Example 207 step 4 from 3-(4-((2-hydroxyethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and MsCl.
The titled compound (10 mg, 36%) was synthesized in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl methanesulfonate. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 11.01 (s, 1H), 8.88-8.80 (m, 3H), 8.27 (s, 2H), 7.89 (s, 1H), 7.38 (s, 1H), 7.30 (t, J=7.7 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H), 6.80 (d, J=8.2 Hz, 2H), 5.45 (s, 1H), 5.11 (dd, J=13.5, 5.4 Hz, 1H), 4.24 (d, J=17.3 Hz, 1H), 4.14 (d, J=16.8 Hz, 1H), 3.77 (s, 3H), 3.02 (d, J=10.5 Hz, 3H), 2.95-2.90 (m, 1H), 2.71 (t, J=10.7 Hz, 3H), 2.64 (s, 2H), 2.57-2.52 (m, 5H), 2.36-2.31 (m, J=20.9 Hz, 7H), 2.02 (d, J=14.3 Hz, 8H), 1.87-1.85 (m, 2H), 1.58 (d, J=12.0 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=979.7.
The titled compound was prepared in a manner similar to that in Example 71. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 10.96 (s, 1H), 8.85 (t, J=13.2 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.00 (d, J=6.4 Hz, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 5.09 (dd, J=13.4, 5.1 Hz, 1H), 4.31 (d, J=16.4 Hz, 1H), 4.18 (d, J=16.4 Hz, 1H), 3.77 (s, 3H), 3.54-3.50 (m, 3H), 3.01 (d, J=10.5 Hz, 2H), 2.97 (s, 3H), 2.94-2.89 (m, 1H), 2.70 (t, J=11.2 Hz, 2H), 2.64-2.57 (m, 2H), 2.55-2.52 (m, 3H), 2.48-2.41 (m, 6H), 2.38 (d, J=17.0 Hz, 1H), 2.31 (s, 1H), 2.02 (d, J=14.4 Hz, 8H), 1.86 (d, J=10.5 Hz, 2H), 1.57 (d, J=9.3 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H); [M+H]+=993.5.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.76 (s, 1H), 8.88-8.85 (m, 2H), 8.81 (d, J=7.3 Hz, 1H), 8.27 (s, 1H), 7.90 (d, J=9.8 Hz, 1H), 7.37 (s, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.81 (s, 1H), 6.40 (d, J=8.4 Hz, 2H), 3.90 (t, J=7.0 Hz, 2H), 3.77 (s, 3H), 3.70 (dd, J=11.0, 4.9 Hz, 1H), 3.56 (t, J=6.2 Hz, 2H), 3.30 (s, 2H), 3.27-3.20 (m, 2H), 3.01 (d, J=11.0 Hz, 2H), 2.70 (t, J=11.0 Hz, 2H), 2.66-2.53 (m, 4H), 2.48-2.42 (m, 5H), 2.40-2.29 (m, 2H), 2.10 (dt, J=11.9, 3.9 Hz, 1H), 2.03 (s, 3H), 2.02-1.97 (m, 4H), 1.86 (dd, J=12.8, 1.7 Hz, 2H), 1.59 (dt, J=21.1, 7.1 Hz, 2H), 0.92 (t, J=6.6 Hz, 3H); [M+H]+=937.6.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.91 (s, 1H), 8.87 (d, J=5.9 Hz, 2H), 8.82 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.22 (d, J=8.6 Hz, 1H), 6.81 (s, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.70 (dd, J=8.5, 2.3 Hz, 1H), 4.01-3.95 (m, 3H), 3.77 (s, 3H), 3.50 (t, J=6.5 Hz, 2H), 3.01 (d, J=10.6 Hz, 2H), 2.94 (dt, J=14.0, 7.2 Hz, 1H), 2.84-2.76 (m, 1H), 2.71 (t, J=11.3 Hz, 2H), 2.60-2.51 (m, 8H), 2.47-2.23 (m, 7H), 2.06-1.97 (m, 7H), 1.86 (d, J=11.2 Hz, 2H), 1.58 (dt, J=20.9, 10.4 Hz, 2H), 0.93 (t, J=7.0 Hz, 3H); [M+H]+=975.6.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.78 (s, 1H), 8.85 (t, J=13.7 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.2 Hz, 1H), 7.38 (s, 1H), 7.03 (t, J=8.5 Hz, 1H), 6.81 (s, 1H), 6.26-6.12 (m, 2H), 3.92 (t, J=7.4 Hz, 2H), 3.85 (dd, J=12.2, 4.8 Hz, 1H), 3.77 (s, 3H), 3.45 (t, J=6.4 Hz, 2H), 3.01 (d, J=10.7 Hz, 2H), 2.96-2.87 (m, 1H), 2.71 (t, J=12.1 Hz, 3H), 2.61-2.52 (m, 9H), 2.43 (dd, J=41.1, 16.0 Hz, 4H), 2.32 (s, 1H), 2.12 (dt, J=14.3, 11.5 Hz, 1H), 2.04 (s, 3H), 2.01 (s, 3H), 1.94 (dd, J=9.2, 4.2 Hz, 1H), 1.86 (d, J=12.6 Hz, 2H), 1.57 (dd, J=20.1, 11.4 Hz, 2H), 0.93 (t, J=7.1 Hz, 3H); [M+H]+=968.8.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.85 (s, 1H), 8.89-8.84 (m, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.11 (d, J=11.2 Hz, 2H), 4.02 (dd, J=12.7, 5.1 Hz, 1H), 3.93 (t, J=7.8 Hz, 2H), 3.77 (s, 3H), 3.48 (t, J=6.6 Hz, 2H), 3.29 (s, 6H), 3.01 (d, J=9.8 Hz, 2H), 2.95-2.89 (m, 1H), 2.78 (dd, J=10.6, 5.3 Hz, 1H), 2.71 (t, J=11.6 Hz, 2H), 2.60-2.53 (m, 4H), 2.43-2.40 (m, 2H), 2.07 (dd, J=10.8, 5.8 Hz, 2H), 2.02 (d, J=14.3 Hz, 6H), 1.96-1.91 (m, 2H), 1.90-1.84 (m, 2H), 1.64-1.52 (m, 2H), 0.92 (t, J=6.8 Hz, 3H); [M+H]+=986.5.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.87 (s, 1H), 8.85 (dt, J=24.0, 12.0 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.2 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.63 (d, J=12.8 Hz, 2H), 4.05 (dd, J=12.7, 4.9 Hz, 1H), 3.79 (d, J=14.6 Hz, 5H), 3.51 (d, J=38.9 Hz, 4H), 3.32 (s, 1H), 3.02 (d, J=11.1 Hz, 2H), 2.90-2.68 (m, 6H), 2.60-2.51 (m, 3H), 2.38 (dd, J=20.7, 6.6 Hz, 4H), 2.15-1.93 (m, 8H), 1.86 (d, J=10.7 Hz, 2H), 1.63 (dd, J=31.1, 11.9 Hz, 6H), 0.93 (t, J=7.1 Hz, 3H); [M+H]+=1030.7.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.84 (s, 1H), 8.86 (dd, J=8.2, 1.7 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.9 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.5, 4.9 Hz, 1H), 3.77 (s, 3H), 3.62-3.42 (m, 6H), 3.26 (dd, J=19.8, 11.2 Hz, 3H), 3.03 (d, J=10.4 Hz, 2H), 2.76 (dt, J=22.5, 8.3 Hz, 3H), 2.56 (d, J=22.9 Hz, 4H), 2.39 (d, J=23.6 Hz, 4H), 2.17 (dd, J=12.4, 5.4 Hz, 1H), 2.09 (dd, J=17.7, 9.0 Hz, 2H), 2.02 (d, J=14.4 Hz, 6H), 1.97-1.91 (m, 1H), 1.87 (d, J=10.4 Hz, 2H), 1.67-1.56 (m, 2H), 0.93 (t, J=7.1 Hz, 3H); [M+H]+=1014.6.
The titled compound was prepared in a manner similar to that in Example 71. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.99 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J=9.5 Hz, 2H), 7.97 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.45-7.33 (m, 3H), 7.15 (d, J=7.3 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.73 (s, 1H), 5.12 (dd, J=13.2, 5.1 Hz, 1H), 4.51 (d, J=16.8 Hz, 1H), 4.38 (d, J=16.8 Hz, 1H), 3.75 (s, 3H), 2.97-2.87 (m, 6H), 2.68-2.57 (m, 8H), 2.47-2.23 (m, 12H), 2.04-1.93 (m, 8H), 1.83-1.76 (m, 2H), 1.51-1.40 (m, 2H), 0.76-0.65 (m, 3H); [M+H]+=1006.5.
The titled compound was prepared in a manner similar to that in Example 309. 1H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 11.15 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.32 (d, J=21.4 Hz, 2H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J=9.1 Hz, 1H), 6.74 (s, 1H), 5.68 (dd, J=11.3, 5.2 Hz, 1H), 3.75 (s, 3H), 2.98-2.90 (m, 2H), 2.88-2.68 (m, 6H), 2.69-2.52 (m, 13H), 2.39-2.24 (m, 5H), 1.98 (d, J=13.3 Hz, 6H), 1.87-1.80 (m, 2H), 1.55-1.57 (m, 2H), 0.86-0.69 (m, 3H); [M+H]+=962.5
The titled compound was prepared in a manner similar to that in Example 59. 1H NMR (400 MHz, dmso) δ 12.71 (s, 1H), 11.08 (s, 1H), 9.58 (s, 1H), 9.05-8.80 (m, J=12.1 Hz, 3H), 8.37 (s, 1H), 8.13 (d, J=9.4 Hz, 1H), 7.64 (d, J=17.0 Hz, 2H), 7.34-7.18 (m, 1H), 7.05-6.89 (m, 1H), 6.78 (s, 1H), 6.64 (d, J=6.7 Hz, 1H), 5.15-5.01 (m, J=7.6 Hz, 1H), 4.18-4.08 (m, 2H), 3.87-3.71 (m, 2H), 3.06-2.82 (m, 8H), 2.69-2.52 (m, J=28.7 Hz, 4H), 2.47-2.28 (m, 4H), 2.12-1.94 (m, J=14.4 Hz, 8H), 1.29-1.14 (m, 2H). [M+H]+=951.8.
The titled compound was prepared in a manner similar to that in Example 57. 1H NMR (400 MHz, dmso) δ 12.71 (s, 1H), 11.08 (s, 1H), 9.57 (s, 1H), 9.00-8.83 (m, 3H), 8.37 (s, 1H), 8.14 (d, J=9.6 Hz, 1H), 7.70-7.59 (m, 2H), 7.25 (d, J=8.0 Hz, 1H), 6.96 (t, J=9.2 Hz, 1H), 6.85-6.80 (m, 1H), 6.68 (d, J=8.4 Hz, 1H), 5.46-5.27 (m, 1H), 5.06 (dd, J=12.8, 5.4 Hz, 1H), 4.22-4.10 (m, 3H), 4.08-3.98 (m, 3H), 3.97-3.91 (m, 1H), 3.80-3.74 (m, 1H), 3.70-3.63 (m, 1H), 3.27-3.18 (m, 2H), 3.02-2.82 (m, 6H), 2.64-2.54 (m, 2H), 2.07-1.99 (m, 7H). [M+H]+=965.7.
The titled compound was prepared in a manner similar to that in Example 207. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.79 (s, 1H), 8.94-8.74 (m, 3H), 8.34-8.22 (m, 2H), 8.17 (s, 1H), 7.96-7.83 (m, 1H), 7.37 (s, 1H), 7.09 (t, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.41 (d, J=7.5 Hz, 2H), 6.35 (s, 1H), 3.78-3.71 (m, 4H), 3.44-3.36 (m, J=8.0 Hz, 2H), 3.29-3.15 (m, 4H), 3.06-2.97 (m, 2H), 2.87-2.80 (m, 1H), 2.74-2.67 (m, 2H), 2.64-2.53 (m, 4H), 2.47-2.41 (m, 4H), 2.38-2.21 (m, 6H), 2.20-2.08 (m, 2H), 2.05-1.98 (m, 5H), 1.89-1.82 (m, 2H), 1.64-1.53 (m, 5H), 0.98-0.87 (m, 3H). [M+H]+=978.6.
To a stirred solution of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.0 g, 5.4 mmol) and K2CO3 (1.49 g, 10.8 mmol) in DMSO (20 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane (1.16 g, 8.1 mmol). The resulting mixture was stirred at 100° C. for 16 hour. The reaction was extracted with DCM (2×50.0 mL). The combined organic layer was washed with brine (2×50.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (PE: EA=2:1˜ 0:100 gradient elution) to give the title product (1.33 g, 80%). [M+H]+=309.2.
To a stirred solution of 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.33 g, 4.3 mmol) in THF (20 mL) was added HCl (4 mol/L). The resulting mixture was stirred at 60° C. for 4 hour.
The reaction was extracted with DCM (2×50.0 mL). The combined organic layer was washed with brine (2×50.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM:MeOH=10:1) to give the title product (800 mg, 70%). [M+H]+=265.1.
To a stirred solution of 1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-one (200 mg, 0.76 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (225 mg, 1.14 mmol) in DCE (10 mL) was added Ti(OiPr)4 (215 mg, 0.76 mmol). The resulting mixture was stirred at rt for 2 hour. Then Na(OAc)3BH (322 mg, 1.52 mmol) was added. The resulting mixture was stirred at rt for 16 hour. The reaction was extracted with DCM (2×50.0 mL). The combined organic layer was washed with brine (2×50.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM:MeOH=10:1) to give the title product (300 mg, 88%). [M+H]+=447.2.
To a stirred solution of tert-butyl 3-(1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 0.66 mmol) in MeOH (10 mL) was added Pd/C (60 mg) under H2. The resulting mixture was stirred at rt for 2 hour. The mixture was concentrated under vacuum to afford the title product (220 mg, 80%). [M+H]+=417.2.
To a stirred solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (100 mg, 0.24 mmol) and tert-butyl 3-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (120 mg, 0.29 mmol) in t-BuOH (10 mL) was added MsOH (96 mg, 0.96 mmol). The resulting mixture was stirred at 95° C. for 16 hour. The reaction was extracted with DCM (2×50.0 mL). The combined organic layer was washed with brine (2×50.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM:MeOH=8:1) to give the title product (100 mg, 60%). [M+H]+=692.2.
To a stirred solution of (6-((2-((4-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide(30 mg, 0.043 mmol) and 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde (22.5 mg, 0.065 mmol) in DCE (10 mL) was added Ti(OiPr)4 (12 mg, 0.043 mmol). The resulting mixture was stirred at rt for 2 hour. Then Na(OAc)3BH (13.8 mg, 0.065 mmol). The resulting mixture was stirred at rt for 16 hour. The reaction was extracted with DCM (2×10.0 mL). The combined organic layer was washed with brine (2×10.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified by prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to give the title product (10 mg, 23%). 1H NMR (500 MHz, DMSO) δ 12.62 (s, 1H), 10.79 (s, 1H), 8.78 (d, J=8.7 Hz, 3H), 8.20 (s, 2H), 7.86 (d, J=9.3 Hz, 1H), 7.30 (s, 1H), 6.70 (s, 1H), 6.53 (d, J=12.8 Hz, 2H), 3.96 (dd, J=12.6, 4.9 Hz, 1H), 3.71 (s, 3H), 3.67 (d, J=12.3 Hz, 2H), 3.03 (d, J=11.2 Hz, 2H), 2.95 (d, J=10.7 Hz, 2H), 2.86-2.57 (m, 12H), 2.52 (d, J=10.5 Hz, 2H), 2.06 (d, J=12.8 Hz, 3H), 1.96 (d, J=14.4 Hz, 6H), 1.90 (d, J=8.6 Hz, 3H), 1.81 (s, 1H), 1.65-1.62 (m, 5H), 1.45 (d, J=11.5 Hz, 1H), 1.25-1.06 (m, 4H); [M+H]+=1026.3.
The titled compound was prepared in a manner similar to that in Example 266. 1H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 10.86 (s, 1H), 8.86 (dd, J=9.7, 1.8 Hz, 3H), 8.31-8.21 (m, 2H), 7.92 (d, J=9.5 Hz, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 6.61 (d, J=12.8 Hz, 2H), 4.04 (dd, J=12.6, 5.0 Hz, 1H), 3.78 (s, 3H), 3.74 (d, J=13.2 Hz, 2H), 3.55 (s, 1H), 3.02 (s, 2H), 2.86-2.51 (m, 14H), 2.09 (s, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.94 (dd, J=16.7, 9.1 Hz, 2H), 1.82 (d, J=9.8 Hz, 1H), 1.72 (d, J=11.7 Hz, 2H), 1.65 (d, J=8.5 Hz, 1H), 1.58 (d, J=8.4 Hz, 2H), 1.49 (d, J=12.2 Hz, 3H), 1.35 (d, J=7.0 Hz, 2H), 1.25-1.13 (m, 2H). [M+H]+=1026.3.
The titled compound was prepared in a manner similar to that in Example 266. 1H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 10.86 (s, 1H), 8.86 (dd, J=9.8, 1.8 Hz, 3H), 8.30-8.25 (m, 2H), 7.92 (d, J=9.6 Hz, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 6.61 (d, J=12.8 Hz, 2H), 4.04 (dd, J=12.4, 5.0 Hz, 1H), 3.78 (s, 3H), 3.74 (d, J=13.2 Hz, 2H), 3.57 (s, 1H), 3.03 (d, J=7.0 Hz, 2H), 2.85-2.56 (m, 14H), 2.09 (s, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.94 (dd, J=15.0, 9.7 Hz, 2H), 1.82 (d, J=10.8 Hz, 1H), 1.72 (d, J=11.9 Hz, 3H), 1.60 (d, J=9.0 Hz, 2H), 1.50 (s, 3H), 1.36 (d, J=6.9 Hz, 2H), 1.23-1.14 (m, 2H). [M+H]+=1026.3.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.91 (s, 1H), 10.80 (s, 1H), 8.92 (s, 1H), 8.81 (d, J=17.1 Hz, 2H), 8.45 (s, 1H), 8.16 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.35 (s, 1H), 6.77 (s, 1H), 6.57 (d, J=12.9 Hz, 2H), 3.98 (dd, J=12.5, 4.9 Hz, 2H), 3.72 (s, 6H), 3.07 (d, J=10.6 Hz, 6H), 2.78-2.62 (m, 6H), 2.51-2.44 (m, 4H), 2.08-1.86 (m, 12H), 1.72-1.68 (m 4H), 1.60-1.37 (m, 4H), 1.20-1.10 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). [M+H]+=984.4.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.20 (s, 1H), 10.86 (s, 1H), 8.57 (s, 2H), 8.26-8.14 (m, 3H), 7.36 (s, 1H), 6.75 (s, 1H), 6.60 (d, J=13.0 Hz, 2H), 4.04 (dd, J=12.1, 4.8 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.98 (d, J=9.3 Hz, 3H), 2.80-2.59 (m, 8H), 2.41 (d, J=6.9 Hz, 6H), 2.31 (d, J=7.1 Hz, 4H), 2.12-1.93 (m, 9H), 1.84 (d, J=10.8 Hz, 2H), 1.71 (d, J=12.0 Hz, 2H), 1.56 (d, J=9.7 Hz, 4H), 1.38 (d, J=6.8 Hz, 2H), 1.17 (d, J=11.3 Hz, 2H), 0.91 (s, 3H); [M+H]+=1058.4.
The titled compound was prepared in a manner similar to that in Example 59. 1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 11.06 (s, 1H), 8.86 (d, J=4.8 Hz, 3H), 8.27 (s, 2H), 7.89 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.37 (s, 1H), 6.91 (s, 1H), 6.81 (s, 2H), 5.04 (s, 1H), 3.77 (s, 3H), 3.61 (m, 4H), 3.03 (s, 6H), 2.88 (s, 2H), 2.69 (d, J=11.4 Hz, 3H), 2.36 (m, 9H), 2.17 (s, 2H), 2.02 (d, J=14.4 Hz, 8H), 1.85 (s, 2H), 1.60 (s, 6H), 0.92 (s, 3H). [M+H]+=1049.9
A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (2.0 g, 4.158 mmol) and ethyl 2-(piperidin-4-yl)acetate (711.0 mg, 4.158 mmol), Cs2CO3 (2.0 g, 6.237 mmol), XPhos(396.7 mg, 0.832 mmol), Pd2(dba)3 (380.5 mg, 0.416 mmol) in dioxane (20 mL) was stirred overnight at 110° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (1.0 g, 42.1%) [M+1]+=573.3.
Into a 100-mL round-bottom flask, was placed ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetate (1.0 g, 1.748 mmol), EtOH (20 mL), THF (8 mL), H2O (4 mL), NaOH (280.0 mg, 7.000 mmol). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to <7 with 1N HCl (aq). The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with EtOAc (200 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (501 mg, 52%). [M+1]+=545.3.
A mixture of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetic acid (500.0 mg, 0.919 mmol) and Pd/C (300.0 mg) in EtOH (10 mL) and DCM (2 mL) was stirred overnight at 45° C. under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (50 mL) and DCM (50 mL). The filtrate was concentrated under reduced pressure to afford the product (282.2 mg, 84.0%) was obtained. [M+1]+=367.0.
The titled compound (14 mg, 26%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetic acid. 1H NMR (400 MHz DMSO) δ 12.64 (s, 1H), 10.87 (s, 1H), 8.86 (d, J=5.2 Hz, 3H), 8.27 (s, 2H), 7.91 (s, 1H), 7.37 (s, 1H), 6.81 (s, 1H), 6.61 (d, J=13.3 Hz, 2H), 4.05 (s, 1H), 3.77 (s, 6H), 3.47 (s, 4H), 3.01 (s, 7H), 2.73 (d, J=12.1 Hz, 4H), 2.50 (s, 3H), 2.27 (s, 2H), 2.02 (d, J=14.2 Hz, 4H), 2.02 (d, J=14.2 Hz, 2H), 1.84 (s, 3H), 1.71 (s, 2H), 1.61 (s, 2H), 1.23 (s, 4H), 0.92 (s, 3H). [M+H]+=1042.1.
To a solution of 2-(4-bromophenyl)propanenitrile (4 g, 19 mmol) in THF(50 mL) was added LDA (2M, 10.5 mL) dropwise in 10 min at −65° C., the reaction solution was stirred for 30 min at this temperature, then to this was added ethyl 3-bromopropanoate (3.8 g, 21 mmol) in THF(10 mL) dropwise in 10 min. The resulting solution was stirred for 30 min at −65° C., then allowed the temperature rise to room temperature naturally. The reaction was quenched by the addition of sat.aq. NH4Cl solution, extracted with EtOAc (50 mL×3), the combined organic layer and washed with brine, dried over anhydrous Na2SO4, after filtration, the filtrate was concentrated under reduced pressure to afford product (5.1 g, 86.4%). [M+H]+=310.1.
To a solution of ethyl 4-(4-bromophenyl)-4-cyanopentanoate (3.1 g, 10 mmol) in THF/H2O (30 mL/10 mL) was added LiOH (720 mg, 30 mmol). The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water, extracted with EtOAc (20 mL×2). The pH value of water phase was adjusted to 4-5, extracted with EtOAc (30 mL×2), The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford product (2.6 g, 92.2%). [M+H]+=282.0.
To a solution of 4-(4-bromophenyl)-4-cyanopentanoic acid (2.6 g, 9.2 mmol) in toluene (20 mL) was added conc. H2SO4(0.6 mL, 10.1 mmol). The resulting solution was stirred at 100° C. for 3 h. The reaction mixture was concentrated under vacuum, then the mixture was poured into water, the pH value was adjusted to 7-8 with sat. aq. NaHCO3 solution, extracted with EtOAc (30 mL×3). The organic layer was washed with water and brine, dried over anhydrous Na2SO4. The solvent was evaporated to dryness to afford product (2.1 g, 80.8%). [M+H]+=282.0.
To a stirred solution of 3-(4-bromophenyl)-3-methylpiperidine-2,6-dione (200 mg, 0.71 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (169 mg, 0.85 mmol) in DMF/H2O (8 mL/2 mL) were added Pd(dtbpf)Cl2 (46 mg, 0.071 mmol) and CsF (216 mg, 1.4 mmol). The resulting mixture was stirred for 2 h at 80° C. under nitrogen atmosphere. The reaction solution was diluted with water, extracted with EtOAc (10 mL×3). The organic layer was washed with water and brine, dried over anhydrous Na2SO4. The solvent was evaporated to dryness and the crude residue was purified by a silica gel column, eluted with PE/EtOAc=1:1 to afford product. (190 mg, 97.9%). [M+H]+=274.1.
(E)-3-(4-(2-ethoxyvinyl)phenyl)-3-methylpiperidine-2,6-dione (190 mg, 0.7 mmol) was dissolved in HCOOH (3 mL). The resulting solution was stirred for 2 h at room temperature. The reaction solution was evaporated to dryness to afford the product (160 mg, 92.9%) which was used directly in the next step without further purification. m/z[M+H]+=246.1.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (40 mg, 0.058 mmol), 2-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde (21 mg, 0.086 mmol) and NaBH(OAc)3 (11 mg, 0.17 mmol) in DCE (3 mL) was stirred in a round bottom flask at room temperature for 2 hours. The reaction was diluted with DCM, washed with water(5 mL) and brine (5 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product, which was purified with pre-HPLC (0.1% FA in water: acetonitrile=90:1˜50:50 gradient elution) to give the title product (18.5 mg, 34.6%). 1H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.90 (s, 1H), 8.82-8.87 (m, 3H), 8.23-8.27 (m, 2H), 7.90 (d, J=8.6 Hz, 1H), 7.38 (s, 1H), 7.18-7.23 (m, 4H), 6.81 (s, 1H), 3.77 (s, 3H), 2.97-3.04 (m, 2H), 2.66-2.75 (m, 4H), 2.54-2.61 (m, 6H), 2.39-2.49 (m, 6H), 2.27-2.38 (m, 3H), 1.97-2.13 (m, 8H), 1.82-1.90 (m, 2H), 1.53-1.63 (m, 2H), 1.42 (s, 3H), 0.93 (t, J=6.9 Hz, 3H). [M+H]+=923.3.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO-d6)6H 12.58 (s, 1H), 10.67 (s, 1H), 8.76-8.80 (m, 3H), 8.20 (s, 2H), 7.84 (d, J=8.6 Hz, 1H), 7.31 (s, 1H), 6.93 (d, J=8.2 Hz, 2H), 6.75 (s, 1H), 6.43 (d, J=8.3 Hz, 2H), 3.58-3.72 (m, 5H), 3.35-3.40 (m, 2H), 3.11-3.17 (m, 2H), 2.77-2.98 (m, 5H), 2.47-2.69 (m, 8H), 2.20-2.30 (m, 3H), 2.01-2.15 (m, 2H), 1.95 (d, J=14.3 Hz, 8H), 1.70-1.84 (m, 3H), 1.46-1.57 (m, 2H), 0.86 (s, 3H).[M+H]+=950.4.
A mixture of 2-bromo-1,3-difluoro-5-iodobenzene (12 g, 37.6 mmol), but-3-yn-1-ol (3.95 g, 56.4 mmol), Pd(PPh3)2Cl2 (2.6 g, 3.76 mmol) and CuI (715 mg, 3.76 mmol) in Et3N/DMF (40 mL/20 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was allowed to cool down to room temperature.
The resulting mixture was diluted with water and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3: 1) to afford the product (7 g, 71.3%). [M+H]+=261.0.
A mixture of 4-(4-bromo-3,5-difluorophenyl)but-3-yn-1-ol (7 g, 26.8 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (11.2 g, 26.8 mmol), Pd(dtbpf)Cl2 (877 mg, 1.34 mmol) and CsF (8.2 g, 53.6 mmol) in DMF (80 mL) and water (20 mL) was stirred in a flask at 90° C. under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2: 1) to afford the product (7 g, 55.3%). [M+H]+=472.2.
To a stirred solution of 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)but-3-yn-1-ol (7 g, 14.8 mmol) in MeOH (100 mL) and DCM (20.00 mL) was added Pd/C (wet, 10%) (1 g) under nitrogen atmosphere. The resulting mixture was stirred for 16 hrs at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/CH3OH (10: 1, 50 mL). The filtrate was concentrated under reduced pressure to afford the product (3.9 g, 88.6%). [M+H]+=298.1.
To a solution of 3-(2,6-difluoro-4-(4-hydroxybutyl)phenyl)piperidine-2,6-dione (200 mg, 0.67 mmol) in DMSO (3 mL) was added IBX (564 mg, 2 mmol). The resulting solution was stirred at 30° C. under nitrogen atmosphere for 3 hrs. The reaction mixture was quenched with water, extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (120 mg, 60.6%), [M+H]+=296.1.
The titled compound (12 mg, 27%) was prepared in a manner similar to that in Example 204 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)butanal. 1H NMR (500 MHz, DMSO-d6)6H 12.64 (s, 1H), 10.94 (s, 1H), 8.81-8.87 (m, 3H), 8.29 (s, 2H), 7.92 (t, J=15.5 Hz, 1H), 7.38 (s, 1H), 6.98 (d, J=10.0 Hz, 2H), 6.81 (s, 1H), 4.20 (dd, J=12.7, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J=11.1 Hz, 2H), 2.87-2.75 (m, 1H), 2.71 (dd, J=19.8, 8.4 Hz, 2H), 2.53-2.62 (m, 6H), 2.26-2.47 (m, 10H), 2.13 (dd, J=26.0, 13.1, 3.8 Hz, 1H), 2.01 (t, J=11.5 Hz, 7H), 1.85 (d, J=10.9 Hz, 2H), 1.53-1.61 (m, 4H), 1.40-1.46 (m, 2H), 0.92 (t, J=7.1 Hz, 3H). [M+H]+=973.3.
Into a 250 mL round-bottom flask was added 3-((benzyloxy)methyl)cyclobutan-1-one (5.0 g, 26.28 mmol) in MeOH (80 mL) at room temperature. NaBH4 (1.49 g, 39.42 mmol) was added in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc (400 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc=1:1 to afford the product (4.9 g, 96.97%). [M+H]+=193.1.
Into a 250 mL 3-necked round-bottom flask were added 3-((benzyloxy)methyl)cyclobutan-1-ol (4.9 g, 25.48 mmol), DMAP (0.62 g, 5.07 mmol), TEA (3.09 g, 30.59 mmol), DCM (50 mL) at room temperature. To a stirred solution was added p-toluenesulfonyl chloride (5.34 g, 27.95 mmol) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0° C. The mixture was acidified to pH=4 with HCl (1 N). The aqueous layer was extracted with DCM (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (9%) to afford the product (6.5 g, 73.62%). [M+H]+=347.4.
To a stirred solution of 3-((benzyloxy)methyl)cyclobutyl 4-methylbenzenesulfonate (6.30 g, 18.18 mmol) and NaI (8.18 g, 54.5 mmol) in DMSO (120 mL) at room temperature under air atmosphere. The resulting mixture was stirred overnight at 120° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (4.0 g, 72.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.40-7.24 (m, 5H), 4.53 (J=9.3, 7.5 Hz, 2H), 4.48 (s, 1H), 4.47 (s, 1H), 3.51-3.41 (m, 2H), 2.84-2.71 (m, 1H), 2.75-2.68 (m, 1H), 2.68-2.55 (m, 1H), 2.59-2.52 (m, 1H).
Into a 250 mL 3-necked round-bottom flask were added tert-butyl N-(4-iodophenyl)carbamate (4.0 g, 12.534 mmol), (((3-iodocyclobutyl)methoxy)methyl)benzene (5.68 g, 18.75 mmol), NaI (0.47 g, 3.13 mmol), Zn (1.64 g, 25.23 mmol), NiCl2(DME) (0.28 g, 1.27 mmol), 1H-Imidazole-4-carbonitrile (0.12 g, 1.29 mmol), DMA (50 mL) and TFA (0.14 g, 1.22 mmol) at room temperature. The resulting mixture was stirred overnight at 60° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford the product (1.2 g, 26.05%). [M+H]+=368.3.
Into a 100 mL round-bottom flask were added tert-butyl (4-(3-((benzyloxy)methyl)cyclobutyl)phenyl)carbamate (1.20 g, 3.26 mmol) and 4 M HCl in 1,4-dioxane (15 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to obtain the product (700 mg, 80.18%). [M+H]+=268.2.
To a stirred solution/mixture of 4-(3-((benzyloxy)methyl)cyclobutyl) aniline (700.0 mg, 2.61 mmol) and 3-bromopiperidine-2,6-dione (502.7 mg, 2.61 mmol) in DMF (7 mL) was added DIEA (1015 mg, 7.85 mmol) in portions at room temperature under air atmosphere. The resulting mixture was stirred overnight at 80° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with PE/EtOAc (1:1) to afford the product (650 mg, 65.60%). [M+H]+=379.2.
Into a 50 mL round-bottom flask were added 3-((4-(3-((benzyloxy)methyl)cyclobutyl)phenyl)amino)piperidine-2,6-dione (650.0 mg, 1.71 mmol) and Pd/C (650.0 mg, 10% wt) in a mixture of EtOH (5 mL) and THF (5 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was diluted with MeOH/DCM (100 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 80% B in 8 min, 80% B; Wave Length: 254 nm to afford the product (400 mg, 80.77%). [M+H]+=289.2.
The titled compound (120 mg, 37%) was prepared in a manner similar to that in Example 207 step 4 from 3-((4-((1r,3r)-3-(hydroxymethyl)cyclobutyl)phenyl)amino)piperidine-2,6-dione and MsCl.
The titled compound (11 mg, 27%) was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and ((1r,3r)-3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)methyl methanesulfonate. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.76 (s, 1H), 8.85 (dt, J=19.5, 9.7 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.7 Hz, 1H), 7.37 (s, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 6.61 (d, J=8.5 Hz, 2H), 5.65 (d, J=7.6 Hz, 1H), 4.31-4.23 (m, 1H), 3.77 (s, 3H), 3.23-3.14 (m, 1H), 3.01 (dd, J=10.0, 1.5 Hz, 2H), 2.80-2.65 (m, 3H), 2.65-2.52 (m, 5H), 2.47 (d, J=7.6 Hz, 2H), 2.43-2.24 (m, 11H), 2.13-2.06 (m, 1H), 2.02 (d, J=14.4 Hz, 6H), 1.91-1.79 (m, 3H), 1.68-1.51 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); [M+H]+=964.5.
The titled compound was prepared in a manner similar to that in Example 291. 1H NMR (500 MHz, DMSO) δ 12.57 (s, 1H), 10.80 (s, 1H), 8.78 (dt, J=17.1, 8.5 Hz, 3H), 8.21 (s, 2H), 7.84 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.14 (t, J=7.9 Hz, 1H), 7.01 (dd, J=22.3, 9.8 Hz, 2H), 6.75 (s, 1H), 3.94 (dd, J=12.5, 4.9 Hz, 1H), 3.71 (s, 3H), 3.42 (d, J=37.3 Hz, 2H), 3.22 (s, 3H), 2.95 (d, J=9.8 Hz, 2H), 2.76 (s, 2H), 2.66 (dd, J=21.3, 8.4 Hz, 7H), 2.57-2.46 (m, 4H), 2.42-2.20 (m, 5H), 2.15-2.05 (m, 1H), 1.95 (d, J=14.4 Hz, 7H), 1.66 (dd, J=87.6, 76.5 Hz, 4H), 0.86 (t, J=6.9 Hz, 3H). [M+H]+=971.7
The titled compound was prepared in a manner similar to that in Example 291. 1H NMR (500 MHz, DMSO) δ 12.58 (s, 1H), 10.79 (s, 1H), 8.83-8.74 (m, 2H), 8.74-8.37 (m, 1H), 8.20 (s, 2H), 7.82 (s, 1H), 7.31 (s, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.98 (dd, J=19.3, 9.8 Hz, 2H), 6.74 (s, 1H), 3.93 (dd, J=12.4, 4.9 Hz, 1H), 3.70 (s, 5H), 3.56 (dd, J=10.8, 3.8 Hz, 1H), 2.95 (d, J=10.9 Hz, 2H), 2.80 (dd, J=22.8, 10.3 Hz, 4H), 2.72-2.50 (m, 8H), 2.47 (s, 1H), 2.38 (d, J=11.6 Hz, 2H), 2.31-2.19 (m, 3H), 2.12 (d, J=9.4 Hz, 2H), 1.93 (dd, J=19.8, 9.6 Hz, 7H), 1.79 (d, J=11.0 Hz, 2H), 1.52 (d, J=11.1 Hz, 2H), 0.86 (t, J=7.0 Hz, 3H). [M+H]+=957.4
The titled compound was prepared in a manner similar to that in Example 291. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.86 (s, 1H), 8.84 (t, J=16.7 Hz, 3H), 8.27 (s, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.14-7.03 (m, 2H), 7.12-7.00 (m, 2H), 6.82 (s, 1H), 4.00 (dd, J=12.4, 4.8 Hz, 2H), 3.77 (s, 3H), 3.51 (d, J=4.0 Hz, 5H), 3.01 (d, J=8.5 Hz, 2H), 3.00 (s, 1H), 2.89 (s, 2H), 2.73 (s, 9H), 2.54 (s, 4H), 2.29 (d, J=7.6 Hz, 3H), 2.24 (dd, J=51.5, 12.0 Hz, 4H), 2.19 (d, J=16.3 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.87 (d, J=10.0 Hz, 1H), 1.71 (s, 2H), 1.95-1.54 (m, 5H), 1.53 (dd, J=22.8, 11.0 Hz, 1H), 1.51 (d, J=8.1 Hz, 1H), 0.92 (t, J=6.6 Hz, 3H), 0.92 (t, J=6.6 Hz, 4H). [M+H]+=971.6.
The titled compound was prepared in a manner similar to that in Example 291. 1H NMR (500 MHz, DMSO) δ 12.58 (s, 1H), 10.80 (s, 1H), 8.80 (d, J=6.9 Hz, 3H), 8.20 (s, 2H), 7.83 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.15 (s, 1H), 7.05-6.92 (m, 2H), 6.74 (s, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.70 (s, 3H), 3.45 (d, J=4.5 Hz, 2H), 3.18 (s, 3H), 2.94 (d, J=10.6 Hz, 2H), 2.76 (d, J=22.4 Hz, 2H), 2.71-2.58 (m, 7H), 2.54 (s, 2H), 2.47 (s, 2H), 2.37 (s, 2H), 2.30 (s, 1H), 2.23 (s, 1H), 2.11 (dd, J=27.7, 14.4 Hz, 2H), 1.95 (d, J=14.4 Hz, 7H), 1.77 (d, J=10.2 Hz, 2H), 1.50 (d, J=3.1 Hz, 2H), 0.86 (t, J=7.0 Hz, 3H). [M+H]+=971.7.
The titled compound was prepared in a manner similar to that in Example 291. 1H NMR (500 MHz, DMSO) δ 12.58 (s, 1H), 10.79 (s, 1H), 8.76 (d, J=22.3 Hz, 3H), 8.20 (s, 2H), 7.83 (s, 1H), 7.31 (s, 1H), 7.14 (d, J=15.7 Hz, 1H), 6.99 (d, J=19.4 Hz, 2H), 6.74 (s, 1H), 3.93 (d, J=17.4 Hz, 1H), 3.70 (s, 3H), 3.45 (d, J=14.3 Hz, 2H), 3.18 (s, 3H), 2.95 (d, J=10.6 Hz, 3H), 2.77 (d, J=16.6 Hz, 2H), 2.65 (dd, J=25.7, 10.1 Hz, 7H), 2.59-2.50 (m, 3H), 2.48 (s, 1H), 2.33 (d, J=41.4 Hz, 2H), 2.17-2.06 (m, 2H), 1.95 (d, J=14.4 Hz, 8H), 1.78 (d, J=11.5 Hz, 2H), 1.50 (d, J=12.1 Hz, 2H), 0.86 (t, J=6.9 Hz, 3H). [M+H]+=971.7.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.74 (s, 1H), 8.89-8.79 (m, 3H), 8.30-8.24 (m, 2H), 7.94-7.87 (m, 1H), 7.41-7.35 (m, 1H), 6.91 (d, J=8.5 Hz, 2H), 6.81 (s, 1H), 6.42 (d, J=8.6 Hz, 2H), 5.91 (d, J=5.9 Hz, 1H), 3.81-3.73 (m, 4H), 3.67-3.60 (m, 1H), 3.53-3.42 (m, 2H), 3.31-3.27 (m, 6H), 3.05-2.99 (m, 2H), 2.75-2.67 (m, 2H), 2.65-2.52 (m, 4H), 2.46-2.41 (m, 3H), 2.37-2.35 (m, 1H), 2.13-1.96 (m, 11H), 1.88-1.82 (m, 2H), 1.67-1.55 (m, 2H), 0.97-0.88 (m, 3H). [M+H]+=978.5.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.78 (s, 1H), 8.85 (t, J=14.2 Hz, 3H), 8.26 (t, J=14.3 Hz, 3H), 7.90 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.04 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.74-3.68 (m, 3H), 3.51 (s, 1H), 3.01 (d, J=11.7 Hz, 3H), 2.67 (dt, J=23.0,11.3 Hz, 7H), 2.54 (s, 3H), 2.46 (d, J=16.7 Hz, 3H), 2.29 (s, 2H), 2.13 (d, J=8.3 Hz, 2H), 2.02 (d, J=14.4 Hz, 6H), 1.85 (s, 4H), 1.60-1.47 (m, 4H), 1.24 (s, 1H), 0.93 (s, 3H). [M+H]+=964.4.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.86 (s, 1H), 8.86 (dd, J=8.1, 1.8 Hz, 2H), 8.84-8.78 (m, 1H), 8.27 (s, 2H), 8.13 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.13 (d, J=11.0 Hz, 2H), 4.03 (dd, J=12.3, 4.8 Hz, 1H), 3.91 (t, J=7.4 Hz, 2H), 3.77 (s, 3H), 3.67-3.60 (m, 2H), 3.30-3.23 (m, 2H), 3.05-2.98 (m, 2H), 2.84-2.66 (m, 4H), 2.66-2.54 (m, 5H), 2.39 (ddd, J=15.1, 12.2, 7.0 Hz, 7H), 2.11-1.98 (m, 8H), 1.97-1.84 (m, 3H), 1.65-1.54 (m, 2H), 0.97-0.90 (m, 3H). [M+H]+=972.5.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.86 (s, 1H), 8.86 (dt, J=18.7, 9.3 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.61 (d, J=12.9 Hz, 2H), 4.04 (dd, J=12.6, 5.0 Hz, 1H), 3.75 (d, J=17.2 Hz, 5H), 3.29 (s, 2H), 3.01 (d, J=10.9 Hz, 2H), 2.83-2.62 (m, 6H), 2.59-2.52 (m, 3H), 2.39 (m, 6H), 2.14 (d, J=6.8 Hz, 3H), 2.02 (d, J=14.4 Hz, 6H), 1.98-1.83 (m, 3H), 1.79-1.67 (m, 3H), 1.58 (dt, J=18.5, 4.8 Hz, 2H), 1.18-1.07 (m, 2H), 0.92 (t, J=7.1 Hz, 3H). [M/2+H]+=507.9.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.92 (s, 1H), 8.85 (dd, J=13.1, 11.5 Hz, 3H), 8.28 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.6 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.88 (t, J=7.4 Hz, 1H), 6.81 (s, 1H), 6.75 (dd, J=8.5, 2.4 Hz, 1H), 4.08 (t, J=7.8 Hz, 2H), 4.03-3.90 (m, 3H), 3.90-3.80 (m, 2H), 3.77 (s, 3H), 3.50 (s, 3H), 3.03 (d, J=10.8 Hz, 2H), 2.79 (dd, J=21.2, 9.2 Hz, 1H), 2.73-2.71 (m, 2H), 2.56 (d, J=3.9 Hz, 3H), 2.48-2.35 (m, 3H), 2.31-2.28 (m, 1H), 2.04-2.00 (m, 8H), 1.85 (d, J=10.3 Hz, 2H), 1.64-1.59 (m, 2H), 0.96-0.90 (m, 3H). [M+H]+=989.3.
