Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
Guo, Yunhang; Liu, Ye; Hu, Nan; Yu, Desheng; Zhou, Changyou; Shi, Gongyin; Zhang, Bo; Wei, Min; Liu, Junhua; Luo, Lusong; Tang, Zhiyu; Song, Huipeng; Guo, Yin; Liu, Xuesong; Su, Dan; Zhang, Shuo; Song, Xiaomin; Zhou, Xing; Hong, Yuan; Chen, Shuaishuai; Cheng, Zhenzhen; Young, Steve; Wei, Qiang; Wang, Haisheng; Wang, Qiuwen; Lv, Lei; Wang, Fan; Xu, Haipeng; Sun, Hanzi; Xing, Haimei; Li, Na; Zhang, Wei; Wang, Zhongbo; Liu, Guodong; Sun, Zhijian; Zhou, Dongping; Li, Wei; Liu, Libin; Wang, Lai; Wang, Zhiwei; Journal of medicinal chemistry 62 (2019) 7923–7940; doi:10.1021/acs.jmedchem.9b00687

data_1552558
_publ_section_title
;
 Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective
 Covalent Inhibitor of Bruton's Tyrosine Kinase.
;
_journal_issue                   17
_journal_name_full               'Journal of medicinal chemistry'
_journal_page_first              7923
_journal_page_last               7940
_journal_paper_doi               10.1021/acs.jmedchem.9b00687
_journal_volume                  62
_journal_year                    2019
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C27 H29 N5 O3'
_chemical_formula_sum            'C27 H29 N5 O3'
_chemical_formula_weight         471.55
_chemical_name_systematic        BGB-3111
_space_group_crystal_system      triclinic
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2018-06-10
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                77.756(4)
_cell_angle_beta                 82.545(4)
_cell_angle_gamma                68.655(3)
_cell_formula_units_Z            2
_cell_length_a                   8.6537(3)
_cell_length_b                   8.8678(3)
_cell_length_c                   16.7811(8)
_cell_measurement_reflns_used    9648
_cell_measurement_temperature    150.01(10)
_cell_measurement_theta_max      70.5510
_cell_measurement_theta_min      5.4080
_cell_volume                     1170.20(8)
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      150.01(10)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 16.0450
_diffrn_detector_type            Eos
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.999
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'SuperNova, Dual, Cu at home/near, Eos'
_diffrn_measurement_method       'phi and omega scans'
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0167
_diffrn_reflns_av_unetI/netI     0.0194
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.999
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -10
_diffrn_reflns_limit_k_max       10
_diffrn_reflns_limit_k_min       -8
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            12410
_diffrn_reflns_point_group_measured_fraction_full 0.743
_diffrn_reflns_point_group_measured_fraction_max 0.743
_diffrn_reflns_theta_full        66.574
_diffrn_reflns_theta_max         66.574
_diffrn_reflns_theta_min         5.404
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'SuperNova (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.722
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.95441
_exptl_absorpt_correction_type   empirical
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.39.46 (Rigaku Oxford Diffraction, 2018)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear light colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   light
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.338
_exptl_crystal_description       block
_exptl_crystal_F_000             500
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.15
_exptl_crystal_size_min          0.15
_refine_diff_density_max         0.162
_refine_diff_density_min         -0.192
_refine_diff_density_rms         0.030
_refine_ls_abs_structure_details
;
 Flack x determined using 1966 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.08(7)
_refine_ls_extinction_coef       0.0020(6)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2017/1 (Sheldrick 2017)'
_refine_ls_goodness_of_fit_ref   1.031
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     676
_refine_ls_number_reflns         6162
_refine_ls_number_restraints     6
_refine_ls_restrained_S_all      1.032
_refine_ls_R_factor_all          0.0293
_refine_ls_R_factor_gt           0.0288
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0523P)^2^+0.1563P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0786
_refine_ls_wR_factor_ref         0.0789
_reflns_Friedel_coverage         0.488
_reflns_Friedel_fraction_full    0.487
_reflns_Friedel_fraction_max     0.487
_reflns_number_gt                6105
_reflns_number_total             6162
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm9b00687_si_003.cif
_cod_data_source_block           81035606a7
_cod_original_cell_volume        1170.20(9)
_cod_database_code               1552558
_shelx_shelxl_version_number     2017/1
_shelx_estimated_absorpt_t_max   0.899
_shelx_estimated_absorpt_t_min   0.869
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H,H) groups
2. Restrained distances
 N1A-H1A
 0.841 with sigma of 0.01
 N1B-C3B \\sim N1B-C3B'
 with sigma of 0.02
 C2B-C3B \\sim C2B-C3B'
 with sigma of 0.02
 C1B-C2B \\sim C1B-C2B'
 with sigma of 0.02
 C2B-C3B \\sim C2B'-C3B
 with sigma of 0.02
 C2B-C3B' \\sim C2B'-C3B'
 with sigma of 0.02
3. Others
 Fixed Sof: H1B(0.75) H1Ba(0.25) H1Bb(0.75) H1Bc(0.25) C2B(0.75) H2Ba(0.75)
 H2Bb(0.75) C3B(0.75) H3Ba(0.75) H3Bb(0.75) C3B'(0.25) H3Bc(0.25) H3Bd(0.25)
 C2B'(0.25) H2Bc(0.25) H2Bd(0.25)
4.a Ternary CH refined with riding coordinates:
 C1A(H1Aa), C20A(H20A), C20B(H20B), C1B(H1Bb), C1B(H1Bc)
4.b Secondary CH2 refined with riding coordinates:
 C22A(H22c,H22d), C2A(H2Aa,H2Ab), C24A(H24c,H24d), C23A(H23c,H23d), C21A(H21c,
 H21d), C21B(H21a,H21b), C23B(H23a,H23b), C24B(H24a,H24b), C22B(H22a,H22b),
 C2B(H2Ba,H2Bb), C3B(H3Ba,H3Bb), C3B'(H3Bc,H3Bd), C2B'(H2Bc,H2Bd)
4.c Aromatic/amide H refined with riding coordinates:
 C13B(H13B), N1B(H1B), N1B(H1Ba), C26A(H26A), C9A(H9A), C10A(H10A), C9B(H9B),
 C16A(H16A), C12B(H12B), C15A(H15A), C12A(H12A), C18B(H18B), C15B(H15B),
 C19B(H19B), C13A(H13A), C10B(H10B), C19A(H19A), C16B(H16B), C17A(H17A),
 C17B(H17B), C26B(H26B), C18A(H18A)
4.d X=CH2 refined with riding coordinates:
 C27B(H27a,H27b), C27A(H27c,H27d)
;
_shelx_res_checksum              69085
_shelx_hkl_checksum              69553
_olex2_submission_original_sample_id 810356-06-A7
_olex2_submission_special_instructions 'No special instructions were received'