To a solution of methyl (1r,3r)-3-aminocyclobutane-1-carboxylate hydrochloride (1.5 g, 9.09 mmol) in dioxane (30 mL) and water (15 mL) was added Na2CO3 (2.89 g, 27.3 mmol) and Boc2O (2.97 g, 13.6 mmol). The mixture was stirred at 20° C. for 13 hrs, the resulting mixture was extracted with EtOAc (70 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=1:1). Methyl (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate (1.7 g, 81.7%) was obtained. [M+H]+=230.1.
To a solution of methyl (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate (1.5 g, 6.52 mmol) in DMF (20 mL) was added NaH (522 mg, 13.04 mmol, 60%) at 0° C. The mixture was stirred at 20° C. for 1 hr, then Mel (1.39 g, 9.78 mmol) was added, the reaction was stirred at r.t for 3 hrs and then quenched by sat. NH4Cl solution (20 mL). The resulting mixture was extracted with EtOAc (40 mL×3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=1:1). Methyl (1r,3r)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1-carboxylate (1.4 g, 88%) was obtained. [M+H]+=244.2.
To a mixture of methyl (1r,3r)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1-carboxylate (1.4 g, 5.76 mmol) and HCl in dioxane (20 mL, 6N) was stirred at 25° C. for 5 hr, then the resulting mixture was concentrated in vacuum. Methyl (1r,3r)-3-(methylamino)cyclobutane-1-carboxylate hydrochloride (700 mg, 84.4%) was obtained. [M+H]+=144.2.
Under the atmosphere of nitrogen, 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (1 g, 2.25 mmol), methyl (1r,3r)-3-(methylamino)cyclobutane-1-carboxylate hydrochloride (603 mg, 3.37 mmol) and Cs2CO3 (2.93 g, 9 mmol) were added to 1,4-dioxane (50 mL). After pumping nitrogen three times, Pd2(dba)3 (211 mg, 0.23 mmol) and Xantphos (266 mg, 0.46 mmol) were added to the mixture, and then nitrogen was pumped for three times again, then temperature was raised to reflux. After 15h, the reaction was cooled to room temperature, water (30 mL) was added, extracted with DCM (3×50 mL). The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified with silica gel column (petroleum ether: ethyl acetate=3: 1) to obtain the product (500 mg, 43.7%). [M+H]+=509.2.
To a solution of methyl (1r,3r)-3-((3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)(methyl)amino)cyclobutane-1-carboxylate (500 mg, 0.98 mmol) in THF (10 mL) and H2O (2 mL) was added lithium hydroxide hydrate (118 mg, 4.91 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 12 h. The reaction was quenched with HCl (1 N) at 0° C. until pH=5 and extracted with DCM (2×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum to afford the crude product (480 mg, 99%), which was used for next step without further purification. [M+H]+=495.2.
To a solution of (1r,3r)-3-((3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)(methyl)amino)cyclobutane-1-carboxylic acid (370 mg, 0.74 mmol) in THF (10 mL) was added BH3 in THF (1M) (1.48 mL, 1.48 mmol), the resulting mixture was stirred at 25° C. for 16 h. The reaction was quenched by addition CH3OH (5 mL), the resulting solution was concentrated in vacuo. The residue was purified with silica gel column (petroleum ether: ethyl acetate=1: 1) to obtain the product (300 mg, 84.2%). [M+H]+=481.1.
To a solution of ((1r,3r)-3-((3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)(methyl)amino)cyclobutyl)methanol (300 mg, 0.62 mmol) in DCM (10 mL) and CH3OH (3 mL) was added Pd/C (150 mg, 10%), the resulting mixture was stirred at 25° C. for 16 h under H2 atmosphere. The catalyst was filtered off, the filtrate was concentrated in vacuo to obtain the product (160 mg, 85.1%). [M+H]+=303.2.
To a solution of 3-(3-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)(methyl)amino)phenyl)piperidine-2,6-dione (100 mg, 0.33 mmol) in DMSO (3 mL) was added IBX (139 mg, 0.5 mmol), water (5 mL) was added, extracted with DCM (3×20 mL). The combined organic phases were washed with sat. NaHCO3 solution (10 mL×3) and brine (15 mL), dried and concentrated. The residue was purified with prep-TLC (pure ethylacetate) to obtain the product (30 mg, 30.3%). [M+H]+=301.2.
The titled compound was prepared in a manner similar to that in Example 204 Step 6 from (1r,3r)-3-((3-(2,6-dioxopiperidin-3-yl)phenyl)(methyl)amino)cyclobutane-1-carbaldehyde and (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.80 (s, 1H), 8.85 (dt, J=23.4, 11.7 Hz, 3H), 8.34-8.19 (m, 3H), 7.90 (d, J=9.2 Hz, 1H), 7.37 (s, 1H), 7.11 (t, J=7.9 Hz, 1H), 6.81 (s, 1H), 6.65 (t, J=7.9 Hz, 1H), 6.60 (s, 1H), 6.52 (t, J=6.1 Hz, 1H), 3.91-3.68 (m, 5H), 3.01 (d, J=10.7 Hz, 3H), 2.78 (s, 1H), 2.75 (s, 2H), 2.72-2.69 (m, 2H), 2.65-2.59 (m, 2H), 2.54 (s, 1H), 2.45 (d, J=4.8 Hz, 2H), 2.41-2.23 (m, 8H), 2.19-2.09 (m, 3H), 2.08-1.95 (m, 8H), 1.85 (d, J=11.0 Hz, 2H), 1.64-1.60 (m, 4H), 0.95-0.90 (m, 3H). [M+H]+=978.4.
To a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (12.5 g, 32.9 mmol) and 5-bromo-2H-indazole (4.3 g, 21.9 mmol) in THF (100 mL) was added KOtBu in THF (1 M, 32.9 mL) at 0° C. Then the mixture was stirred at 20° C. for 48 hrs. Upon cooling with ice, the reaction was quenched by water (50.0 mL) and the resulting mixture was extracted with EtOAc (1000.0 mL). The combined organic phase was washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=2:1). 3-(5-bromo-2H-indazol-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (2 g, 21.3%) was obtained. [M+H]+=428.2.
To a mixture of 3-(5-bromo-2H-indazol-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1 g, 2.34 mmol), methyl piperidine-4-carboxylate (502 mg, 3.51 mmol), Ruphos Pd G3 (198 mg, 0.23 mmol), Cs2CO3 (1.53 g, 4.68 mmol) in toluene (15 mL) was stirred at 100° C. for 15 hrs. After cooling to r.t, the solid was filtered off, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE:EA=1:1) to afford product (520 mg, 45.3%). [M+H]+=491.3.
To a solution of methyl 1-(2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)piperidine-4-carboxylate (520 mg, 1.06 mmol) in THF (12 mL) and water (6 mL) was added LiOH (127 mg, 5.30 mmol). Then the mixture was stirred at 20° C. for 16 hrs. HCl (1N) was added to PH=5-6, the resulting mixture was extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum. 1-(2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)piperidine-4-carboxylic acid (490 mg, 97%) was obtained. [M+H]+=477.2.
To a mixture of 1-(2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)piperidine-4-carboxylic acid (490 mg, 1.03 mmol) in toluene (6 mL) was added MsOH (2 mL) was stirred at 80° C. for 15 hrs. After cooling to r.t, the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase column (CH3CN:H2O (FA)=30:100) to afford the desired product (100 mg, 27.3%). [M+H]+=357.1.
The titled compound (5 mg, 16%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 1-(2-(2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)piperidine-4-carboxylic acid. 1H NMR (500 MHz, DMSO) δ 12.58 (s, 1H), 11.06 (s, 1H), 8.78 (t, J=16.0 Hz, 3H), 8.21 (s, 2H), 8.12 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.40 (d, J=9.4 Hz, 1H), 7.31 (s, 1H), 7.09 (d, J=9.7 Hz, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.59-5.44 (m, 1H), 3.73 (d, J=27.0 Hz, 3H), 3.58-3.38 (m, 7H), 3.10 (d, J=4.9 Hz, 1H), 2.96 (d, J=10.3 Hz, 3H), 2.84-2.54 (m, 9H), 2.51 (s, 2H), 2.31-2.27 (m, 2H), 1.96-1.92 (m, 6H), 1.80 (d, J=10.9 Hz, 2H), 1.68 (s, 4H), 1.59-1.43 (m, 2H), 0.90-0.84 (m, 3H). [M+H]+=1032.4.
To a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (12.5 g, 32.9 mmol) and 5-bromo-2H-indazole (4.3 g, 21.9 mmol) in THF (100 mL) was added KOtBu in THF (1 M, 32.9 mL) at 0° C. Then the mixture was stirred at 20° C. for 48 hrs. Upon cooling with ice, the reaction was quenched by water (50.0 mL) and the resulting mixture was extracted with EtOAc (100.0 mL). The combined organic phase was washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=2:1). 3-(5-bromo-2H-indazol-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (2 g, 21.3%) was obtained. [M+H]+=428.2.
To a mixture of 3-(5-bromo-2H-indazol-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1 g, 2.33 mmol) in toluene (5 mL) was added MsOH (5 mL). Then the mixture was stirred at 100° C. for 16 hrs. Upon cooling with ice, the reaction was concentrated in vacuo. The residue was purified by silica gel column (PE:EA=1:2). 3-(5-bromo-2H-indazol-2-yl)piperidine-2,6-dione (520 mg, 72.5%) was obtained. [M+H]+=308.
To a mixture of 3-(5-bromo-2H-indazol-2-yl)piperidine-2,6-dione (520 mg, 1.69 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (436 mg, 2.2 mmol), Pd(dppf)Cl2 (124 mg, 0.17 mmol), CsF (514 mg, 3.38 mmol) in DMF (10 mL) and H2O (2 mL) was stirred at 100° C. under N2 atmosphere for 1 hr. After cooling to r.t, the reaction mixture was extracted with EtOAc (20.0 mL×3). The combined organic phase was washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=1:1). (E)-3-(5-(2-ethoxyvinyl)-2H-indazol-2-yl)piperidine-2,6-dione (460 mg, 91%) was obtained. [M+H]+=300.1.
To a solution of (E)-3-(5-(2-ethoxyvinyl)-2H-indazol-2-yl)piperidine-2,6-dione (460 mg, 1.54 mmol) in FA (5 mL) was stirred at 30° C. for 2 hrs. The reaction solution was concentrated in vacuum. 2-(2-(2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)acetaldehyde (400 mg, 96%) was obtained. [M+H]+=272.1.
The titled compound (12 mg, 23%) was prepared in a manner similar to that in Example 204 step 6 from 2-(2-(2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)acetaldehyde and (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. 1H NMR (500 MHz, DMSO) δ =12.68 (d, J=34.8, 1H), 11.16 (s, 1H), 8.86 (dt, J=18.9, 9.4, 3H), 8.33 (d, J=14.0, 1H), 8.27 (s, 2H), 7.90 (d, J=8.8, 1H), 7.61-7.43 (m, 2H), 7.38 (s, 1H), 7.16 (d, J=10.1, 1H), 6.96-6.65 (m, 1H), 5.68 (dd, J=11.4, 5.1, 1H), 3.84-3.69 (m, 3H), 3.01 (d, J=11.1, 2H), 2.92-2.63 (m, 8H), 2.63-2.52 (m, 7H), 2.47 (d, J=7.3, 3H), 2.35-2.30 (m, 3H), 2.02 (d, J=14.4, 6H), 1.85-1.81 (m, 2H), 1.69-1.43 (m, 2H), 0.93-0.87 (m, 3H). [M+H]+=949.3.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 10.76 (s, 1H), 8.85 (dt, J=20.1, 10.0 Hz, 3H), 8.27 (s, 2H), 7.90 (d, J=9.3 Hz, 1H), 7.38 (s, 1H), 7.02 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 6.81 (s, 1H), 3.77 (s, 3H), 3.71 (dd, J=10.9, 4.9 Hz, 1H), 3.41 (s, 2H), 3.10 (s, 2H), 3.01 (d, J=6.5 Hz, 4H), 2.78-2.57 (m, 5H), 2.54-2.52 (m, 1H), 2.49-2.41 (m, 3H), 2.32 (t, J=18.1 Hz, 4H), 2.21-2.07 (m, 2H), 2.06 (s, 3H), 2.04-2.00 (m, 1H), 1.99 (s, 3H), 1.96-1.86 (m, 2H), 1.85 (d, J=10.9 Hz, 2H), 1.67-1.46 (m, 8H), 0.92 (t, J=7.0 Hz, 3H). [M+H]+=1004.4.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.86 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J=14.2 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.48-7.28 (m, 2H), 6.73 (s, 1H), 6.60 (d, J=12.8 Hz, 2H), 4.04 (dd, J=12.6, 5.1 Hz, 1H), 3.76-3.72 (m, 6H), 2.93 (d, J=11.7 Hz, 2H), 2.83-2.68 (m, 3H), 2.66 (d, J=15.0 Hz, 6H), 2.54-2.51 (m, 2H), 2.42-2.19 (m, 9H), 2.07 (t, J=12.7 Hz, 1H), 1.98 (d, J=13.3 Hz, 8H), 1.83 (d, J=10.8 Hz, 2H), 1.71 (d, J=11.0 Hz, 2H), 1.61-1.44 (m, 3H), 1.38 (d, J=6.7 Hz, 2H), 1.23-1.19 (m, 2H), 0.80-0.76 (m, 3H). [M+H]+=1041.4.
To a solution of 2-chloro-6-nitroquinoline (5 g, 24.03 mmol) in EtOH (60 mL) and water (25 mL) was added Fe (powder, 6.73 g, 120 mmol) and NH4Cl (6.36 g, 120 mmol). The mixture was stirred at 70° C. for 3 hrs. After cooling to r.t, the solid was filtered off, the filtrate was extracted with DCM (70 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. 2-chloroquinolin-6-amine (4 g, 93%) was obtained. [M+H]+=179.2.
To a solution of 2-chloroquinolin-6-amine (4 g, 22.3 mmol) in HOAc (20 mL) was added ICl (4.24 g, 33.45 mmol). The mixture was stirred at 20° C. for 3 hrs and then sat. Na2CO3 solution was added to PH=8-9, the resulting mixture was extracted with EtOAc (70 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. 5-iodo-2-(trifluoromethyl)quinolin-6-amine (6.7 g, 88.6%) was obtained. [M+H]+=304.9.
To a mixture of 2-chloro-5-iodoquinolin-6-amine (6.5 g, 21.3 mmol), dimethyl phosphine oxide (2.43 g, 32 mmol), Pd(OAc)2 (477 mg, 2.13 mmol), Xantphos (2.46 g, 4.26 mmol), K3PO4 (9.03 g, 42.6 mmol) in dioxane (110 mL) was stirred at 100° C. under N2 atmosphere for 18 hrs. After cooling to r.t, the reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH=15:1). (6-amino-2-chloroquinolin-5-yl)dimethylphosphine oxide (5.1 g, 94%) was obtained. [M+H]+=255.
To a mixture of (6-amino-2-chloroquinolin-5-yl)dimethylphosphine oxide (1.1 g, 4.31 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.09 g, 6.47 mmol), Pd(dppf)Cl2 (314 mg, 0.43 mmol), Na2CO3 (914 mg, 8.62 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred at 100° C. under N2 atmosphere for 3 hrs. After cooling to r.t, the reaction mixture was extracted with EtOAc (20.0 mL×3). The combined organic phase was washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (DCM:CH3OH=15:1). (6-amino-2-(prop-1-en-2-yl)quinolin-5-yl)dimethylphosphine oxide (850 mg, 75.9%) was obtained. [M+H]+=261.1.
To a solution of (6-amino-2-(prop-1-en-2-yl)quinolin-5-yl)dimethylphosphine oxide (850 mg, 3.27 mmol) in CH3OH (10 mL) was added Pd/C (300 mg, 10%) under H2 atmosphere. The reaction mixture was concentrated in vacuum. (6-amino-2-isopropylquinolin-5-yl)dimethylphosphine oxide (800 mg, 93%) was obtained. [M+H]+=263.1.
The titled compound (610 mg, 51%) was prepared in a manner similar to that in Example 208 Step 6 from (6-amino-2-isopropylquinolin-5-yl)dimethylphosphine oxide and 5-bromo-2,4-dichloropyrimidine. [M+H]+=453.2.
The titled compound (210 mg, 34%) was prepared in a manner similar to that in Example 208 Step 7 from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-isopropylquinolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=735.3.
The titled compound (12 mg, 23%) was prepared in a manner similar to that in Example 204 Step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-isopropylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.82 (s, 1H), 10.86 (s, 1H), 8.54 (d, J=8.8 Hz, 1H), 8.23 (d, J=26.8 Hz, 3H), 8.03 (s, 1H), 7.86 (d, J=9.4 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.28 (s, 1H), 6.76 (s, 1H), 6.60 (d, J=12.9 Hz, 3H), 4.04 (dd, J=12.6, 4.9 Hz, 1H), 3.85-3.66 (m, 6H), 3.23-3.18 (m, 2H), 2.95 (d, J=10.7 Hz, 3H), 2.84-2.63 (m, 6H), 2.32-2.27 (m, 8H), 2.12-2.06 (m, 1H), 1.98 (s, 3H), 1.97 (s, 3H), 1.84 (d, J=11.7 Hz, 2H), 1.78-1.66 (m, 2H), 1.55-1.51 (m, 3H), 1.39 (s, 2H), 1.32 (s, 3H), 1.30 (s, 3H), 1.23-1.05 (m, 3H), 0.82-0.75 (m, 3H). [M+H]+=1069.4.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.95 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J=10.9 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.48-7.25 (m, 2H), 7.03 (d, J=10.1 Hz, 2H), 6.73 (s, 1H), 4.20 (dd, J=12.7, 5.0 Hz, 1H), 3.75 (s, 3H), 2.93 (d, J=10.7 Hz, 2H), 2.87-2.70 (m, 3H), 2.67-2.60 (m, 6H), 2.56-2.52 (m, 6H), 2.46-2.39 (m, 4H), 2.29 (s, 4H), 2.16-2.10 (m, 1H), 1.99, (s, 3H), 1.97 (s, 3H), 1.86-1.81 (m, 2H), 1.57-1.52 (m, 2H), 0.82-0.75 (m, 3H). [M+H]+=958.3.
The titled compound (310 mg, 45%) was prepared in a manner similar to that in Example 308 Step 2 from 3-(5-bromo-2H-indazol-2-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione and HCl salt of tert-butyl azetidine-3-carboxylate. [M+H]+=505.3.
To a mixture of tert-butyl 1-(2-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)azetidine-3-carboxylate (410 mg, 0.81 mmol) in toluene (6 mL) was added MsOH (2 mL) was stirred at 80° C. for 15 hrs. After cooling to r.t, the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase column (CH3CN:H2O(FA)=30:100). 1-(2-(2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)azetidine-3-carboxylic acid (90 mg, 34%) was obtained. [M+H]+=329.2.
The titled compound (12 mg, 14%) was prepared in a manner similar to that in Example 208 Step 8 from 1-(2-(2,6-dioxopiperidin-3-yl)-2H-indazol-5-yl)azetidine-3-carboxylic acid and (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. 1H NMR (500 MHz, DMSO) δ 12.58 (s, 1H), 11.06 (s, 1H), 8.79 (dt, J=20.8, 10.4 Hz, 3H), 8.19 (d, J=14.1 Hz, 2H), 8.05 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.31 (s, 1H), 6.75 (s, 1H), 6.65 (dd, J=9.2, 2.0 Hz, 1H), 6.44 (d, J=35.7 Hz, 1H), 5.54 (dd, J=11.5, 5.2 Hz, 1H), 3.96 (t, J=7.3 Hz, 2H), 3.78 (dt, J=14.3, 6.7 Hz, 3H), 3.71 (s, 3H), 3.43 (s, 2H), 3.29 (s, 2H), 2.96 (d, J=11.1 Hz, 3H), 2.82-2.74 (m, 1H), 2.70-2.54 (m, 5H), 2.52-2.46 (m, 2H), 2.37-2.15 (m, 4H), 1.97 (s, 3H), 1.94 (s, 3H), 1.79 (d, J=12.0 Hz, 2H), 1.53-1.49 (m, 2H), 0.92-0.83 (m, 3H). [M+H]+=1004.3.
The titled compound was prepared in a manner similar to that in Example 208. 1H NMR (500 MHz, DMSO) δ 11.81 (s, 1H), 10.95 (s, 1H), 8.55 (d, J=9.0 Hz, 1H), 8.22 (d, J=16.9 Hz, 2H), 8.03 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.29 (s, 1H), 7.03 (d, J=10.1 Hz, 2H), 6.76 (s, 1H), 4.38-3.91 (m, 1H), 3.76 (s, 3H), 3.29-3.27 (m, 2H), 3.20 (dt, J=13.7, 6.9 Hz, 2H), 2.98-2.93 (m, 2H), 2.87-2.73 (m, 3H), 2.72-2.63 (m, 3H), 2.58-2.52 (m, 5H), 2.47-2.40 (m, 2H), 2.28 (d, J=7.3 Hz, 3H), 2.17-2.12 (m, 1H), 2.08-2.02 (m, 1H), 2.00 (s, 3H), 1.98 (s, 3H), 1.86 (s, 2H), 1.64-1.48 (m, 2H), 1.33 (d, J=6.9 Hz, 6H), 0.82-0.74 (m, 3H). [M+H]+=986.4.
To a solution of 6-bromo-N1-methylbenzene-1,2-diamine (4 g, 19.9 mmol) in CH3CN (50 mL) was added CDI (6.4 g, 39.8 mmol). The resulting solution was stirred for 6 h at 90° C. under nitrogen atmosphere.
The solid was collected by filtration. This was resulted in 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.1 g, 90.7%). [M+H]+=227.0.
To a solution of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (600 mg, 2.6 mmol) in THF (10 mL) was added t-BuOK (1M in THF, 3.2 mL, 3.1 mmol) dropwise in 10 min at 0° C., the reaction solution was stirred for 30 min at this temperature, then to this was added 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.1 g, 2.9 mmol) in THF (5 mL) dropwise in 10 min. The resulting solution was stirred for 2 h at 0-10 degrees C. The reaction was quenched by the addition of sat.aq. NH4Cl solution, extracted with EtOAc (10 mL×3), combined the organic layer, and washed with brine, dried over anhydrous Na2SO4, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column, eluted with PE/EtOAc to afford product (910 mg, 75.2%). [M+H]+=458.1.
3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (800 mg, 1.75 mmol) was dissolved in MeSO2H/toluene(2 mL/6 mL). The resulting mixture was stirred for 3 h at 100° C. Solvent was removed and the residue was poured into ice/water. The solid was collected by filtration. 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione was obtained (510 mg, 86.4%). [M+H]+=338.1.
To a stirred solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (250 mg, 0.74 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (176 mg, 0.89 mmol) in DMF/H2O (8 mL/2 mL) were added Pd(dtbpf)Cl2 (48 mg, 0.074 mmol) and CsF (225 mg, 1.48 mmol). The resulting mixture was stirred for 2 h at 80° C. under nitrogen atmosphere. The reaction solution was diluted with water, extracted with EtOAc (10 mL×3). The organic layer was washed with water and brine, dried over anhydrous Na2SO4 which was evaporated to dryness. The residue was purified by a silica gel column, eluted with PE/EtOAc=1:1 to afford the product. (180 mg, 73.8%). m/z[M+H]+=330.2.
(E)-3-(4-(2-ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(180 mg, 0.55 mmol) was dissolved in HCOOH(2 mL). The resulting solution was stirred for 2 h at room temperature. The reaction solution was evaporated to dryness to afford product (125 mg, 75.3%) which was used directly in the next step. m/z[M+H]+=302.1.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.056 mmol), 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde (17 mg, 0.070 mmol) and NaBH(OAc)3 (24 mg, 0.11 mmol) in DCE (3 mL) was stirred in a round bottom flask at room temperature for 12 hours. The reaction was diluted with DCM, washed with brine (2×5 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product, which was purified with pre-HPLC (0.1% FA in water: acetonitrile=90:1˜50:50 gradient elution) to give the title product (12 mg, 28%). 1H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 11.03 (s, 1H), 8.78 (d, J=23.1 Hz, 3H), 8.20 (s, 2H), 7.85 (s, 1H), 7.32 (s, 1H), 6.68-7.07 (m, 4H), 5.32 (s, 1H), 3.70 (s, 4H), 3.52 (s, 5H), 2.78-3.11 (m, 8H), 2.60 (d, J=47.5 Hz, 8H), 2.25 (s, 2H), 1.76-2.09 (m, 10H), 1.53 (s, 2H), 0.86 (s, 3H). [M+H]+=979.4.
The titled compound (3.8 g, 43%) was synthesized in a manner similar to that in Example 434 step 1 from 6-bromo-3-fluoroquinoline. [M+H]+=327.1.
The titled compound (1.8 g, 63%) was synthesized in a manner similar to that in Example 434 step 2 from N-(3-fluoroquinolin-6-yl)-1,1-diphenylmethanimine. [M+H]+=163.2.
The titled compound (710 mg, 56%) was synthesized in a manner similar to that in Example 434 step 3 from 3-fluoroquinolin-6-amine. [M+H]+=289.3.
The titled compound (310 mg, 45%) was synthesized in a manner similar to that in Example 434 step 4 from 3-fluoro-5-iodoquinolin-6-amine. [M+H]1=239.1.
The titled compound (210 mg, 56%) was synthesized in a manner similar to that in Example 434 step 5 from (6-amino-3-fluoroquinolin-5-yl)dimethylphosphine oxide and 5-bromo-2,4-dichloropyrimidine. [M+H]+=429.2.
The titled compound (130 mg, 45%) was synthesized in a manner similar to that in Example 434 step 6 from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=711.3.
The titled compound (11 mg, 34%) was prepared in a manner similar to that in Example 204 Step 6 from 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde and (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoroquinolin-5-yl)dimethylphosphine oxide. 1H NMR (500 MHz, DMSO) δ 11.54 (s, 1H), 10.95 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.02 (d, J=9.2 Hz, 1H), 7.96 (s, 1H), 7.36 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.72 (s, 1H), 4.20 (dd, J=12.5, 5.1 Hz, 1H), 3.78 (d, J=20.1 Hz, 3H), 2.91 (d, J=10.6 Hz, 2H), 2.86-2.80 (m, 1H), 2.76 (dd, J=14.9, 7.3 Hz, 3H), 2.63 (t, J=11.0 Hz, 3H), 2.53 (d, J=7.5 Hz, 5H), 2.36 (s, 3H), 2.27 (d, J=11.2 Hz, 1H), 2.20 (s, 2H), 2.16-2.07 (m, 1H), 1.98 (d, J=13.4 Hz, 8H), 1.82 (d, J=10.7 Hz, 2H), 1.52 (dd, J=20.5, 11.4 Hz, 2H), 0.70 (s, 3H). [M+H]+=962.3.
To a solution of 3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione(30 mg, 0.313 mmol) and SeO2(5.22 mg, 0.047 mmol) in dioxane(2 mL), the mixture was stirred at 100° C. for 2 h. And then water (30 mL) was poured into the mixture. The reaction mixture was filtered and extracted with DCM (2×20 mL). The combined organic phase was washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by Prep-TLC (10% MeOH in DCM) to afford product (15 mg, 49.2%). [M+H]+=971.3.
A mixture of 6-((5-bromo-2-((4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)quinoline-2-carbaldehyde (30 mg, 0.313 mmol) and NaOH(25.2 mg, 0.626 mmol) in dioxane(2 mL) was stirred at 100° C. for 2 h. Water (30 mL) was poured into the mixture. The reaction mixture was filtered and extracted with DCM (2×20 mL). The combined organic phase was washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by Prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford product (3.2 mg, 31.25%). 1H NMR (500 MHz, DMSO) δ 11.82 (s, 1H), 10.88 (s, 1H), 8.58 (d, J=8.9 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.31 (s, 1H), 6.96 (d, J=10.0 Hz, 2H), 6.67 (s, 1H), 5.52 (s, 1H), 4.64 (s, 2H), 4.13 (dd, J=12.6, 5.0 Hz, 1H), 3.69 (d, J=5.7 Hz, 4H), 2.87 (d, J=10.9 Hz, 3H), 2.80-2.64 (m, 4H), 2.58 (dd, J=14.7, 7.4 Hz, 3H), 2.54-2.46 (m, 6H), 2.30-2.19 (m, 4H), 2.11-2.00 (m, 2H), 1.93 (t, J=12.6 Hz, 8H), 1.77 (d, J=10.6 Hz, 2H), 1.47 (dd, J=20.2, 11.5 Hz, 2H), 0.71 (s, 3H). [M+H]+=974.2.
To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (30.0 g, 81.0 mmol) and diphenylmethanimine (17.6 g, 97.2 mmol) in dry 1,4-dioxane (400 mL), was added Cs2CO3 (52.8 g, 162 mmol) at room temperature. BINAP (5.0 g, 8.1 mmol) and Pd2(dba)3 (7.4 g, 8.1 mmol) were added to the mixture at room temperature. The suspension was degassed under vacuum and purged with N2 three times. Then the mixture was stirred at 100° C. overnight. After cooling to room temperature, the mixture was filtered through a pad of celite, the filtrate was collected and concentrated to afford the residue which was purified by column chromatography (0-5% EA in PE). N-(2,6-bis(benzyloxy)pyridin-3-yl)-1,1-diphenylmethanimine (25.0 g, 65.6%) was obtained. [M+H]+=471.2.
To a stirred solution of N-(2,6-bis(benzyloxy)pyridin-3-yl)-1,1-diphenylmethanimine (25.0 g, 53.1 mmol) in THF (200 mL), was added 1N HCl (200 mL) at room temperature. The suspension was stirred at room temperature for 16h, following by rotary evaporation in vacuum to remove the organic solvent. The solid precipitated out during evaporation was collected by filtration, then triturated with PE/EA (200 mL, 10/1) twice, and dried under vacuum to afford product (14.0 g, 76.9%). [M+H]+=307.2.
Into a stirred mixture of 2,6-bis(benzyloxy)pyridin-3-aminium chloride (14.0 g, 40.8 mmol) and 2-(2,5-dibromophenyl)-2-methylpropanoic acid (13.1 g, 40.8 mmol) in dry MeCN (200 mL) under N2 atmosphere, was added 1-methyl-1H-imidazole (16.8 g, 204 mmol) via a syringe. The mixture was stirred at room temperature for 10 minutes, then a solution of TCFH (13.8 g, 49.1 mmol) in dry MeCN (50 mL) was added into the mixture via a syringe. The mixture was stirred at 50° C. under N2 atmosphere for 4 hrs. After cooling to room temperature, the reaction was quenched by addition of water (2 mL), then the mixture was concentrated in vacuum by an evaporator to afford the residue which was purified by column chromatography (5% EA in PE) to afford product (15.0 g, 60.2%). [M+H]+=611.2.
To a stirred mixture of N-(2,6-bis(benzyloxy)pyridin-3-yl)-2-(2,5-dibromophenyl)-2-methylpropanamide (10.0 g, 16.4 mmol) and K2CO3 (11.3 g, 81.9 mmol) in NMP (150 mL), was added CuCl (1.62 g, 16.4 mmol). The suspension was degassed under vacuum and purged with N2 three times. Pentane-2,4-dione (3.28 g, 32.8 mmol) was added into the mixture via syringe. The suspension was stirred at 85° C. under N2 atmosphere for 2 hrs. After cooling to room temperature, the mixture was poured into EA (500 mL), and washed with brine (200 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (7% EA in PE) to afford product (6.0 g, 69.2%). [M+H]+=529.2.
A mixture of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3,3-dimethylindolin-2-one (1.0 g, 1.889 mmol) and ethyl azetidine-3-carboxylate hydrochloride (375.4 mg, 2.267 mmol), Cs2CO3 (2.5 g, 7.556 mmol), RuPhos (88.1 mg, 0.189 mmol), Pd2(dba)3 (173.0 mg, 0.189 mmol) in dioxane (20 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1). Ethyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)azetidine-3-carboxylate (290.0 mg, 26.5%) was obtained. [M+H]+=578.3.
A mixture of ethyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)azetidine-3-carboxylate (290.0 mg, 0.502 mmol) and NaOH (180.7 mg, 4.518 mmol) in MeOH (40 mL), THF (8 mL) and H2O (8 mL) was stirred overnight at room temperature. The mixture was acidified to pH<7 with 2N HCl (aq.). The resulting mixture was extracted with EtOAc (300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)azetidine-3-carboxylic acid (270.0 mg, 97.8%) was obtained. [M+H]+=550.2.
A mixture of 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)azetidine-3-carboxylic acid (270.0 mg, 0.491 mmol) and Pd/C (200.0 mg, 1.879 mmol) in EtOH (10 mL) and DCM (2 mL) was stirred overnight at 50° C. under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH (150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (pure EtOAc with 0.5% TFA). 1-[1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindol-5-yl]azetidine-3-carboxylic acid (84.4 mg, 46.2%) was obtained. [M+H]+=372.2.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide(50 mg, 0.0708 mmol), HATU (41 mg, 0.106 mmol) and 1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)azetidine-3-carboxylic acid (32 mg, 0.085 mmol) in DMF (2 mL) was added DIEA (18.2 mg 0.142 mmol) at 0° C. Then the mixture was stirred at RT for 5 h. Water (10 mL) was poured into the mixture. The reaction mixture was extracted with DCM (2×20 mL). The combined organic phase was washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by Prep-HPLC with C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford the product (21 mg, 28.03%). 1H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 10.96 (s, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J=11.5 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 6.77-6.66 (m, 2H), 6.53 (d, J=2.2 Hz, 1H), 6.22 (dd, J=8.4, 2.1 Hz, 1H), 5.07 (s, 1H), 3.93 (dd, J=17.5, 10.2 Hz, 2H), 3.82-3.72 (m, 3H), 3.70 (d, J=9.5 Hz, 3H), 3.42 (s, 3H), 2.88 (d, J=10.6 Hz, 2H), 2.83-2.70 (m, 1H), 2.68-2.56 (m, 6H), 2.55-2.47 (m, 5H), 2.31 (dd, J=15.5, 6.5 Hz, 1H), 2.23 (d, J=7.0 Hz, 2H), 1.93 (t, J=12.4 Hz, 6H), 1.85 (d, J=5.0 Hz, 1H), 1.76 (d, J=10.7 Hz, 2H), 1.50 (dd, J=20.3, 11.6 Hz, 2H), 1.20 (d, J=3.3 Hz, 6H), 0.75 (m, 3H).[M+H]+=1060.1.
The titled compound was prepared in a manner similar to that in Example 409. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 11.04 (s, 1H), 8.86 (dd, J=8.9, 1.8 Hz, 2H), 8.82 (s, 1H), 8.27 (s, 2H), 7.90 (d, J=9.1 Hz, 1H), 7.38 (s, 1H), 7.10 (d, J=1.9 Hz, 1H), 6.78 (dd, J=21.0, 10.4 Hz, 3H), 5.16 (s, 1H), 3.77 (s, 3H), 3.60-3.53 (m, 4H), 3.49 (d, J=11.4 Hz, 2H), 3.30 (s, 2H), 3.03 (d, J=9.6 Hz, 2H), 2.85 (d, J=12.8 Hz, 1H), 2.74-2.68 (m, 5H), 2.62-2.57 (m, 3H), 2.48-2.46 (m, 3H), 2.02 (d, J=14.4 Hz, 7H), 1.93-1.90 (m, 1H), 1.85 (s, 2H), 1.71 (s, 4H), 1.64-1.59 (m, 2H), 1.28 (d, J=3.1 Hz, 6H), 0.93 (t, J=6.9 Hz, 3H); [M+H]+=1075.7.
A 50 mL three-neck round bottom flask equipped with a magnetic stirrer were charged with 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3,3-dimethylindolin-2-one (1.00 g, 1.89 mmol), ((3-iodocyclobutoxy)methyl)benzene (815 mg, 2.83 mmol), NiI2 (118 mg, 0.38 mmol), picolinimidamide (46 mg, 0.38 mmol), NaI (142 mg, 0.95 mmol), Mn (325 mesh, 312 mg, 5.67 mmol) and DMA (20 mL). The resulting mixture was degassed under vacuum and purged with N2 three times. Into this stirred mixture, a solution of TFA (70 μL, 0.95 mmol) in DMA (1 mL) was added dropwise by a syringe. The suspension was stirred at 100° C. for 3 hrs. After cooled to room temperature, the suspension was poured into EA (200 mL), then washed with brine (100 mL), water (3×100 mL) and brine (100 mL) in turn, dried over anhydrous Na2SO4, concentrated in vacuum. The residue was purified by prep TLC (PE/EA=1:1) to afford the product (450 mg, 39.0%). [M+H]+=611.5.
A 50 mL round bottom flask equipped with a magnetic stirrer were charged with 5-(3-(benzyloxy)cyclobutyl)-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethylindolin-2-one (430 mg, 0.70 mmol), Pd/C (10 wt %, 400 mg), EtOH (20 mL) and AcOH (200 μL). The suspension was degassed under vacuum and purged with H2 five times by a H2 balloon. The mixture was stirred at 50° C. for 2 days. After cooling to room temperature, the mixture was poured into a mixture of DCM (30 mL) and EtOH (10 mL), and filtered through a pad of celite. The filtrate was collected and concentrated in vacuum, the residue was dissolved in DCM (20 mL), re-concentrated and dried in vacuum to afford the product (270 mg, 112%), which is used directly for next step without further purification. [M+H]+=343.1.
A25 mL round bottom flask equipped with a magnetic stirrer was charged with 3-(5-(3-hydroxycyclobutyl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione (260 mg, 0.76 mmol), DCM (4.5 mL), dry THF (1.5 mL) and NaHCO3 (638 mg,). To this suspension, Dess-martin periodinane (419 mg, 099 mmol) was added portionwise. The mixture was stirred at room temperature for 2 hrs and then poured into a mixture of DCM (50 mL) and dry THF (50 mL). The mixture was filtered through a pad of celite, the filtrate was collected and concentrated in vacuum. The residue was purified by prep TLC (pure EA) to give the crude product, which is further purified by trituration with PE. 3-(3,3-dimethyl-2-oxo-5-(3-oxocyclobutyl) indolin-1-yl)piperidine-2,6-dione was obtained (140 mg, 54.1%). [M+H]+=341.2.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (40 mg, 0.058 mmol), 3-(3,3-dimethyl-2-oxo-5-(3-oxocyclobutyl) indolin-1-yl)piperidine-2,6-dione(17 mg, 0.070 mmol) and Ti(iPrO)4 (2 drops) in DCE(3 mL) was added NaBH(OAc)3 (11 mg, 0.17 mmol). The resulting solution was stirred at room temperature for 12 hours. The reaction was diluted with DCM, washed with brine (2×5 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product, which was purified with pre-HPLC (0.1% FA in water: acetonitrile=90:1˜50:50 gradient elution) to give the title product (12 mg, 28%). 1H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.99 (s, 1H), 8.77 (d, J=22.4 Hz, 3H), 8.27 (d, J=69.5 Hz, 3H), 7.83 (s, 1H), 7.25 (d, J=56.7 Hz, 2H), 7.04 (d, J=43.6 Hz, 1H), 6.75 (t, J=32.0 Hz, 2H), 5.13 (s, 1H), 3.65 (s, 3H), 2.90-3.06 (m, 7H), 2.48-2.64 (m, 7H), 2.18-2.35 (m, 6H), 1.69-1.97 (m, 12H), 1.46-1.57 (m, 2H), 1.23 (s, 6H), 0.86 (s, 3H). [M+H]+=1018.4.
To a stirred solution of 1-tert-butyl 3-methyl propanedioate (30.88 g, 177.275 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (32.50 g, 147.729 mmol) in DMF (200.00 mL) was added Cs2CO3 (96.27 g, 295.459 mmol) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 70° C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×500 mL). The solution was acidified to pH 7-8 with HCl (aq., 1 M). The resulting mixture was diluted with water (1.5 L). The resulting solution was extracted with EA (3×1000 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (40:1) to afford product (47.1 g, 85.21%).[M+H]+=373.9
To a stirred solution of 1-(tert-butyl) 3-methyl 2-(4-bromo-2-nitrophenyl)malonate (46.10 g, 123.200 mmol) in toluene (200.00 mL) was added TsOH·H2O (11.72 g, 61.600 mmol) at 110° C. under nitrogen atmosphere for 16 h. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with aqueous NaHCO3 (3×100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1˜ 30% EtOAc in PE to afford product (26.5 g, 78.48%). [M+H]+=273.9
To a stirred solution of methyl 2-(4-bromo-2-nitrophenyl)acetate (12.00 g, 43.784 mmol) in ACN (240.00 mL) was added Cs2CO3 (28.53 g, 87.569 mmol) at 0° C. under nitrogen atmosphere at ambient temperature. To the mixture was added CH3I (31.07 g, 218.922 mmol) dropwise over 20 min. The resulting mixture was stirred for 16 h at 80° C. After cooling down to ambient temperature, the resulting mixture was filtered, and the filtrate was washed with EtOAc (3×200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1˜ 40% EtOAc in PE to afford product (5.6 g, 42.33%). [M+H]+=301.9.
To a stirred solution of methyl 2-(4-bromo-2-nitrophenyl)-2-methylpropanoate (5.50 g, 10.923 mmol) in AcOH (50.00 mL) was added Fe (2.44 g, 43.692 mmol) at room temperature. The resulting mixture was stirred for 2 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10˜ 50% EtOAc in PE to afford product (1.95 g, 74.36%). [M+H]+=239.9.
To a stirred mixture of 6-bromo-3,3-dimethylindolin-2-one (1.80 g, 7.497 mmol) in THF (160.00 mL) was added t-BuOK (0.93 g, 8.247 mmol) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the mixture was added 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (This intermediate was prepared according the same manner described in WO 2020113233A1) (3.14 g, 8.247 mmol) in THF (20 mL) at 0° C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with sat. aq. NH4Cl (30 mL) at 0° C. and diluted with water (1 L). The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford product (2.6 g, 73.58%). [M+H]+=471.1.
A solution of 3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (2.60 g, 5.516 mmol) and CH3SO3H (10.60 g, 110.321 mmol) in Toluene (260.00 mL) was stirred for 2 h at 110° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (400 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1˜ 50% EtOAc in PE to afford 3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione (1.4 g, 72.27%). [M+H]+=351.05.
To a stirred solution of 3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione (800.00 mg, 2.278 mmol) and tributyl(prop-2-en-1-yl)stannane (1131.39 mg, 3.417 mmol) in DMF (50.00 mL) was added Pd(PPh3)2Cl2 (239.83 mg, 0.342 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 105° C. under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1˜ 40% EtOAc in petroleum ether to afford product (500 mg, 70.27%). [M+H]+=313.20
To a stirred solution of 3-(6-allyl-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione (500.00 mg, 1.601 mmol) in dioxane (60.00 mL) and water (12.00 mL) were added K2OsO4·2H2O (88.47 mg, 0.240 mmol) and NaIO4 (1369.48 mg, 6.403 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, ACN in water (0.1% FA), 10% to 50% gradient in 10 min; Detector, UV 220 nm; to afford product (300.1 mg, 59.64%). [M+H]+=315.20.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide(50.0 mg, 0.071 mmol), 2-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-6-yl)acetaldehyde (22.2 mg, 0.071 mmol) and AcOH (0.1 mL) in a mixture of DCM (4 mL) and MeOH (4 mL) was stirred at rt for 2 h. Then NaBH(OAc)3 (111 mg, 0.425 mmol) was added to the mixture. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with water (50 mL), extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Anal Column: SunFire PrepC18 OBD, 5 μm, 19×150 mm, Column Temp: Room temperature, Mobile Phase A: H2O (0.1% FA), Mobile Phase B: ACN, Gradient Table: Mobile Phase B (15-35%), Time (min):0-17 min to afford the product (10.8 mg, 15.2%). 1H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 11.06 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (m, 1H), 8.20 (d, J=13.1 Hz, 3H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.18 (t, J=7.9 Hz, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.80-6.87 (m, 1H), 6.74 (s, 1H), 5.22 (s, 1H), 3.77 (d, J=12.0 Hz, 3H), 3.00-2.75 (m, 6H), 2.72-2.52 (m, 15H), 2.30-2.60 (m, 3H), 1.98 (d, J=13.3 Hz, 8H), 1.84 (d, J=11.2 Hz, 2H), 1.45-1.59 (m, 2H), 1.38 (d, J=4.2 Hz, 7H), 0.78 (s, 3H). [M+H]+=1004.4.
To a solution of 2-chloro-6-nitroquinoline (5 g, 24.03 mmol) in EtOH (60 mL) and water (25 mL) was added iron powder (6.73 g, 120 mmol) and NH4Cl (6.36 g, 120 mmol). The mixture was stirred at 70° C. for 3 hrs. After cooling to r.t, the solid was filtered off, the filtrate was extracted with DCM (70 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. 2-chloroquinolin-6-amine (4 g, 93%) was obtained. [M+H]+=179.1.
To a solution of 2-chloroquinolin-6-amine (4 g, 22.3 mmol) in HOAc (20 mL) was added ICl (4.24 g, 33.45 mmol). The mixture was stirred at 20° C. for 3 hrs and then sat. aq. Na2CO3 solution was added to PH=8-9, the resulting mixture was extracted with EtOAc (70 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. 5-iodo-2-(trifluoromethyl)quinolin-6-amine (6.7 g, 88.6%) was obtained. [M+H]+=304.9.
To a mixture of 2-chloro-5-iodoquinolin-6-amine (6.5 g, 21.3 mmol), dimethylphosphine oxide (2.43 g, 32 mmol), Pd(OAc)2 (477 mg, 2.13 mmol), Xantphos (2.46 g, 4.26 mmol), K3PO4 (9.03 g, 42.6 mmol) in dioxane (110 mL) was stirred at 100° C. under N2 atmosphere for 18 hrs. After cooling to r.t, the reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH=15:1). (6-amino-2-chloroquinolin-5-yl)dimethylphosphine oxide (5.1 g, 94%) was obtained. [M+H]+=255.
To a solution of (6-amino-2-chloroquinolin-5-yl)dimethylphosphine oxide (2.0 g, 7.9 mmol), cyclopropylboronic acid (2.04 g, 23.7 mmol), Pd(dppf)Cl2 (0.58 g, 0.79 mmol) and Na2CO3 (1.7 g, 15.8 mmol) in a mixture of dioxane (20 mL) and H2O (4 mL) was stirred at 100° C. for overnight. The mixture was concentrated in vacuum. The residue was purified by column chromatography to afford product (380 mg, 19.0%). [M+H]+=261.1.
The titled compound (550 mg, 86%) was prepared in a manner similar to that in Example 200 step 13 from (6-amino-2-cyclopropylquinolin-5-yl)dimethylphosphine oxid and 5-bromo-2,4-dichloropyrimidine. [M+H]+=451.0.
The titled compound (550 mg, 86%) was prepared in a manner similar to that in Example 200 step 14 from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=733.3.
The titled compound was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide and (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)methyl methanesulfonate (this material was obtained through the similar method of example 237). 1H NMR (500 MHz, DMSO) δ 11.75 (s, 1H), 10.93 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.19 (s, 2H), 8.03 (s, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.28 (s, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 5.03 (dd, J=13.2, 5.1 Hz, 1H), 4.30 (d, J=16.9 Hz, 1H), 4.17 (d, J=16.9 Hz, 1H), 4.02 (t, J=7.0 Hz, 2H), 3.75 (s, 3H), 3.55 (s, 2H), 3.27-3.20 (m, 2H), 3.01-2.84 (m, 4H), 2.67 (t, J=11.0 Hz, 2H), 2.62-2.52 (m, 6H), 2.44-2.24 (m, 8H), 1.96 (t, J=11.1 Hz, 7H), 1.86 (d, J=10.9 Hz, 2H), 1.59-1.48 (m, 2H), 1.07 (d, J=6.3 Hz, 4H), 0.78 (s, 3H). [M+H]+=1044.4
The titled compound was prepared in a manner similar to that in Example 426. 1H NMR (500 MHz, DMSO) δ 11.75 (s, 1H), 10.95 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.22 (d, J=24.3 Hz, 2H), 8.03 (s, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.75 (s, 1H), 4.20 (dd, J=12.6, 5.1 Hz, 1H), 3.75 (s, 3H), 3.28-3.21 (m, 2H), 2.95 (d, J=11.0 Hz, 2H), 2.86-2.73 (m, 3H), 2.67 (t, J=11.0 Hz, 2H), 2.53 (d, J=6.6 Hz, 5H), 2.49-2.39 (m, 4H), 2.28 (dd, J=12.7, 6.3 Hz, 4H), 2.18-2.07 (m, 1H), 2.04-1.92 (m, 7H), 1.86 (d, J=11.0 Hz, 2H), 1.55 (dd, J=20.2, 11.3 Hz, 2H), 1.06 (d, J=6.4 Hz, 4H), 0.78 (s, 3H). [M+H]+=984.3.
To a stirred mixture of 6-bromoisoquinolin-1(2H)-one (5.00 g, 22.3 mmol), tetrabutylammonium bromide (1.08 g, 3.35 mmol) and iodomethane (1.67 mL, 26.8 mmol) in toluene (300 mL), was added aqueous NaOH solution (50 wt %, 50 mL). The resulting mixture was stirred vigorously at ambient temperature. After 14 hrs, the mixture was diluted with ethyl ether (500 mL) and washed with water, saturated NaHCO3, and brine in turn. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuum to give product (4.20 g, 79.1%). [M+H]+=238.1.
A high-pressure reactor equipped with a magnetic stirrer, was charged with 6-bromo-2-methylisoquinolin-1(2H)-one (4.10 g, 17.2 mmol), copper (powder, 1.31 g, 20.7 mmol), ammonium hydroxide (10 mL) and isopropanol (10 mL). The resulting suspension was stirred at 100° C. for 21 hrs. After cooling to room temperature, the mixture was concentrated in vacuum and purified by column chromatography (0-5% MeOH in DCM) to afford product (2.50 g, 83.4%). [M+H]+=175.2.
To a stirred solution of 6-amino-2-methylisoquinolin-1(2H)-one (2.40 g, 13.8 mmol) in AcOH (40 mL), was added a solution of ICl (2.70 g, 16.6 mmol) in AcOH (10 mL) dropwise at room temperature. After being stirred 2 hrs, the reaction mixture was concentrated in vacuum to afford the residue which was purified by column chromatography (DCM/MeOH) to afford product (3.00 g, 72.4%). [M+H]+=301.2.
A mixture of 6-amino-5-iodo-2-methylisoquinolin-1(2H)-one (2.20 g, 7.33 mmol), dimethylphosphine oxide (859 mg, 11.00 mmol), K3PO4 (3.11 g, 14.7 mmol), XANTPHOS (424 mg, 0.73 mmol), Pd(OAc)2 (165 mg, 0.73 mmol), DMF (25 mL) and water (5 mL) was stirred at room temperature. The suspension was degassed under vacuum and purged with N2 three times, then stirred at 120° C. for 1 hr. After cooling to room temperature, the mixture was concentrated in vacuum, the residue was purified by column chromatography (0-10% MeOH in DCM) to afford the product (1.45 g, 79.1%). [M+H]+=251.2.
To a stirred solution of 6-amino-5-(dimethylphosphoryl)-2-methylisoquinolin-1(2H)-one (300 mg, 1.2 mmol) and 5-bromo-2,4-dichloropyrimidine (542 mg, 2.4 mmol) in DMF (10 mL) was added NaH (96 mg, 2.4 mmol) at 0° C. The resulting mixture was stirred at rt for 2 hours. The reaction was extracted with DCM (2×10.0 mL). The combined organic layer was washed with brine (2×10.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM:MeOH=10:1) to give the title product (300 mg, 57%). [M+H]+=441.6.
To a stirred solution of 6-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-2-methylisoquinolin-1(2H)-one (300 mg 0.57 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (286 mg, 0.68 mmol) in t-BuOH (10 mL) was added MsOH (218 mg, 2.28 mmol). The resulting mixture was stirred at 95° C. for 16 hours. The reaction was extracted with DCM (2×20.0 mL). The combined organic layer was washed with brine (2×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=8:1) to give the title product (300 mg, 73%). [M+H]+=723.6.
The titled compound was synthesized in the procedures similar to Example 200; 1H NMR (500 MHz, DMSO) δ 12.43 (s, 1H), 10.95 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=4.4 Hz, 1H), 8.16 (dd, J=14.2, 8.9 Hz, 2H), 7.46 (d, J=7.9 Hz, 1H), 7.38 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.76 (s, 1H), 6.63 (d, J=7.8 Hz, 1H), 4.20 (dd, J=12.6, 5.0 Hz, 1H), 3.75 (s, 3H), 3.50 (s, 3H), 3.01 (d, J=10.9 Hz, 2H), 2.83-2.65 (m, 6H), 2.54 (t, J=7.5 Hz, 7H), 2.49-2.43 (m, 4H), 2.38-2.30 (m, 1H), 2.14-2.10 (m, 1H), 1.97 (dd, J=13.2, 7.9 Hz, 8H), 1.86 (d, J=10.7 Hz, 2H), 1.63-1.52 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); [M+H]+=974.4.
To a stirred mixture of 6-bromophthalazin-1(2H)-one (5 g, 22.2 mmol) and NaH (1.1 g, 60% wt, 27.5 mmol) in DMF (50 mL), was added methyl iodide (2.1 mL, 33.3 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred for 3 days at room temperature under nitrogen atmosphere. The reaction was quenched with sat. aq. NH4Cl solution and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH, 0-5%) to afford product (4.6 g, 86.6%). [M+H]+=239.1.
A high pressure reactor equipped with a magnetic stirrer, was charged with 6-bromo-2-methylphthalazin-1(2H)-one (4.50 g, 18.8 mmol), copper (powder, 1.20 g, 18.8 mmol) and NH4OH (11.0 m1, 312.5 mmol) in isopropanol (20 mL). The resulting suspension was stirred overnight at 100° C. After cooling to room temperature, the mixture was concentrated in vacuum and purified by column chromatography (DCM/MeOH, 0-5%) to afford the product (2.3 g, 69.7%). [M+H]+=176.2.
To a stirred solution of 6-amino-2-methylphthalazin-1(2H)-one (2.20 g, 12.6 mmol) in AcOH (40 mL), was added a solution of iodine monochloride (2.45 g, 15.1 mmol) in AcOH (10 mL) dropwise at room temperature.
The reaction mixture was stirred at rt for 2 h and concentrated in vacuum to afford the residue which was purified by column chromatography (DCM/MeOH, 0-5%) to provide product (3.00 g, 72.4%) [M+H]+=302.2.
A mixture of 6-amino-5-iodo-2-methylphthalazin-1(2H)-one (2.0 g, 6.6 mmol), dimethylphosphineoxide (622.1 mg, 7.9 mmol), K3PO4 (2.1 g, 9.9 mmol), Pd(OAc)2 (149.1 mg, 0.6 mmol) and XantPhos (384.3 mg, 0.6 mmol) in DMF (20 mL) and H2O (4 mL) was stirred for 2 h at 120° C. under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuum, the residue was purified by column chromatography (DCM/MeOH, 0-10%) to afford the product (1.07 g, 64.12%). [M+H]+=252.2.
To a stirred solution of 6-amino-5-(dimethylphosphoryl)-2-methylphthalazin-1(2H)-one (500 mg, 2.0 mmol) and 5-bromo-2,4-dichloropyrimidine (912 mg, 4.0 mmol) in DMF (10 mL) was added NaH (96 mg, 2.4 mmol) at 0° C. The resulting mixture was stirred at rt for 2 hours. The reaction was extracted with DCM (2×10.0 mL). The combined organic layer was washed with brine (2×10.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=10:1) to give the product (600 mg, 68%). [M+H]+=442.6.
To a stirred solution of 6-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-2-methylphthalazin-1(2H)-one (100 mg, 0.23 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (147 mg, 0.35 mmol) in t-BuOH (10 mL) was added MsOH (88 mg, 0.92 mmol). The resulting mixture was stirred at 95° C. for 16 hours. Water (20 mL) was poured into the mixture. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 solution and extracted with DCM (2×20.0 mL). The combined organic layer was washed with brine (2×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=8:1) to give the title product (100 mg, 63%). [M+H]+=724.6.
The titled compound (8 mg, 30%) was prepared in a manner similar to that in Example 204 step 6 from 6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-2-methylphthalazin-1(2H)-one and 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.21 (s, 1H), 10.94 (s, 1H), 8.57 (s, 1H), 8.20 (t, J=18.3 Hz, 3H), 7.31 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.75 (s, 1H), 4.23-4.17 (m, 1H), 3.73 (d, J=16.1 Hz, 6H), 2.98 (s, 2H), 2.85-2.62 (m, 7H), 2.54 (d, J=7.3 Hz, 8H), 2.33 (d, J=27.0 Hz, 4H), 2.02 (d, J=12.2 Hz, 9H), 1.85 (d, J=11.0 Hz, 2H), 1.56 (d, J=10.0 Hz, 2H), 0.92 (s, 3H); [M+H]+=975.4.
Into a 250 mL round-bottom flask were added 6-nitro-3H-quinazolin-4-one (10.0 g, 52.31 mmol) and Cs2CO3 (25.57 g, 78.44 mmol) in dimethylformamide (150 mL) at room temperature. CH3I (11.14 g, 78.45 mmol) was added in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (350 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (9 g, 83.85%). [M+H]+=206.2.
Into a 250 mL round-bottom flask were added 3-methyl-6-nitroquinazolin-4-one (5.0 g, 24.37 mmol) and Pd/C (3.0 g, 10% wt) in MeOH (150 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was diluted with MeOH (100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (3.2 g, 74.95%). [M+H]+=176.2.
Into a 250 mL round-bottom flask were added 6-amino-3-methylquinazolin-4-one (3.0 g, 17.12 mmol) and AcOH (50 mL) at room temperature. ICl (3.06 g, 18.88 mmol) was added in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was extracted with EtOAc (250 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford the product (1.5 g, 29.09%). [M+H]+=302.2.
A mixture of 6-amino-5-iodo-3-methylquinazolin-4-one (1.5 g, 4.98 mmol), dimethylphosphine oxide (0.58 g, 7.44 mmol), Pd(OAc)2 (0.11 g, 0.49 mmol), XantPhos (0.29 g, 0.50 mmol), K3PO4 (1.59 g, 7.54 mmol) in DMF (15 mL) and H2O (3.0 mL) was stirred at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at 120° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC PE/EtOAc (1:1) to afford the product (659.8 mg, 52.72%). [M+H]+=252.2.
The titled compound (450 mg, 89%) was prepared in a manner similar to that in Example 431 step 4 from 6-amino-5-(dimethylphosphoryl)-3-methylquinazolin-4-one and 5-bromo-2,4-dichloropyrimidine. [M+H]+=442.0.
The titled compound (230 mg, 45%) was prepared in a manner similar to that in Example 431 step 5 from 6-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-3-methylquinazolin-4(3H)-one and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=724.2
The titled compound (11 mg, 16%) was prepared in a manner similar to that in Example 204 step 6 from 6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-3-methylquinazolin-4(3H)-one and 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 13.04 (s, 1H), 10.95 (s, 1H), 8.46 (d, J=6.7 Hz, 1H), 8.39 (s, 1H), 8.20 (d, J=1.1 Hz, 1H), 7.96 (s, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.43 (s, 1H), 7.03 (d, J=10.3 Hz, 2H), 6.75 (s, 1H), 4.20 (dd, J=12.6, 4.8 Hz, 1H), 3.76 (s, 3H), 3.49 (s, 3H), 3.29 (s, 2H), 2.97 (d, J=11.3 Hz, 2H), 2.87-2.74 (m, 3H), 2.64 (dd, J=41.0, 29.5 Hz, 8H), 2.41 (dd, J=24.2, 16.9 Hz, 6H), 2.13 (dt, J=22.6, 11.2 Hz, 1H), 2.00 (d, J=14.5 Hz, 7H), 1.86 (d, J=9.7 Hz, 2H), 1.56 (d, J=10.1 Hz, 2H), 0.87 (s, 3H). [M+H]+=975.3.
To a stirred solution of 1-(2-fluoro-4-methoxy-5-nitrophenyl)ethan-1-one (500 mg, 2.34 mmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (944 mg, 3.51 mmol) in DMF (15 mL) was added K2CO3 (646 mg, 4.68 mmol). The resulting mixture was stirred at 100° C. for 16 hours. The reaction was concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=15:1) to give the title product (800 mg, 74%). [M+H]+=463.3.
To a stirred solution of tert-butyl 4-(1-(2-acetyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (800 mg, 1.73 mmol) in THF (15 mL) and H2O (15 mL) was added NH4Cl (366 mg, 6.92 mmol). The resulting mixture was stirred at rt for 2 hours. The reaction was extracted with DCM (2×20.0 mL). The combined organic layer was washed with brine (2×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=10:1) to give the title product (600 mg, 80%). [M+H]+=433.3.
The titled compound (510 mg, 60%) was prepared in a manner similar to that in Example 200 step 14 from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(2-acetyl-4-amino-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=708.4.
To a stirred solution of 1-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)ethan-1-one (500 mg, 0.7 mmol) in MeOH (15 mL) was added NaBH4 (53 mg, 1.4 mmol). The resulting mixture was stirred at rt for 16 hours. The reaction was extracted with DCM (2×20.0 mL). The combined organic layer was washed with brine (2×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the title product (400 mg, 80%). [M+H]+=710.4.
The titled compound (5 mg, 12%) was prepared in a manner similar to that in Example 204 step 6 from (6-((5-bromo-2-((5-(1-hydroxyethyl)-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 10.95 (s, 1H), 8.84 (dd, J=7.7, 1.8 Hz, 3H), 8.47 (s, 1H), 8.26 (d, J=9.1 Hz, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.44 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.87 (s, 1H), 5.03 (dt, J=18.3, 9.0 Hz, 2H), 4.20 (dd, J=12.7, 5.0 Hz, 1H), 3.76 (s, 3H), 3.14 (d, J=10.6 Hz, 1H), 2.96 (d, J=10.2 Hz, 1H), 2.86-2.63 (m, 6H), 2.59-2.51 (m, 8H), 2.48-2.42 (m, 2H), 2.33 (t, J=11.2 Hz, 1H), 2.13 (dd, J=13.1, 3.8 Hz, 1H), 2.01 (d, J=14.1 Hz, 7H), 1.87 (t, J=12.5 Hz, 2H), 1.57 (dd, J=7.5, 4.1 Hz, 2H), 1.21 (d, J=6.2 Hz, 3H); [M+H]+=961.4.
To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (500 mg, 1.03 mmol) and methyl 2-aminoacetate (138 mg, 1.6 mmol) in toluene (20 mL) was added Ruphos G3 (85 mg, 0.1 mmol) and Cs2CO3 (669 mg, 2.06 mmol). The resulting mixture was stirred at 100° C. for 16 hours under N2 atmosphere. The reaction was concentrated under vacuum to afford the crude product, which was purified with silica gel column chromatography (PE:EA=3:1) to give the title product (400 mg, 79%). [M+H]+=491.3.
To a stirred solution of methyl 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)acetate (400 mg, 0.82 mmol) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was added LiOH (43 mg, 1.64 mmol).
The resulting mixture was stirred at rt for 1 hour. The reaction was extracted with EA (2×20.0 mL). The combined organic layer was washed with brine (2×20.0 mL), dried over Na2SO4 and concentrated under vacuum to afford the title product (300 mg, 76%). [M+H]+=477.4.
To a stirred solution of 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)acetic acid (300 mg, 0.63 mmol) in MeOH (15 mL) was added Pd/C (60 mg). The resulting mixture was stirred at rt for 16 hour under H2 atmosphere. The reaction was filtrated, the filtration was concentrated under vacuum to afford the title product (150 mg, 80%). [M+H]+=299.2.
The titled compound (12 mg, 24%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)acetic acid. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.83 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.74 (s, 1H), 6.41 (d, J=12.0 Hz, 2H), 6.23 (d, J=4.5 Hz, 1H), 3.99 (dd, J=12.6, 5.0 Hz, 1H), 3.93 (d, J=4.7 Hz, 2H), 3.76 (s, 3H), 3.49 (s, 3H), 2.95 (d, J=11.0 Hz, 2H), 2.82-2.73 (m, 1H), 2.69 (s, 6H), 2.57 (s, 2H), 2.45-2.35 (m, 2H), 2.30 (d, J=6.7 Hz, 2H), 2.12-2.02 (m, 1H), 1.98 (d, J=13.3 Hz, 7H), 1.83 (d, J=10.0 Hz, 2H), 1.59-1.56 (m, 2H), 0.77 (s, 3H); [M+H]+=987.7.
The titled compound (500 mg, 80%) was prepared in a manner similar to that in Example 432 step 1 from 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridineand 2-(methylamino)ethan-1-ol. [M+H]+=477.7.
The titled compound (250 mg, 80%) was prepared in a manner similar to that in Example 432 step 3 from 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)(methyl)amino)ethanol and Pd/C. [M+H]+=299.3.
The titled compound (200 mg, 75%) was prepared in a manner similar to that in Example 207 step 4 from 3-(2,6-difluoro-4-((2-hydroxyethyl)(methyl)amino)phenyl)piperidine-2,6-dione and MsCl. [M+H]+=377.1.
The titled compound (12 mg, 23%) was prepared in a manner similar to that in Example 207 step 5 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)(methyl)amino)ethyl methanesulfonate. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.85 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 6.74 (s, 1H), 6.35 (d, J=12.8 Hz, 2H), 4.02 (dd, J=12.5, 5.0 Hz, 1H), 3.76 (d, J=5.1 Hz, 3H), 3.44 (t, J=6.6 Hz, 2H), 2.97-2.88 (m, 5H), 2.78 (s, 1H), 2.66 (d, J=14.7 Hz, 6H), 2.54 (s, 4H), 2.43 (s, 6H), 2.29 (d, J=7.0 Hz, 3H), 2.07 (s, 1H), 1.98-1.95 (m, 7H), 1.84 (d, J=9.4 Hz, 2H), 1.55 (d, J=9.9 Hz, 2H), 0.77 (s, 3H); [M+H]+=987.7.
To a mixture of 6-bromo-2-(trifluoromethyl)quinoline (2 g, 7.27 mmol), diphenylmethanimine (1.97 g, 10.9 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), BINAP (910 mg, 1.46 mmol), Cs2CO3 (4.74 g, 14.5 mmol) in dioxane (60 mL) was stirred at 100° C. under N2 atmosphere for 18 hrs. After cooling to r.t, the reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA=4:1). 1,1-diphenyl-N-(2-(trifluoromethyl)quinolin-6-yl)methanimine (2.6 g, 95%) was obtained. [M+H]+=377.2.
To a solution of 1,1-diphenyl-N-(2-(trifluoromethyl)quinolin-6-yl)methanimine (2.6 g, 6.9 mmol) in THF (30 mL) was added HCl (6 mL, 2N). The mixture was stirred at 20° C. for 30 mins and then sat. aq. Na2CO3 solution was added to PH=8-9, the resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE: EA=1:1). 2-(trifluoromethyl)quinolin-6-amine (1.2 g, 82%) was obtained. [M+H]+=213.2.
To a solution of 2-(trifluoromethyl)quinolin-6-amine (1.2 g, 5.63 mmol) in HOAc (10 mL) was added ICl (1.06 g, 8.45 mmol). The mixture was stirred at 20° C. for 3 hrs and then sat. aq. Na2CO3 solution was added to PH=8-9, the resulting mixture was extracted with EtOAc (70 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. 5-iodo-2-(trifluoromethyl)quinolin-6-amine (1.7 g, 88%) was obtained. [M+H]+=339.1.
To a mixture of 5-iodo-2-(trifluoromethyl)quinolin-6-amine (1.7 g, 5.01 mmol), dimethylphosphine oxide (496 mg, 6.52 mmol), Pd(OAc)2 (112 mg, 0.5 mmol), Xantphos (578 mg, 1 mmol), K3PO4 (2.12 g, 10.02 mmol) in dioxane (40 mL) was stirred at 100° C. under N2 atmosphere for 8 hrs. After cooling to r.t, the reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH=15:1). (6-amino-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide (1.2 g, 83%) was obtained. [M+H]+=289.3.
To a solution of (6-amino-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide (1 g, 3.46 mmol) in DMF (16 mL) was added NaH (346 mg, 8.65 mmol, 60%) at 0° C. The mixture was stirred at 0° C. for 20 min, then 5-bromo-2,4-dichloropyrimidine (1.56 g, 6.92 mmol) was added, the resulting solution was stirred at r.t for 2 hrs. The reaction was quenched by sat. aq. NH4Cl solution and the resulting mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (DCM:CH3OH=15:1). (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide (600 mg, 36.3%) was obtained. [M+H]+=479.2.
To a mixture of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide (400 mg, 0.84 mmol), tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (349 mg, 0.84 mmol), TsOH·H2O (479 mg, 2.52 mmol) in n-BuOH (8 mL) was stirred at 100° C. for 14 hrs. After cooling to r.t, the reaction mixture was concentrated in vacuo. The residue was diluted with DCM, washed with NaOH solution (20 mL, 1N) and brine, dried over Na2SO4 and then concentrated in vacuo. The residue was purified by silica gel column (DCM: CH3OH (0.05 NH3H2O)=2:1). (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide (370 mg, 58%) was obtained. [M+H]+=761.3.
The titled compound (6 mg, 16%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide and 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-3-carboxylic acid. 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 10.94 (s, 1H), 8.89 (s, 1H), 8.49 (s, 1H), 8.34-8.10 (m, 2H), 8.03 (d, J=9.0 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.29 (s, 1H), 6.78 (s, 1H), 6.57 (s, 1H), 6.52 (dd, J=8.3, 1.8 Hz, 1H), 5.04 (dd, J=13.3, 5.1 Hz, 1H), 4.31 (d, J=16.9 Hz, 1H), 4.19 (d, J=17.0 Hz, 1H), 4.13 (t, J=7.8 Hz, 2H), 4.00 (t, J=6.2 Hz, 2H), 3.92-3.87 (m, 1H), 3.50 (s, 2H), 3.35 (s, 3H), 2.95 (d, J=11.4 Hz, 2H), 2.91-2.83 (m, 1H), 2.68 (s, 2H), 2.57 (d, J=28.9 Hz, 4H), 2.42-2.25 (m, 5H), 2.05 (t, J=13.2 Hz, 6H), 1.99-1.89 (m, 2H), 1.82 (d, J=10.3 Hz, 2H), 1.65-1.45 (m, 2H), 0.79 (s, 3H). [M+H]+=1086.3.
The titled compound was prepared in a manner similar to that in Example 200. 1H NMR (500 MHz, DMSO) δ 8.89 (d, J=9.3 Hz, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.05 (d, J=9.7 Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.29 (s, 1H), 7.03 (d, J=10.1 Hz, 2H), 6.78 (s, 1H), 4.20 (dd, J=12.8, 4.7 Hz, 1H), 3.76 (s, 3H), 3.31 (d, J=11.8 Hz, 2H), 3.12 (s, 1H), 2.94 (d, J=9.6 Hz, 3H), 2.87-2.73 (m, 4H), 2.70-2.60 (m, 5H), 2.54 (s, 4H), 2.32-2.24 (m, 4H), 2.13 (d, J=9.4 Hz, 1H), 2.03 (t, J=13.6 Hz, 8H), 1.83 (s, 2H), 1.53 (s, 2H), 0.79 (s, 3H). [M+H]+=1012.3.
A mixture of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3,3-dimethylindol-2-one (the material was obtained through the similar method of example 409) (1.0 g, 1.889 mmol) and tert-butyl piperidine-4-carboxylate (419.9 mg, 2.267 mmol), Cs2CO3 (923.1 g, 2.833 mmol), XPhos (180.1 mg, 0.378 mmol), Pd2(dba)3 (173.0 mg, 0.189 mmol) in dioxane (20 mL) was stirred overnight at 110° C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford product (620.0 mg, 51.7%). [M+H]+=634.1.
To a stirred mixture of tert-butyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-4-carboxylate (620.0 mg, 0.978 mmol) and Pd/C (300.0 mg, 10% wt) in EtOH (10 mL) was added AcOH (50 mL, 872 mmol) dropwise and stirred overnight at 50° C. under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (150 mL). The filtrate was concentrated under reduced pressure to afford the product (300.0 mg, 67.3%). [M+H]+=456.2.
A mixture of tert-butyl 1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-4-carboxylate (300.0 mg, 0.659 mmol) in TFA (1.5 mL) and DCM (3 mL) was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (10 mL). 1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-4-carboxylic acid (158.8 mg, 60.3%) was obtained. [M+H]+=400.2.
The titled compound (12 mg, 17%) was prepared in a manner similar to that in Example 208 step 8 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and 1-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)piperidine-4-carboxylic acid. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 11.04 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J=16.5 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.48-7.28 (m, 2H), 7.10 (d, J=1.9 Hz, 1H), 6.77 (dd, J=21.1, 10.8 Hz, 3H), 5.15 (s, 1H), 3.76 (s, 3H), 3.64-3.51 (m, 4H), 3.47 (s, 2H), 2.95 (d, J=10.6 Hz, 2H), 2.87 (t, J=13.2 Hz, 1H), 2.72 (d, J=7.6 Hz, 1H), 2.71-2.66 (m, 3H), 2.65 (s, 4H), 2.62-2.53 (m, 4H), 2.49-2.45 (m, 2H), 2.37 (t, J=11.1 Hz, 1H), 2.30 (d, J=6.9 Hz, 2H), 1.98 (d, J=13.3 Hz, 6H), 1.93 (dd, J=10.5, 5.2 Hz, 1H), 1.83 (d, J=10.2 Hz, 2H), 1.77-1.65 (m, 4H), 1.56 (dt, J=30.8, 15.3 Hz, 2H), 1.26 (t, J=11.3 Hz, 6H), 0.77 (s, 3H). [M+H]+=1088.4.
The titled compound was prepared in a manner similar to that in Example 204 Step 6 from 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde and (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-(trifluoromethyl)quinolin-5-yl)dimethylphosphine oxide. 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 10.86 (s, 1H), 8.89 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 8.17 (d, J=13.9 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 6.60 (d, J=12.8 Hz, 2H), 4.04 (dd, J=12.5, 4.9 Hz, 1H), 3.74 (d, J=18.3 Hz, 5H), 2.93 (d, J=10.5 Hz, 2H), 2.84-2.72 (m, 2H), 2.68 (dd, J=19.8, 9.0 Hz, 4H), 2.53 (d, J=11.1 Hz, 3H), 2.48-2.45 (m, 1H), 2.39 (s, 3H), 2.35-2.21 (m, 6H), 2.10 (dd, J=12.9, 9.1 Hz, 1H), 2.04 (d, J=13.3 Hz, 6H), 1.98-1.90 (m, 1H), 1.83 (d, J=10.9 Hz, 2H), 1.76-1.64 (m, 2H), 1.53 (dd, J=20.2, 10.9 Hz, 3H), 1.42-1.31 (m, 2H), 1.26-1.08 (m, 2H), 0.79 (s, 3H). [M+H]+=1095.4.
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (10 g, 43.1 mmol) in THF (150 mL) was added LDA (2 M in THF, 24 mL, 48 mmol) dropwise in 20 min at −65° C., the reaction solution was stirred for 1 hour at this temperature, then to this was added ethyl 3-bromopropanoate (9.4 g, 51.7 mmol) in THF (30 mL) dropwise in 10 min. The resulting solution was stirred for 30 min at −65° C., and then allowed to warm to room temperature naturally. The reaction was quenched by the addition of sat. aq. NH4Cl (50 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (13.8 g, 96.5%). [M+H]+=332.0.
To a solution of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 40.7 mmol) in THF/H2O (90 mL/30 mL) was added LiOH (2.9 g, 0.122 mol). The reaction mixture was stirred for 12 h at room temperature. The resulting mixture was diluted with water, and extracted with EtOAc (50 mL×2). The pH value of water phase was adjusted to 4-5 with 1 N HCl (10 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (10.2 g, 82.5%). [M+H]+=304.2.
To a stirred solution of 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid (10.2 g, 33.5 mmol) in toluene (100 mL) was added conc. H2SO4 (2 mL, 36.9 mmol). The resulting solution was stirred at 100° C. for 3 h. The reaction mixture was concentrated under vacuum, then the mixture was poured into water. The pH value was adjusted to 7-8 with sat. aq. NaHCO3(40 mL), and resulting solution was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the product (8.2 g, 80.4%). [M+H]+=304.3.
To a stirred solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (8.2 g, 27.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.4 g, 32.4 mmol) in DMF/H2O (100 mL/20 mL) were added Pd(dtbpf)Cl2 (883 mg, 1.35 mmol) and CsF (8.2 g, 54.0 mmol). The resulting mixture was stirred for 2 h at 80° C. under nitrogen atmosphere. The reaction solution was diluted with water, extracted with EtOAc (100 mL×2). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SFC (IH (3*25 cm, 5 um), 13% EtOH/87% CO2, 100 bar, 100 ml/min) and the title compound corresponded to peak A @ 1.679 min/254 nm. (3.1 g, 39.0%). [M+H]+=296.1.
(R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (3.1 g, 10.4 mmol) was dissolved in FA(50 mL). The resulting solution was stirred for 2 h at room temperature. The reaction solution was evaporated to dryness to afford the product (2.6 g, 91.8%). [M+H]+=268.1.
To a stirred solution of quinolin-2-ol (6 g, 41.3 mmol) in conc. H2SO4 (98%, 50 mL) was added dropwise a solution of conc. HNO3 (65%, 3.12 g, 49.6 mmol) at 0° C. Then the mixture was stirred at rt for 1h. The mixture was diluted with water (200 mL) at 0° C. The resulting mixture was filtered and the filter cake was washed with H2O (500 ml), and dried in vacuum to afford 6-nitroquinolin-2-ol (5.5 g 69.9%) [M+H]+=191.1.
A solution of 6-nitroquinolin-2-ol (5.5 g, 28.78 mmol) in POCl3 (50 mL) was stirred at 100° C. for 2 hrs. Then the mixture was cooled to rt, and concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 40 g, DCM:MeOH=15:1) to give 2-chloro-6-nitroquinoline(5 g, 82.9%) [M+H]+=209.1.
To a suspension of 2-chloro-6-nitroquinoline (5 g, 23.9 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.37 g, 47.8 mmol) in dioxane (40 mL) and water (10 mL) was added K2CO3 (9.91 g, 71.8 mmol) and Pd(dppf)Cl2 (1.74 g, 2.39 mmol) under nitrogen atmosphere. The mixture was warmed to 100° C. and stirred for 16 hrs. Then the mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 40 g, DCM:MeOH=15:1) to give 6-nitro-2-vinylquinoline (4.5 g, 93.9%). [M+H]+=201.1.
To a suspension of 6-nitro-2-vinylquinoline (4.5 g, 22.38 mmol) in MeOH (20 mL) was added Pd/C (10 wt. %, wet, 1.5 g). The mixture was stirred at rt for 16 hrs under hydrogen atmosphere. Then the mixture was filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to afford 2-ethylquinolin-6-amine (3.84 g, 99.2%). [M+H]+=173.1.
The title compound (4.5 g, 75.3%) was prepared in a manner similar to that in Example 486 step 4 from 2-ethylquinolin-6-amine and ICl [M+H]+=299.1.
The title compound (3.5 g, 93.5%). was prepared in a manner similar to that in Example 486 step 5 from 2-ethyl-5-iodoquinolin-6-amine and dimethylphosphineoxide. [M+H]+=249.1.
The title compound (2.5 g, 40.4%). was prepared in a manner similar to that in Example 486 step 6 from (6-amino-2-ethylquinolin-5-yl)dimethylphosphine oxide and 5-bromo-2,4-dichloropyrimidine. [M+H]+=439.6.
The title compound (2.0 g, 48.8%). was prepared in a manner similar to that in Example 486 step 7 from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=721.5.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (500 mg, 0.694 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (222.49 mg, 0.832 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 2 hour. To the mixture was added sodium triacetoxyborohydride (146.34 mg, 0.694 mmol) and the reaction was stirred at room temperature for another 2 h. The resulting mixture was diluted with H2O (60 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the crude product (600 mg), which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (480 mg, 71.2%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.88 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=12.4 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J=9.4 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J=10.0 Hz, 2H), 6.68 (s, 1H), 4.13 (dd, J=12.6, 5.0 Hz, 1H), 3.69 (s, 3H), 2.86 (dd, J=15.2, 7.6 Hz, 4H), 2.79-2.65 (m, 4H), 2.59 (t, J=11.3 Hz, 3H), 2.47 (s, 4H), 2.41-2.31 (m, 4H), 2.22 (d, J=4.7 Hz, 3H), 2.05 (s, 2H), 1.92 (d, J=13.3 Hz, 7H), 1.77 (d, J=10.2 Hz, 2H), 1.47 (d, J=8.8 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H), 0.70 (s, 3H). [M+H]+=972.7
To a stirred mixture of 4-bromo-2-fluoroaniline (10 g, 52.6 mmol) and BTEAC (1 g) in aqueous HCl (6M) was added (E)-pent-2-enal (8.84 g, 105.3 mmol) in toluene (50 mL) dropwise at 100° C. The resulting mixture was stirred for 15 h at 100° C. under nitrogen atmosphere. The reaction was extracted with EA. The aqueous layer was concentrated under reduced pressure. The residue was dissolved in water, and the pH was adjusted to 8-9 with aqueous NaOH (3M). The resulting mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-15% EA in PE) to afford product (3.5 g, 26.2%). [M+H]+=254.1.
A mixture of 6-bromo-2-ethyl-8-fluoroquinoline (3.5 g, 13.8 mmol), BocNH2 (1.93 g, 16.5 mmol), Pd2(dba)3 (631 mg, 0.69 mmol), XantPhos (799 mg, 1.38 mmol), and Cs2CO3 (11.2 g, 34.5 mmol) in dioxane (80 mL) was stirred at 100° C. under nitrogen atmosphere for 15 hrs. After cooling to r.t, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (PE: EA=4:1) to afford product (2.8 g, 70%). [M+H]+=291.1.
To a stirred solution of tert-butyl (2-ethyl-8-fluoroquinolin-6-yl)carbamate (2.8 g, 9.7 mmol) in DCM (20 mL) was added TFA (10 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuum to afford the product (1.8 g, 98.5%) [M+H]+=191.1.
To a solution of 2-ethyl-8-fluoroquinolin-6-amine (1.8 g, 9.5 mmol) in HOAc (20 mL) was added ICl (1.84 g, 11.4 mmol). The mixture was stirred at 20° C. for 3 hrs and then sat. aq. Na2CO3 was added to adjust the PH to 8-9. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (60 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. 2-Ethyl-8-fluoro-5-iodoquinolin-6-amine (1.7 g, 56.7%) was obtained. [M+H]+=317.0.
A mixture of 2-ethyl-8-fluoro-5-iodoquinolin-6-amine (1.7 g, 5.4 mmol), dimethylphosphineoxide (627 mg, 8 mmol), K3PO4 (2.8 g, 13.5 mmol), Pd(OAc)2 (120 mg, 0.54 mmol) and XantPhos (310 mg, 0.54 mmol) in dioxane (30 mL) was stirred for 3 h at 100° C. under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was purified by column chromatography (0-10% MeOH in DCM) to afford the product (1.2 g, 83.3%). [M+H]+=267.1.
To a solution of (6-amino-2-ethyl-8-fluoroquinolin-5-yl)dimethylphosphine oxide (1.2 g, 4.5 mmol) in THF (30 mL) was added 5-bromo-2,4-dichloropyrimidine (2.6 g, 11.2 mmol). LiHMDS (1 M in THF, 9 mL, 9 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at 20° C. for 3 hrs. The mixture was diluted with water (20 mL), and the layers were separated. The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=20/1 to 10/1) to afford prodcut (1.3 g, 63.4%). [M+H]+=457.0.
To a stirred solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethyl-8-fluoroquinolin-5-yl)dimethylphosphine oxide (800 mg, 1.7 mmol) and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (755 mg, 1.7 mmol) in n-BuOH (40 mL) was added TsOH (877 mg, 5.1 mmol). The resulting mixture was stirred at 95° C. for 16 hours. The reaction mixture was concentrated under vacuum before aqueous NaOH (1M, 10 mL) was added into the mixture. Then the mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude residue, which was purified with silica gel column chromatography (DCM:MeOH=6:1) to give the title product (790 mg, 60.8%). [M+H]+=753.3.
To a solution of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethyl-8-fluoroquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (40 mg, 0.15 mmol) in DCM (3 mL) was added STAB (32 mg, 0.15 mmol) at 20° C. The mixture was stirred at 20° C. for 1 hr. The mixture was diluted with water (20 mL), and the layers were separated. The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford the product (24.5 mg, 19.6%). 1H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 10.88 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.31-8.11 (m, 2H), 7.97 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.33 (s, 1H), 6.95 (d, J=10.1 Hz, 2H), 6.64 (s, 1H), 4.13 (dd, J=12.6, 4.9 Hz, 1H), 3.94 (q, J=6.9 Hz, 2H), 2.86-2.91 (m, 5H), 2.67-2.78 (m, 3H), 2.45-2.60 (m, 9H), 2.15-2.42 (m, 7H), 2.00-2.10 (m, 1H), 1.93 (d, J=13.3 Hz, 6H), 1.74-1.77 (m, 2H), 1.36-1.46 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 1.19 (t, J=6.9 Hz, 3H), 0.68 (s, 3H). [M+H]+=1004.7.
To a solution of quinolin-2(1H)-one (25.0 g, 0.17 mol) in MeCN (30 mL) was added Selectfluor (64.0 g, 0.18 mol) at room temperature. The resulting mixture was stirred at 80° C. overnight. The reaction was concentrated to give the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜20: 1 gradient elution) to give a mixture (10.4 g, 37%) containing the desired product. [M+H]+=164.2.
To the mixture from above step (10.4 g, 63.4 mmol) in conc. H2SO4 (98%, 80 mL) was added conc. HNO3 (65%, 7.4 g, 76.1 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. The reaction was poured into ice water (200 mL) and stirred for 10 mins. The mixture was filtered and the solid was washed with water (50 mL×2), dried under reduced pressure to give the crude product (7.5 g, 56.8%).
1H NMR (500 MHz, DMSO) δ 12.84 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.31 (dd, J=9.1, 2.5 Hz, 1H), 8.09 (d, J=10.7 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H). [M+H]+=209.2.
A solution of 3-fluoro-6-nitroquinolin-2(1H)-one (7.5 g, 35.9 mmol) in POCl3 (60 mL) was heated at 100° C. overnight. The reaction was concentrated, basified with sat. aq. NaHCO3, and then extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the crude residue, which was purified by silica gel column chromatography (PE: EA=100: 0˜10: 1 gradient elution) to give the desired product (3.7 g, 32%). [M+H]+=227.0.
A mixture of 2-chloro-3-fluoro-6-nitroquinoline (3.7 g, 16.3 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.0 mL, 48.9 mmol), Pd(dppf)Cl2 (1.2 g, 1.63 mmol) and K3PO4 (6.9 g, 32.6 mmol) in DME (100 mL) and H2O (20 mL) was stirred in a round bottom flask at 80° C. overnight under nitrogen atmosphere. The mixture was evaporated under reduced pressure to afford the crude product, which was purified with silica gel column chromatography (PE: EA=100: 0˜20: 1 gradient elution) to give the title product (2.6 g, 77%). [M+H]+=207.1.
To a solution of 3-fluoro-2-methyl-6-nitroquinoline (2.6 g, 12.5 mmol) in MeOH (50 mL)/DCM (25 mL) was added Pd/C (10 wt. %, wet, 800 mg) at 25° C. under nitrogen atmosphere. The flask was evacuated and backfilled with hydrogen three times. After stirring under hydrogen atmosphere at 25° C. for 5 hours, the mixture was filtered through a pad of Celite and the solid was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to afford the desired product (2.2 g, 99%). [M+H]+=177.1.
To a solution of 3-fluoro-2-methylquinolin-6-amine (2.2 g, 12.4 mmol) in AcOH (60 mL) was added ICl (16.1 mL, 16.1 mmol) at 20° C. Then the mixture was stirred at 20° C. for 1 hour. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (3.3 g, 88%). [M+H]+=303.0.
To a solution of 3-fluoro-5-iodo-2-methylquinolin-6-amine (3.3 g, 10.9 mmol) and dimethylphosphine oxide (1.3 g, 16.3 mmol) in dioxane (120 mL) was added K3PO4 (6.9 g, 32.7 mmol) at 20° C. Pd(OAc)2 (244 mg, 1.09 mmol) and Xantphos (1.2 g, 2.18 mmol) were then added to the mixture at the same temperature. The flask was evacuated and backfilled with nitrogen three times, before the mixture was stirred at 100° C. overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give the desired product (2.5 g, 91%). [M+H]+=253.1.
To a solution of (6-amino-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (2.5 g, 9.9 mmol) and 5-bromo-2,4-dichloropyrimidine (6.7 g, 29.7 mmol) in n-BuOH (100 mL) was added DIEA(3.8 g, 29.7 mmol) at room temperature. The resulting mixture was stirred at 120° C. overnight. The reaction was concentrated to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜15: 1 gradient elution) to give the desired product (2.9 g, 66%). [M+H]+=443.1.
To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (1.7 g, 3.8 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.6 g, 3.8 mmol) in n-BuOH (100 mL) was added Ts-OH (2.0 g, 11.4 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was concentrated and basified with 0.5N NaOH (50 mL). The resulting mixture was extracted with DCM (3×80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜5: 1 gradient elution) to give the desired product (960 mg, 35%). [M+H]+=725.2.
To the solution of 2-bromo-1,3-difluoro-5-iodobenzene (15 g, 47 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (8.56 g, 51.7 mmol) and K3PO4 (20 g, 94 mmol) in 250 mL DMSO, were added CuI (893 mg, 4.7 mmol) and L-proline (1 g, 9.4 mmol). The mixture was stirred at 80° C. for 16 hours. After LCMS showed the reaction was completed, the mixture was diluted with water and extracted by EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (PE:EA=50:1-30:1) to afford the product (4.9 g, 32.5%). [M+H]+=320.1.
To the solution of methyl (R)-1-(4-bromo-3,5-difluorophenyl)pyrrolidine-3-carboxylate (4.9 g, 15.3 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.7 g, 16 mmol) and CsF (4.6 g, 30.6 mmol) in 150 mL DMF and 15 mL water, was added Pd(dtbpf)Cl2 (498 mg, 0.8 mmol). The mixture was stirred at 80° C. for 4 hours. After LCMS showed the reaction was completed, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The resulting mixture was purified by combi-flash (EA:PE=0-12%) to afford the product (7.9 g, 97.4%). [M+H]+=531.30.
To the solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate (7.9 g, 14.9 mmol) in 100 mL THF and 20 mL water, LiOH (394 mg, 16.4 mmol) in 10 mL water was added dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes. After TLC showed the reaction was completed, the mixture was concentrated in vacuum at room temperature. The residue was diluted with water and adjust pH<5 with 1 N HCl. The liquid was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford the product (7.4 g, 96.0%). [M+H]+=517.1.
To the solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (7.4 g, 14.3 mmol) in 50 mL DCM and 250 mL iPrOH, Pd/C (7.4 g, 10 wt. %, wet) was added. The mixture was stirred at 40° C. for 16 hours under hydrogen atmosphere (balloon). After LCMS showed the reaction was completed, the mixture was cooled to room temperature and filtered by celite directly. The filtrate was concentrated in vacuum to afford the crude product which was purified by SFC (IH (3*25 cm, 5 um), 13% EtOH/87% CO2, 100 bar, 100 ml/min) and the title compound corresponded to peak A @ 0.655 min/254 nm (1.6 g, 34%). [M+H]+=339.2.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (450 mg, 0.62 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (230 mg, 0.68 mmol) and DIEA (162 mg, 1.24 mmol) in DCM (30 mL) was added T3P (788 mg, 1.24 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (50 mL) and extracted with DCM (2×60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC (C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to give the desired product (302 mg, 47%). 1H NMR (500 MHz, DMSO) δ 11.30 (s, 1H), 10.84 (s, 1H), 8.63 (d, J=12.6 Hz, 1H), 8.23 (s, 2H), 7.95 (d, J=9.2 Hz, 2H), 7.33 (s, 1H), 6.72 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.02 (dd, J=12.7, 5.0 Hz, 1H), 3.75 (s, 3H), 3.60-3.42 (m, 6H), 3.35 (s, 2H), 3.26 (s, 3H), 2.92 (d, J=10.7 Hz, 2H), 2.83-2.73 (m, 1H), 2.64 (d, J=2.4 Hz, 5H), 2.56 (s, 3H), 2.37 (d, J=3.6 Hz, 1H), 2.25-2.05 (m, 5H), 1.95 (d, J=13.4 Hz, 7H), 1.82 (d, J=11.0 Hz, 2H), 1.62-1.51 (m, 2H), 0.71 (s, 3H); [M+H]+=1045.5.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (1.15 g, 1.60 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (595 mg, 1.76 mmol), DIEA (411 mg, 3.19 mmol) and T3P (763 mg, 2.4 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 0.5 h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (800 mg, 48.3%).
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 10.84 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.3, 4.7 Hz, 1H), 3.76 (s, 3H), 3.65-3.41 (m, 7H), 3.31-3.23 (m, 4H), 3.01-2.88 (m, 4H), 2.84-2.74 (m, 1H), 2.68 (t, J=11.1 Hz, 2H), 2.59-2.55 (m, 3H), 2.39-2.35 (m, 1H), 2.31-2.28 (m, 2H), 2.19-2.06 (m, 3H), 1.98 (d, J=13.3 Hz, 6H), 1.96-1.91 (m, 1H), 1.84 (d, J=10.1 Hz, 2H), 1.57 (d, J=9.9 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H), 0.77 (s, 3H). [M+H]+=1041.7
The title compound (19 mg, 20%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 11.22 (s, 1H), 8.57 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.19-7.02 (m, 3H), 6.75 (s, 1H), 3.76 (s, 3H), 3.01-2.82 (m, 9H), 2.79-2.53 (m, 14H), 2.29 (d, J=6.7 Hz, 2H), 2.20-2.10 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.90 (d, J=9.9 Hz, 2H), 1.59 (d, J=9.4 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.83-0.71 (s, 3H); [M+H]+=993.5.
The title compound (35 mg, 42%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 11.19 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 6.95 (s, 1H), 6.87 (s, 1H), 6.75 (s, 1H), 5.33 (dd, J=13.1, 5.3 Hz, 1H), 3.76 (s, 3H), 2.92 (dt, J=16.1, 8.0 Hz, 5H), 2.85-2.78 (m, 2H), 2.73-2.60 (m, 5H), 2.55 (dd, J=10.1, 5.0 Hz, 5H), 2.49-2.40 (m, 4H), 2.31 (s, 6H), 2.17-2.07 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.84 (d, J=10.4 Hz, 2H), 1.60-1.47 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1007.4.
The title compound (23.52 mg, 38%) was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.21 (s, 1H), 8.55 (d, J=9.0 Hz, 1H), 8.26 (d, J=13.4 Hz, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 7.17 (dd, J=8.5, 2.5 Hz, 1H), 6.97 (dd, J=10.7, 2.4 Hz, 1H), 6.75 (s, 1H), 5.37-5.34 (m, 1H), 3.76 (s, 3H), 2.94-2.92 (m, 4H), 2.88-2.84 (m, 3H), 2.75-2.64 (m, 4H), 2.61-2.53 (m, 5H), 2.32 (m, 4H), 2.18-2.08 (m, 1H), 1.99-1.94 (m, 7H), 1.86-1.82 (m, 2H), 1.64-1.41 (m, 2H), 1.41-1.20 (m, 3H), 0.77 (s, 3H). [M+H]+=1011.6.
The title compound (15 mg, 16%) was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.22 (s, 1H), 8.55 (d, J=9.0 Hz, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 7.16-7.12 (m, 1H), 7.07 (d, J=8.6 Hz, 1H), 6.75 (s, 1H), 5.37 (dd, J=13.1, 5.3 Hz, 1H), 3.76 (s, 3H), 2.98-2.80 (m, 8H), 2.73-2.62 (m, 5H), 2.58-2.51 (m, 8H), 2.33-2.23 (m, 3H), 2.20-2.09 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.89-1.78 (m, 2H), 1.60-1.44 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.83-0.71 (m, 3H); [M+H]+=1011.5.
The title compound (20 mg, 60.5%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.19 (s, 1H), 8.60 (d, J=8.5 Hz, 1H), 8.22 (s, 2H), 7.96-7.81 (m, 2H), 7.48-7.36 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 6.71 (s, 1H), 6.53 (d, J=7.8 Hz, 1H), 6.40 (d, J=8.5 Hz, 1H), 5.30 (dd, J=12.9, 5.4 Hz, 1H), 4.01 (t, J=6.9 Hz, 2H), 3.67 (s, 1H), 3.60 (dd, J=16.4, 6.7 Hz, 3H), 3.54-3.45 (m, 6H), 2.93 (dd, J=15.0, 7.4 Hz, 5H), 2.65 (dd, J=20.2, 7.2 Hz, 4H), 2.55 (d, J=11.2 Hz, 2H), 2.35 (d, J=11.9 Hz, 1H), 2.25 (d, J=6.7 Hz, 2H), 2.20-2.03 (m, 4H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=10.1 Hz, 2H), 1.57 (s, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1076.4.
A mixture of 7-bromo-3H-1,3-benzoxazol-2-one (6 g, 28.03 mmol), Cu(OAc)2 (5.09 g, 28.03 mmol), pyridine (6.65 mL, 84.1 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (11.7 g, 28.03 mmol) and 4A MS (6 g) in 1,4-dioxane (120 mL) was stirred overnight at 80° C. under oxygen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the solid was washed with EtOAc (500 mL). The combined organic filtrates were washed with brine (500 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse flash chromatography (DCM in PE, 10% to 50% gradient in 30 min) afforded the product (9.6 g, 68.03%). [M+H]+=503.2.
A mixture of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromobenzo[d]oxazol-2(3H)-one (1.1 g, 2.18 mmol), benzyl 1-(2,2,2-trifluoroacetyl)azetidine-3-carboxylate (0.94 g, 3.277 mmol), Cs2CO3 (2.14 g, 6.55 mmol), Pd2(dba)3 (0.20 g, 0.22 mmol) and RuPhos (0.10 g, 0.22 mmol) in 1,4-dioxane (20 mL) was stirred for 2 h at 100° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (200 mL), which was washed with brine (200 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE/EA 1:1) afforded the product (620 mg, 46.23%). [M+H]+=614.3.
A mixture of_benzyl 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylate (600 mg, 0.98 mmol) and Pd/C (10 wt. %, wet, 600 mg) in THF (10 mL) was stirred for 5 h at 50° C. under hydrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the solid was washed with THF. The filtrate was concentrated under reduced pressure to afford the product (241 mg, 71.38%), which was used without further purification. [M+H]+=346.2.
The title compound (45 mg, 65.2%) was prepared in a manner similar to that in Example 447 step 4 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 1-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylic acid.
1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 11.19 (s, 1H), 8.56 (d, J=9.1 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.75 (s, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.3 Hz, 1H), 5.30 (dd, J=12.9, 5.2 Hz, 1H), 4.22 (t, J=7.7 Hz, 2H), 4.08 (t, J=6.8 Hz, 2H), 3.93-3.83 (m, 1H), 3.76 (s, 3H), 3.49 (s, 3H), 2.93 (s, 6H), 2.61-2.55 (m, 6H), 2.58 (s, 3H), 2.43-2.25 (m, 6H), 2.13 (d, J=5.1 Hz, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=10.9 Hz, 2H), 1.57 (d, J=9.2 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1048.3
A mixture of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (1 g, 1.92 mmol, obtained by the similar way to example 446), methyl azetidine-3-carboxylate hydrochloride (435 mg, 2.88 mmol), Pd2(dba)3 (176 mg, 0.192 mmol), Xantphos (222 mg, 0.384 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) in dioxane (30 mL) was stirred at 100° C. for 18 hrs under nitrogen atmosphere. After cooling to rt, the reaction was diluted with EA (60 mL) and then washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column (PE:EA=1:1) to afford methyl 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylate (560 mg, 52.4%). [M+H]+=556.3.
To a solution of methyl 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylate (500 mg, 0.99 mmol) in THF (30 mL) and H2O (8 mL) was added LiOH H2O (210 mg, 5 mmol). The reaction was stirred at rt for 3 hr, before HCl (1 N) was added to PH=5-6. The layers were separated and the aqueous layer was extracted with EA (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylic acid (495 mg, 92.3%). [M+H]+=542.3.
The title compound (260 mg, 89%) was prepared in a manner similar to that in Example 458 step 9 from 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylic acid. [M+H]+=364.3.
To a solution of (6-((5-bromo-2-((2-methoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.069 mmol), 1-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carboxylic acid (30 mg, 0.083 mmol) in DMF (3 mL) was added HATU (31.5 mg, 0.083 mmol) and DIEA (22 mg, 0.166 mmol). After stirring at r. t. for 30 min, the reaction was quenched with water (6 mL), and the resulting mixture was extracted with DCM (10 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (12.15 mg, 23%).
1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 11.19 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 6.61 (dd, J=8.5, 2.3 Hz, 1H), 6.17 (dd, J=11.9, 2.3 Hz, 1H), 5.29 (dd, J=12.8, 5.1 Hz, 1H), 4.24 (t, J=8.0 Hz, 2H), 4.11 (t, J=6.9 Hz, 2H), 3.93-3.83 (m, 1H), 3.76 (s, 3H), 3.49 (s, 2H), 3.32-3.31 (m, 3H), 3.03-2.87 (m, 4H), 2.87-2.82 (m, 1H), 2.75-2.60 (m, 5H), 2.54 (s, 2H), 2.37 (d, J=10.9 Hz, 1H), 2.29 (d, J=7.1 Hz, 2H), 2.19-2.06 (m, 1H), 2.00 (s, 3H), 1.98 (s, 3H), 1.84 (d, J=9.3 Hz, 2H), 1.57 (d, J=9.6 Hz, 2H), 1.33-1.31 (m, 3H), 0.77 (s, 3H). [M+H]+=1066.7.
To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromobenzo[d]oxazol-2(3H)-one (3 g, 5.01 mmol), 3-((benzyloxy)methyl)azetidine (2 g, 6.90 mmol) in dry 1,4-dioxane (50 mL), were added tris(dibenzylideneacetone)dipalladium (600 mg, 0.66 mmol), Ruphos (600 mg, 1.29 mmol), and cesium carbonate (6.00 g, 18.4 mmol). The mixture was stirred overnight at 100° C. under nitrogen atmosphere. After cooled to room temperature, the mixture was diluted with ethyl acetate (300 mL). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 15%˜20%) to afford the target product (1.42 g, 46.7%). [M+H]+=600.1.
To a solution of 7-(3-((benzyloxy)methyl)azetidin-1-yl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)benzo[d]oxazol-2(3H)-one (1.4 g, 2.34 mmol) in tetrahydrofuran (40 mL), was added Pd/C (10 wt. %, wet, 1.5 g). The flask was evacuated and backfilled with hydrogen gas for 5 times, and stirred overnight under hydrogen atmosphere at 50° C. After cooled to rt, the resulting mixture was filtered, and the solid was washed with THF. The filtrate was concentrated under reduced pressure. The crude solid was washed by petroleum ether and dried under vacuum to afford the target product (650 mg, 83.9%). [M+H]+=332.1.
A mixture of 3-(7-(3-(hydroxymethyl)azetidin-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (100 mg, 0.30 mmol) and IBX (132 mg, 0.47 mmol) in DMSO (10 mL) was stirred in a flask at room temperature overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with sat. aq. NaCl (30 mL×3), sat. aq. NaHCO3(30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the product (70 mg, 70.1%). [M+H]+=330.1.
The title compound (15 mg, 26.3%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 1-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carbaldehyde.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.20 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.76 (s, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 5.30 (dd, J=12.9, 5.5 Hz, 1H), 4.11 (t, J=7.4 Hz, 2H), 3.76 (s, 3H), 3.65 (t, J=6.6 Hz, 2H), 3.28-3.23 (m, 2H), 2.93-2.90 (m, 6H), 2.68-2.64 (m, 4H), 2.60-2.51 (m, 5H), 2.41-2.37 (m, 3H), 2.31-2.27 (m, 3H), 2.15-2.11 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.84 (d, J=10.5 Hz, 2H), 1.58-1.52 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1034.7
The title compound (20.25 mg, 41%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 1-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carbaldehyde.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.18 (s, 1H), 8.55 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 6.75 (s, 1H), 6.56 (dd, J=8.5, 2.3 Hz, 1H), 6.10 (dd, J=11.9, 2.3 Hz, 1H), 5.28 (dd, J=12.8, 5.2 Hz, 1H), 4.13 (t, J=7.6 Hz, 2H), 3.76 (s, 3H), 3.68 (t, J=6.7 Hz, 2H), 3.32 (s, 2H), 2.95-2.92 (m, 5H), 2.85-2.81 (m, 1H), 2.68-2.64 (m, 4H), 2.57-2.53 (m, 1H), 2.41-2.37 (m, 4H), 2.28 (s, 3H), 2.16-2.06 (m, 1H), 2.02 (s, 3H), 1.98 (s, 6H), 1.84 (d, J=11.0 Hz, 2H), 1.55-1.51 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1052.6.
The title compound (50 mg, 55%) was prepared in a manner similar to that in Example 447.
1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 11.20 (s, 1H), 8.65-8.52 (m, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.09 (t, J=8.2 Hz, 1H), 6.81-6.69 (m, 3H), 5.33 (d, J=18.5 Hz, 1H), 3.76 (s, 3H), 3.71 (d, J=11.9 Hz, 2H), 3.55 (s, 2H), 3.47 (s, 2H), 3.01-2.78 (m, 9H), 2.70-2.62 (m, 4H), 2.55 (d, J=10.0 Hz, 2H), 2.36 (d, J=1.9 Hz, 1H), 2.29 (d, J=7.8 Hz, 2H), 2.14 (t, J=5.2 Hz, 1H), 1.98 (d, J=13.3 Hz, 7H), 1.84 (s, 2H), 1.73 (s, 4H), 1.58 (d, J=11.9 Hz, 2H), 1.31 (d, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1076.3.
The title compound (50 mg, 55.2%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.09 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (s, J=8.9 Hz, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.03-6.94 (m, 2H), 6.91 (dd, J=6.3, 2.8 Hz, 1H), 6.76 (s, 1H), 5.37 (dd, J=12.7, 5.4 Hz, 1H), 3.76 (s, 3H), 3.59 (s, 3H), 3.09-3.04 (m, 2H), 2.94 (t, J=9.7 Hz, 4H), 2.90 (d, J=7.0 Hz, 1H), 2.86 (d, J=5.5 Hz, 1H), 2.73 (dd, J=13.0, 4.5 Hz, 1H), 2.71-2.66 (m, 2H), 2.66-2.63 (m, 1H), 2.61 (d, J=3.6 Hz, 1H), 2.55 (t, J=8.6 Hz, 7H), 2.30 (s, 4H), 1.98 (d, J=13.3 Hz, 7H), 1.85 (d, J=12.0 Hz, 2H), 1.61-1.48 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.78 (s, 3H). [M+H]+=1006.2
A mixture of 6-bromo-5-fluoro-N1-methylbenzene-1,2-diamine (2.8 g, 12.8 mmol) and CDI (2.5 g, 15.4 mmol) in THF (40 mL) was stirred in a flask at 70° C. for 4 hrs. The reaction was diluted with H2O (160 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford 7-bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.8 g, 89.3%). [M+H]+=245.0.
To a solution of 7-bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.6 g, 10.7 mmol) was added sodium tert-butoxide (1 M in THF, 21.4 mmol, 21.4 mL) at 0° C. After stirring at 20° C. for 2 hrs, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (6.1 g, 16.0 mmol) in THF (50 mL) was added at 0° C. The mixture was stirred at 20° C. for another 2 hrs. The reaction was diluted with sat. aq. sodium bicarbonate (160 mL), and the layers were separated. The aqueous layer was extracted with DCM (200 mL×3). The combined organic layers were washed with brine (150 mL×3), dried over Na2SO4, filtered and concentrated under vacuum to afford 3-(4-bromo-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (2.8 g, 55%). [M+H]+=476.1.
A mixture of 3-(4-bromo-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (1.0 g, 2.1 mmol) and MsOH (2.0 g, 21 mmol) in toluene (10 mL) was stirred in a flask at 100° C. for 4 hrs. The reaction was diluted with H2O (80 mL), and the layers were separated. The aqueous layer was extracted with DCM (60 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford 3-(4-bromo-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (670 mg, 90%). [M+H]+=356.0.
A mixture of 3-(4-bromo-5-fluoro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (670 mg, 1.9 mmol), Pd(dtbpf)Cl2 (130 mg, 0.2 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (560 mg, 2.8 mmol), CsF (574 mg, 3.8 mmol), DMF (20 mL) and H2O (3 mL) was stirred in a flask at 100° C. for 2 hrs under nitrogen atmosphere. The reaction was diluted with H2O (160 mL) and EtOAc, and the layers were separated. The aqueous layer was extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford (E)-3-(4-(2-ethoxyvinyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-TH-benzo[d]imidazol-1-yl)piperidine-2,6-dione (510 mg, 77.9%). [M+H]+=348.1.
(E)-3-(4-(2-ethoxyvinyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (510 mg, 1.5 mmol) was stirred in FA (40 mL) at RT for 2 hrs. The mixture was concentrated under vacuum to afford 2-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-TH-benzo[d]imidazol-4-yl)acetaldehyde (460 mg, 97.9%), which was used without further purification. [M+H]+=320.1.
The title compound (14 mg, 26.2%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.11 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.25 (m, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.00 (dd, J=8.6, 4.3 Hz, 1H), 6.89 (dd, J=10.5, 8.7 Hz, 1H), 6.76 (s, 1H), 5.37 (dd, J=12.7, 5.4 Hz, 1H), 3.76 (s, 3H), 3.59 (s, 3H), 3.22 (m, 2H), 3.11-3.04 (m, 2H), 2.98-2.82 (m, 5H), 2.75-2.62 (m, 4H), 2.62-2.51 (m, 8H), 2.31-2.27 (m, 3H), 2.01-1.96 (m, 7H), 1.84 (d, J=10.5 Hz, 2H), 1.54 (dd, J=20.2, 11.4 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1024.7
To a flask was added of 2,6-bis(benzyloxy)pyridin-3-amine (8 g, 26.14 mmol), LiHMDS (1 M in THF, 31 mL, 31 mmol) and 1-bromo-3-fluoro-2-nitrobenzene(5.7 g, 26.14 mmol) in THF at −78° C. After stirring for 1 h at −78° C., the reaction mixture was warmed to room temperature and stirred for another 3 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. Purification by silica gel column (PE:EA 1:1) afforded 2,6-bis(benzyloxy)-N-(3-bromo-2-nitrophenyl)pyridin-3-amine (8.1 g, 60.44%). [M+H]+=506.2.
A mixture of 2,6-bis(benzyloxy)-N-(3-bromo-2-nitrophenyl)pyridin-3-amine (8 g, 15.84 mmol), Fe (5.3 g, 94.64 mmol), NH4Cl (21.1 g, 39.60 mmol), MeOH (240 m1) and H2O (120 m1) was stirred at 70° C. overnight under nitrogen atmosphere. The resulting mixture was filtered, and the solid was washed with EA. The filtrate was diluted with H2O (300 mL) and extracted with EA (200 mL×3). The combined organic layers were washed with brine (200 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel column (DCM:MeOH 20:1) afforded N1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-bromobenzene-1,2-diamine (5.9 g, 77.63%). [M+H]+=476.3.
To a 250-mL round-bottom flask was added N1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-bromobenzene-1,2-diamine (5.8 g, 12.21 mmol), ACN (60 mL), and CDI (3.6 g, 12.16 mmol). The resulting solution was stirred for 1.5 hr at 25° C. The resulting mixture was diluted with H2O (150 mL) and extracted with EA (80 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel column with (PE:EA 5:1) afforded 4.7 g (77.04%) of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one, [M+H]+=502.3.
Into a 100-mL round-bottom flask were placed 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.00 g, 1.99 mmol), DMF (10 mL), Cs2CO3 (1.9 g, 5.84 mmol), and EtI (479 mL, 5.98 mmol). The resulting solution was stirred overnight at room temperature. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (100:0˜ 70:30). The collected fractions were combined and concentrated under vacuum. This resulted in 1.00 g (94.70%) of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-ethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one, [M+H]+=530.1.
To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-ethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 1.89 mmol), [(2-bromoethoxy)methyl]benzene (490 mg, 2.29 mmol) and benzamidine (60 mg, 0.38 mmol) in DMA (10 mL) were added Mn (310 mg, 5.64 mmol), nickel(II) iodide (120 mg, 0.38 mmol), NaI (140 mg, 0.93 mmol) and TFA (110 mg, 0.97 mmol) at 0° C. The mixture was stirred for 15 min at room temperature and then 2 h at 100° C. under nitrogen atmosphere. The reaction was quenched with H2O (300 mL) at room temperature. The resulting mixture was filtered, and the solid was washed with EA (100 mL). The filtrate was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was applied onto a silica gel column with PE:EA (100:0-75:25). This resulted in 4-(2-(benzyloxy)ethyl)-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-ethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (110 mg, 10.4%), [M+H]+=586.3.
Into a 50-mL round-bottom flask were placed 4-(2-(benzyloxy)ethyl)-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-ethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (110 mg, 0.34 mmol), THF (4 mL), and Pd/C (110 mg, 10 wt. %, wet). The resulting solution was stirred overnight at 25° C. under hydrogen atmosphere. The resulting mixture was filtered and concentrated under vacuum, which afforded 42.5 mg (71.3%) of 3-(3-ethyl-4-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, which was used without further purification. [M+H]+=318.2
1H NMR (500 MHz, DMSO) δ 11.10 (d, J=3.2 Hz, 1H), 7.31-7.15 (m, 1H), 7.07-6.86 (m, 3H), 5.40-5.35 (m, 1H), 4.86 (t, J=5.2 Hz, 2H), 4.08-4.04 (m, 2H), 3.86-3.58 (m, 2H), 3.04-2.57 (m, 4H), 1.30-1.12 (m, 3H).
The title compound (130 mg, 89.2%) was prepared in a manner similar to that in Example 486 step 8 from 3-(3-ethyl-4-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and DMP. [M+H]+=316.1.
The title compound (26 mg, 23.5%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(2,6-dioxopiperidin-3-yl)-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.11 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 6.98 (t, J=6.5 Hz, 2H), 6.96-6.90 (m, 1H), 6.76 (s, 1H), 5.37 (dd, J=12.5, 5.2 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 3.76 (s, 3H), 3.28-3.22 (m, 2H), 2.94 (m, 7H), 2.77-2.52 (m, 12H), 2.32-2.26 (m, 3H), 2.05-2.01 (m, 1H), 1.99 (d, J=13.3 Hz, 6H), 1.85 (d, J=10.9 Hz, 2H), 1.58-1.52 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.24 (t, J=7.0 Hz, 3H), 0.77 (s, 3H). [M+H]+=1020.7
The title compound (33 mg, 28.9%) was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.10 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 7.02-6.96 (m, 1H), 6.94 (d, J=6.7 Hz, 2H), 6.76 (s, 1H), 5.31 (dd, J=12.4, 5.2 Hz, 1H), 3.76 (s, 3H), 3.32-3.21 (m, 6H), 3.17-3.12 (m, 1H), 2.94-2.88 (m, 5H), 2.71-2.53 (m, 10H), 2.33-2.27 (m, 3H), 1.98 (d, J=13.3 Hz, 6H), 1.96-1.92 (m, 1H), 1.85 (d, J=10.7 Hz, 2H), 1.58-1.53 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.15-1.02 (m, 4H), 0.77 (s, 3H). [M+H]+=1032.7
The title compound (15 mg, 15%) was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.21 (s, 1H), 8.60-8.53 (m, 2H), 8.32-7.98 (m, 3H), 7.33 (s, 1H), 7.18-6.98 (m, 3H), 6.72 (s, 1H), 5.36 (dd, J=12.9, 5.3 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.00 (q, J=6.9 Hz, 2H), 3.00-2.91 (m, 2H), 2.90-2.81 (m, 3H), 2.74-2.60 (m, 5H), 2.58-2.54 (m, 9H), 2.40-2.36 (m, 2H), 2.29 (dd, J=12.0, 5.1 Hz, 1H), 2.19-2.10 (m, 1H), 2.08-1.93 (m, 6H), 1.88-1.76 (m, 2H), 1.65-1.51 (m, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.92-0.77 (m, 3H); [M+H]+=1024.6.
The title compound (22.98 mg, 43.7%) was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.20 (s, 1H), 8.55 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.75 (s, 1H), 5.35 (dd, J=12.9, 5.3 Hz, 1H), 3.75 (s, 3H), 2.93 (t, J=7.5 Hz, 6H), 2.75-2.58 (m, 8H), 2.56-2.52 (m, 2H), 2.36 (s, 3H), 2.27 (d, J=7.2 Hz, 5H), 2.18-2.08 (m, 1H), 2.00 (s, 3H), 1.98 (s, 3H), 1.84 (d, J=11.0 Hz, 2H), 1.77-1.64 (m, 2H), 1.63-1.43 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1007.5.
The title compound (24.65 mg, 31%) was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.20 (s, 1H), 8.55 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.42 (dd, J=14.1, 7.5 Hz, 2H), 7.36-7.21 (m, 2H), 6.75 (s, 1H), 5.34 (d, J=13.1 Hz, 1H), 3.76 (s, 3H), 2.94-2.92 (m, 6H), 2.78-2.76 (m, 3H), 2.72-2.60 (m, 4H), 2.53-2.51 (m, 4H), 2.49-2.46 (m, 3H), 2.29 (d, J=4.3 Hz, 4H), 2.15-2.12 (m, 1H), 1.99 (s, 3H), 1.97 (s, 3H), 1.84 (d, J=10.8 Hz, 2H), 1.55-1.53 (m, 2H), 1.33-1.31 (m, 3H), 0.77 (s, 3H). [M+H]+=1011.6.
To a 100-mL round-bottom flask was added 2-fluoro-6-nitrophenol (10 g, 63.69 mmol), THF (100 mL), and Pd/C (10 g, 10 wt. %, wet). The mixture was stirred overnight at 25° C. under hydrogen atmosphere. The resulting mixture was then filtered and concentrated under vacuum to afford 7 g (86.53%) of 2-amino-6-fluorophenol, which was used without further purification. [M+H]+=128.4.
Into a 500-mL round-bottom flask were placed 2-amino-6-fluorophenol (7 g, 55.11 mmol), ACN (210 mL), and CDI (11 g, 67.90 mmol). The resulting solution was stirred for 1.5 hr at 25° C. The resulting mixture was diluted with H2O (400 mL) and extracted with EA (150 mL×3). The combined organic layers were washed with brine (200 mL×3) and concentrated under reduced pressure. The residue was applied onto a silica gel column with PE:EA (5:1) This resulted in 5 g (59.3%) of 7-fluorobenzo[d]oxazol-2(3H)-one, [M+H]+=154.2.
Into a 100-mL round-bottom flask were placed 7-fluorobenzo[d]oxazol-2(3H)-one (5 g, 32.67 mmol), DMF (40 mL), and NBS(6.3 g, 35.94 mmol). The reaction was stirred overnight at room temperature. The resulting mixture was diluted with H2O (500 mL) and extracted with EA (150 mL×3). The combined organic layers were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (5:1). This resulted in 4 g (54.7%) of 6-bromo-7-fluorobenzo[d]oxazol-2(3H)-one, [M+H]+=232.1.
A mixture of 6-bromo-7-fluorobenzo[d]oxazol-2(3H)-one (4 g, 17.31 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.3 g, 17.60 mmol), Cu(OAc)2 (3.1 g, 17.30 mmol), pyridine (4.1 g, 51.90 mmol) and 4A MS (2.5 g) in dioxane (40 mL) was stirred at 80° C. overnight under oxygen atmosphere. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE:EA (1:1). This resulted in 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-7-fluorobenzo[d]oxazol-2(3H)-one (4 g, 44.44%), [M+H]+=521.2.
Into a 30-mL microwave vial #1, purged and maintained with nitrogen atmosphere, was placed Zn (1.1 g, 16.82 mmol), THF (8 mL), and TMSCI (86 μl, 73.1 mmol). The resulting solution was stirred for 10 min at room temperature. To this was added ethyl bromoacetate (1124 mg, 6.73 mmol). The resulting solution was stirred for 1.5 hrs at 60° C. Into a 100-mL 3-necked round-bottom flask, purged and maintained with nitrogen atmosphere, was placed 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-7-fluorobenzo[d]oxazol-2(3H)-one (1 g, 1.923 mmol), THF (10 mL), XPhos (184 mg, 3.85 mmol), and Pd2(dba)3 (176 mg, 0.192 mmol). To the above mixture was added the solution in vial #1 by a syringe through a millipore filter. The resulting solution was stirred for another 3 hrs at 60° C. The resulting solution was diluted with EA (50 mL). The pH value of the solution was adjusted to <7 with 2N HCl, and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was applied onto a silica gel column with EA/PE (1:1). This resulted in 600 mg (59.1%) of ethyl 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetate, [M+H]+=529.3.
Into a 50-mL round-bottom flask were placed ethyl 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetate (500 mg, 0.946 mmol), and THF (5 mL). LiBH4 (103 mg, 4.7 mmol) was then added at room temperature. The reaction was stirred overnight at room temperature. The reaction was then quenched by the addition of H2O (60 mL). The resulting mixture was extracted with EA (20 mL×3). The combined organic layers were washed with brine (40 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel column with DCM/MeOH (4:1) resulted in 290 mg (66.5%) of 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluoro-3-(2-hydroxyethyl)phenol, [M+H]+=461.4.
Into a 100-mL round-bottom flask were placed 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluoro-3-(2-hydroxyethyl)phenol (270 mg, 0.58 mmol), DCM (5 mL), TBSCI (97 mg, 0.61 mml), and imidazole (64 mg, 0.94 mmol). The resulting solution was stirred for 1 hr at 25° C. The resulting mixture was diluted with H2O (30 mL), and the layers were separated. The aqueous layer was extracted with EA (20 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel column with DCM/MeOH (10:1) resulted in 230 mg (68.2%) of 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenol. [M+H]+=575.2.
Into a 25-mL round-bottom flask were placed 6-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenol (220 mg, 0.38 mmol), ACN (5 mL), and CDI (81 mg, 0.50 mmol). The resulting solution was stirred for 1.5 hr at 25° C. The resulting mixture was diluted with H2O (30 mL), and the layers were separated. The aqueous layer was extracted with EA (20 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was applied onto a silica gel column with PE:EA (5:1). This resulted in 170 mg (74.2%) of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluorobenzo[d]oxazol-2(3H)-one, [M+H]+=601.4.
Into a 25-mL round-bottom flask was placed 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluorobenzo[d]oxazol-2(3H)-one (170 mg, 0.28 mmol), THF (3 mL), and Pd/C (170 mg, 10 wt. %, wet). The resulting solution was stirred overnight at 25° C. under hydrogen atmosphere. The resulting mixture was filtered and concentrated under vacuum. This resulted in 110 mg (92.4%) of 3-(6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione, which was used without further purification ([M+H]+=423.2).
Into a 25-ml round-bottom flask were placed 3-(6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (110 mg, 0.26 mmol), DCM (4 mL), and TFA (2 mL). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. This resulted in 79.4 mg (99%) of 3-(7-fluoro-6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione, [M+H]+=308.2.
1H NMR (500 MHz, DMSO) δ 11.24 (s, 1H), 7.21-7.02 (m, 2H), 5.42-5.34 (m, 1H), 4.58-4.44 (m, 1H), 3.77-3.46 (m, 2H), 2.95-2.78 (m, 2H), 2.71-2.62 (m, 2H), 2.22-2.11 (m, 1H), 1.25 (d, J=4.0 Hz, 1H).
The title compound (60 mg, 80%) was prepared in a manner similar to that in Example 448 step 3 from 3-(7-fluoro-6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione and DMP.
The title compound (30 mg, 40.5%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde.
1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 11.23 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.29 (d, J=17.1 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.21-7.15 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.75 (s, 1H), 5.38 (dd, J=13.0, 5.3 Hz, 1H), 3.76 (s, 3H), 2.93-2.88 (m, 9H), 2.67 (dd, J=14.2, 8.4 Hz, 5H), 2.49-2.38 (m, 5H), 2.28 (s, 4H), 2.22-2.14 (m, 1H), 2.02-1.95 (m, 7H), 1.82 (s, 2H), 1.53 (dd, J=20.1, 11.4 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1011.3.
To a solution of 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (4 g, 15.7 mmol) in DMSO (50 mL) was added cyclopropanol (912 mg, 15.7 mmol) and K2CO3 (4.34 g, 31.4 mmol) at 20° C. Then the mixture was warmed to 70° C. and stirred for 16 hrs. Then the mixture was diluted with EA (200 mL), washed with water (100 mL×2) and brine (100 mL×2). Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 80 g, PE:EA=10:1) to give the product (3.5 g, 76.2%).
To a solution of 1-bromo-2-chloro-4-cyclopropoxy-5-nitrobenzene (3.5 g, 12.0 mmol) in MeCN (50 mL) was added tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (3.56 g, 13.2 mmol) and K2CO3 (3.31 g, 24.0 mmol) at 25° C. Then the mixture was stirred at 80° C. for 16 hrs.
Then the mixture was cooled to rt and filtered. The solid was washed with EA. Then the filtrate was concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 80 g, DCM: MeOH=30:1) to give tert-butyl 4-(1-(2-bromo-5-cyclopropoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (4 g, 63.3%). [M+H]+=525.3.
To a suspension of tert-butyl 4-(1-(2-bromo-5-cyclopropoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2 g, 3.8 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (879 mg, 5.7 mmol) in dioxane (16 mL) and water (4 mL) was added K2CO3 (1.57 g, 11.4 mmol) and Pd(dppf)Cl2 (139 mg, 0.19 mmol). The mixture was warmed to 100° C. and stirred for 16 hrs under nitrogen atmosphere. Then the mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 40 g, DCM: MeOH=15: 1) to give tert-butyl 4-(1-(5-cyclopropoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.4 g, 77.9%). [M+H]+=473.3.
To a suspension of tert-butyl 4-(1-(5-cyclopropoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.4 g, 3.0 mmol) in MeOH (20 mL) was added Pd/C (1 g, 10 wt. %, wet). The mixture was stirred at rt for 16 hrs under hydrogen atmosphere. Then the mixture was filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to afford tert-butyl 4-(1-(4-amino-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.2 g, 90.0%). [M+H]+=445.3.
To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (553 mg, 1.3 mmol) in n-BuOH (10 mL) was added tert-butyl 4-(1-(4-amino-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (600 mg, 1.3 mmol) at 20° C. 4-Methylbenzenesulfonic acid (783 mg, 4.6 mmol) was added to the reaction mixture at 20° C. Then the mixture was stirred at 100° C. for 13 hrs. The mixture was diluted with water (100 mL), adjusted to pH=8 with 5N NaOH solution and then extracted with DCM (150 mL×3). The combined organic layers were washed with brine (150 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH (0.5% NH4OH)=10/1 to 5/1). (6-((5-bromo-2-((2-cyclopropoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (500 mg, 52%) was obtained. [M+H]+=733.2.
The title compound (32 mg, 48%) was prepared in a manner similar to that in Example 484 step 15 from (6-((5-bromo-2-((2-cyclopropoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 10.95 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.27 (d, J=7.5 Hz, 1H), 8.21 (s, 1H), 7.85-7.84 (m, 2H), 7.43 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.04 (d, J=10.0 Hz, 2H), 6.98 (s, 1H), 4.20 (dd, J=12.5, 5.0 Hz, 1H), 3.81 (dq, J=9.0, 3.0 Hz, 1H), 2.98 (d, J=10.5 Hz, 2H), 2.85-2.76 (m, 4H), 2.75-2.51 (m, 14H), 2.19-2.15 (m, 5H), 1.99-1.95 (m, 9H), 1.69-1.53 (m, 2H), 0.75 (t, J=7.5, 3H), 0.74-0.69 (m, 2H), 0.61-0.56 (m, 2H). [M+H]+=984.3.
To a solution of 2-fluoro-5-nitrobenzaldehyde (10.0 g, 59.17 mmol) in MeCN (150 mL) was added propionimidamide hydrochloride (9.59 g, 88.75 mmol) and K2CO3 (20.4 g, 147.93 mmol) at room temperature. The resulting mixture was stirred at 80° C. overnight. The reaction was concentrated to give the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-98: 2 gradient elution) to give a mixture (3.6 g, 30%) containing the desired product. [M+H]+=204.2.
To a solution of 2-ethyl-6-nitroquinazoline (3.6 g, 17.73 mmol) in THF (100 mL)/H2O (20 mL) was added Fe (4.96 g, 88.67 mmol) and NH4Cl (4.7 g, 88.67 mmol) at 25° C. Then the mixture was stirred at 25° C. overnight. The mixture was filtered through a pad of Celite and washed with EA (150 mL) and H2O (60 mL). The filtrate was separated and the organic layer was concentrated to give the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-20: 1 gradient elution) to give a mixture (1.8 g, 58%) containing the desired product. [M+H]+=174.2.
To a solution of 2-ethylquinazolin-6-amine (1.8 g, 10.4 mmol) in AcOH (30 mL) was added ICI (15.6 mL, 15.6 mmol) at 20° C. Then the mixture was stirred at 20° C. for 3 hours. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 and extracted with DCM (2×100 mL). The organic phase was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford the desired product (2.6 g, 84%). [M+H]+=300.1.
To a solution of 2-ethyl-5-iodoquinazolin-6-amine (2.6 g, 8.69 mmol) and dimethylphosphine oxide (1.36 g, 17.39 mmol) in dioxane (100 mL) was added K3PO4 (4.6 g, 21.73 mmol) at 20° C. Pd(OAc)2 (390 mg, 1.74 mmol) and Xantphos (1.0 g, 1.74 mmol) were added to the mixture at 20° C. The suspension was degassed under vacuum and purged with N2 three times. Then the mixture was stirred at 100° C. overnight. The mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give the desired product (2.1 g, 97%). [M+H]+=250.1.
To a solution of (6-amino-2-ethylquinazolin-5-yl)dimethylphosphine oxide (2.1 g, 8.4 mmol) and 5-bromo-2,4-dichloropyrimidine (5.7 g, 25.2 mmol) in n-BuOH (90 mL) was added DIEA(3.3 g, 25.2 mmol) at room temperature. The resulting mixture was stirred at 120° C. overnight. The reaction was concentrated to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-15: 1 gradient elution) to give the desired product (2.3 g, 62%).
1H NMR (500 MHz, DMSO) δ 12.44 (s, 1H), 9.83 (s, 1H), 8.59 (s, 1H), 8.56 (dd, J=9.3, 3.8 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 3.07 (q, J=7.6 Hz, 2H), 2.12-2.08 (m, 6H), 1.38 (t, J=7.6 Hz, 3H). [M+H]+=440.1.
To a solution of 4-ethyl-3-fluorophenol (35 g, 0.25 mol) in DMF (200 mL) was added K2CO3 (69 g, 0.5 mol), and EtI (50.7 g, 0.32 mol). The mixture was stirred at 20-30° C. for 18 hours. The reaction was quenched by H2O (200 mL) and extracted with EA (150 mL×2). The combined organic phases were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography with pure PE to give product. (35 g, 83.3%). [M+H]+=168.2.
To a solution of 4-ethoxy-1-ethyl-2-fluorobenzene (35 g, 0.2 mol) in Ac2O (100 mL) was added HNO3 (23.4 g, 0.26 mol) dropwise at 0° C. The mixture was stirred at r.t. for 2hs. The reaction was then quenched with Na2CO3 solution (500 mL). The layers were separated and the organic layer was concentrated to afford the product (25 g, 58.7%) which was used in the next step without further purification. 1H NMR (500 MHz, DMSO) δ 7.90 (d, J=8.0 Hz, 1H), 7.26 (d, J=12.0 Hz, 1H), 4.2 (q, J=7.0 Hz, 2H), 2.60 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.15 (t, J=7.5 Hz, 3H).
To a solution of 1-ethoxy-4-ethyl-5-fluoro-2-nitrobenzene (20 g, 94 mmol) in DMF (300 mL) was added tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (30 g, 112 mmol), and K2CO3 (32 g, 235 mmol). The mixture was stirred at 120° C. for 28 hours. The mixture was poured into ice water. The product (20 g, 46.1%) was isolated by filtration, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO) δ 7.74 (s, 1H), 6.73 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.30 (m, 4H), 3.23 (d, J=11.0 Hz, 2H), 2.71 (t, J=11.5 Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 2.47 (br s, 4H), 2.39 (t, J=11.0 Hz, 1H), 1.84 (d, J=11.5 Hz, 2H), 1.58 (q, J=10.5 Hz, 2H), 1.39 (s, 9H), 1.34 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H).
To a solution of tert-butyl 4-(1-(5-ethoxy-2-ethyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (20 g, 94 mmol) in THF (150 mL) was added Pd/C (2 g, 10 wt. %, wet). The mixture was stirred at r.t. under hydrogen atmosphere (1 atm) for 48 h. The solid was filtered off. The filtrate was concentrated for next step directly without further purification. [M+H]+=433.4.
To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (1.0 g, 2.27 mmol) and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.18 g, 2.73 mmol) in n-BuOH (30 mL) was added Ts-OH (1.17 g, 6.81 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was concentrated and basified with 0.5N NaOH (40 mL), then extracted with DCM (3×80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-5: 1 gradient elution) to give the desired product (720 mg, 43%). [M+H]+=736.2.
To a solution of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (60 mg, 0.082 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (33 mg, 0.123 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC to give the desired product (13.54 mg, 16%).
1H NMR (500 MHz, DMSO) δ 11.52 (s, 1H), 10.95 (s, 1H), 9.91 (s, 1H), 8.42 (s, 1H), 8.25 (d, J=19.9 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=9.3 Hz, 1H), 7.33 (s, 1H), 7.03 (d, J=10.2 Hz, 2H), 6.70 (s, 1H), 4.20 (dd, J=12.9, 5.2 Hz, 1H), 3.99 (q, J=6.9 Hz, 2H), 3.05 (q, J=7.5 Hz, 2H), 2.91 (d, J=10.3 Hz, 2H), 2.81-2.74 (m, 3H), 2.65-2.57 (m, 3H), 2.54-2.49 (m, 7H), 2.46 (s, 3H), 2.27-2.21 (m, 3H), 2.13 (d, J=9.6 Hz, 1H), 2.02 (d, J=13.4 Hz, 7H), 1.82 (d, J=10.9 Hz, 2H), 1.52 (d, J=9.1 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.68 (s, 3H); [M+H]+=987.7.
The title compound (32 mg, 45%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.66 (s, 1H), 11.01 (s, 1H), 8.53 (d, J=8.6 Hz, 1H), 8.15 (s, 2H), 7.88-7.77 (m, 2H), 7.37 (s, 1H), 7.32 (s, 1H), 6.81 (s, 2H), 6.65 (s, 1H), 5.27 (dd, J=12.6, 5.3 Hz, 1H), 3.94 (d, J=7.0 Hz, 2H), 3.54 (s, 3H), 3.03-2.95 (m, 2H), 2.92-2.77 (m, 6H), 2.57-2.48 (m, 12H), 2.25 (s, 7H), 2.02-1.88 (m, 7H), 1.77 (d, J=10.6 Hz, 2H), 1.47 (dd, J=20.1, 11.0 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H), 1.19 (t, J=6.9 Hz, 3H), 0.64 (s, 3H). [M+H]+=1034.4
The title compound (46 mg, 43%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.10 (s, 1H), 8.60 (d, J=9.1 Hz, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.01-7.82 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.80 (dd, J=11.0, 2.3 Hz, 1H), 6.71 (s, 1H), 5.35 (dd, J=12.4, 5.3 Hz, 1H), 4.00 (d, J=7.0 Hz, 2H), 3.57 (s, 3H), 3.11-3.03 (m, 2H), 2.93 (d, J=7.5 Hz, 4H), 2.84 (d, J=12.4 Hz, 1H), 2.73 (dt, J=17.1, 10.7 Hz, 2H), 2.62-2.55 (m, 12H), 2.26 (s, 3H), 2.02-1.92 (m, 7H), 1.83 (d, J=10.2 Hz, 2H), 1.61-1.41 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1038.4
A mixture of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (the compound was obtained similar to example 484) (75 mg, 0.10 mmol) and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde (35 mg, 0.12 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 10 min. To the mixture was added sodium triacetoxyborohydride (65 mg, 0.31 mmol), and the reaction was stirred at room temperature for another 0.5 h. Then the mixture was concentrated under vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (34 mg, 33.2%).
1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.20 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 5.35 (dd, J=12.9, 5.2 Hz, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.32-3.19 (m, 6H), 2.99-2.86 (m, 5H), 2.80-2.57 (m, 7H), 2.48-2.39 (m, 3H), 2.29-2.24 (m, 3H), 2.16 (dd, J=10.7, 5.2 Hz, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.82 (d, J=11.9 Hz, 2H), 1.52 (dd, J=19.9, 11.3 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1007.7
The title compound (42 mg, 36.8%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.18 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.22 (s, 2H), 7.96-7.83 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.24-7.15 (m, 1H), 7.08 (s, 1H), 6.71 (s, 1H), 5.32 (dd, J=13.0, 5.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.01-2.81 (m, 5H), 2.79-2.68 (m, 3H), 2.64 (dd, J=19.2, 8.3 Hz, 4H), 2.55 (d, J=7.8 Hz, 3H), 2.46 (d, J=7.8 Hz, 4H), 2.38-2.34 (m, 1H), 2.30 (s, 6H), 2.17-2.07 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.84 (d, J=11.3 Hz, 2H), 1.54 (dd, J=20.4, 11.2 Hz, 3H), 1.32 (s, 3H), 1.25 (s, 3H), 0.71 (s, 3H). [M+H]+=1021.4
The title compound (45 mg, 54.3%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.09 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.22 (s, 2H), 7.99-7.81 (m, 2H), 7.46 (t, J=10.0 Hz, 1H), 7.39 (s, 1H), 6.82-6.67 (m, 2H), 6.61-6.46 (m, 1H), 5.31 (dd, J=12.6, 5.1 Hz, 1H), 4.07 (t, J=6.4 Hz, 2H), 4.04-3.93 (m, 4H), 3.82-3.72 (m, 1H), 3.54 (s, 3H), 3.47-3.43 (m, 2H), 2.93 (q, J=7.4 Hz, 4H), 2.89-2.80 (m, 1H), 2.78-2.68 (m, 1H), 2.63 (t, J=16.1 Hz, 4H), 2.51 (s, 4H), 2.36 (s, 1H), 2.30-2.19 (m, 4H), 1.98 (d, J=13.3 Hz, 7H), 1.81 (d, J=10.7 Hz, 2H), 1.55 (dd, J=20.2, 11.2 Hz, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 0.89-0.55 (m, 3H). [M+H]+=1093.3.
The title compound (25 mg, 35%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.08 (s, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.22 (s, 2H), 7.99-7.72 (m, 2H), 7.53-7.31 (m, 2H), 6.71 (s, 2H), 6.45 (dd, J=12.3, 2.0 Hz, 1H), 5.30 (dd, J=12.6, 5.1 Hz, 1H), 3.99 (s, 4H), 3.52 (s, 6H), 2.93 (d, J=7.4 Hz, 6H), 2.56 (d, J=7.1 Hz, 9H), 2.38 (d, J=20.0 Hz, 4H), 2.25 (d, J=7.1 Hz, 3H), 1.98 (d, J=13.3 Hz, 7H), 1.82 (d, J=11.9 Hz, 2H), 1.52 (d, J=9.0 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (s, 3H), 0.70 (s, 3H). [M+H]+=1079.4
The title compound (25 mg, 27.3%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.09 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.02-6.96 (m, 1H), 6.96-6.89 (m, 2H), 6.71 (s, 1H), 5.38-5.25 (m, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.32-3.26 (m, 6H), 3.17-3.13 (m, 1H), 2.95-2.92 (m, 5H), 2.70-2.54 (m, 10H), 2.28-2.24 (m, 3H), 1.98 (d, J=13.3 Hz, 6H), 1.96-1.93 (m, 1H), 1.83 (d, J=10.2 Hz, 2H), 1.53 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 1.09 (m, 4H), 0.71 (s, 3H). [M+H]+=1046.7
To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-5-methylbenzo[d]oxazol-2(3H)-one (1 g, 1.933 mmol, the compound was obtained by the way similar to example 505), [(2-bromoethoxy)methyl]benzene (0.54 g, 2.51 mmol) and benzamidine (0.05 g, 0.387 mmol) in DMA(10 mL) were added Mn (0.37 g, 6.77 mmol), nickel(II) iodide (0.18 g, 0.58 mmol), NaI (0.06 g, 0.39 mmol) and TFA (0.11 g, 0.97 mmol) at 0° C. The mixture was stirred for 15 min at room temperature and then 2 h at 100° C. under nitrogen atmosphere. The reaction was quenched with H2O (150 mL) at room temperature. The resulting mixture was filtered, and the solid was washed with EA (50 mL). The filtrate was extracted with EA (50 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was applied onto a silica gel column with PE: EA (100: 0˜ 70: 30). This resulted in 7-(2-(benzyloxy)ethyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylbenzo[d]oxazol-2(3H)-one (500 mg, 45.2%), [M+H]+=573.2.
Into a 100-mL round-bottom flask was placed 7-(2-(benzyloxy)ethyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylbenzo[d]oxazol-2(3H)-one (497 mg, 0.87 mmol), THF (15 mL) and Pd/C (500 mg, 10 wt. %, wet). The resulting solution was stirred overnight at room temperature under hydrogen atmosphere. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 196 mg (74.0%) of 3-(7-(2-hydroxyethyl)-5-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione[M+H]+=305.2.
1H NMR (500 MHz, DMSO) δ 11.18 (s, 1H), 6.95 (s, 1H), 6.85 (s, 1H), 5.35-5.29 (m, 1H), 4.75 (t, J=5.4 Hz, 1H), 3.69-3.63 (m, 2H), 2.99-2.57 (m, 5H), 2.30 (s, 3H), 2.21-2.02 (m, 1H).
The title compound (48 mg, 89%) was prepared in a manner similar to that in Example 448 step 3 from 3-(7-(2-hydroxyethyl)-5-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione and DMP.
The title compound (30 mg, 46.8%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(3-(2,6-dioxopiperidin-3-yl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.19 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 8.22 (s, 2H), 7.91 (s, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 5.33 (dd, J=13.1, 5.3 Hz, 1H), 4.00 (d, J=7.0 Hz, 2H), 2.99-2.88 (m, 6H), 2.81 (s, 2H), 2.77-2.60 (m, 5H), 2.59-2.51 (m, 2H), 2.49-2.40 (m, 5H), 2.31-2.25 (m, 7H), 2.19-2.09 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=10.8 Hz, 2H), 1.53 (dd, J=20.1, 11.1 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1021.4
The title compound (28 mg, 37%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.65 (s, 1H), 11.10 (s, 1H), 8.53 (d, J=8.9 Hz, 1H), 8.17 (s, 1H), 8.15 (s, 1H), 7.95-7.69 (m, 2H), 7.38 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 6.88 (q, J=8.1 Hz, 2H), 6.64 (s, 1H), 5.31 (dd, J=12.0, 5.5 Hz, 1H), 3.93 (q, J=6.9 Hz, 2H), 2.86 (dd, J=15.0, 7.5 Hz, 6H), 2.80-2.69 (m, 3H), 2.56 (t, J=12.9 Hz, 6H), 2.41 (s, 6H), 2.30-2.12 (m, 6H), 1.91 (d, J=13.3 Hz, 7H), 1.75 (d, J=10.9 Hz, 2H), 1.45 (d, J=9.1 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H), 1.19 (t, J=6.9 Hz, 3H), 0.64 (s, 3H). [M+H]+=1021.4
The title compound (12 mg, 26%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.22 (s, 1H), 8.59 (d, J=8.8 Hz, 1H), 8.22 (d, J=4.8 Hz, 2H), 7.91 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.14 (dd, J=8.7, 4.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.71 (s, 1H), 5.40-5.32 (m, 1H), 4.00 (q, J=7.0 Hz, 2H), 2.97-2.83 (m, 8H), 2.73-2.57 (m, 7H), 2.57-2.51 (m, 6H), 2.30-2.20 (m, 3H), 2.16 (dd, J=10.2, 5.0 Hz, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.82 (d, J=11.6 Hz, 2H), 1.52 (d, J=8.9 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H); [M+H]+=1025.5.
The title compound (17.41 mg, 36%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.21 (s, 1H), 8.59 (d, J=8.8 Hz, 1H), 8.24 (d, J=16.3 Hz, 2H), 7.96-7.78 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.16 (dd, J=8.5, 2.5 Hz, 1H), 6.97 (dd, J=10.7, 2.5 Hz, 1H), 6.71 (s, 1H), 5.35 (dd, J=13.0, 5.4 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 2.93 (dd, J=15.0, 7.5 Hz, 4H), 2.86 (t, J=7.3 Hz, 3H), 2.76-2.68 (m, 1H), 2.68-2.61 (m, 3H), 2.58 (dd, J=14.3, 6.6 Hz, 3H), 2.53-2.51 (m, 1H), 2.51-2.50 (m, 3H), 2.49-2.46 (m, 3H), 2.32-2.20 (m, 3H), 2.20-2.09 (m, 1H), 1.99 (s, 3H), 1.97 (s, 3H), 1.82 (d, J=11.9 Hz, 2H), 1.56-1.51 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1025.6.
A mixture of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (75 mg, 0.10 mmol) and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetaldehyde (35 mg, 0.12 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 10 min. To the mixture was added sodium triacetoxyborohydride (65 mg, 0.31 mmol) and the reaction was stirred at room temperature for another 0.5 h. Then the mixture was concentrated under vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜50:50 gradient elution) to give the product (31 mg, 30.0%). 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.21 (s, 1H), 8.59 (d, J=9.0 Hz, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.13-7.09 (m, 3H), 6.71 (s, 1H), 5.36 (dd, J=12.9, 5.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.29-3.21 (m, 4H), 2.93-2.87 (m, 7H), 2.74-2.52 (m, 10H), 2.28-2.25 (m, 3H), 2.19-2.12 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=11.7 Hz, 2H), 1.53 (dd, J=20.3, 11.3 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1007.7
The title compound (16.4 mg, 32.1%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.28 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 8.23 (d, J=11.1 Hz, 2H), 7.96-7.74 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.25 (dd, J=12.5, 7.5 Hz, 1H), 6.71 (s, 1H), 4.02-3.98 (m, 2H), 3.29 (s, 4H), 2.95-2.91 (m, 5H), 2.84-2.82 (m, 2H), 2.75-2.55 (m, 9H), 2.30-2.26 (m, 6H), 1.99 (s, 3H), 1.97 (s, 3H), 1.82 (s, 2H), 1.55-1.52 (m, 2H), 1.33-1.31 (m, 3H), 1.28-1.24 (m, 3H), 0.71 (s, 3H). [M+H]+=1043.8.
The title compound (15.23 mg, 30%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.19 (s, 1H), 8.60 (d, J=8.7 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.01-7.85 (m, 2H), 7.44 (d, J=8.9 Hz, 1H), 7.39 (s, 1H), 6.71 (s, 1H), 6.48 (dd, J=8.3, 2.3 Hz, 1H), 6.17 (dd, J=13.0, 2.3 Hz, 1H), 5.28 (dd, J=12.9, 5.3 Hz, 1H), 4.04-3.98 (m, 2H), 3.62-3.58 (m, 2H), 3.51-3.49 (m, 2H), 3.42-3.39 (m, 2H), 3.23-3.12 (m, 2H), 2.93 (dd, J=14.9, 7.4 Hz, 4H), 2.84 (s, 1H), 2.71-2.60 (m, 4H), 2.56-2.52 (m, 4H), 2.42-2.34 (m, 6H), 2.12 (s, 2H), 1.99 (s, 3H), 1.97 (s, 3H), 1.85-1.82 (m, 2H), 1.69-1.66 (m, 1H), 1.55-1.52 (m, 2H), 1.34-1.31 (m, 3H), 1.27-1.24 (m, 3H), 0.71 (s, 3H). [M+H]+=1080.9.
The title compound (15.63 mg, 31%) was prepared in a manner similar to that in Example 447. 1HNMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.19 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 8.23 (d, J=10.7 Hz, 2H), 7.99-7.78 (m, 2H), 7.54-7.28 (m, 2H), 6.71 (s, 1H), 6.52 (dd, J=8.3, 2.2 Hz, 1H), 6.22 (dd, J=12.9, 2.2 Hz, 1H), 5.28 (dd, J=12.9, 5.2 Hz, 1H), 4.02-3.98 (m, 2H), 3.76-3.48 (m, 9H), 3.29-3.27 (m, 2H), 2.97-2.91 (m, 4H), 2.87-2.81 (m, 1H), 2.68-2.63 (m, 4H), 2.56-2.53 (m, 2H), 2.36 (s, 1H), 2.25 (d, J=7.0 Hz, 2H), 2.22-2.01 (m, 3H), 2.00 (s, 3H), 1.98 (s, 3H), 1.83 (d, J=10.5 Hz, 2H), 1.57-1.55 (m, 2H), 1.32-1.28 (m, 6H), 0.71 (s, 3H). [M+H]+=1094.7.
The title compound (30 mg, 45%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 11.19 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.02 (t, J=7.9 Hz, 1H), 6.76 (s, 1H), 6.54 (d, J=7.4 Hz, 1H), 6.40 (d, J=8.2 Hz, 1H), 5.30 (d, J=7.9 Hz, 1H), 3.76 (s, 3H), 3.71-3.44 (m, 11H), 2.94-2.90 (m, 6H), 2.67 (dd, J=22.2, 12.8 Hz, 5H), 2.57 (s, 2H), 2.35-2.31 (m, 3H), 2.16-2.11 (m, 3H), 1.98 (d, J=13.2 Hz, 6H), 1.84 (d, J=10.9 Hz, 2H), 1.57 (d, J=10.6 Hz, 2H), 1.32 (dd, J=8.6, 6.5 Hz, 3H), 0.77 (s, 3H). [M+H]+=1076.4
The title compound (14.2 mg, 27.6%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.18 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.23 (d, J=10.9 Hz, 2H), 8.00-7.64 (m, 2H), 7.53-7.21 (m, 2H), 6.71 (s, 1H), 6.56 (dd, J=8.5, 2.2 Hz, 1H), 6.10 (dd, J=11.9, 2.2 Hz, 1H), 5.28 (dd, J=12.9, 5.3 Hz, 1H), 4.13-4.11 (m, 2H), 4.01-3.99 (m, 2H), 3.69-3.67 (m, 2H), 2.95-2.92 (m, 5H), 2.86-2.82 (m, 1H), 2.68-2.65 (m, 5H), 2.57 (d, J=7.3 Hz, 2H), 2.54-2.51 (m, 3H), 2.40 (s, 4H), 2.31-2.19 (m, 3H), 2.11-2.09 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.82 (d, J=10.9 Hz, 2H), 1.53-1.51 (m, 2H), 1.33-1.31 (m, 3H), 1.27-1.24 (m, 3H), 0.71 (s, 3H). [M+H]+=1066.6.
The title compound (22.05 mg, 42.1%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.18 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.23 (d, J=11.0 Hz, 2H), 7.98-7.80 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.71 (s, 1H), 6.49-6.47 (m, 1H), 6.14 (dd, J=13.0, 2.1 Hz, 1H), 5.28-5.26 (m, 1H), 4.01-3.99 (m, 2H), 3.70 (d, J=5.7 Hz, 2H), 3.60 (s, 2H), 3.52 (s, 2H), 3.36 (s, 3H), 3.30-3.22 (m, 2H), 2.92 (s, 4H), 2.86-2.82 (m, 1H), 2.69-2.66 (m, 4H), 2.56-2.52 (m, 2H), 2.34 (d, J=11.8 Hz, 1H), 2.25 (d, J=6.7 Hz, 2H), 2.19-2.06 (m, 1H), 1.99 (s, 3H), 1.97 (s, 3H), 1.84-1.82 (m, 2H), 1.57-1.54 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (s, 3H), 1.21 (s, 3H), 1.01 (s, 3H), 0.71 (s, 3H). [M+H]+=1121.9.
The title compound (50 mg, 65%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.20 (s, 1H), 8.60 (d, J=9.2 Hz, 1H), 8.35-8.18 (m, 2H), 7.91 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.39 (s, 1H), 7.09 (t, J=8.1 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.72 (d, J=7.4 Hz, 2H), 5.33 (dd, J=12.9, 5.3 Hz, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.71 (d, J=11.9 Hz, 2H), 3.55 (s, 2H), 3.48 (s, 2H), 2.97-2.82 (m, 8H), 2.69-2.65 (m, 5H), 2.54 (s, 2H), 2.36 (s, 1H), 2.26 (s, 2H), 2.15 (d, J=5.4 Hz, 1H), 1.98 (d, J=13.3 Hz, 7H), 1.82 (d, J=11.4 Hz, 2H), 1.73 (s, 4H), 1.56 (d, J=8.8 Hz, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 0.71 (s, 3H). [M+H]+=1090.4.
The title compound (23.56 mg, 17.3%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 10.95 (s, 1H), 8.59 (d, J=9.0 Hz, 1H), 8.27 (br s, 1H), 8.22 (s, 1H), 7.95-7.81 (m, 2H), 7.48-7.38 (m, 2H), 7.03 (d, J=10.0 Hz, 2H), 6.70 (s, 1H), 4.20 (dd, J=13.0, 5.0 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 2.91 (d, J=11.0 Hz, 2H), 2.86-2.71 (m, 4H), 2.69-2.50 (m, 14H), 2.30-2.19 (m, 3H), 2.13-2.11 (m, 1H), 2.03-1.90 (m, 8H), 1.82 (d, J=11.0 Hz, 2H), 1.56-1.50 (m, 2H), 1.27-1.20 (m, 6H). [M+H]+=972.5.
A mixture of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (75 mg, 0.10 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (32 mg, 0.12 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 10 min. To the mixture was added sodium triacetoxyborohydride (65 mg, 0.31 mmol) and the reaction was stirred at room temperature for another 0.5 h. Then the mixture was concentrated under vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (29 mg, 29.2%). 1H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 10.97 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.23 (d, J=6.2 Hz, 2H), 7.93 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.03 (d, J=10.1 Hz, 2H), 6.70 (s, 1H), 4.20 (dd, J=12.7, 5.0 Hz, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.33-3.25 (m, 2H), 2.95-2.91 (m, 4H), 2.86-2.73 (m, 3H), 2.66-2.63 (m, 7H), 2.48-2.44 (m, 4H), 2.24 (d, J=7.2 Hz, 3H), 2.15-2.12 (m, 1H), 2.03-1.96 (m, 7H), 1.82 (d, J=11.1 Hz, 2H), 1.60-1.44 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H).[M+H]+=986.7.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (500 mg, 0.694 mmol) and 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (222.49 mg, 0.832 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 2 hour. To the mixture was added sodium triacetoxyborohydride (146.34 mg, 0.694 mmol) and the reaction was stirred at room temperature for another 2 h. The resulting mixture was diluted with H2O (60 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the crude product (600 mg), which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (450 mg, 66.7%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.88 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=12.4 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J=9.4 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J=10.0 Hz, 2H), 6.68 (s, 1H), 4.13 (dd, J=12.6, 5.0 Hz, 1H), 3.69 (s, 3H), 2.86 (dd, J=15.2, 7.6 Hz, 4H), 2.79-2.65 (m, 4H), 2.59 (t, J=11.3 Hz, 3H), 2.47 (s, 4H), 2.41-2.31 (m, 4H), 2.22 (d, J=4.7 Hz, 3H), 2.05 (s, 2H), 1.92 (d, J=13.3 Hz, 7H), 1.77 (d, J=10.2 Hz, 2H), 1.47 (d, J=8.8 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H), 0.70 (s, 3H). [M+H]+=972.7.
To a stirred solution of (R)-4,4-dimethylpyrrolidine-3-carboxylic acid (2 g, 13.96 mmol) in MeOH (30 mL) was added SOCl2 (1.66 g, 13.96 mmol) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 hrs at 60° C. temperature. The resulting mixture was concentrated under reduced pressure to afford the product (2.1 g, 95.8%) which was used for next step without further purification. [M+H]+=158.1
To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (9.25 g, 20.25 mmol) and_methyl (R)-4,4-dimethylpyrrolidine-3-carboxylate (2.1 g, 13.35 mmol) in dioxane (50 mL) were added Cs2CO3 (10.95 g, 33.37 mmol), Xantphos (1.54 g, 2.67 mmol) and Pd2(dba)3 (1.22 g, 1.35 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with water (3×200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5: 1) to afford the product (4.5 g, 60.8%); [M+H]+=559.6
To a solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylate (4.5 g, 8.05 mmol) in THF (40 mL) and H2O (10 mL) was added lithium hydroxide hydrate (337.9 mg, 8.05 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 5 h. The reaction was quenched with HCl (1 N) at 0° C. until pH=6 and the resulting mixture was extracted with EA (2×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the crude product (4.05 g, 92.46%), which was used for next step without further purification. [M+H]+=545.6
(R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid (4.5 g, 8.25 mmol) was dissolved in DCM (30 mL) and iPr-OH (30 mL). Pd/C (1 g, 10 wt. %, wet) was added to the solution in one portion. The resulting mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The solid was filtered off and the filtrate was concentrated to give the crude product. The crude was triturated with MTBE to give the desired product which was purified by HPLC (IF (2*25 cm, 5 um), 60% MtBE/40% MeOH:DCM=1:1, 80 bar, 20 ml/min) and corresponded to peak A @ 1.216 min/254 nm (1.13 g, 25%). [M+H]+=367.4.
A mixture of(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.0708 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid (28.5 mg, 0.0779 mmol), T3P (67.45 mg, 0.212 mmol) and DIEA (27.39 mg, 0.212 mmol) in DCM (4 mL) was stirred in a flask at room temperature for 1 hours. The mixture was diluted with water (20 mL), and the layers were separated. The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude (30 mg) product was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (30 mg, 40.21%). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.84 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.74 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (dd, J=12.4, 5.0 Hz, 1H), 3.76 (s, 3H), 3.46-3.41 (m, 8H), 3.09 (dd, J=18.7, 9.1 Hz, 2H), 2.95 (d, J=10.7 Hz, 2H), 2.84-2.72 (m, 1H), 2.65 (s, 5H), 2.54 (s, 2H), 2.41-2.24 (m, 3H), 2.08 (dd, J=23.4, 13.7 Hz, 1H), 1.98 (d, J=13.3 Hz, 8H), 1.83 (d, J=11.2 Hz, 2H), 1.57 (d, J=11.0 Hz, 2H), 1.23 (s, 1H), 1.18 (s, 3H), 0.99 (s, 3H), 0.77 (s, 3H). [M+H]+=1055.4.
A mixture of 3-(6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (4 g, 13.37 mmol) and DMP (8.76 g, 20.68 mmol) in DCM (50 mL) and THF (50 mL) was stirred in a flask at room temperature for 4 h. The reaction was quenched with water (200 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with saturated aqueous NaCl (50 mL×3) and saturated aqueous NaHCO3(50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford the product (2.0 g, 51.8%). [M+H]+=289.1.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.0708 mmol) and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde (24.48 mg, 0.0849 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 2 hour. To the mixture was added NaBH3CN (14.9 mg, 0.0708 mmol) and the reaction was stirred at room temperature for another 2 h. The resulting mixture was diluted with H2O (30 mL), and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the crude product (30 mg), The crude (30 mg) product was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (24 mg, 34.6%). 1H NMR (500 MHz, DMSO) δ 11.69 (s, 1H), 11.14 (s, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.38-7.29 (m, 2H), 7.24 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.67 (s, 1H), 5.28 (dd, J=12.9, 5.3 Hz, 1H), 3.69 (s, 3H), 2.88 (d, J=11.2 Hz, 4H), 2.72 (s, 3H), 2.68-2.60 (m, 4H), 2.58 (s, 7H), 2.51 (s, 4H), 2.23 (d, J=7.0 Hz, 2H), 2.12-2.05 (m, 1H), 1.91 (d, J=13.3 Hz, 7H), 1.80 (s, 2H), 1.51 (d, J=8.9 Hz, 2H), 0.70 (s, 3H). [M+H]+=979.3.
A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (72 mg, 0.10 mmol) and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde (35 mg, 0.12 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 10 min. To the mixture was added NaBH3CN (65 mg, 0.31 mmol) and the reaction was stirred at room temperature for another 0.5 h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (23 mg, 23.3%). 1H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 11.21 (s, 1H), 8.58 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.75 (s, 1H), 5.35 (dd, J=12.9, 5.3 Hz, 1H), 3.76 (s, 3H), 3.31-3.20 (m, 6H), 2.93-2.88 (m, 9H), 2.76-2.56 (m, 8H), 2.31-2.28 (m, 2H), 2.19-2.11 (m, 1H), 1.98-1.95 (m, 7H), 1.61 (s, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.76 (s, 3H). [M+H]+=993.7.
A mixture of 2-amino-5-bromo-4-fluorophenol (3 g, 14.63 mmol), CDI (2.84 g, 17.6 mmol) in THF (50 mL) was stirred at 80° C. for 3 hrs. After cooling to rt, the reaction mixture was concentrated in vacuo. The residue was dissolved in EA (60 mL), which was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford 6-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (3.2 g, 94.1%). [M+H]+=231.9.
To a mixture of 6-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (3 g, 12.9 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.47 g, 15.5 mmol) in dioxane (30 mL) was added pyridine (10.2 g, 129 mmol), Cu(OAc)2 (2.58 g, 12.9 mmol) and 4A molecular sieve (2.5 g). The mixture was stirred at 80° C. under oxygen atmosphere for 3ds. After cooling to r.t, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (PE:EA=8:1) to afford the product (3.3 g, 49.1%). [M+H]+=521.1.
To a mixture of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (1 g, 1.92 mmol), NiI2 (120 mg, 0.38 mmol), ((2-bromoethoxy)methyl)benzene (619 mg, 2.88 mmol), picolinimidamide hydrochloride (60 mg, 0.38 mmol), NaI (144 mg, 0.96 mmol), and Mn (317 mg, 5.76 mmol) in DMA (20 mL), was added TFA (66 mg, 0.58 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 3 hrs. After cooling to r.t, the reaction was diluted with EA (60 mL) and then washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=10:1) to afford 6-(2-(benzyloxy)ethyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzo[d]oxazol-2(3H)-one (330 mg, 29.8%). [M+H]+=577.2.
To a mixture of 6-(2-(benzyloxy)ethyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzo[d]oxazol-2(3H)-one (330 mg, 0.57 mmol) in DMF (8 mL) and EtOH (2 mL) was added Pd/C (150 mg, 10 wt. %, wet). The resulting mixture was stirred at r.t under hydrogen atmosphere for 16 hrs. The reaction mixture was filtered and concentrated in vacuo to afford 3-(5-fluoro-6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (160 mg, 91%). [M+H]+=309.1.
To a solution of 3-(5-fluoro-6-(2-hydroxyethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (160 mg, 0.52 mmol) in THF (3 mL) and DCM (3 mL) was added DMP (329 mg, 0.78 mmol). After stirring at r. t. for 2hs, the reaction was diluted with water (6 mL), and the layers were separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (DCM:CH3OH=15:1) to afford 2-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde (100 mg, 62.5%). [M+H]+=307.1.
To a solution of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.068 mmol, the compound was obtained similar to example 484), 2-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde (25 mg, 0.082 mmol) in DCM (4 mL) was added STAB (28.8 mg, 0.136 mmol). After stirring at r. t. for 2 h, the reaction was diluted with water (6 mL), and the layers were separated. The aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (C-18 column chromatography (0.1% FA in water: acetonitrile=90: 10˜ 60: 40 gradient elution) to afford the product (16.7 mg, 24%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.21 (s, 1H), 8.59 (d, J=8.9 Hz, 1H), 8.26-8.24 (m, 1H), 8.23 (s, 1H), 8.00-7.77 (m, 2H), 7.53-7.36 (m, 3H), 7.29-7.27 (m, 1H), 6.65 (s, 1H), 5.36-5.31 (m, 1H), 4.06-3.92 (m, 2H), 2.96-2.91 (m, 4H), 2.89-2.81 (m, 1H), 2.81-2.74 (m, 2H), 2.73-2.70 (m, 1H), 2.65-2.61 (m, 4H), 2.53-2.51 (m, 3H), 2.49-2.42 (m, 4H), 2.27-2.23 (m, 4H), 2.19-2.10 (m, 1H), 2.00 (s, 3H), 1.97 (s, 3H), 1.82 (d, J=12.3 Hz, 2H), 1.54-1.51 (m, 2H), 1.33-1.30 (m, 3H), 1.27-1.24 (m, 4H), 0.75-0.69 (m, 3H). [M+H]+=1025.9.
The title compound (31 mg, 56%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 11.21 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.39-8.10 (m, 2H), 8.04 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 7.17-7.01 (m, 3H), 6.71 (s, 1H), 5.36 (dd, J=12.8, 5.2 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 3.01-2.81 (m, 7H), 2.77-2.52 (m, 13H), 2.38-2.08 (m, 5H), 2.00 (d, J=13.3 Hz, 6H), 1.85-1.83 (m, 2H), 1.57-1.50 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.75 (s, 3H). [M+H]+=1025.8.
The title compound (180 mg, 32.6%) was prepared in a manner similar to that in Example 492 step 3 from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-5-fluorobenzo[d]oxazol-2(3H)-one and ((3-bromopropoxy)methyl)benzene. [M+H]+=591.2.
The title compound (90 mg, 78.9%) was prepared in a manner similar to that in Example 492 step 4 from 7-(3-(benzyloxy)propyl)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluorobenzo[d]oxazol-2(3H)-one and Pd/C (10 wt. %, wet). [M+H]+=323.1.
The title compound (60 mg, 87.6%) was prepared in a manner similar to that in Example 492 step 5 from 3-(5-fluoro-7-(3-hydroxypropyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione and HCOOH. [M+H]+=321.1.
A mixture of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (75 mg, 0.10 mmol) and 3-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)propanal (38 mg, 0.12 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 10 min. To the mixture was added sodium triacetoxyborohydride (65 mg, 0.31 mmol) and the reaction was stirred at room temperature for another 0.5 h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜50:50 gradient elution) to give the product (30 mg, 28.4%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.21 (s, 1H), 8.59 (d, J=8.8 Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J=6.2 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.71 (s, 1H), 5.35 (dd, J=13.0, 5.5 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.29 (s, 1H), 2.97-2.82 (m, 5H), 2.76-2.54 (m, 10H), 2.42-2.23 (m, 8H), 2.18-2.13 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.82-1.77 (m, 4H), 1.54-1.51 (m, 2H), 1.32 (s, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1039.7
A mixture of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (75 mg, 0.10 mmol) and 1-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)azetidine-3-carbaldehyde (40 mg, 0.12 mmol) in DCM (8 mL) was stirred in a flask at room temperature for 10 min. To the mixture was added sodium triacetoxyborohydride (65 mg, 0.31 mmol) and the reaction was stirred at room temperature for another 0.5 h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (33 mg, 31.2%). 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.19 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J=4.7 Hz, 1H), 7.91 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.39 (s, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.71 (s, 1H), 6.57 (d, J=7.9 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 5.29 (dd, J=12.9, 5.4 Hz, 1H), 4.11 (t, J=7.5 Hz, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.65 (t, J=6.6 Hz, 2H), 3.26-3.20 (m, 2H), 2.98-2.83 (m, 6H), 2.70-2.52 (m, 9H), 2.44-2.38 (m, 3H), 2.32-2.20 (m, 3H), 2.16-2.08 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=11.5 Hz, 2H), 1.54-1.51 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1048.7
The title compound was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 11.14 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.09-8.34 (m, 2H), 7.97 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.34 (d, J=6.1 Hz, 2H), 7.22 (d, J=9.5 Hz, 1H), 6.64 (s, 1H), 5.28 (dd, J=13.0, 5.3 Hz, 1H), 3.94 (q, J=6.9 Hz, 2H), 2.75-2.94 (m, 5H), 2.46-2.74 (m, 11H), 2.15-2.40 (m, 8H), 2.05-2.10 (m, 1H), 1.93 (d, J=13.3 Hz, 6H), 1.74-1.76 (m, 2H), 1.38-1.56 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 1.19 (t, J=6.9 Hz, 3H), 0.68 (s, 3H). [M+H]+=1043.7.
To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (300 mg, 0.68 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (342 mg, 0.82 mmol) in n-BuOH (10 mL) was added Ts-OH (350 mg, 2.04 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was concentrated and basified with 0.5N NaOH (10 mL), then extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-5: 1 gradient elution) to give the desired product (230 mg, 46%). [M+H]+=722.2.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (60 mg, 0.083 mmol) and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde (36 mg, 0.125 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC to give the desired product (14.62 mg, 17.8%). 1H NMR (500 MHz, DMSO) δ 11.60 (s, 1H), 11.20 (s, 1H), 9.86 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.29 (d, J=13.2 Hz, 2H), 7.16 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.74 (s, 1H), 5.35 (dd, J=12.6, 5.1 Hz, 1H), 3.75 (s, 3H), 3.05 (q, J=7.5 Hz, 2H), 2.96-2.86 (m, 3H), 2.77 (t, J=7.3 Hz, 2H), 2.71-2.63 (m, 5H), 2.57-2.51 (s, 6H), 2.47-2.43 (m, 2H), 2.26 (s, 3H), 2.17-2.13 (m, 1H), 2.03 (d, J=13.4 Hz, 7H), 1.84 (d, J=11.5 Hz, 2H), 1.54 (d, J=10.2 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H), 0.75 (s, 3H); [M+H]+=994.7.
The title compound was prepared in a procedure similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 11.21 (s, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.17-8.38 (m, 2H), 8.04 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 5.35 (dd, J=12.9, 5.2 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 2.88-2.98 (m, 6H), 2.51-2.80 (m, 11H), 2.21-2.48 (m, 7H), 2.09-2.19 (m, 1H), 2.00 (d, J=13.3 Hz, 6H), 1.82-1.84 (m, 2H), 1.49-1.56 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.74 (s, 3H). [M+H]+=1025.6.
To a stirred solution of 6-bromophthalazin-1(2H)-one (10 g, 44.6 mmol) and Cs2CO3 (29.1 g, 89.2 mmol) in DMF (200 mL) was added iodoethane (10.4 g, 66.9 mmol). The resulting mixture was stirred at rt for 16 hours. The mixture was filtrated and the filtrate was concentrated under vacuum to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH=100:0˜ 100:10 gradient elution) to give the title product (10 g, 88.5%). [M+H]+=253.2.
To a stirred solution of 6-bromo-2-ethylphthalazin-1(2H)-one (10 g, 39.7 mmol), Cs2CO3 (25.9 g, 79.4 mmol), Pd2(dba)3 (3.6 g, 4.0 mmol), and BINAP(4.9 g, 7.9 mmol) in dioxane (200 mL) was added diphenylmethanimine (14.4 g, 79.4 mmol). The resulting mixture was stirred at 100° C. for 16 hours under nitrogen atmosphere. The mixture was filtrated and the filtrate was concentrated under vacuum to afford the crude product, which was purified with silica gel column chromatography (PE: EA=100:0˜ 1:1 gradient elution) to give the title product (12 g, 85.6%). [M+H]+=354.4.
A solution of 6-((diphenylmethylene)amino)-2-ethylphthalazin-1(2H)-one (12 g, 34 mmol) in 4N HCl in 1,4-dioxane (150 mL) was stirred in a round bottom flask at room temperature overnight. The mixture was concentrated under reduced pressure to afford the crude product (6 g, 93%), which was used for next step without further purification. [M+H]+=190.0.
To a stirred solution of 6-amino-2-ethylphthalazin-1(2H)-one (6 g, 31.6 mmol) in AcOH (100 mL) was added ICl (7.7 g, 47.7 mmol) at 20° C. Then the mixture was stirred at 20° C. for 1 hour.
Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×80 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH=100:0˜ 10:1 gradient elution) to give the title product (8 g, 80%). [M+H]+=316.0.
To a solution of 6-amino-2-ethyl-5-iodophthalazin-1(2H)-one (8 g, 25.4 mmol) and dimethylphosphine oxide (3.9 g, 50.8 mmol) in dioxane (120 mL) was added K3PO4 (10.8 g, 50.8 mmol) at 20° C. Pd(OAc)2 (569 mg, 2.54 mmol) and Xantphos (2.8 g, 5.1 mmol) were added to the mixture at 20° C. The flask was evacuated and backfilled with nitrogen three times. Then the mixture was stirred at 100° C. overnight. The mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give the desired product (6 g, 89%). [M+H]+=266.0.
To a solution of 6-amino-5-(dimethylphosphoryl)-2-ethylphthalazin-1(2H)-one (6 g, 22.6 mmol) and 5-bromo-2,4-dichloropyrimidine (10.2 g, 45.2 mmol) in THF (100 mL) was added LiHMDS (1 M in THF, 45.2 mL, 45.2 mmol) at room temperature. The resulting mixture was stirred at rt for 1 hour. The reaction was concentrated to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜15: 1 gradient elution) to give the desired product (8 g, 78%). [M+H]+=456.2.
To a solution of 6-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-2-ethylphthalazin-1(2H)-one (3 g, 6.6 mmol) and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (2.9 g, 6.6 mmol) in n-BuOH (100 mL) was added Ts-OH (3.5 g, 19.8 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was concentrated and basified with 0.5N NaOH (50 mL), then extracted with DCM (3×80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜5: 1 gradient elution) to give the desired product (3 g, 61%). [M+H]+=752.2.
To a solution of 6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-2-ethylphthalazin-1(2H)-one (50 mg, 0.06 mmol) and 2-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)acetaldehyde (23 mg, 0.07 mmol, the compound was obtained by the way similar to example 413) in DCM (10 mL) was added NaBH(OAc)3 (30 mg, 0.14 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0˜10: 1 gradient elution) to give the product (20 mg, 32%). 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.06 (s, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 8.19 (d, J=9.3 Hz, 1H), 8.10 (s, 1H), 7.33 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 6.74 (s, 1H), 5.21 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 4.00 (q, J=6.9 Hz, 2H), 2.98 (d, J=10.5 Hz, 2H), 2.84 (s, 4H), 2.72-2.53 (m, 11H), 2.40 (d, J=7.4 Hz, 4H), 2.04 (d, J=13.4 Hz, 6H), 1.95-1.90 (m, 4H), 1.58 (s, 2H), 1.38 (d, J=4.1 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 0.89 (s, 3H). [M+H]+=1050.4.
The title compound (497 mg, 60%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 10.85 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=8.9 Hz, 1H), 8.09 (s, 1H), 7.34 (s, 1H), 6.73 (s, 1H), 6.10 (d, J=11.1 Hz, 2H), 4.17 (d, J=7.1 Hz, 2H), 4.00 (d, J=6.9 Hz, 3H), 3.93 (s, 2H), 3.47 (s, 3H), 3.00-2.87 (m, 3H), 2.81-2.73 (m, 1H), 2.64 (t, J=11.1 Hz, 3H), 2.55 (d, J=6.8 Hz, 4H), 2.37-2.32 (m, 6H), 2.03-2.01 (m, 7H), 1.97-1.91 (m, 1H), 1.83 (d, J=11.0 Hz, 2H), 1.55 (dd, J=20.3, 11.3 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H). [M+H]+=989.4.
The title compound (40 mg, 32.2%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.69 (s, 1H), 11.11 (s, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.26-8.21 (m, 2H), 7.89 (d, J=12.0 Hz, 2H), 7.46 (d, J=8.9 Hz, 1H), 7.42 (s, 1H), 7.02 (s, 1H), 6.91 (t, J=9.5 Hz, 1H), 6.72 (s, 1H), 5.38 (dd, J=12.7, 5.5 Hz, 1H), 4.01 (d, J=7.0 Hz, 2H), 3.60 (s, 3H), 3.32-3.24 (m, 7H), 3.10 (s, 3H), 2.98-2.83 (m, 6H), 2.67-2.64 (m, 7H), 2.27-2.24 (m, 2H), 2.01-1.97 (m, 8H), 1.60-1.57 (m, 2H), 1.33 (t, J=7.6 Hz, 3H), 1.27 (t, J=6.9 Hz, 3H), 0.70 (s, 3H). [M+H]+=1038.7.
The title compound (24 mg, 28.1%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.11 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.99 (d, J=5.3 Hz, 2H), 6.95-6.88 (m, 1H), 6.71 (s, 1H), 5.37 (dd, J=12.9, 5.2 Hz, 1H), 4.03-4.00 (m, 4H), 3.02-2.87 (m, 8H), 2.59-2.55 (m, 13H), 2.29-2.26 (m, 3H), 2.03-2.00 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=10.8 Hz, 2H), 1.55-1.51 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.27-1.23 (m, 6H), 0.71 (s, 3H). [M+H]+=1034.7
To a solution of 6-bromo-3-fluoro-2-nitrophenol (5 g, 21.3 mmol) in MeOH (100 mL) was added Raney Ni (5 g) at room temperature under hydrogen atmosphere. The resulting mixture was stirred at rt for 2 hours. The reaction was filtered and concentrated under reduced pressure to afford the desired product (4 g, 92%). [M+H]+=206.2.
To a solution of 2-amino-6-bromo-3-fluorophenol (4 g, 19.5 mmol) in THF (100 mL) was added CDI (4 g, 23.4 mmol) at room temperature. The resulting mixture was stirred at rt for 2 hours. The reaction was diluted with water (100 mL) and extracted with EA (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography(PE/EA=100:0˜1:1 gradient elution) to give the desired product (3.5 g, 77%). [M+H]+=232.3.
To a solution of 7-bromo-4-fluorobenzo[d]oxazol-2(3H)-one (3.5 g, 15.2 mmol) and 3-bromopiperidine-2,6-dione (5.8 g, 30.4 mmol) in DMF (50 mL) was added Cs2CO3 (9.9 g, 30.4 mmol) at room temperature. The resulting mixture was stirred at 60° C. overnight. The mixture was filtered, concentrated under reduced pressure and diluted with water (100 mL). The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was mashed with MeOH to give the desired product (1.5 g, 29%). [M+H]+=343.2.
To a solution of 3-(7-bromo-4-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (1.5 g, 4.4 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 8.8 mmol) in DMF (30 mL) was added Pd(dtbpf)Cl2 (286 mg, 0.44 mmol) and CsF (1.3 g, 8.8 mmol) at 20° C. The flask was evacuated and backfilled with nitrogen three times. Then the mixture was stirred at 100° C. overnight. The mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE:EA=100: 0-0: 100 gradient elution) to give the desired product (1.0 g, 68%). [M+H]+=335.4.
A solution of (E)-3-(7-(2-ethoxyvinyl)-4-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (1 g, 3.0 mmol) in FA (20 mL) was stirred at rt for 4 hours. The mixture was concentrated under reduced pressure to afford the desired product (600 mg, 65%). [M+H]+=307.1.
To a solution of (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol) and 2-(3-(2,6-dioxopiperidin-3-yl)-4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetaldehyde (26 mg, 0.08 mmol) in DCM (10 mL) was added NaBH(OAc)3 (30 mg, 0.14 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC to give the desired product (12 mg, 17%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.24 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.23 (d, J=9.9 Hz, 2H), 7.95-7.83 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.15-7.07 (m, 2H), 6.71 (s, 1H), 5.44 (s, 1H), 3.99 (t, J=7.0 Hz, 2H), 2.93 (dd, J=15.0, 7.5 Hz, 6H), 2.84 (t, J=7.5 Hz, 2H), 2.68-2.53 (m, 11H), 2.32-2.14 (m, 6H), 1.98 (d, J=13.3 Hz, 6H), 1.82 (d, J=11.1 Hz, 2H), 1.52 (d, J=8.7 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1025.4.
A mixture of 7-bromobenzo[d]oxazol-2(3H)-one (2.13 g, 10 mmol), 3-bromopiperidine-2,6-dione (3.8 g, 20 mmol) and Cs2CO3 (6.5 g, 20 mmol) in DMF (50 mL) was stirred in a round bottom flask at 50° C. for 16 hours. The reaction was quenched with water (300 mL) and the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine (60 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from MeOH to afford the product (2 g, 62%), [M+H]+=325.1.
A mixture of 3-(7-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (3.2 g, 10 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3 g, 15 mmol), Pd(Dtbpf)Cl2 (0.6 g, 1 mmol) and CsF (4.5 g, 30 mmol) in DMF (40 mL) was stirred in a round bottom flask at 100° C. overnight under nitrogen atmosphere. The reaction was quenched with water (300 mL) and the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine (60 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=100: 0˜ 10: 1 gradient elution) to afford the product (2.1 g, 68%), [M+H]+=317.1.
(E)-3-(7-(2-ethoxyvinyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (1.6 g, 5 mmol) in HCOOH (20 mL) was stirred in a round bottom flask at 25° C. for 2 hours. After concentration, the crude product was used directly for the next step without purification. [M+H]+=289.1.
The title compound (15 mg, 30%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 11.21 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.13 (dt, J=14.8, 7.5 Hz, 2H), 7.07 (d, J=7.8 Hz, 1H), 6.74 (s, 1H), 5.36 (dd, J=12.8, 5.1 Hz, 1H), 3.75 (s, 3H), 2.96-2.93 (m, 2H), 2.90-2.87 (m, 3H), 2.70-2.67 (m, 3H), 2.63-2.61 (m, 6H), 2.58-2.56 (m, 7H), 2.31-2.29 (m, 3H), 2.20-2.11 (m, 1H), 1.98 (d, J=13.3 Hz, 7H), 1.88-1.79 (m, 2H), 1.62-1.49 (m, 2H), 0.77 (s, 3H); [M+H]+=979.5.
The title compound (20.8 mg, 35%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 11.03 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.10 (s, 1H), 6.74 (s, 1H), 6.47 (s, 1H), 6.28 (d, J=8.3 Hz, 1H), 5.15 (s, 1H), 4.13 (d, J=5.6 Hz, 2H), 4.08-3.95 (m, 2H), 3.77 (d, J=12.3 Hz, 4H), 3.51 (s, 2H), 3.39 (s, 2H), 2.95 (d, J=11.0 Hz, 3H), 2.72-2.62 (m, 6H), 2.56 (dd, J=13.0, 8.2 Hz, 4H), 2.43-2.34 (m, 1H), 2.30 (d, J=7.1 Hz, 2H), 2.07 (s, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.93 (s, 1H), 1.83 (d, J=10.2 Hz, 2H), 1.57 (d, J=8.9 Hz, 2H), 1.35 (d, J=4.8 Hz, 6H), 0.77 (s, 3H). [M+H]+=1060.4.
The title compound (21 mg, 31.5%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.77 (d, J=13.3 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.23 (d, J=25.9 Hz, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.80 (d, J=9.3 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.26 (s, 1H), 6.68 (s, 1H), 6.04 (d, J=11.2 Hz, 2H), 3.97-3.92 (m, 1H), 3.86 (t, J=7.7 Hz, 2H), 3.69 (s, 3H), 3.47-3.38 (m, 3H), 2.86 (dd, J=15.0, 7.6 Hz, 5H), 2.70 (dd, J=21.2, 9.1 Hz, 2H), 2.60 (t, J=11.2 Hz, 2H), 2.47 (d, J=7.4 Hz, 4H), 2.33 (s, 3H), 2.22 (d, J=6.8 Hz, 4H), 2.00 (d, J=9.0 Hz, 1H), 1.91 (d, J=13.3 Hz, 8H), 1.76 (d, J=8.9 Hz, 2H), 1.46 (d, J=8.7 Hz, 2H), 1.29-1.20 (m, 3H), 0.70 (s, 3H). [M+H]+=1013.4
The title compound (12 mg, 26%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 11.22 (s, 1H), 8.57 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.19-7.02 (m, 3H), 6.75 (s, 1H), 3.76 (s, 3H), 3.01-2.82 (m, 9H), 2.79-2.53 (m, 14H), 2.29 (d, J=6.7 Hz, 2H), 2.20-2.10 (m, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.90 (d, J=9.9 Hz, 2H), 1.59 (d, J=9.4 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H); [M+H]+=993.5.
To a stirred mixture of 4-bromo-2-fluoroaniline (10 g, 52.6 mmol) in aqueous HCl (6M) (5 mL) was added (E)-but-2-enal (7.4 g, 105.3 mmol) in toluene (50 mL) dropwise at 100° C. The resulting mixture was stirred for 15 h at 100° C. under nitrogen atmosphere. The mixture was diluted with EA (50 mL) and the layers were separated. The aqueous layer was concentrated under reduced pressure.
The residue was dissolved in water (100 mL), and the pH was adjusted to 8-9 with aqueous NaOH (3M). The aqueous layer was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE/EA, 0-15%) to afford product (9 g, 71.3%). [M+H]+=240.0.
A mixture of 6-bromo-8-fluoro-2-methylquinoline (9 g, 37.5 mmol), diphenylmethanimine (7.5 g, 41.3 mmol), Pd2(dba)3 (1.7 g, 1.9 mmol), XantPhos (2.17 g, 3.8 mmol), and Cs2CO3 (30.6 g, 93.8 mmol) in dioxane (120 mL) was stirred at 100° C. under nitrogen atmosphere for 15 hrs. After cooling to r.t, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (PE: EA=4:1) to afford product (9.5 g, 74.2%). [M+H]+=341.1.
To a solution of N-(8-fluoro-2-methylquinolin-6-yl)-1,1-diphenylmethanimine (7.7 g, 22.5 mmol) in THF (50 mL) was added HCl (30 mL, 2N). The mixture was stirred at 20° C. for 30 mins and then sat. aq. Na2CO3 was added to PH=8-9. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE: EA=1:1). 8-fluoro-2-methylquinolin-6-amine (3.2 g, 80%) was obtained. [M+H]+=177.1.
To a solution of 8-fluoro-2-methylquinolin-6-amine (1.6 g, 9.1 mmol) in HOAc (15 mL) was added ICl (1.8 g, 10.9 mmol). The mixture was stirred at 20° C. for 3 hrs and then sat. aq. Na2CO3 was added to PH=8-9. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuum. 8-fluoro-5-iodo-2-methylquinolin-6-amine (2.1 g, 76.3%) was obtained. [M+H]+=303.0.
A mixture of 8-fluoro-5-iodo-2-methylquinolin-6-amine (2.1 g, 7 mmol), dimethylphosphineoxide (819 mg, 10.5 mmol), K3PO4 (3.7 g, 17.5 mmol), Pd(OAc)2 (160 mg, 0.7 mmol) and XantPhos (420 mg, 0.7 mmol) in dioxane (30 mL) was stirred for 3 h at 100° C. under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuum, the residue was purified by column chromatography (0-10% MeOH in DCM) to afford the product (1.2 g, 68.2%). [M+H]+=253.1.
To a solution of (6-amino-8-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (1.2 g, 4.8 mmol) in THF (30 mL) was added 5-bromo-2,4-dichloropyrimidine (2.8 g, 11.9 mmol). LiHMDS (1 M in THF, 11.9 mL, 11.9 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at 20° C. for 3 hrs. The mixture was diluted with water (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=20/1 to 10/1) to afford product (820 mg, 39.1%). [M+H]+=443.0.
To a stirred solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-8-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (820 mg, 1.85 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (775 mg, 1.85 mmol) in n-BuOH (40 mL) was added TsOH (890 mg, 5.6 mmol). The resulting mixture was stirred at 95° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in aqueous NaOH (1M, 10 mL). Then the aqueous layer was extracted with DCM (2×20 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=6:1) to give the title product (710 mg, 58.5%). [M+H]+=725.2.
The title compound (15 mg, 24%) was prepared in a manner similar to that in Example 484 step 15 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-8-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 10.95 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 8.23 (d, J=2.7 Hz, 1H), 8.15 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.34 (s, 1H), 7.03 (d, J=12.1 Hz, 2H), 6.74 (s, 1H), 4.20 (d, J=13.3 Hz, 1H), 3.77 (d, J=2.8 Hz, 3H), 2.97-2.95 (m, 2H), 2.81-2.76 (m, 3H), 2.70-2.53 (m, 13H), 2.50-2.35 (m, 6H), 2.17-2.09 (m, 1H), 2.05-1.94 (m, 7H), 1.86-1.84 (m, 2H), 1.55 (d, J=11.7 Hz, 2H), 0.82 (s, 3H). [M+H]+=976.4
The title compound was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 10.84 (s, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.40 (d, J=11.3 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 6.75 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.05-3.96 (m, 1H), 3.77 (s, 3H), 3.62-3.40 (m, 7H), 3.35-3.33 (m, 2H), 3.30-3.17 (m, 2H), 2.99-2.97 (m, 2H), 2.84-2.72 (m, 1H), 2.71-2.54 (m, 7H), 2.50-2.35 (m, 4H), 2.23-1.90 (m, 10H), 1.85-1.83 (m, 2H), 1.66-1.49 (m, 2H), 0.82 (s, 3H). [M+H]+=1045.6.
The title compound was prepared in a manner similar to that in Example 488.
1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 10.87 (s, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.39 (d, J=10.6 Hz, 1H), 8.25-8.11 (m, 2H), 7.51 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 6.74 (s, 1H), 6.63 (d, J=12.8 Hz, 2H), 4.05 (dd, J=12.6, 4.9 Hz, 1H), 3.80-3.76 (m, 5H), 3.54-3.46 (m, 5H), 2.98-2.96 (m, 2H), 2.91-2.72 (m, 4H), 2.72-2.51 (m, 8H), 2.50-2.29 (m, 4H), 2.16-1.91 (m, 8H), 1.84-1.82 (m, 2H), 1.71-1.49 (m, 6H), 0.81 (s, 3H). [M+H]+=1059.6.
The title compound (16 mg, 35%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.84 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 8.20-8.15 (m, 2H), 7.31 (s, 1H), 6.71 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.02 (dd, J=12.5, 5.0 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.53-3.43 (m, 9H), 3.28-3.18 (m, 4H), 3.09 (d, J=10.8 Hz, 2H), 2.82 -2.73 (m, 1H), 2.65 (t, J=11.1 Hz, 2H), 2.59 (s, 2H), 2.41 (t, J=11.1 Hz, 1H), 2.21-2.02 (m, 11H), 1.98-1.92 (m, 1H), 1.86 (d, J=10.5 Hz, 2H), 1.65-1.58 (m, 2H). [M+H]+=1030.4.
The title compound (20 mg, 29%) was prepared in a manner similar to that in Example 413. 1H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 11.00 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=9.3 Hz, 1H), 7.42-7.25 (m, 2H), 7.11 (t, J=7.8 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 5.14 (s, 1H), 3.70 (d, J=11.9 Hz, 4H), 2.87 (d, J=10.4 Hz, 2H), 2.77 (dd, J=18.7, 11.2 Hz, 4H), 2.60 (d, J=16.3 Hz, 6H), 2.55 (s, 1H), 2.53-2.45 (m, 7H), 2.23 (d, J=8.3 Hz, 3H), 1.92 (d, J=13.3 Hz, 7H), 1.78 (d, J=10.9 Hz, 2H), 1.49 (dd, J=20.3, 11.0 Hz, 2H), 1.33 (t, J=11.0 Hz, 7H), 0.71 (s, 3H). [M+H]+=1005.4
The title compound (42.5 mg, 55%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.78 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.19-8.16 (m, 2H), 7.94 (s, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.27 (s, 1H), 6.69 (s, 1H), 6.16 (d, J=12.3 Hz, 2H), 3.95 (dd, J=12.4, 4.5 Hz, 1H), 3.69 (s, 3H), 3.55-3.33 (m, 7H), 3.18 (d, J=7.8 Hz, 4H), 2.94-2.82 (m, 4H), 2.75-2.67 (m, 1H), 2.61 (t, J=11.0 Hz, 2H), 2.49 (d, J=12.2 Hz, 4H), 2.36-2.18 (m, 2H), 2.15-1.98 (m, 3H), 1.92 (d, J=13.3 Hz, 7H), 1.77 (d, J=10.7 Hz, 2H), 1.51 (d, J=9.9 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H), 0.71 (s, 3H). [M+H]+=1041.4.
The title compound (50 mg, 65%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 11.09 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.02-6.94 (m, 2H), 6.91 (dd, J=6.2, 2.6 Hz, 1H), 6.76 (s, 1H), 5.37 (dd, J=12.6, 5.3 Hz, 1H), 3.76 (s, 3H), 3.59 (s, 3H), 3.11-3.04 (m, 2H), 2.96-2.91 (m, 6H), 2.77-2.63 (m, 5H), 2.57 (dd, J=20.5, 12.4 Hz, 8H), 2.29 (d, J=4.6 Hz, 3H), 1.98 (d, J=13.3 Hz, 7H), 1.85 (d, J=10.9 Hz, 2H), 1.55 (d, J=9.0 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.78 (s, 3H). [M+H]+=1006.4
The title compound (14.71 mg, 14%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.87 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.30 (d, J=9.7 Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.74 (s, 1H), 6.63 (d, J=12.8 Hz, 2H), 4.05 (dd, J=12.5, 5.0 Hz, 1H), 3.84-3.70 (m, 5H), 3.54 (s, 2H), 3.46 (s, 2H), 2.95 (d, J=10.9 Hz, 2H), 2.90-2.73 (m, 4H), 2.71-2.61 (m, 5H), 2.55 (d, J=4.7 Hz, 3H), 2.45 (s, 2H), 2.41-2.33 (m, 1H), 2.30 (dd, J=13.3, 6.0 Hz, 2H), 2.15-2.03 (m, 1H), 2.03-1.91 (m, 7H), 1.83 (d, J=10.2 Hz, 2H), 1.72-1.49 (m, 6H), 0.93-0.60 (m, 3H). [M+H]+=1041.5.
The title compound (7.36 mg, 7%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.87 (s, 1H), 8.56 (d, J=9.0 Hz, 1H), 8.30 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 6.74 (s, 1H), 6.62 (d, J=12.8 Hz, 2H), 4.04 (dd, J=12.4, 5.0 Hz, 1H), 3.82-3.70 (m, 5H), 3.28-3.23 (m, 2H), 2.93 (d, J=10.6 Hz, 2H), 2.83-2.70 (m, 3H), 2.69-2.59 (m, 6H), 2.59-2.52 (m, 6H), 2.35-2.21 (m, 4H), 2.14-2.03 (m, 1H), 2.02-1.91 (m, 7H), 1.88-1.75 (m, 4H), 1.53 (dd, J=20.6, 10.4 Hz, 2H), 1.43 (dd, J=21.0, 10.8 Hz, 2H), 0.88-0.65 (m, 3H). [M+H]+=1013.7.
The title compound (13 mg, 26%) was prepared in a manner similar to that in Example 447. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 11.19 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=6.6 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44-7.33 (m, 2H), 7.03 (t, J=8.1 Hz, 1H), 6.74 (s, 1H), 6.61 (d, J=7.9 Hz, 1H), 6.31 (d, J=8.2 Hz, 1H), 5.30 (dd, J=13.0, 5.5 Hz, 1H), 4.21 (t, J=7.8 Hz, 2H), 4.08 (t, J=6.8 Hz, 2H), 3.88 (dd, J=14.9, 7.6 Hz, 1H), 3.74 (d, J=15.2 Hz, 3H), 3.51 (d, J=13.9 Hz, 2H), 3.01-2.79 (m, 3H), 2.74-2.65 (m, 4H), 2.58-2.51 (m, 5H), 2.48-2.43 (m, 2H), 2.42-2.23 (m, 4H), 2.19-2.09 (m, 1H), 1.97 (t, J=14.3 Hz, 7H), 1.83 (d, J=10.3 Hz, 2H), 1.57 (d, J=8.7 Hz, 2H), 0.77 (s, 3H); [M+H]+=1034.5.
The title compound (8 mg, 20%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.20 (s, 1H), 10.86 (s, 1H), 8.57 (s, 2H), 8.27-8.09 (m, 3H), 7.34 (s, 1H), 6.76 (s, 1H), 6.17 (d, J=11.1 Hz, 2H), 4.04 (s, 2H), 3.94-3.90 (m, 2H), 3.86-3.81 (m, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.49 (s, 4H), 2.99 (d, J=9.3 Hz, 2H), 2.83-2.64 (m, 6H), 2.42 (s, 3H), 2.12-1.91 (m, 10H), 1.84 (d, J=10.4 Hz, 2H), 1.65-1.54 (m, 2H), 0.92 (s, 3H). [M+H]+=1030.4.
The title compound (12 mg, 20%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.22 (s, 1H), 10.95 (s, 1H), 8.56 (s, 2H), 8.20-8.17 (m, 3H), 7.33 (s, 1H), 7.03 (d, J=10.1 Hz, 2H), 6.76 (s, 1H), 4.20 (dd, J=12.6, 4.9 Hz, 1H), 4.05-4.03 (m, 1H), 3.74-3.72 (m, 3H), 2.99 (d, J=10.0 Hz, 2H), 2.85-2.72 (m, 3H), 2.68 (t, J=11.0 Hz, 2H), 2.58-2.53 (m, 7H), 2.49-2.37 (m, 6H), 2.36-2.26 (m, 1H), 2.19-2.07 (m, 1H), 2.01 (d, J=13.2 Hz, 7H), 1.85 (d, J=11.4 Hz, 2H), 1.57 (dd, J=20.1, 11.2 Hz, 2H), 1.03 (d, J=12.0 Hz, 2H), 1.00-0.95 (m, 2H), 0.92 (s, 3H); [M+H]+=1001.5.
The title compound (16 mg, 22%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.23 (s, 1H), 11.20 (s, 1H), 8.55 (s, 2H), 8.25 (s, 1H), 8.17 (d, J=8.6 Hz, 2H), 7.30 (s, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.09-7.02 (m, 1H), 6.76 (s, 1H), 5.35 (dd, J=12.9, 5.2 Hz, 1H), 4.06-4.03 (m, 1H), 3.78-3.75 (m, 3H), 2.99-2.97 (m, 2H), 2.91-2.87 (m, 1H), 2.78-2.76 (m, 2H), 2.73-2.61 (m, 5H), 2.55-2.53 (m, 5H), 2.48-2.38 (m, 6H), 2.32-2.28 (m, 1H), 2.16-2.14 (m, 1H), 2.06-2.03 (m, 6H), 1.88-1.85 (m, 2H), 1.58-1.55 (m, 2H), 1.06-0.82 (m, 7H); [M+H]+=1022.5.
The title compound (10 mg, 30%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.14 (s, 1H), 11.13 (s, 1H), 8.50 (s, 2H), 8.22-8.06 (m, 3H), 7.23 (s, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.69 (s, 1H), 5.29 (s, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 2.92 (d, J=9.4 Hz, 2H), 2.86-2.79 (m, 1H), 2.71 (d, J=7.2 Hz, 2H), 2.65-2.55 (m, 5H), 2.46 (d, J=8.6 Hz, 5H), 2.36 (s, 7H), 2.09 (d, J=10.6, 1H), 1.96 (d, J=13.2 Hz, 6H), 1.78 (d, J=10.6 Hz, 2H), 1.50 (d, J=8.8 Hz, 2H), 0.85 (s, 3H). [M+H]+=996.4.
The title compound (9.05 mg, 12.7%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.86-11.58 (m, 1H), 11.16 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J=11.8 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.48-7.27 (m, 2H), 7.03 (d, J=8.6 Hz, 1H), 6.74 (s, 1H), 6.60-6.58 (m, 1H), 6.33 (dd, J=8.7, 2.1 Hz, 1H), 5.26 (dd, J=13.1, 5.3 Hz, 1H), 4.34 (d, J=4.6 Hz, 2H), 3.76 (s, 3H), 3.52-3.40 (m, 4H), 3.03-2.76 (m, 5H), 2.69-2.63 (m, 7H), 2.57-2.54 (m, 3H), 2.40-2.21 (m, 7H), 2.18-2.03 (m, 2H), 2.00 (s, 3H), 1.98 (s, 3H), 1.86-1.82 (m, 2H), 1.75-1.66 (m, 1H), 1.57-1.53 (m, 2H), 0.77 (s, 3H). [M+H]+=1034.5.
The title compound (20 mg, 26%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.23 (s, 1H), 10.84 (s, 1H), 8.55 (s, 2H), 8.25 (s, 1H), 8.19 (d, J=16.1 Hz, 2H), 7.30 (s, 1H), 6.77 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.07-3.97 (m, 2H), 3.75 (s, 3H), 3.60-3.40 (m, 7H), 3.34 (d, J=9.8 Hz, 1H), 3.30-3.21 (m, 4H), 3.06-2.93 (m, 2H), 2.77 (t, J=7.1 Hz, 1H), 2.69-2.67 (m, 2H), 2.59-2.58 (m, 2H), 2.42-2.39 (m, 4H), 2.15-2.10 (m, 1H), 2.09-2.07 (m, 2H), 2.04-2.02 (m, 5H), 1.96-1.91 (m, 1H), 1.89-1.81 (m, 2H), 1.62-1.60 (m, 2H), 1.02 (s, 2H), 1.00-0.85 (m, 5H); [M+H]+=1070.5.
The title compound (22 mg, 27%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.33 (s, 1H), 10.84 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 8.18 (s, 2H), 7.30 (s, 1H), 6.71 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.03-4.01 (m, 1H), 3.76-3.73 (m, 6H), 3.61-3.41 (m, 7H), 3.29-3.19 (m, 4H), 3.09-3.07 (m, 2H), 2.87-2.71 (m, 1H), 2.62-2.59 (m, 5H), 2.43-2.41 (m, 1H), 2.18-2.15 (m, 1H), 2.12-2.01 (m, 10H), 2.01-1.90 (m, 2H), 1.88-1.85 (d, 2H), 1.68-1.52 (m, 2H); [M+H]+=1030.5.
The title compound (15 mg, 29%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.21 (s, 1H), 10.84 (s, 1H), 8.56 (s, 2H), 8.25 (s, 1H), 8.21-8.14 (m, 2H), 7.30 (s, 1H), 6.77 (s, 1H), 6.24 (s, 1H), 6.22 (s, 1H), 4.02 (dd, J=12.6, 4.9 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.60-3.41 (m, 8H), 3.01 (d, J=9.6 Hz, 2H), 2.82-2.68 (m, 4H), 2.58 (s, 2H), 2.45-2.36 (m, 4H), 2.04 (d, J=13.3 Hz, 11H), 1.97-1.92 (m, 1H), 1.85 (d, J=11.3 Hz, 2H), 1.61 (d, J=10.2 Hz, 2H), 0.94 (s, 3H). [M+H]+=1044.7
The title compound (20 mg, 40%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.23 (s, 1H), 10.77 (s, 1H), 8.50 (s, 2H), 8.19 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.28 (s, 1H), 6.62 (s, 1H), 6.17 (s, 1H), 6.15 (s, 1H), 3.94 (d, J=6.9 Hz, 3H), 3.65 (s, 3H), 3.54-3.34 (m, 7H), 3.21-3.16 (m, 4H), 3.00 (d, J=10.0 Hz, 2H), 2.76-2.66 (m, 1H), 2.57-2.51 (m, 4H), 2.33 (t, J=11.3 Hz, 2H), 2.14-1.84 (m, 13H), 1.78 (d, J=11.1 Hz, 2H), 1.54 (d, J=10.5 Hz, 2H), 1.19 (s, 3H). [M+H]+=1044.7
The title compound (25 mg, 38%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.08 (s, 1H), 10.78 (s, 1H), 8.50 (s, 2H), 8.15-8.06 (m, 2H), 8.03 (s, 1H), 7.30 (s, 1H), 6.67 (s, 1H), 6.17 (s, 1H), 6.15 (s, 1H), 4.04-3.85 (m, 4H), 3.55-3.33 (m, 9H), 3.20-3.15 (m, 2H), 2.91 (d, J=10.1 Hz, 2H), 2.70 (d, J=12.6 Hz, 1H), 2.59 (t, J=11.1 Hz, 2H), 2.51 (s, 2H), 2.33 (d, J=7.4 Hz, 4H), 2.15-1.84 (m, 12H), 1.77 (d, J=10.6 Hz, 2H), 1.53 (d, J=10.1 Hz, 2H), 1.18 (t, J=6.9 Hz, 3H), 0.82 (s, 3H). [M+H]+=1058.4.
The title compound (40 mg, 55%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 10.84 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.89 (d, J=3.5 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 6.70 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.00 (d, J=7.0 Hz, 3H), 3.61-3.42 (m, 7H), 3.25 (dd, J=16.2, 8.7 Hz, 3H), 2.93 (d, J=11.0 Hz, 2H), 2.84-2.70 (m, 1H), 2.64 (d, J=10.3 Hz, 8H), 2.37 (s, 1H), 2.26 (d, J=7.0 Hz, 2H), 2.20-2.04 (m, 4H), 1.98 (d, J=13.3 Hz, 7H), 1.82 (d, J=11.2 Hz, 2H), 1.62-1.49 (m, 2H), 1.26 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1041.3.
The title compound (50 mg, 50%) was prepared in a manner similar to that in Example 492. [M+H]+=993.3. 1H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 11.20 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.22 (s, 2H), 7.93-7.81 (m, 2H), 7.48-7.39 (m, 2H), 7.30 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 5.35 (s, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.45 (s, 1H), 2.91 (d, J=11.2 Hz, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.72-2.57 (m, 8H), 2.53 (d, J=9.7 Hz, 4H), 2.36 (s, 4H), 2.27 (d, J=9.1 Hz, 3H), 2.16 (dd, J=10.8, 5.2 Hz, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.82 (d, J=11.9 Hz, 2H), 1.53 (d, J=8.8 Hz, 2H), 1.26 (t, J=6.9 Hz, 3H), 0.71 (s, 3H).
The title compound was prepared in the same procedure as Example 488. 1H NMR (500 MHz, DMSO) δ 12.14 (s, 1H), 10.84 (s, 1H), 8.54 (d, J=9.0 Hz, 1H), 8.32-8.16 (m, 3H), 7.53 (d, J=9.0 Hz, 1H), 7.32 (s, 1H), 6.75 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.5, 4.9 Hz, 1H), 3.77 (s, 3H), 3.62-3.43 (m, 6H), 3.35-3.34 (m, 3H), 3.28-3.23 (m, 2H), 3.02-2.90 (m, 4H), 2.84-2.70 (m, 1H), 2.70-2.52 (m, 5H), 2.40-2.33 (m, 3H), 2.22-1.90 (m, 10H), 1.85-1.83 (m, 2H), 1.60-1.54 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.80 (s, 3H). [M+H]+=1059.6.
The title compound was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.12 (s, 1H), 10.94 (s, 1H), 8.56-8.54 (m, 1H), 8.39-8.36 (m, 1H), 8.24-8.18 (m, 1H), 8.03 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 7.02 (d, J=10.1 Hz, 2H), 6.71 (s, 1H), 4.20 (dd, J=12.7, 5.0 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 2.95-2.93 (m, 2H), 2.86-2.72 (m, 3H), 2.70-2.52 (m, 12H), 2.48-2.22 (m, 7H), 2.13-2.09 (m, 1H), 2.04-1.95 (m, 7H), 1.84-1.82 (m, 2H), 1.56-1.50 (m, 2H), 1.26 (t, J=6.9 Hz, 3H), 0.76 (s, 3H). [M+H]+=990.6.
The title compound (10 mg, 32%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.08 (s, 1H), 10.78 (s, 1H), 8.50 (s, 2H), 8.18 (s, 2H), 8.11 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 7.29 (s, 1H), 6.66 (s, 1H), 4.00-3.90 (m, 4H), 3.87 (d, J=7.5 Hz, 3H), 3.66 (s, 3H), 3.40 (t, J=6.0 Hz, 3H), 2.95-2.80 (m, 4H), 2.76-2.65 (m, 2H), 2.58 (t, J=11.0 Hz, 3H), 2.33 (s, 5H), 2.22 (t, J=11.0 Hz, 2H), 2.06-1.83 (m, 10H), 1.77 (d, J=10.7 Hz, 2H), 1.48 (d, J=11.1 Hz, 2H), 1.18 (t, J=6.9 Hz, 3H), 0.82 (s, 3H). [M+H]+=1030.4
The title compound was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 11.20 (s, 1H), 8.53 (d, J=6.7 Hz, 1H), 8.40-8.37 (m, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.74 (s, 1H), 5.35 (dd, J=13.0, 5.3 Hz, 1H), 3.76 (s, 3H), 3.01-2.83 (m, 4H), 2.80-2.52 (m, 14H), 2.47-2.22 (m, 6H), 2.19-2.09 (m, 1H), 2.00 (d, J=13.3 Hz, 7H), 1.88-1.83 (m, 2H), 1.57-1.51 (m, 2H), 0.81 (s, 3H). [M+H]+=997.5.
The title compound (4.91 mg, 7.56%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 11.18 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 6.53 (s, 1H), 6.23 (d, J=8.7 Hz, 1H), 5.30-5.25 (m, 1H), 3.92-3.89 (m, 2H), 3.76 (s, 3H), 3.47-3.39 (m, 4H), 2.98-2.82 (m, 5H), 2.73-2.63 (m, 7H), 2.56-2.53 (m, 4H), 2.42-2.39 (m, 3H), 2.30-2.28 (m, 3H), 2.13-2.10 (m, 1H), 2.00 (s, 3H), 1.97 (s, 3H), 1.83 (d, J=11.3 Hz, 2H), 1.56-1.52 (m, 2H), 0.77 (s, 3H). [M+H]+=1020.5.
To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.069 mmol, the compound was obtained by the way similar to example 484), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (35 mg, 0.10 mmol) and DIEA (45 mg, 0.35 mmol) in DMF (2 mL) was added HATU (38 mg, 0.10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was purified with prep-HPLC chromatography (0.1% FA in water: acetonitrile=90:10˜ 50:50 gradient elution) to give the product (9.8 mg, 13%).
1H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 10.85 (s, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.48 (s, 1H), 8.30 (d, J=5.7 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 6.83 (s, 1H), 6.25 (d, J=12.1 Hz, 2H), 4.54 (d, J=13.3 Hz, 1H), 4.26 (d, J=13.3 Hz, 2H), 4.04-3.99 (m, 3H), 3.79 (s, 3H), 3.59 (d, J=6.9 Hz, 4H), 3.49 (s, 1H), 3.39-3.27 (m, 4H), 3.12 (d, J=8.6 Hz, 3H), 3.00 (d, J=7.6 Hz, 3H), 2.83-2.74 (m, 3H), 2.19 (s, 5H), 2.02 (d, J=14.4 Hz, 7H), 1.98-1.85 (m, 3H), 1.35 (t, J=7.6 Hz, 3H), 0.94 (s, 3H); [M+H]+=1042.6.
The title compound (20 mg, 35.0%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.89 (s, 1H), 10.84 (s, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.89 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.29 (s, 1H), 6.70 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.4, 4.7 Hz, 1H), 3.76 (s, 3H), 3.58-3.43 (m, 8H), 3.28-3.20 (m, 2H), 3.04 (d, J=10.1 Hz, 2H), 2.92 (q, J=7.5 Hz, 2H), 2.83-2.73 (m, 1H), 2.64 (t, J=11.0 Hz, 2H), 2.58-2.55 (m, 4H), 2.38-2.35 (m, 1H), 2.23-2.03 (m, 4H), 1.99 (d, J=13.3 Hz, 6H), 1.91 (s, 3H), 1.85 (d, J=10.5 Hz, 2H), 1.59 (d, J=10.8 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H). [M+H]+=1027.7
The title compound (34 mg, 27.5%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.85 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=9.4 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.71 (s, 1H), 6.10 (d, J=11.1 Hz, 2H), 4.06-3.97 (m, 3H), 3.93 (t, J=7.5 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 3.30-3.28 (m, 2H), 2.96-2.93 (m, 5H), 2.82-2.73 (m, 1H), 2.63 (t, J=11.2 Hz, 2H), 2.56-2.51 (m, 6H), 2.41-2.38 (m, 3H), 2.29-2.25 (m, 3H), 2.07 (dt, J=12.7, 9.2 Hz, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.96-1.89 (m, 1H), 1.82 (d, J=11.8 Hz, 2H), 1.52 (dd, J=20.4, 11.3 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1027.7
The title compound (55 mg, 54%) was prepared according to the procedure shown in WO2021036922A. 1H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 10.98 (s, 1H), 8.87 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.26 (s, 2H), 8.24 (s, 1H), 7.92 (d, J=9.1 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.29 (m, 2H), 7.25 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.38 (d, J=17.3 Hz, 1H), 4.23 (d, J=17.3 Hz, 1H), 4.13 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 2.97-2.87 (m, 1H), 2.81 (s, 4H), 2.59 (d, J=17.8 Hz, 3H), 2.44 (dd, J=13.1, 4.5 Hz, 4H), 2.08 (s, 3H), 2.06-2.01 (m, 8H), 1.83-1.71 (m, 2H), 1.59-1.56 (m, 10H), 1.49-1.41 (m, 2H). [M+H]+=993.4.
The title compound (7 mg, 10%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 10.84 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.94-7.79 (m, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.6, 4.8 Hz, 1H), 3.83-3.79 (m, 1H), 3.61-3.43 (m, 8H), 3.28-3.22 (m, 3H), 3.01-2.94 (m, 4H), 2.83-2.74 (m, 1H), 2.70-2.53 (m, 5H), 2.43-2.55 (m, 3H), 2.21-1.92 (m, 8H), 1.87-1.83 (m, 2H), 1.58 (dd, J=20.4, 10.7 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.83-0.67 (m, 5H), 0.61-0.55 (m, 2H). [M+H]+=1053.3.
The title compound (7 mg, 10%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.95 (s, 1H), 8.58 (d, J=8.9 Hz, 1H), 8.25 (d, J=5.0 Hz, 1H), 8.20 (s, 1H), 7.90-7.81 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.99 (s, 1H), 4.20 (dd, J=12.6, 5.0 Hz, 1H), 3.81 (ddd, J=8.9, 5.9, 2.9 Hz, 1H), 2.98-2.90 (m, 4H), 2.85-2.74 (m, 3H), 2.69-2.52 (m, 11H), 2.47-2.21 (m, 5H), 2.13 (qd, J=13.0, 3.8 Hz, 1H), 2.01-1.97 (m, 7H), 1.86 (d, J=10.8 Hz, 2H), 1.61-1.52 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.83-0.67 (m, 5H), 0.61-0.55 (m, 2H). [M+H]+=998.7.
The title compound was synthesized in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.44 (s, 1H), 11.14 (s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.17 (t, J=16.1 Hz, 2H), 7.77 (d, J=9.7 Hz, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.74 (s, 1H), 5.33-5.22 (m, 1H), 3.69 (s, 3H), 2.98-2.88 (m, 4H), 2.82 (s, 1H), 2.74-2.54 (m, 7H), 2.47 (s, 6H), 2.41 (s, 5H), 2.25 (s, 1H), 2.09 (d, J=7.4 Hz, 1H), 1.94 (d, J=14.3 Hz, 6H), 1.79 (d, J=10.1 Hz, 2H), 1.52 (d, J=10.3 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H), 0.87 (s, 3H); [M+H]+=994.6.
The title compound (26 mg, 56%) was prepared in a manner similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.60 (s, 1H), 10.84 (s, 1H), 9.86 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.28 (s, 1H), 6.75 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.4, 4.9 Hz, 1H), 3.75 (s, 3H), 3.62-3.55 (m, 4H), 3.53-3.48 (m, 3H), 3.33-3.29 (m, 2H), 3.27-3.22 (m, 1H), 3.08-3.03 (m, 2H), 2.95 (d, J=10.0 Hz, 2H), 2.77 (d, J=12.3 Hz, 1H), 2.68 (d, J=11.3 Hz, 2H), 2.57 (s, 3H), 2.38 (s, 1H), 2.27 (s, 2H), 2.17 (d, J=9.0 Hz, 1H), 2.08 (d, J=8.5 Hz, 2H), 2.03 (d, J=13.4 Hz, 7H), 1.97-1.92 (m, 1H), 1.84 (d, J=10.1 Hz, 2H), 1.57 (d, J=9.8 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H), 0.75 (s, 3H); [M+H]+=1042.7.
To a solution of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 g, 4.0 mmol) and cyclopropylboronic acid (688 mg, 8.0 mmol) in dioxane/H2O (20/5 mL) was added K2CO3 (1.1 g, 8.0 mmol) at 20° C. Pd(dppf)Cl2 (303 mg, 0.4 mmol) was added to the mixture at 20° C. The flask was evacuated and backfilled with nitrogen three times. Then the mixture was stirred at 100° C. overnight. The mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE: EA=100: 0-1: 1 gradient elution) to give the desired product (600 mg, 71%). [M+H]+=212.1.
To a solution of 1-cyclopropyl-2-fluoro-4-methoxy-5-nitrobenzene (600 mg, 2.8 mmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (915 mg, 3.4 mmol) in DMSO (20 mL) was added K2CO3 (773 mg, 5.6 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give the desired product (800 mg, 66%). [M+H]+=461.2.
To a solution of tert-butyl 4-(1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (800 mg, 1.9 mmol) in MeOH (20 mL) was added Pd/C (wet, 10 wt. %, 160 mg) at room temperature under hydrogen atmosphere. The resulting mixture was stirred at rt for 2 hours. The mixture was filtered and concentrated under reduced pressure to afford the desired product (700 mg, 90%). [M+H]+=431.2.
To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (500 mg, 1.1 mmol) and tert-butyl 4-(1-(4-amino-2-cyclopropyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (473 mg, 1.1 mmol) in n-BuOH (20 mL) was added Ts-OH (580 g, 3.3 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was concentrated and basified with 0.5N NaOH (10 mL), then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-5: 1 gradient elution) to give the desired product (500 mg, 62%). [M+H]+=733.4.
To a solution of (6-((5-bromo-2-((5-cyclopropyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (22 mg, 0.08 mmol) in DCM (10 mL) was added NaBH(OAc)3 (30 mg, 0.14 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with H2O (30 mL), and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC to give the desired product (12 mg, 17%). 1H NMR (500 MHz, DMSO) δ 12.07 (s, 1H), 10.95 (s, 1H), 8.42 (d, J=8.7 Hz, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=9.4 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.04 (s, 1H), 7.02 (s, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 4.20 (dd, J=12.6, 4.9 Hz, 1H), 3.74 (s, 3H), 3.26 (d, J=10.8 Hz, 2H), 2.91 (d, J=7.6 Hz, 2H), 2.81-2.74 (m, 3H), 2.71-2.66 (m, 4H), 2.57-2.53 (m, 9H), 2.47-2.41 (m, 2H), 2.37-2.28 (m, 2H), 2.01-1.99 (m, 10H), 1.87 (d, J=11.1 Hz, 2H), 1.60 (d, J=11.3 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H). [M+H]+=984.4.
The title compound (30 mg, 41%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 10.85 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=8.9 Hz, 1H), 8.09 (s, 1H), 7.34 (s, 1H), 6.73 (s, 1H), 6.12 (s, 1H), 6.09 (s, 1H), 4.17 (d, J=7.1 Hz, 2H), 4.00 (d, J=6.9 Hz, 3H), 3.93 (s, 2H), 3.47 (s, 3H), 3.00-2.86 (m, 3H), 2.82-2.73 (m, 1H), 2.64 (t, J=11.1 Hz, 2H), 2.55 (d, J=6.8 Hz, 6H), 2.39-2.34 (m, 8H), 2.03 (d, J=13.4 Hz, 6H), 1.96-1.90 (m, 2H), 1.83 (d, J=11.0 Hz, 2H), 1.55 (d, J=11.3 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.87 (s, 3H). [M+H]+=1044.4.
The title compound (14 mg, 24.4%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 11.20 (s, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.89 (d, J=9.4 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.66 (s, 1H), 5.35 (dd, J=13.0, 5.4 Hz, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.32 (m, 2H), 3.29 (s, 1H), 3.01 (d, J=10.9 Hz, 2H), 2.97-2.85 (m, 3H), 2.79-2.74 (m, 2H), 2.66-2.61 (m, 12H), 2.19-2.14 (m, 1H), 1.99 (d, J=13.3 Hz, 6H), 1.89-1.84 (m, 5H), 1.56 (s, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H). [M+H]+=993.7
The title compound was prepared in a manner similar to that in Example 492.
1H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 11.12 (s, 1H), 8.51-8.50 (m, 1H), 8.24-8.17 (m, 2H), 7.97 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.33 (s, 1H), 7.15 (s, 1H), 7.02 (s, 1H), 6.64 (s, 1H), 5.25 (dd, J=13.0, 5.3 Hz, 1H), 3.94 (q, J=7.0 Hz, 2H), 2.95-2.76 (m, 6H), 2.72-2.45 (m, 10H), 2.41-2.13 (m, 11H), 2.10-2.01 (m, 1H), 1.93 (d, J=13.3 Hz, 6H), 1.77-1.75 (m, 2H), 1.49-1.43 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 1.19 (t, J=6.9 Hz, 3H), 0.68 (s, 3H). [M+H]+=1039.4.
To a stirred solution of 2-amino-4-methylphenol (10.0 g, 81.2 mmol) in THF (100 mL) was added CDI (15.8 g, 97.4 mmol) at room temperature, then it was refluxed for 2 hrs. After cooled to rt, the reaction mixture was diluted with EA (200 mL). The organic layer was then washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford product (9.0 g, 74.3%), which was used without further purification. [M−H]−=148.0.
To a stirred solution of 5-methylbenzo[d]oxazol-2(3H)-one (9.0 g, 60.3 mmol) in AcOH (50 mL), was added NBS (12.9 g, 72.4 mmol) portionwise. The resulting mixture was stirred at rt overnight. The solvent was removed under reduced pressure, the residue was dissolved in EA (800 mL), and washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered, then concentrated. The residue was purified by column chromatography (DCM/MeOH, 20:1) to afford product (11.0 g, 80.0%). [M−H]−=226.0.
A 50 mL three-neck round bottle flask was charged with 6-bromo-5-methylbenzo[d]oxazol-2(3H)-one (2.0 g, 8.8 mmol), dry DMF (10 mL), and Cs2CO3 (5.7 g, 17.5 mmol) at rt. The RBF was evacuated and backfilled with nitrogen three times. The resulting mixture was stirred at 70° C. for 1 hr. Then a solution of 3-bromopiperidine-2,6-dione (6.7 g, 35.1 mmol) in dry DMF (10 mL) was injected into the RBF by a syringe pump during a period of 2 hrs at 70° C. The resulting mixture was stirred overnight at 70° C. After cooled to rt, the mixture was diluted with EA (500 mL), washed with 1 N HCl (200 mL), water (3×200 mL), and brine (200 mL), then dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE/EA, 60%-30%) to afford product (1.2 g, 40.2%). [M−H]−=336.9.
A 20 mL microwave vial were charged with 3-(6-bromo-5-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione (1.2 g, 3.5 mmol), CsF (797 mg, 5.2 mmol), Pd(dtbpf)Cl2 (228 mg, 0.35 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.2 mmol), and DMF/H2O (12 mL/4 mL). The vial was evacuated and backfilled with nitrogen three times. The resulting mixture was stirred at 50° C. for 1 hr. After cooled to rt, the mixture was diluted with EA (200 mL), washed with water (2×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE/EA, 60%-30%) to afford crude product, which is triturated with Et2O to afford the target product (775 mg, 65.7%). [M+H]+=331.1.
The title compound (210 mg, 55%) was prepared in a manner similar to that in Example 506 step 3 from (E)-3-(6-(2-ethoxyvinyl)-5-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione and HCOOH.
The title compound (40 mg, 45%) was prepared in a manner similar to that in Example 492 step 6 from 6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)-2-ethylphthalazin-1(2H)-one and 2-(3-(2,6-dioxopiperidin-3-yl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.18 (s, 1H), 8.66 (s, 2H), 8.50 (s, 1H), 8.25 (s, 1H), 8.18 (d, J=9.1 Hz, 1H), 8.08 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 6.73 (s, 1H), 5.32 (dd, J=13.0, 5.3 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.02-2.90 (m, 4H), 2.77-2.69 (m, 3H), 2.68-2.61 (m, 3H), 2.59-2.51 (m, 3H), 2.49-2.43 (m, 4H), 2.42-2.35 (m, 2H), 2.31 (d, J=8.7 Hz, 5H), 2.17-2.09 (m, 1H), 2.03 (d, J=13.4 Hz, 6H), 1.85 (d, J=10.9 Hz, 2H), 1.56 (d, J=8.9 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.87 (s, 3H). [M+H]+=1038.4.
The title compound (29 mg, 41%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.18 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.18 (d, J=9.1 Hz, 1H), 8.08 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 6.73 (s, 1H), 5.32 (dd, J=13.0, 5.3 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (q, J=7.0 Hz, 2H), 2.98-2.86 (m, 4H), 2.77-2.69 (m, 3H), 2.68-2.61 (m, 4H), 2.59-2.54 (m, 3H), 2.49-2.43 (m, 4H), 2.42-2.35 (m, 2H), 2.34-2.31 (m, 5H), 2.17-2.09 (m, 1H), 2.03 (d, J=13.4 Hz, 6H), 1.85 (d, J=10.9 Hz, 2H), 1.56 (d, J=8.9 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.87 (s, 3H). [M+H]+=1038.4.
To a solution of 2-bromo-4-fluoro-6-nitrophenol (5 g, 21.3 mmol) in CH3OH (50 mL) was added Raney-Ni (3 g). The resulting mixture was stirred at rt under hydrogen atmosphere for 3 hrs. The mixture was filtered and concentrated in vacuum to afford 2-amino-6-bromo-4-fluorophenol (3.8 g, 86.6%). [M+H]+=206.1.
The title compound (4.1 g, 93%) was prepared in a manner similar to that in Example 492 step 1 from 2-amino-6-bromo-4-fluorophenol and CDI. [M+H]+=231.9.
The title compound (4.2 g, 93%) was prepared in a manner similar to that in Example 492 step 2 from 7-bromo-5-fluorobenzo[d]oxazol-2(3H)-one and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. [M+H]+=521.1.
A mixture of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (1 g, 1.92 mmol), 2-(piperidin-4-yl)ethan-1-ol (371.5 mg, 2.88 mmol), CuI (73 mg, 0.384 mmol), L-proline (44.1 mg, 0.384 mmol), and K3PO4 (814 mg, 3.84 mmol) in DMSO (15 mL) was heated to 100° C. for 18 hrs under nitrogen atmosphere. After cooling to r.t, the reaction was diluted with EA (60 mL) and then washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=1:1) to afford the product (450 mg, 41.1%). [M+H]+=570.3.
The title compound (220 mg, 95%) was prepared in a manner similar to that in Example 492 step 4 from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-7-(4-(2-hydroxyethyl)piperidin-1-yl)benzo[d]oxazol-2(3H)-one. [M+H]+=392.3.
The title compound (100 mg, 80%) was prepared in a manner similar to that in Example 492 step 5 from 3-(5-fluoro-7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione. [M+H]+=390.1.
The title compound (21.45 mg, 43%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxo-2,3-dihydrobenzo [d]oxazol-7-yl)piperidin-4-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 11.20 (s, 1H), 8.72 (d, J=8.8 Hz, 1H), 8.28 (s, 2H), 8.13 (s, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.42 (s, 1H), 6.83-6.67 (m, 2H), 6.56 (dd, J=12.9, 2.3 Hz, 1H), 5.33-5.30 (m, 1H), 4.03-4.01 (m, 4H), 3.75-3.73 (m, 3H), 2.99-2.94 (m, 7H), 2.89-2.76 (m, 4H), 2.74-2.60 (m, 5H), 2.54 (s, 1H), 2.24-2.21 (m, 2H), 2.18-2.09 (m, 1H), 2.01 (s, 5H), 1.98 (s, 3H), 1.81-1.78 (m, 2H), 1.75-1.45 (m, 6H), 1.35-1.31 (m, 5H), 1.29-1.24 (m, 4H), 0.70 (s, 3H). [M+H]+=1107.9.
The title compound (12 mg, 18%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.87 (s, 1H), 11.22 (s, 1H), 8.71 (d, J=8.9, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.91 (d, J=8.5, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.99 (s, 1H), 5.37 (dd, J=12.9, 5.2 Hz, 1H), 3.86-3.80 (m, 1H), 3.75-3.26 (m, 5H), 3.25-2.85 (m, 6H), 2.99-2.83 (m, 4H), 2.76-2.60 (m, 8H), 2.40-2.25 (m, 2H), 2.19-2.13 (m, 1H), 2.15-2.00 (m, 2H), 2.00 (d, J=13.3 Hz, 6H), 1.82-1.67 (m, 2H), 0.86-0.68 (m, 5H), 0.63-0.57 (m, 2H). [M+H]+=1005.7.
The title compound (10.53 mg, 10%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.11 (s, 1H), 8.73 (d, J=5.9 Hz, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.43 (s, 1H), 7.10 (d, J=9.2 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.73 (s, 1H), 5.39 (dd, J=12.5, 4.9 Hz, 1H), 4.12-3.91 (m, 4H), 3.73-3.47 (m, 2H), 3.32 (m, 4H), 3.19-2.95 (m, 7H), 2.94-2.83 (m, 1H), 2.72-2.68 (m, 6H), 2.55 (d, J=8.9 Hz, 3H), 2.33-2.21 (m, 2H), 2.22-2.18 (m, 1H), 2.03 (t, J=10.8 Hz, 7H), 1.92-1.77 (m, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.30-1.20 (m, 6H), 0.70 (t, J=6.7 Hz, 3H). [M+H]+=1052.3.
The title compound (6.73 mg, 6%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.11 (s, 1H), 8.66 (s, 1H), 8.53 (d, J=5.9 Hz, 1H), 8.28 (s, 1H), 8.19 (d, J=8.9 Hz, 1H), 8.12 (s, 1H), 7.37 (s, 1H), 7.04 (s, 1H), 6.93 (t, J=9.6 Hz, 1H), 6.75 (s, 1H), 5.39 (dd, J=12.5, 4.9 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.12-3.91 (m, 4H), 3.73-3.47 (m, 2H), 3.32 (s, 3H), 3.19-2.95 (m, 7H), 2.94-2.83 (m, 1H), 2.71-2.67 (m, 6H), 2.55 (d, J=10.0 Hz, 2H), 2.46-2.32 (m, 2H), 2.19 (dd, J=6.9, 0.8 Hz, 1H), 2.03 (t, J=10.8 Hz, 7H), 1.92-1.77 (m, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.30-1.20 (m, 6H), 0.89 (t, J=6.5 Hz, 3H). [M+H]+=1070.9.
The title compound (32 mg, 45%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 12.12 (s, 1H), 11.18 (s, 1H), 8.61-8.58 (m, 2H), 8.20 (dd, J=21.8, 12.2 Hz, 3H), 7.36 (s, 1H), 7.00 (t, J=8.1 Hz, 1H), 6.73 (s, 1H), 6.50 (d, J=7.8 Hz, 1H), 6.36 (d, J=8.4 Hz, 1H), 5.29 (dd, J=12.9, 5.4 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 4.01 (q, J=6.9 Hz, 2H), 3.65-3.41 (m, 5H), 3.27-3.17 (m, 3H), 2.99-2.80 (m, 3H), 2.71-2.53 (m, 8H), 2.36-2.32 (m, 6H), 2.16-1.97 (m, 8H), 1.84 (d, J=10.8 Hz, 2H), 1.67 (dd, J=12.1, 7.7 Hz, 1H), 1.60-1.46 (m, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.87 (s, 3H). [M+H]+=1079.4.
The title compound (20 mg, 31%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.66 (s, 1H), 11.12 (s, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.17 (d, J=13.9 Hz, 2H), 7.89-7.70 (m, 2H), 7.38 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.64 (s, 1H), 6.43 (d, J=7.8 Hz, 1H), 6.29 (d, J=8.4 Hz, 1H), 5.22 (dd, J=12.9, 5.3 Hz, 1H), 3.93 (q, J=6.9 Hz, 2H), 3.58-3.34 (m, 5H), 3.17-3.06 (m, 2H), 2.95-2.73 (m, 6H), 2.61-2.55 (m, 5H), 2.35-2.11 (m, 8H), 2.10-1.86 (m, 8H), 1.76 (d, J=10.8 Hz, 2H), 1.60 (dd, J=11.8, 7.7 Hz, 1H), 1.52-1.38 (m, 2H), 1.22 (dt, J=13.8, 7.2 Hz, 7H), 0.64 (s, 3H). [M+H]+=1064.2.
The title compound was prepared according to the same procedure as Example 492. 1H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 11.19 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.14-8.38 (m, 2H), 8.04 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.71 (s, 1H), 6.57 (d, J=7.9 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 5.29 (dd, J=12.9, 5.3 Hz, 1H), 4.11 (t, J=7.4 Hz, 2H), 4.01 (q, J=6.9 Hz, 2H), 3.65 (t, J=6.5 Hz, 2H), 3.01-2.80 (m, 6H), 2.74-2.52 (m, 10H), 2.46-2.21 (m, 7H), 2.14-2.11 (m, 1H), 2.00 (d, J=13.3 Hz, 6H), 1.84-1.82 (m, 2H), 1.56-1.49 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.75 (s, 3H). [M+H]+=1066.8.
The title compound (26 mg, 56%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.54 (s, 1H), 11.21 (s, 1H), 9.90 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=9.3 Hz, 1H), 7.32 (s, 1H), 7.15-7.10 (m, 2H), 7.07 (d, J=7.3 Hz, 1H), 6.71 (s, 1H), 5.36 (dd, J=12.7, 5.2 Hz, 1H), 4.00 (t, J=6.9 Hz, 2H), 3.29 (s, 1H), 3.08-3.03 (m, 2H), 2.95-2.82 (m, 5H), 2.67 (s, 1H), 2.63 (s, 3H), 2.61-2.54 (m, 5H), 2.36 (s, 1H), 2.24-2.19 (m, 2H), 2.17-2.13 (m, 1H), 2.03 (d, J=13.4 Hz, 7H), 1.82 (s, 2H), 1.54 (s, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 6H), 0.70 (s, 3H); [M+H]+=1008.7.
The title compound (26 mg, 56%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.53 (s, 1H), 11.21 (s, 1H), 9.90 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.31 (s, 1H), 7.16 (dd, J=8.4, 2.5 Hz, 1H), 6.92 (dd, J=10.7, 2.4 Hz, 1H), 6.70 (s, 1H), 5.35 (dd, J=13.0, 5.2 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.30 (s, 2H), 3.05 (q, J=7.5 Hz, 2H), 2.91 (d, J=10.9 Hz, 2H), 2.87-2.82 (m, 1H), 2.75-2.70 (m, 2H), 2.69 (d, J=5.0 Hz, 1H), 2.67 (s, 1H), 2.64-2.62 (m, 2H), 2.60 (s, 1H), 2.54 (s, 2H), 2.37-2.35 (m, 1H), 2.31 (s, 2H), 2.20 (s, 2H), 2.17-2.13 (m, 1H), 2.03 (d, J=13.4 Hz, 7H), 1.83-1.77 (m, 4H), 1.53 (d, J=9.4 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 5H), 0.69 (s, 3H); [M+H]+=1040.7.
The title compound (26 mg, 56%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.54 (s, 1H), 11.20 (s, 1H), 9.89 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.41 (d, J=6.0 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J=9.6 Hz, 1H), 6.70 (s, 1H), 5.34 (dd, J=13.0, 5.2 Hz, 1H), 4.03-3.97 (m, 2H), 3.29 (s, 1H), 3.05 (q, J=7.6 Hz, 2H), 2.91 (d, J=10.3 Hz, 2H), 2.87-2.83 (m, 1H), 2.76 (d, J=7.5 Hz, 2H), 2.70 (d, J=12.6 Hz, 1H), 2.66-2.61 (m, 5H), 2.54 (s, 2H), 2.48-2.43 (m, 3H), 2.36 (s, 1H), 2.28-2.19 (m, 3H), 2.15 (d, J=5.7 Hz, 1H), 2.03 (d, J=13.4 Hz, 7H), 1.82 (d, J=10.2 Hz, 2H), 1.52 (d, J=8.8 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H), 0.69 (s, 3H); [M+H]+=1026.7.
The title compound (26 mg, 56%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.53 (s, 1H), 11.18 (s, 1H), 9.90 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.32 (s, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.71 (s, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.25 (d, J=8.1 Hz, 1H), 5.29 (dd, J=12.9, 5.2 Hz, 1H), 4.11 (t, J=7.4 Hz, 2H), 4.01-3.97 (m, 2H), 3.66 (s, 2H), 3.29 (s, 2H), 3.08-3.04 (m, 2H), 2.91 (d, J=10.8 Hz, 3H), 2.89-2.83 (m, 1H), 2.68-2.57 (m, 7H), 2.54 (s, 1H), 2.40 (s, 3H), 2.36 (s, 1H), 2.20 (s, 2H), 2.14-2.10 (m, 1H), 2.03 (d, J=13.4 Hz, 7H), 1.81 (s, 2H), 1.54 (s, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.69 (s, 3H); [M+H]+=1049.7.
The title compound (26 mg, 56%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 10.95 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.33 (d, J=10.1 Hz, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 6.99 (d, J=10.1 Hz, 2H), 6.71 (s, 1H), 4.20 (dd, J=12.6, 4.8 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 2.95 (dd, J=15.1, 7.7 Hz, 4H), 2.85-2.76 (m, 1H), 2.65-2.53 (m, 8H), 2.49-2.20 (m, 10H), 2.18-2.07 (m, 1H), 2.00 (d, J=13.3 Hz, 7H), 1.82 (d, J=10.7 Hz, 2H), 1.78-1.68 (m, 2H), 1.52 (d, J=9.9 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.74 (s, 3H). [M+H]+=1018.6.
The title compound (12 mg, 18%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((2-cyclopropoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.96 (s, 1H), 11.22 (s, 1H), 8.66 (d, J=8.5 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.35 (s, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 6.96 (s, 1H), 5.37 (dd, J=12.9, 5.2 Hz, 1H), 3.84 (ddd, J=8.9, 5.8, 2.9 Hz, 1H), 3.60-3.39 (m, 3H), 3.19-3.08 (m, 4H), 3.00-2.85 (m, 7H), 2.75-2.58 (m, 8H), 2.22-2.04 (m, 3H), 2.00 (d, J=13.3 Hz, 6H), 1.90 (s, 3H), 1.80-1.69 (m, 2H), 1.33 (t, J=7.6 Hz, 3H), 0.75-0.69 (m, 2H), 0.64-0.59 (m, 2H).[M+H]+=1005.7.
To a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (The intermediate can be prepared according to the way described in WO2017197046) (8.3 g, 20 mmol) and 4-bromoiodobenzene (5.6 g, 20 mmol) in dioxane (100 mL) and H2O (10 mL) were added K2CO3 (5.5 g, 40 mmol) and Pd(dppf)Cl2 (1.4 g, 2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80° C. under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE=0-8%) to afford the product (4.5 g, 50%). [M+H]+=446.2.
To the solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4.5 g, 10 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (2.5 g, 15 mmol) and Cs2CO3 (15 g, 45 mmol) in 50 mL dioxane, was added Pd2(dba)3 (915 mg, 1 mmol) and Xantphos (1.5 g, 2 mmol). The mixture was stirred at 80° C. for 16 hours under nitrogen atmosphere. Once the reaction has completed determined by LCMS, the mixture was concentrated under reduced pressure and purified by silica column chromatography (EA:PE=0-12%) to afford the product (2.1 g, 42.5%). [M+H]+=494.9.
To the solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-carboxylate (2.1 g, 4.25 mmol) in 30 mL THF and 10 mL water, was added LiOH H2O (178 mg, 4.25 mmol) in 2 mL water dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes. Once the reaction has completed determined by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjust to pH<5 with 1 N HCl aqueous. The liquid was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (60 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford the product (2 g, 98%). [M+H]+=481.6.
To the solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-carboxylic acid (2 g, 4.17 mmol) in 5 mL DCM and 100 mL iPrOH, was added Pd/C (2 g, 10 wt. %, wet). The mixture was stirred at 45° C. for 16 hours under hydrogen atmosphere (balloon). Once the reaction has completed determined by LCMS, the mixture was cooled to room temperature and filtered through celite directly. The solid was dispensed in DCM (5 mL) and MeOH (50 mL), which was sonicated for 5 min. The mixture was then filtered through celite and the combined filtrate was concentrated in vacuum to afford the product (1.2 g, 95% yield). [M+H]+=303.6.
To the solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (140 mg, 0.2 mmol), (3R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-carboxylic acid (60 mg, 0.2 mmol) and DIEA (51 mg, 0.4 mmol) in 5 mL anhydrous DCM, T3P (190 mg, 0.3 mmol, 50% w.t. EtOAc solution) were added. The mixture was stirred at room temperature for 30 minutes. Once the reaction has completed determined by LCMS, the mixture was diluted with 10 mL water. The mixture was extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. Purification by prep-TLC (DCM:MeOH=15:1) afforded the mixture of two diastereomers, which could be separated by chiral-HPLC (IF (2*25 cm, 5 um), 60% MtBE/40% MeOH:DCM=1:1/0.1% DEA, 80 bar, 20 ml/min) and the title compound corresponded to peak A @ 1.192 min/254 nm) (2.7 mg, 1%). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.84 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.46-7.31 (m, 2H), 7.01 (d, J=9.8 Hz, 2H), 6.74 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.5, 4.9 Hz, 1H), 3.76 (s, 3H), 3.52-3.48 (m, 6H), 3.38-3.33 (m, 1H), 3.31-3.22 (m, 2H), 2.95 (d, J=10.6 Hz, 2H), 2.83-2.73 (m, 1H), 2.72-2.62 (m, 5H), 2.57 (s, 2H), 2.51 (s, 1H), 2.49-2.45 (m, 2H), 2.37 (dd, J=20.5, 9.9 Hz, 1H), 2.34-2.26 (m, 2H), 2.21-2.04 (m, 3H), 2.02-1.91 (m, 7H), 1.84 (d, J=10.2 Hz, 2H), 1.58 (dd, J=20.3, 10.6 Hz, 2H), 0.87-0.67 (m, 3H). [M+H]+=991.3.
To a mixture of (E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (0.4 g, 1.356 mmol, 1 eq) and Et3N (2.2 g, 21.67 mmol, 16 eq) in 10 mL of ACN was added TMS-Cl (1.18 g, 10.85 mmol, 8 eq) dropwise. The mixture was stirred at 80° C. in a sealed tube for 12 hours. After cooled to 0° C., 5 mL of D2O was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The mixture was extracted with DCM (3×50 mL) and concentrated to dryness. The residue was purified with silica gel column, eluting with MeOH in DCM (0%-5%) to afford the target compound (0.305 g, 75.5%). 1H NMR (500 MHz, DMSO) δ 7.98 (s, 1H), 7.00 (d, J=12.9 Hz, 1H), 6.76 (d, J=10.1 Hz, 2H), 5.72 (d, J=12.9 Hz, 1H), 3.91 (q, J=7.0 Hz, 2H), 2.32 (d, J=13.4 Hz, 1H), 2.20-2.08 (m, 1H), 1.35 (t, J=7.0 Hz, 3H); [M+H]+=299.1.
A solution of (E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione-3,5,5-d3 (60 mg, 0.2 mmol) in FA (3 mL) was stirred for 2 hrs at room temperature. The mixture was concentrated in vacuum, and 2-(4-(2,6-dioxopiperidin-3-yl-3,5,5-d3)-3,5-difluorophenyl)acetaldehyde (70 mg, crude) was obtained, which was used in the next step without further purification. [M+H]+=271.2.
To a solution of 2-(4-(2,6-dioxopiperidin-3-yl-3,5,5-d3)-3,5-difluorophenyl)acetaldehyde (70 mg crude, 0.2 mmol) in DCM (8 mL) was added (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (72 mg, 0.1 mmol, the compound was obtained by the way similar to example 314) at room temperature. After 1 h, NaBH(OAc)3 (42.4 mg, 0.2 mmol) was added to the mixture. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water (10 mL) and extraction with DCM (3×50 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (ACN in water with 0.1% of FA, 0% to 90%) to afford the product (7.2 mg, 7.4%). 1H NMR (500 MHz, DMSO) δ 11.71 (s, 1H), 10.97 (s, 1H), 8.60 (d, J=10.3 Hz, 1H), 8.30-8.24 (m, 1H), 8.22 (s, 1H), 7.91-7.85 (m, 2H), 7.43 (d, J=10.2 Hz, 2H), 7.03 (d, J=10.2 Hz, 2H), 6.07 (s, 1H), 4.00 (dd, J=25, 10.4 Hz, 2H), 2.91 (d, J=10.4 Hz, 2H), 2.75-2.66 (m, 2H), 2.64-2.51 (m, 9H), 2.49-2.08 (m, 9H), 2.00 (s, 3H), 1.96 (s, 3H), 1.83-1.79 (m, 2H), 1.58-1.49 (m, 2H), 1.26 (t, J=10.2 Hz, 3H), 0.71 (t, J=10.1 Hz, 3H); [M+H]+=975.2.
The title compound (14 mg, 27%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(1′-(2,6-dioxopiperidin-3-yl)-2′-oxospiro[cyclopropane-1,3′-indolin]-4′-yl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.67 (s, 1H), 11.09 (s, 1H), 8.64 (s, 1H), 8.24 (s, 2H), 7.90 (s, 2H), 7.46 (d, J=8.9 Hz, 2H), 7.18 (s, 1H), 6.91 (d, J=7.8 Hz, 2H), 6.72 (s, 1H), 5.36-5.31 (m, 1H), 4.02 (q, J=6.9 Hz, 2H), 3.58-3.53 (m, 2H), 3.33-3.29 (m, 4H), 3.20-2.83 (m, 9H), 2.76-2.51 (m, 8H), 2.36 (s, 1H), 2.23 (s, 2H), 2.13 (s, 1H), 1.99-1.95 (m, 9H), 1.75 (s, 1H), 1.56-1.51 (m, 2H), 1.33 (t, J=7.6 Hz, 3H), 1.27 (t, J=6.9 Hz, 3H), 0.69 (s, 3H). [M+H]+=1031.7.
The title compound (15 mg, 25%) was prepared in a manner similar to that in Example 492 step 6 from (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)acetaldehyde.
1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.07 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 5.21 (s, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.26-3.16 (m, 2H), 2.90-2.87 (m, 8H), 2.64-2.60 (m, 11H), 2.32-2.18 (m, 3H), 2.01-1.96 (m, 7H), 1.83 (d, J=10.7 Hz, 2H), 1.57-1.51 (m, 2H), 1.38 (s, 6H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1033.7.
The title compound (10.39 mg, 10%) was prepared in a manner similar to that in Example 488 step 14 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)acetic acid. The product was purified by HPLC (IF (2*25 cm, 5 um), 60% MtBE/40% MeOH:DCM=1:1, 80 bar, 20 ml/min) and the title compound corresponded to peak A @ 1.634 min/254 nm. 1H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 10.87 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.30 (dd, J=10.0, 3.9 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.87 (d, J=9.4 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 6.74 (s, 1H), 6.10 (d, J=11.2 Hz, 2H), 4.06-3.92 (m, 3H), 3.75 (s, 3H), 3.52-3.39 (m, 6H), 3.02-2.90 (m, 4H), 2.83-2.71 (m, 3H), 2.71-2.61 (m, 5H), 2.49-2.45 (m, 4H), 2.33-2.29 (m, 3H), 2.14-1.90 (m, 8H), 1.82 (d, J=10.8 Hz, 2H), 1.58-1.53 (m, 2H), 0.82-0.71 (m, 3H). [M+H]+=1028.4.
The title compound (21 mg, 39%) was prepared in a manner similar to that in Example 488 step 14 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid. 1H NMR (500 MHz, DMSO) δ 11.28 (s, 1H), 10.84 (s, 1H), 8.64 (d, J=12.3 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.95 (d, J=9.2 Hz, 2H), 7.33 (s, 1H), 6.71 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (dd, J=12.4, 5.0 Hz, 1H), 3.75 (s, 3H), 3.66-3.39 (m, TOH), 3.12-3.05 (m, 2H), 2.91 (d, J=11.0 Hz, 2H), 2.83-2.73 (m, 1H), 2.68-2.54 (m, 7H), 2.35 (d, J=11.9 Hz, 1H), 2.19 (s, 2H), 2.07 (t, J=11.0 Hz, 1H), 1.98-1.92 (m, 7H), 1.82 (d, J=11.3 Hz, 2H), 1.55 (d, J=11.1 Hz, 2H), 1.18 (s, 3H), 0.99 (s, 3H), 0.71 (s, 3H). [M+H]+=1073.6.
The title compound (27 mg, 55%) was prepared in a manner similar to that in Example 488 step 14 from (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid. 1H NMR (500 MHz, DMSO) δ 11.20 (s, 1H), 10.84 (s, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.85 (s, 1H), 7.38 (s, 1H), 6.68 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.00 (d, J=6.9 Hz, 3H), 3.58-3.43 (m, 8H), 3.29-3.23 (m, 3H), 2.89 (d, J=10.4 Hz, 2H), 2.82-2.74 (m, 1H), 2.65-2.63 (m, 8H), 2.34 (d, J=11.2 Hz, 1H), 2.21-2.03 (m, 5H), 1.98-1.91 (m, 7H), 1.81 (d, J=11.2 Hz, 2H), 1.60-1.49 (m, 2H), 1.27 (t, J=6.9 Hz, 3H), 0.64 (s, 3H). [M+H]+=1059.6.
The title compound (19 mg, 20%) was prepared in a manner similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.23 (s, 1H), 10.86 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.23-8.13 (m, 2H), 7.29 (s, 1H), 6.77 (s, 1H), 6.61 (d, J=12.8 Hz, 2H), 4.06-4.03 (m, 2H), 3.74-3.72 (m, 5H), 3.01-2.99 (m, 2H), 2.80-2.61 (m, 6H), 2.48-2.18 (m, 8H), 2.09-2.07 (m, 1H), 2.05-2.02 (m, 7H), 1.95 (s, 1H), 1.84 (s, 2H), 1.73-1.70 (m, 2H), 1.57-1.54 (m, 2H), 1.52-1.42 (m, 2H), 1.39-1.36 (m, 2H), 1.29-1.10 (m, 4H), 1.06-0.88 (m, 8H); [M+H]+=1084.5.
The title compound (25.5 mg, 35%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.88 (s, 1H), 11.21 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 8.29 (d, J=11.8 Hz, 3H), 7.95 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.42 (s, 1H), 7.10 (t, J=8.1 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.76-6.70 (m, 2H), 5.35-5.31 (m, 1H), 4.03 (d, 2H), 3.70 (d, 3H), 3.57 (s, 3H), 3.47-3.44 (m, 2H), 3.23 (s, 3H), 3.01-2.97 (m, 5H), 2.87-2.84 (m, 5H), 2.75-2.62 (m, 4H), 2.29-2.25 (m, 2H), 2.09 (d, 2H), 2.00 (d, 6H), 1.87 (d, 3H), 1.75 (d, J=9.7 Hz, 2H), 1.38-1.33 (m, 5H), 1.28 (t, 3H), 0.70 (s, 3H). [M+H]+=1076.4
The title compound (27.5 mg, 31.5%) was prepared in a manner similar to that in Example 492. 1H NMR (500 MHz, DMSO) 12.12 (s, 1H), 11.20 (s, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.33-8.15 (m, 2H), 8.06 (s, 1H), 7.36 (s, 1H), 7.08 (t, 1H), 6.83-6.65 (m, 3H), 5.35-5.31 (m, 1H), 4.19-4.15 (m, 2H), 4.05-4.00 (m, 2H), 3.66 (d, 2H), 2.96 (d, 2H), 2.88 (t, 1H), 2.75 (t, 2H), 2.65 (d, 4H), 2.54 (s, 4H), 2.38 (d, 5H), 2.31 (d, 2H), 2.21-2.10 (m, 3H), 2.03 (d, 6H), 1.83 (t, J=13.7 Hz, 4H), 1.69 (s, 1H), 1.55 (d, J=10.5 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.25 (t, J=6.8 Hz, 4H), 1.06 (t, J=7.0 Hz, 1H), 0.87 (s, 3H). [M+H]+=1093.4.
To a solution of tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (1.5 g, 4.62 mmol) in DMF (20 mL) was added triphenylphosphane (1.33 g, 5.08 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was concentrated and 20 mL EA was added. Then the mixture was filtered to give the desired product (2 g, 71%). [M+H]+=460.2.
To a solution of ((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (2 g, 3.41 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF, 3.5 mL, 3.5 mmol) at −40° C. The mixture was stirred at −40° C. for 0.5 h. Then 4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorobenzaldehyde (1.5 g, 3.5 mmol) in 5 mL THF was added. The reaction was stirred at −40° C. for 3 h and quenched with sat. NH4Cl (30 mL). The resulting mixture was extracted with EA (2×100 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (PE: EA=100: 0-10: 1 gradient elution) to give the desired product (0.9 g, 43%). [M+H]+=613.3.
To a suspension of tert-butyl(E)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorostyryl)piperidine-1-carboxylate (0.45 g, 0.74 mmol) in MeOH (10 mL) was added Pd/C (0.5 g, 10 wt. %, wet). The mixture was stirred at rt for 16 hrs under hydrogen atmosphere. Then the mixture was filtered and washed with MeOH. The filtrate was concentrated in vacuo to give the desired product (230 mg, 72%). [M+H]+=437.2.
A solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperidine-1-carboxylate (230 mg, 0.53 mmol) in TFA (5 mL) was stirred at r.t. for 2 h. The reaction was concentrated to near dryness and basified with sat. aq. NaHCO3, then extracted with DCM (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-20: 1 gradient elution) to give the desired product (160 mg, 90%). [M+H]+=337.2.
A solution of 3-(2,6-difluoro-4-(2-(piperidin-4-yl)ethyl)phenyl)piperidine-2,6-dione (160 mg, 0.48 mmol), 1-(2-ethyl-5-methoxy-4-nitrophenyl)piperidin-4-one (132 mg, 0.48 mmol) and titanium(IV) isopropoxide (270 mg, 0.96 mmol) in DCE (10 mL) was stirred at 50° C. overnight. The reaction was cooled to r.t. and STAB (201 mg, 0.96 mmol) was added. The reaction was stirred at r.t. for 2 h and 100 mL EA was added. The mixture was washed with sat. aq. NaCl (2×40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (PE: EA=100: 0-50: 1 gradient elution) to give the desired product (130 mg, 46%). [M+H]+=599.3.
A solution of 3-(4-(2-(1′-(2-ethyl-5-methoxy-4-nitrophenyl)-[1,4′-bipiperidin]-4-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione (130 mg, 0.22 mmol) and Zn (139 mg, 2.2 mmol) in AcOH (5 mL) was stirred at 60° C. for 3 h. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 and extracted with DCM (2×100 mL). The organic phase was washed with brine (1×80 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford the desired product (90 mg, 73%). [M+H]+=569.3.
A solution of 3-(4-(2-(1′-(4-amino-2-ethyl-5-methoxyphenyl)-[1,4′-bipiperidin]-4-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione (40 mg, 0.07 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (31 mg, 0.07 mmol) and TsOH (36 mg, 0.21 mmol) in 2-methyl-2-butano (5 mL) was stirred at 100° C. for 4 h. Then the mixture was adjusted to pH=8 with sat. aq. NaHCO3 and extracted with DCM (2×100 mL). The organic phase was washed with brine (1×80 mL), dried over Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC to give the desired product (10.38 mg, 19%). 1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 10.94 (s, 1H), 8.55 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (s, 1H), 6.98 (d, J=10.0 Hz, 2H), 6.74 (s, 1H), 4.19 (dd, J=12.6, 5.1 Hz, 1H), 3.75 (s, 3H), 3.31-3.28 (m, 1H), 2.92 (dt, J=16.0, 8.0 Hz, 6H), 2.82 (dd, J=21.8, 8.9 Hz, 1H), 2.71-2.59 (m, 4H), 2.40-2.27 (m, 3H), 2.20-2.08 (m, 3H), 1.98 (d, J=13.3 Hz, 7H), 1.80 (d, J=11.9 Hz, 2H), 1.72 (d, J=10.7 Hz, 2H), 1.63-1.47 (m, 4H), 1.32 (t, J=7.6 Hz, 3H), 1.25-1.11 (m, 3H), 0.77 (s, 3H); [M+H]+=971.7.
The title compound (32 mg, 46%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.88 (s, 1H), 11.09 (s, 1H), 8.55 (d, J=8.8 Hz, 1H), 8.34 (dd, J=5.1 Hz, 1H), 8.19 (s, 1H), 7.91-7.84 (m, 2H), 7.44 (d, J=8.9 Hz, 1H), 7.30 (s, 1H), 7.01-6.94 (m, 3H), 6.91 (dd, J=6.2, 2.6 Hz, 1H), 5.37 (dd, J=12.8, 5.4 Hz, 1H), 3.81 (tt, J=5.9, 2.9 Hz, 1H), 3.59 (s, 3H), 3.12-3.01 (m, 4H), 2.97-2.84 (m, 3H), 2.78-2.52 (m, 13H), 2.31 (t, J=11.2 Hz, 1H), 2.07-1.91 (m, 8H), 1.94-1.81 (m, 5H), 1.57 (dd, J=20.2, 11.2 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.70 (q, J=6.0 Hz, 2H), 0.61-0.55 (m, 2H). [M+H]+=1018.3
The title compound (29 mg, 40%) was prepared in a manner similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 11.09 (s, 1H), 8.57 (d, J=8.8 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.91-7.82 (m, 2H), 7.44 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 7.03-6.95 (m, 3H), 6.90 (dd, J=6.2, 2.6 Hz, 1H), 5.37 (dd, J=12.8, 5.4 Hz, 1H), 3.81 (tt, J=6.0, 3.0 Hz, 1H), 3.59 (s, 3H), 3.10-3.02 (m, 2H), 2.99-2.86 (m, 5H), 2.78-2.51 (m, 13H), 2.30 (t, J=9.1 Hz, 3H), 1.98 (d, J=13.3 Hz, 8H), 1.85 (d, J=10.9 Hz, 2H), 1.55 (dd, J=20.2, 11.4 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.82-0.67 (m, 5H), 0.61-0.55 (m, 2H). [M+H]+=1032.8.
The title compound (10 mg, 30%) was prepared in a manner similar to that in Example 488 step 14 from (7-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-methylisoquinolin-8-yl)dimethylphosphine oxide and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid. 1H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 10.84 (s, 1H), 9.47 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.66 (s, 1H), 7.42 (s, 1H), 6.73 (s, 1H), 6.24 (s, 1H), 6.22 (s, 1H), 4.02 (dd, J=12.7, 4.9 Hz, 1H), 3.76 (s, 3H), 3.56-3.43 (m, 7H), 3.34 (d, J=6.5 Hz, 2H), 3.31-3.22 (m, 4H), 2.94 (d, J=10.8 Hz, 2H), 2.68-2.63 (m, 2H), 2.62 (s, 3H), 2.55 (d, J=14.8 Hz, 2H), 2.30 (d, J=7.0 Hz, 2H), 2.22-2.12 (m, 2H), 2.10 (d, J=6.7 Hz, 2H), 2.05 (d, J=13.3 Hz, 6H), 1.96-1.93 (m, 1H), 1.83 (d, J=11.2 Hz, 2H), 1.64-1.53 (m, 2H), 0.75 (s, 3H). [M+H]+=1027.9.
A mixture of 2-chloro-6-nitroquinoline (12 g, 57.7 mmol) and Fe (16 g, 0.29 mol) in EtOH (50 mL) and sat. NH4Cl (200 mL) was stirred at 80° C. for 4 hrs. After cooling to r.t, the reaction mixture was filtered, and the filtrate was extracted with EA (3×200 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (PE: EA=2:1) to give the product (9 g, 87%). [M+H]+=179.1.
The title compound (9 g, 59%) was prepared in a manner similar to that in Example 486 step 4 from 2-chloroquinolin-6-amine and ICL. [M+H]+=305.0.
The title compound (6 g, 80%). was prepared in a manner similar to that in Example 486 step 5 from 2-chloro-5-iodoquinolin-6-amine and dimethylphosphineoxide. [M+H]+=255.1.
A mixture of (6-amino-2-chloroquinolin-5-yl)dimethylphosphine oxide (3.5 g, 13.8 mmol), cyclopropanecarboxamide (2.5 g, 69 mmol), Pd(OAc)2 (132 mg, 0.59 mmol), XantPhos (799 mg, 1.38 mmol), and Cs2CO3 (3.83 g, 11.8 mmol) in dioxane (60 mL) was stirred at 100° C. under nitrogen atmosphere for 15 hrs. After cooling to r.t, the reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH=10:1) to afford product (1 g, 56%). [M+H]+=304.1.
To a solution of N-(6-amino-5-(dimethylphosphoryl)quinolin-2-yl)cyclopropanecarboxamide (500 mg, 1.7 mmol) in i-PrOH (50 mL) was added 5-bromo-2,4-dichloropyrimidine (743 mg, 3.4 mmol). DIEA (638 mg, 5.1 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. overnight. The reaction was concentrated in vacuum and the residue was purified by column chromatography (DCM/MeOH=20/1) to afford the product (490 mg, 60%). [M+H]+=494.1.
To a stirred solution of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-(dimethylphosphoryl)quinolin-2-yl)cyclopropanecarboxamide (50 mg, 0.1 mmol) and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (42 mg, 0.1 mmol) in n-BuOH (40 mL) was added TsOH (52 mg, 0.3 mmol). The resulting mixture was stirred at 100° C. for 16 hours. The reaction mixture was concentrated to dryness, and aq. Na2CO3 (0.1M, 10 mL) was poured into the mixture. Then the mixture was extracted with DCM (2×20 mL). The combined organic layer was washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude residue, which was purified with silica gel column chromatography (DCM: MeOH=6:1) to give the title product (40 mg, 51%). [M+H]+=776.3.
A solution of N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphoryl)quinolin-2-yl)cyclopropanecarboxamide (40 mg, 0.05 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (18 mg, 0.05 mmol), T3P (66 mg, 0.1 mol, 50% in EA) and DIEA (20 mg, 0.15 mmol) in DCM (5 mL) was stirred at r.t. for 1 h. Then the mixture was washed with brine (1×10 mL), dried over Na2SO4, filtered and evaporated in vacuum to afford the crude residue, which was purified by silica gel column chromatography (DCM: MeOH=100: 0-10: 1 gradient elution) to give an impure product, which was further purified with prep-HPLC to give the desired product (9.86 mg, 17%). 1H NMR (500 MHz, DMSO) δ 11.54 (s, 1H), 11.15 (s, 1H), 10.84 (s, 1H), 8.74 (d, J=9.6 Hz, 1H), 8.34 (d, J=9.4 Hz, 1H), 8.23 (d, J=16.9 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J=9.3 Hz, 1H), 7.45 (s, 1H), 6.69 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.02 (dd, J=12.3, 4.8 Hz, 1H), 3.76 (s, 3H), 3.62-3.43 (m, 6H), 3.35 (s, 1H), 3.31-3.22 (m, 3H), 2.90 (d, J=13.8 Hz, 2H), 2.85-2.72 (m, 1H), 2.67-2.51 (m, 6H), 2.37 (s, 1H), 2.30-2.05 (m, 6H), 1.95 (dd, J=17.4, 9.4 Hz, 7H), 1.83 (d, J=10.0 Hz, 2H), 1.56 (d, J=9.3 Hz, 2H), 0.86 (dd, J=10.9, 6.0 Hz, 4H), 0.71 (s, 3H); [M+H]+=1096.7.
The title compound (320 mg, 65%) was prepared in a manner similar to that in Example 488 step 4 from 2-chloro-3-fluoro-6-nitroquinoline and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane. [M+H]+=219.1.
To a solution of 3-fluoro-6-nitro-2-vinylquinoline (320 mg, 1.46 mmol) in MeOH (20 mL)/DCM (10 mL) was added 10% Pd/C (100 mg, 10 wt. %, wet) at 25° C. The flask was evacuated and backfilled with hydrogen three times. The mixture was stirred under hydrogen atmosphere at 25° C. for 2 hours. The mixture was filtered through a pad of celite and washed with MeOH (20 mL). The filtrate was concentrated under vacuum to afford the desired product (255 mg, 91%). [M+H]+=191.1.
The title compound (400 mg, 95%) was prepared in a manner similar to that in Example 488 step 6 from 2-ethyl-3-fluoroquinolin-6-amine and ICl [M+H]+=317.0.
The title compound (320 mg, 95%) was prepared in a manner similar to that in Example 488 step 7 from 2-ethyl-3-fluoro-5-iodoquinolin-6-amine and dimethylphosphine oxide. [M+H]+=267.1.
The title compound (280 mg, 51%) was prepared in a manner similar to that in Example 488 step 8 from (6-amino-2-ethyl-3-fluoroquinolin-5-yl)dimethylphosphine oxide and 5-bromo-2,4-dichloropyrimidine. [M+H]+=457.1.
The title compound (120 mg, 43%) was prepared in a manner similar to that in Example 488 step 9 from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethyl-3-fluoroquinolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=753.2.
The title compound (16 mg, 38%) was prepared in a manner similar to that in Example 484 step 15 from (6-((5-bromo-2-((2-ethoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethyl-3-fluoroquinolin-5-yl)dimethylphosphine oxide and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 11.27 (s, 1H), 10.95 (s, 1H), 8.64 (d, J=12.4 Hz, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.89 (s, 1H), 7.31 (s, 1H), 7.02 (d, J=10.0 Hz, 2H), 6.69 (s, 1H), 4.20 (dd, J=12.7, 5.2 Hz, 1H), 3.99 (q, J=6.9 Hz, 2H), 2.99 (q, J=7.1 Hz, 2H), 2.93-2.71 (m, 6H), 2.65-2.52 (m, 8H), 2.36 (s, 3H), 2.26 (s, 1H), 2.16-2.10 (m, 3H), 2.02-1.92 (m, 8H), 1.82 (d, J=11.0 Hz, 2H), 1.51 (d, J=9.0 Hz, 2H), 1.33 (t, J=7.5 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.66 (s, 3H); [M+H]+=1004.5.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 10.88 (s, 1H), 9.79 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.21 (s, 1H), 6.96 (d, J=10.6 Hz, 2H), 6.67 (s, 1H), 4.15-4.11 (m, 1H), 3.68 (s, 3H), 3.00-2.96 (m, 2H), 2.86 (d, J=9.2 Hz, 2H), 2.77-2.74 (m, 1H), 2.70-2.67 (m, 2H), 2.61-2.56 (m, 3H), 2.48-2.45 (m, 7H), 2.40 (s, 2H), 2.22-2.16 (m, 3H), 2.10-2.03 (m, 2H), 1.96 (d, J=13.3 Hz, 7H), 1.77 (d, J=11.4 Hz, 2H), 1.47 (d, J=11.0 Hz, 2H), 1.31 (t, J=7.4 Hz, 3H), 0.68 (s, 3H); [M+H]+=973.1.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 10.85 (s, 1H), 9.91 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.32 (s, 1H), 6.70 (s, 1H), 6.11 (d, J=11.4 Hz, 2H), 4.03-3.98 (m, 3H), 3.94-3.92 (m, 2H), 3.48 (s, 2H), 3.08-3.03 (m, 2H), 2.91 (s, 3H), 2.81-2.74 (m, 1H), 2.66-2.62 (m, 3H), 2.57-2.52 (m, 5H), 2.36 (s, 2H), 2.19 (s, 2H), 2.03 (d, J=13.4 Hz, 7H), 1.96-1.91 (m, 2H), 1.82 (s, 2H), 1.53 (s, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.29-1.20 (m, 6H), 0.69 (s, 3H); [M+H]+=1028.2.
A mixture of (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethyl-8-fluoroquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione (40 mg, 0.04 mmol) and Pd/C(10 mg, 10 wt. %, wet) in MeOH/DCM (10 mL) was stirred in a round bottom flask at 25° C. for 1 hour under hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with prep-HPLC (0.1% FA in water: acetonitrile=90:1-50:50 gradient elution) to give the title product (15 mg, 40%). 1H NMR (500 MHz, DMSO) δ 12.15 (s, 1H), 10.95 (s, 1H), 8.73 (d, J=13.3 Hz, 1H), 8.61 (d, J=9.2 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.57 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.75 (s, 1H), 6.08 (d, J=5.6 Hz, 1H), 4.20 (dd, J=12.9, 5.1 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H), 3.02-2.90 (m, 4H), 2.85-2.82 (m, 1H), 2.78-2.71 (m, 2H), 2.69-2.62 (m, 2H), 2.55-2.53 (m, 7H), 2.45-2.42 (m, 6H), 2.32-2.29 (m, 1H), 2.19-2.07 (m, 1H), 2.02-1.98 (d, 7H), 1.86-1.84 (m, 2H), 1.61-1.49 (m, 2H), 1.34-1.24 (m, 6H), 0.91 (t, J=7.2 Hz, 3H); [M+H]+=926.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1043.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1057.2.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1069.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1043.5.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1070.1.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1052.1
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1067.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1058.3.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1046.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1023.1.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1004.8.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1071.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1053.9.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1028.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1037.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1049.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1026.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1008.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1079.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1108.9.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1055.9.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1043.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1021.9.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1075.2
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1040.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1037.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1051.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1057.8.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1095.2.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1079.1.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1080.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1041.6.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1090.7.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1058.9.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1040.9.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1042.7.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1060.7.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1021.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1005.7.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1053.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1020.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1021.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1043.7.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1034.9.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1049.9.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1102.1.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1151.9.
The title compound was prepared in a procedure similar to that in Example 413. [M+H]+=1080.7.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1017.9.
The title compound was prepared in a procedure similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 11.03 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.16-8.14 (m, 1H), 7.97 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.33 (s, 1H), 6.96-6.82 (m, 3H), 6.65 (s, 1H), 5.32-5.28 (m, 1H), 3.95-3.93 (m, 4H), 2.96-2.77 (m, 8H), 2.70-2.46 (m, 13H), 2.30-2.20 (m, 3H), 1.93 (d, J=13.3 Hz, 7H), 1.78-1.75 (m, 2H), 1.50-1.43 (m, 2H), 1.28-1.13 (m, 9H), 0.68 (s, 3H). [M+H]+=1052.7.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1024.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1065.7.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1008.7.
The title compound was prepared in a procedure similar to that in Example 413. [M+H]+=1052.1.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1038.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1095.8.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1041.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1011.7.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1068.4.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=998.35.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=936.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1067.8.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1014.7.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1017.2.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1047.1.
The title compound was prepared in a procedure similar to that in Example 413. [M+H]+=1049.8.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1041.4.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=965.2.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1055.2.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1081.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=992.2.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1071.1.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=964.6.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=985.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1014.3.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1008.5.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=973.2.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1038.3.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=990.2.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1058.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1038.1.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1057.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=993.2.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1057.5.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1045.2.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1003.7.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1071.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1056.7.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=969.9.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1008.8.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=958.7.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1033.7.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1019.6.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=998.7.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=948.5.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=988.6.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1041.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1032.1.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=972.1.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1013.9.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1055.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1043.3.
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1006.3.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1009.4.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1067.1.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1040.2.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1044.3.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=992.8.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=988.6.
The title compound was prepared in a procedure similar to that in Example 318. [M+H]+=1008.5.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1029.4.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=972.34.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=1041.4.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=965.8.
The title compound was prepared in a procedure similar to that in Example 413. [M+H]+=1003.4.
The title compound was prepared in a procedure similar to that in Example 413. 1H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 10.99 (s, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=9.3 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.00 (d, J=7.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.67 (s, 1H), 5.12 (s, 1H), 3.69 (s, 3H), 2.87 (d, J=10.9 Hz, 4H), 2.68-2.61 (m, 3H), 2.60-2.54 (m, 7H), 2.49 (d, J=18.1 Hz, 4H), 2.40 (s, 4H), 2.23 (d, J=7.3 Hz, 3H), 1.91 (d, J=13.3 Hz, 7H), 1.77 (d, J=11.0 Hz, 2H), 1.48 (d, J=8.7 Hz, 2H), 1.21 (d, J=2.9 Hz, 6H), 0.70 (s, 3H). [M+H]+=1006.4
The title compound was prepared in a procedure similar to that in Example 447. [M+H]+=1049.3.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=972.3.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=950.4.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=972.7.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=986.5.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=984.5.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1042.1.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1045.4.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1057.7.
The title compound was prepared in a procedure similar to that in Example 484. [M+H]+=1058.7.
The title compound was prepared in a procedure similar to that in Example 488. [M+H]+=988.5.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1074.2.
The title compound was prepared in a procedure similar to that in Example 492. [M+H]+=1055.0.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.87 (s, 1H), 10.84 (s, 1H), 8.55 (d, J=8.9 Hz, 1H), 8.37 (d, J=5.5 Hz, 1H), 8.22 (s, 1H), 7.93-7.84 (m, 2H), 7.49-7.37 (m, 2H), 6.65 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (q, J=7.0 Hz, 3H), 3.64-3.38 (m, 7H), 3.12-2.98 (m, 4H), 2.74-2.82 (m, 1H), 2.65 (s, 3H), 2.54-2.61 (m, 7H), 2.36 (s, 1H), 2.14-2.03 (m, 1H), 2.03-1.92 (m, 7H), 1.92-1.78 (m, 5H), 1.58 (q, J=12.4 Hz, 2H), 1.26 (t, J=6.9 Hz, 3H), 1.18 (s, 3H), 0.99 (s, 3H). [M+H]+=1055.0.
The title compound was prepared in a procedure similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 11.19 (s, 1H), 10.95 (s, 1H), 8.69 (d, J=12.0 Hz, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.85 (s, 1H), 7.37 (s, 1H), 7.02 (d, J=10.1 Hz, 2H), 6.68 (s, 1H), 4.20 (dd, J=12.7, 4.9 Hz, 1H), 3.99 (d, J=6.9 Hz, 2H), 2.90-2.73 (m, 6H), 2.66-2.53 (m, 11H), 2.48-2.40 (m, 3H), 2.26 (s, 1H), 2.17-2.08 (m, 3H), 2.02-1.92 (m, 8H), 1.81 (d, J=10.9 Hz, 2H), 1.56-1.47 (m, 2H), 1.26 (t, J=6.9 Hz, 3H), 0.64 (s, 3H). [M+H]+=990.5.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.51 (s, 1H), 10.84 (s, 1H), 8.53 (d, J=12.0 Hz, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.30 (s, 1H), 6.66 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (dd, J=12.7, 4.8 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 2H), 3.53-3.38 (m, 6H), 3.09 (dd, J=18.4, 9.1 Hz, 2H), 3.00 (d, J=10.7 Hz, 2H), 2.83-2.74 (m, 1H), 2.66-2.54 (m, 8H), 2.36 (s, 1H), 2.07 (t, J=12.7 Hz, 1H), 1.99-1.93 (m, 8H), 1.86-1.80 (m, 5H), 1.57 (d, J=11.4 Hz, 2H), 1.18 (s, 3H), 0.99 (s, 3H). [M+H]+=1059.6.
The title compound was prepared in a procedure similar to that in Example 484. 1H NMR (500 MHz, DMSO) δ 12.43 (s, 1H), 10.95 (s, 1H), 8.53 (d, J=8.8 Hz, 2H), 8.17 (s, 1H), 8.10 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.73 (s, 1H), 4.20 (dd, J=12.8, 5.3 Hz, 1H), 4.02 (q, J=6.9 Hz, 2H), 3.01-2.91 (m, 4H), 2.85-2.71 (m, 4H), 2.66-2.64 (m, 5H), 2.56-2.53 (m, 6H), 2.40-2.33 (m, 2H), 2.30-2.28 (m, 1H), 2.18-2.07 (m, 2H), 2.01-1.99 (m, 7H), 1.88-1.81 (m, 2H), 1.60-1.49 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.85-0.82 (m, 3H). [M+H]+=960.3.
The title compound was prepared in a procedure similar to that in Example 492. 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.26 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.22 (s, 2H), 7.91 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.27 (t, J=10.9 Hz, 1H), 6.70 (s, 1H), 5.43 (s, 1H), 4.00 (d, J=7.0 Hz, 2H), 2.98-2.83 (m, 8H), 2.70-2.52 (m, 8H), 2.38-2.34 (m, 4H), 2.32-2.16 (m, 5H), 1.98 (d, J=13.3 Hz, 6H), 1.82 (d, J=10.7 Hz, 2H), 1.56-1.48 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1043.5.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.50 (s, 1H), 10.84 (s, 1H), 8.53 (d, J=12.4 Hz, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.95 (d, J=11.9 Hz, 2H), 7.30 (s, 1H), 6.67 (s, 1H), 6.23 (d, J=12.1 Hz, 2H), 4.02 (dd, J=12.4, 5.0 Hz, 1H), 3.75 (s, 3H), 3.60-3.41 (m, 8H), 3.29-3.22 (m, 3H), 3.01 (d, J=10.7 Hz, 2H), 2.82-2.73 (m, 1H), 2.66-2.54 (m, 8H), 2.36 (s, 1H), 2.19-2.04 (m, 3H), 1.99-1.93 (m, 7H), 1.87-1.80 (m, 5H), 1.58 (d, J=9.8 Hz, 2H). [M+H]+=1031.5.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.95 (s, 1H), 8.79 (d, J=14.1 Hz, 1H), 8.46 (d, J=9.5 Hz, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.74 (s, 1H), 4.20 (dd, J=12.6, 5.0 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H), 2.99-2.91 (m, 4H), 2.86-2.71 (m, 3H), 2.65-2.62 (m, 3H), 2.58-2.55 (m, 7H), 2.48-2.35 (m, 5H), 2.29-2.26 (m, 1H), 2.19-2.08 (m, 4H), 2.03-2.01 (m, 7H), 1.86-1.83 (m, 2H), 1.56-1.54 (m, 2H), 1.34-1.27 (m, 6H), 0.85 (t, J=7.4 Hz, 3H). [M+H]+=940.3.
The title compound was prepared in a procedure similar to that in Example 486. [M+H]+=1002.2.
The title compound was prepared in a procedure similar to that in Example 486. [M+H]+=1033.4.
The title compound was prepared in a procedure similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.46 (s, 1H), 11.11 (s, 1H), 9.94 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.94 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.35 (s, 1H), 7.02 (s, 1H), 6.91 (t, J=9.9 Hz, 1H), 6.71 (s, 1H), 5.38 (dd, J=12.7, 5.0 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 3.60 (s, 3H), 3.31-3.28 (m, 2H), 3.08-3.04 (m, 5H), 2.89-2.86 (m, 4H), 2.68-2.62 (m, 8H), 2.49-2.45 (m, 5H), 2.20 (s, 2H), 2.04-2.01 (m, 8H), 1.62-1.61 (m, 1H), 1.39 (t, J=7.6 Hz, 3H), 1.25 (dd, J=13.4, 6.5 Hz, 3H), 0.68 (s, 3H). [M+H]+=1039.4.
The title compound was prepared in a procedure similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.46 (s, 1H), 11.10 (s, 1H), 9.94 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.87 (d, J=9.4 Hz, 1H), 7.34 (s, 1H), 7.01 (s, 2H), 6.94 (dd, J=5.9, 3.0 Hz, 1H), 6.71 (s, 1H), 5.37 (dd, J=12.8, 5.3 Hz, 1H), 4.01-3.96 (m, 4H), 3.30-3.26 (m, 2H), 3.13-2.84 (m, 10H), 2.79-2.57 (m, 8H), 2.50-2.47 (m, 2H), 2.19-2.16 (m, 2H), 1.99-1.85 (m, 9H), 1.62-1.58 (m, 2H), 1.39 (t, J=7.6 Hz, 3H), 1.25-1.13 (m, 6H), 0.68 (s, 3H). [M+H]+=1035.4.
The title compound was prepared in a procedure similar to that in Example 460. 1H NMR (500 MHz, DMSO) δ 11.44 (s, 1H), 10.95 (s, 1H), 9.91 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.93 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.36 (s, 1H), 7.04 (d, J=10.1 Hz, 2H), 6.69 (s, 1H), 4.20 (dd, J=12.7, 5.0 Hz, 1H), 4.00 (q, J=6.9 Hz, 2H), 3.31-3.28 (m, 2H), 2.91 (d, J=9.5 Hz, 2H), 2.86-2.70 (m, 7H), 2.68-2.51 (m, 9H), 2.36 (s, 2H), 2.15-2.11 (m, 3H), 2.01-1.92 (m, 7H), 1.86 (s, 2H), 1.56-1.51 (m, 2H), 1.25 (t, J=6.9 Hz, 3H), 0.68 (s, 3H). [M+H]+=973.3.
The title compound was prepared in a procedure similar to that in Example 460. 1H NMR (500 MHz, DMSO) δ 11.46 (s, 1H), 10.88 (s, 1H), 9.79 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.24 (s, 1H), 6.96 (d, J=10.1 Hz, 2H), 6.66 (s, 1H), 4.13 (dd, J=12.7, 4.9 Hz, 1H), 3.68 (s, 3H), 3.25-3.09 (m, 2H), 2.85 (d, J=10.6 Hz, 2H), 2.79-2.65 (m, 6H), 2.57 (t, J=11.1 Hz, 2H), 2.47-2.32 (m, 6H), 2.39-2.36 (m, 3H), 2.19 (s, 3H), 2.06 (dt, J=13.3, 9.7 Hz, 1H), 1.94-1.86 (m, 7H), 1.76 (d, J=10.9 Hz, 2H), 1.47-1.42 (m, 2H), 0.68 (s, 3H). [M+H]+=959.3.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.53 (s, 1H), 10.84 (s, 1H), 9.86 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 6.73 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (dd, J=12.5, 4.9 Hz, 1H), 3.75 (s, 3H), 3.47-3.21 (m, 9H), 3.09-3.02 (m, 2H), 2.93 (d, J=10.3 Hz, 2H), 2.84-2.73 (m, 4H), 2.65 (t, J=10.8 Hz, 2H), 2.54-2.49 (m, 3H), 2.36-2.31 (m, 1H), 2.26-2.21 (m, 2H), 2.14-1.92 (m, 8H), 1.83 (d, J=10.4 Hz, 2H), 1.56 (d, J=10.6 Hz, 2H), 1.18 (s, 3H), 0.99 (s, 3H), 0.75 (s, 3H). [M+H]+=1056.4.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 11.75 (s, 1H), 10.95 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.21-8.17 (m, 2H), 8.03 (s, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.27 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.76 (s, 1H), 4.20 (dd, J=12.6, 5.0 Hz, 1H), 3.76 (s, 3H), 3.29-3.24 (m, 2H), 2.95 (d, J=10.9 Hz, 2H), 2.86-2.72 (m, 3H), 2.67 (t, J=11.2 Hz, 2H), 2.54-2.38 (m, 7H), 2.48-2.39 (m, 2H), 2.34-2.23 (m, 4H), 2.13 (dt, J=12.9, 9.0 Hz, 1H), 1.99-1.89 (m, 7H), 1.86 (d, J=11.8 Hz, 2H), 1.55-1.51 (m, 2H), 1.06 (d, J=6.4 Hz, 4H), 0.78 (s, 3H). [M+H]+=984.3.
The title compound was prepared in a procedure similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 11.16 (s, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.22 (s, 2H), 7.91 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 7.09 (dd, J=12.5, 7.8 Hz, 1H), 6.71 (s, 1H), 5.57 (dd, J=12.9, 5.2 Hz, 1H), 4.08-3.94 (m, 4H), 2.94 (dt, J=14.4, 7.1 Hz, 8H), 2.71-2.60 (m, 4H), 2.59-2.52 (m, 8H), 2.25 (s, 4H), 2.13 (s, 1H), 1.98 (d, J=13.3 Hz, 6H), 1.83 (d, J=11.2 Hz, 2H), 1.53-1.47 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 6H), 0.71 (s, 3H). [M+H]+=1070.4
The title compound was prepared in a procedure similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 11.16 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.21-8.15 (m, 1H), 8.10 (s, 1H), 7.33 (s, 1H), 7.09 (dd, J=12.6, 7.9 Hz, 1H), 6.73 (s, 1H), 5.57 (dd, J=12.5, 5.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 3H), 4.04-4.00 (m, 5H), 2.97 (d, J=7.9 Hz, 6H), 2.73-2.54 (m, 4H), 2.29 (d, J=7.8 Hz, 6H), 2.13 (s, 1H), 2.03 (d, J=13.3 Hz, 7H), 1.85 (d, J=10.9 Hz, 2H), 1.63-1.49 (m, 3H), 1.32 (s, 4H), 1.25 (s, 7H), 0.88 (s, 3H). [M+H]+=1087.4
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 10.96 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.14 (d, J=6.9 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.06 (d, J=10.1 Hz, 2H), 6.76 (s, 1H), 4.21 (d, J=8.5 Hz, 1H), 3.77 (s, 3H), 3.54 (s, 1H), 3.01 (s, 4H), 2.93 (q, J=7.5 Hz, 2H), 2.86-2.76 (m, 2H), 2.74-2.67 (m, 4H), 2.55 (s, 2H), 2.52 (s, 6H), 2.45-2.30 (m, 3H), 2.21-2.10 (m, 2H), 2.00 (d, J=13.3 Hz, 7H), 1.81 (s, 1H), 1.58 (s, 1H), 1.32 (t, J=7.6 Hz, 3H), 0.82 (s, 3H). [M+H]+=928.4.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 10.96 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=10.0 Hz, 2H), 6.74 (s, 1H), 4.22 (dd, J=12.6, 4.9 Hz, 1H), 3.76 (s, 3H), 2.93 (s, 7H), 2.80 (dd, J=13.2, 5.0 Hz, 1H), 2.63 (t, J=10.9 Hz, 3H), 2.54-2.50 (m, 6H), 2.29 (d, J=6.7 Hz, 2H), 2.13-2.09 (m, 1H), 1.98 (d, J=13.3 Hz, 7H), 1.87-1.73 (m, 4H), 1.32 (t, J=7.6 Hz, 7H), 1.23 (s, 1H), 0.77 (s, 3H). [M+H]+=971.3.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 10.84 (s, 1H), 8.57 (d, J=7.0 Hz, 1H), 8.32-8.27 (m, 2H), 8.05 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 6.71 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (d, J=7.0 Hz, 3H), 3.70-3.57 (m, 8H), 3.15-3.05 (m, 3H), 2.95 (d, J=7.6 Hz, 4H), 2.84-2.73 (m, 2H), 2.68-2.59 (m, 4H), 2.40-2.23 (m, 3H), 2.00 (d, J=13.3 Hz, 8H), 1.83 (d, J=10.6 Hz, 2H), 1.55 (d, J=10.8 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.27 (d, J=6.9 Hz, 3H), 1.18 (s, 3H), 0.99 (s, 3H), 0.74 (s, 3H). [M+H]+=1101.4.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.62 (s, 1H), 10.77 (s, 1H), 8.53 (d, J=8.9 Hz, 1H), 8.18 (d, J=21.2 Hz, 2H), 7.95-7.77 (m, 2H), 7.36 (d, J=8.7 Hz, 2H), 6.63 (s, 1H), 6.09 (d, J=12.2 Hz, 2H), 3.93 (q, J=6.9 Hz, 3H), 3.60-3.45 (m, 8H), 3.02 (dd, J=18.7, 9.2 Hz, 2H), 2.86 (d, J=10.7 Hz, 2H), 2.76-2.67 (m, 2H), 2.58 (s, 6H), 2.29 (s, 1H), 2.19 (d, J=5.8 Hz, 2H), 2.06-1.85 (m, 9H), 1.75 (d, J=10.6 Hz, 2H), 1.49 (d, J=10.7 Hz, 2H), 1.19 (t, J=6.9 Hz, 4H), 1.10 (d, J=10.9 Hz, 3H), 0.92 (s, 3H), 0.64 (s, 3H). [M+H]+=1069.4.
The title compound was prepared in a procedure similar to that in Example 460. 1H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 10.95 (s, 1H), 9.82 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.84 (s, 1H), 7.23 (s, 1H), 7.02 (d, J=10.0 Hz, 2H), 6.67 (s, 1H), 4.20 (dd, J=12.6, 5.0 Hz, 1H), 3.75 (s, 3H), 3.01 (s, 4H), 2.85-2.82 (m, 1H), 2.77-2.74 (m, 3H), 2.62-2.57 (m, 3H), 2.55-2.53 (m, 6H), 2.48-2.45 (m, 2H), 2.27 (s, 1H), 2.19-2.10 (m, 2H), 2.03-1.98 (m, 6H), 1.89-1.82 (m, 6H), 1.54 (d, J=9.7 Hz, 2H), 1.36 (d, J=6.8 Hz, 3H). [M+H]+=959.0.
The title compound was prepared in a procedure similar to that in Example 460. 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 10.95 (s, 1H), 10.18 (s, 1H), 8.57 (s, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.04 (d, J=10.1 Hz, 2H), 6.71 (s, 1H), 6.18 (d, J=5.6 Hz, 1H), 4.20 (dd, J=12.6, 4.9 Hz, 1H), 4.05-4.01 (m, 2H), 3.07-3.03 (m, 2H), 2.92 (d, J=10.2 Hz, 2H), 2.83-2.79 (m, 1H), 2.78-2.75 (m, 3H), 2.66-2.59 (m, 5H), 2.55-2.52 (m, 7H), 2.24-2.21 (m, 2H), 2.13 (dd, J=13.4, 3.7 Hz, 1H), 1.99 (d, J=13.4 Hz, 8H), 1.89 (s, 2H), 1.57 (s, 2H), 1.37 (t, J=7.6 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 0.72 (s, 3H). [M+H]+=909.2.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.84 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.74 (s, 1H), 6.23 (d, J=12.2 Hz, 2H), 4.02 (dd, J=12.5, 4.9 Hz, 1H), 3.76 (s, 3H), 3.59-3.42 (m, 6H), 3.36-3.32 (m, 1H), 3.31-3.22 (m, 2H), 2.95 (d, J=10.6 Hz, 2H), 2.83-2.73 (m, 1H), 2.71-2.62 (m, 5H), 2.61-2.51 (m, 3H), 2.48-2.44 (m, 2H), 2.42-2.35 (m, 1H), 2.35-2.25 (m, 2H), 2.20-2.04 (m, 3H), 2.02-1.91 (m, 7H), 1.84 (d, J=10.2 Hz, 2H), 1.65-1.51 (m, 2H), 0.77 (s, 3H). [M+H]+=1027.7.
The title compound was prepared in a procedure similar to that in Example 486.
1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.96 (s, 1H), 8.86 (dt, J=22.8, 11.4 Hz, 3H), 8.28 (d, J=9.1 Hz, 2H), 7.90 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.03 (d, J=10.0 Hz, 2H), 6.81 (s, 1H), 4.20 (dd, J=12.8, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J=11.5 Hz, 2H), 2.76 (m, 6H), 2.54 (d, J=1.8 Hz, 6H), 2.48 (s, 5H), 2.36 (s, 2H), 2.13 (d, J=9.6 Hz, 1H), 2.02 (d, J=14.4 Hz, 7H), 1.87 (d, J=11.4 Hz, 2H), 1.58 (d, J=8.8 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H); [M+H]+=945.4.
The title compound was prepared in a procedure similar to that in Example 318. 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 11.10 (s, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.29-8.17 (m, 2H), 7.92 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.39 (s, 1H), 7.05-6.95 (m, 2H), 6.90 (dd, J=6.3, 2.5 Hz, 1H), 6.71 (s, 1H), 5.37 (dd, J=12.7, 5.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.58 (s, 3H), 3.22-3.20 (m, 2H), 3.09-3.03 (m, 2H), 2.96-2.85 (m, 5H), 2.76-2.51 (m, 12H), 2.27-2.23 (m, 3H), 2.02-1.93 (m, 7H), 1.83 (d, J=10.7 Hz, 2H), 1.53-1.49 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H), 0.71 (s, 3H). [M+H]+=1020.5.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.95 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 8.18 (d, J=6.0 Hz, 2H), 7.31 (s, 1H), 7.04 (s, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 4.22-4.15 (m, 3H), 3.75 (s, 3H), 2.98 (d, J=10.6 Hz, 2H), 2.85-2.74 (m, 4H), 2.67 (t, J=11.1 Hz, 3H), 2.55-2.53 (m, 7H), 2.48-2.38 (m, 5H), 2.32 (t, J=11.1 Hz, 1H), 2.17-2.10 (m, 1H), 2.03 (d, J=13.4 Hz, 6H), 1.85 (d, J=10.9 Hz, 2H), 1.56 (d, J=11.4 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H), 0.91 (s, 3H). [M+H]+=989.7.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 11.79 (s, 1H), 10.84 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=9.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.33 (s, 1H), 6.75 (s, 1H), 6.15 (d, J=12.2 Hz, 2H), 4.01 (dd, J=12.4, 4.9 Hz, 1H), 3.76 (s, 3H), 3.60 (s, 2H), 3.52 (d, J=13.0 Hz, 2H), 3.45 (d, J=5.3 Hz, 2H), 3.42-3.35 (m, 4H), 3.05-3.15 (m, 2H), 3.00-2.89 (m, 4H), 2.83-2.73 (m, 1H), 2.68 (t, J=11.3 Hz, 2H), 2.50-2.55 (m, 2H), 2.37 (s, 1H), 2.29 (d, J=6.6 Hz, 2H), 2.08-2.12 (m, 1H), 1.98 (d, J=13.3 Hz, 7H), 1.84 (d, J=10.5 Hz, 2H), 1.57 (d, J=11.2 Hz, 2H), 1.32 (s, 3H), 1.19 (s, 3H), 0.99 (s, 3H), 0.77 (s, 3H). [M+H]+=1069.4.
The title compound was prepared in a procedure similar to that in Example 488. 1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 10.86 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.28 (d, J=7.3 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 6.17 (d, J=11.1 Hz, 2H), 4.07-4.00 (m, 3H), 3.92 (t, J=6.0 Hz, 2H), 3.87-3.79 (m, 1H), 3.76 (s, 3H), 3.49 (s, 2H), 3.32 (s, 3H), 3.00-2.88 (m, 4H), 2.84-2.73 (m, 1H), 2.72-2.63 (m, 2H), 2.51-2.44 (m, 4H), 2.42-2.34 (m, 1H), 2.34-2.25 (m, 2H), 2.13-2.03 (m, 1H), 2.02-1.92 (m, 7H), 1.82 (d, J=10.5 Hz, 2H), 1.63-1.51 (m, 2H), 1.32 (t, J=7.6 Hz, 3H), 0.77 (s, 3H). [M+H]+=1027.7.
The title compound was prepared in a procedure similar to that in Example 486. 1H NMR (500 MHz, DMSO) δ 12.21 (s, 1H), 11.08 (s, 1H), 8.63-8.51 (m, 2H), 8.23-8.16 (m, 3H), 7.34 (s, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.88 (d, J=7.7 Hz, 2H), 6.76 (s, 1H), 5.31 (s, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.99 (d, J=10.3 Hz, 2H), 2.88 (t, J=12.5 Hz, 1H), 2.71-2.60 (m, 4H), 2.57-2.54 (m, 6H), 2.49-2.37 (m, 9H), 2.32 (t, J=11.0 Hz, 1H), 2.03 (d, J=13.4 Hz, 6H), 1.95 (d, J=3.4 Hz, 2H), 1.85 (d, J=10.8 Hz, 2H), 1.57 (d, J=11.4 Hz, 2H), 1.48 (d, J=3.7 Hz, 2H), 0.93 (s, 3H). [M+H]+=1020.7.
The titled compound (740 mg, 88%) was prepared in a manner similar to that in Example 460 step 8 from 1-ethoxy-5-fluoro-4-methyl-2-nitrobenzene and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate. [M+H]+=449.3.
The titled compound (520 mg, 78%) was prepared in a manner similar to that in Example 460 step 9 from tert-butyl 4-(1-(5-ethoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate and Pd/C. [M+H]+=419.3.
Cell Degradation
Cell Line Generation
H1975-clone #36(L858R/T790M). H1975 cell heterozygously (from ATCC) contains alleles of WT and L858R/T790M EGFR. H1975-clone #36(L858R/T790M) was generated by gene knockout, in which the EGFR targeting sgRNA was designed to specifically target WT EGFR but preserve the L858R/T790M copy. Followed by the gene knockout, the edited H1975 cells were seeded in 96 well plates at the concentration of 1 cell/well, cultured for about 2 weeks to allow single clones formation. The formed clones were screened by DNA sequencing for the desired edition. H1975-clone #36 was confirmed as a homozygous L858R/T790M EGFR clone.
H1975-clone #28(Del19/T790M/C797S) and H1975-clone #23(Del19/C797S). EGFR-Del19/T790M/C797S and EGFR-Del19/C797S were stably expressed in H1975 cell lines by lentivirus-mediated over-expression, respectively. The EGFR over-expressed cells then underwent gene knockout, in which the EGFR targeting sgRNA was designed to only target the endogenous EGFR copies and preserve the exogenous EGFR copies. Followed by the gene knockout, the edited H1975 cells were seeded in 96 well plates at the concentration of 1 cell/well, cultured for about 2 weeks to allow single clones formation. The formed clones were screened by DNA sequencing and whole exon sequencing analysis for the desired edition. H1975-clone #28 and H1975-clone #23 were finally confirmed as homozygous Del19/T790M/C797S EGFR and Del19/C797S EGFR clones, respectively.
Cell Treatment
1a). BaF3 WT, BaF3-LTC(L858R/T790M/C797S), BaF3-DTC(Del19/T790M/C797S) and BaF3 LC(L858R/C797S) cells are seeded at 50000 cells/well (WT) or 20000 cells/well (LTC, DTC&LC) in cell culture medium [RPMI1640(Gibco, phenol red free, Cat #11835-030), 10% heat-inactive FBS, 1% PS(Gibco, Cat #10378)] in Corning 96 well plate (Cat #3799).
1b). On day 1, HCC827, H1975-clone #36(L858R/T790M, homozygous), H1975-clone #28(Del19/T790M/C797S) and H1975-clone #23(Del19/C797S) cells are seeded at 20000 cells/well, 30000cells/well, 10000 cells/well or 5000 cells/well correspondingly in cell culture medium [RPMI1640(Gibco, Cat #72400-047), 10% heat-inactive FBS, 1% PS(Gibco, Cat #10378)] in Corning 96 well plate (Cat #3599).
BaF3 WT(wild type), BaF3-LTC(L858R/T790M/C797S) and BaF3-DTC(Del19/T790M/C797S) cells are treated with compounds diluted in 0.2% DMSO cell culture medium and incubate for 16h, 37° C., 5% CO2, H1975-#36, H1975-#28, H1975-#23 and HCC827 cells are treated with compounds diluted in 0.2% DMSO cell culture medium on day 2, incubate for 16h, 37° C., 5% CO2.the final concentriation of compounds in all assay is start with 10 uM, 5-fold dilution, total 8 doses were included.
HTRF Assay
After 16h treatment, add HTRF lysis buffer to each well; seal the plate and incubate 1 hour at room temperature on a plate shaker; Once the cells are lysed, 16 μL of cell lysate are transferred to a PE 384-well HTRF detection plate; 4 μL of pre-mixed HTRF antibodies are added to each well; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337 nm-665 nm-620 nm).
The inhibition (degradation) percentage of the compound was calculated by the following equation: Inhibition percentage of Compound=100-100×(Signal-low control)/(High control-low control), wherein signal=each test compound group
Low control=only lysis buffer without cells, indicating that EGFR is completely degraded;
High control=Cell group with added DMSO and without compound, indicating microplate readings without EGFR degradation;
Dmax is the maximum percentage of inhibition (degradation).
The IC50 (DC50) value of a compound can be obtained by fitting the following equation
Y=Bottom+(TOP−Bottom)/(1+((IC50/X){circumflex over ( )}hillslope))
Wherein, X and Y are known values, and IC50, Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation), X is the concentration of the compound; IC50 is the concentration of the compound when the 50% inhibition is reached. The smaller the IC50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC50 value is, the weaker the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1*; Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%±20%; Top represents the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
The foregoing examples and description of certain embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entireties.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/CN2020/102501 | Jul 2020 | WO | international |
| PCT/CN2020/113237 | Sep 2020 | WO | international |
| PCT/CN2021/070896 | Jan 2021 | WO | international |
| PCT/CN2021/101275 | Jun 2021 | WO | international |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/106482 | 7/15/2021 | WO |
