Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4- b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors.
Xue, Yu; Song, Peiran; Song, Zilan; Wang, Aoli; Tong, Linjiang; Geng, Meiyu; Ding, Jian; Liu, Qingsong; Sun, Liping; Xie, Hua; Zhang, Ao; Journal of medicinal chemistry 61 (2018) 4608–4627; doi:10.1021/acs.jmedchem.8b00441

data_1553255
_publ_section_title
;
 Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4-
 b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors.
;
_journal_issue                   10
_journal_name_full               'Journal of medicinal chemistry'
_journal_page_first              4608
_journal_page_last               4627
_journal_paper_doi               10.1021/acs.jmedchem.8b00441
_journal_volume                  61
_journal_year                    2018
_chemical_absolute_configuration rmad
_chemical_formula_moiety         'C12 H11 N O3'
_chemical_formula_sum            'C12 H11 N O3'
_chemical_formula_weight         217.22
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2017-03-30
_audit_creation_method
;
Olex2 1.2-alpha
(compiled 2017.03.28 svn.r3405 for OlexSys, GUI svn.r5332)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   6.9170(3)
_cell_length_b                   8.4769(3)
_cell_length_c                   18.1729(7)
_cell_measurement_reflns_used    5898
_cell_measurement_temperature    173
_cell_measurement_theta_max      68.076
_cell_measurement_theta_min      4.867
_cell_volume                     1065.56(7)
_computing_cell_refinement       'SAINT v8.37A (Bruker, 2015)'
_computing_data_reduction        'SAINT v8.37A (Bruker, 2015)'
_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_temperature      173
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.993
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0383
_diffrn_reflns_av_unetI/netI     0.0274
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.993
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       8
_diffrn_reflns_limit_k_min       -10
_diffrn_reflns_limit_l_max       21
_diffrn_reflns_limit_l_min       -21
_diffrn_reflns_number            10395
_diffrn_reflns_point_group_measured_fraction_full 0.995
_diffrn_reflns_point_group_measured_fraction_max 0.990
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         68.470
_diffrn_reflns_theta_min         4.867
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.815
_exptl_absorpt_correction_T_max  0.7531
_exptl_absorpt_correction_T_min  0.6915
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1372 before and 0.0596 after correction. The Ratio of minimum to maximum transmission is 0.9182. The \l/2 correction factor is Not present.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.354
_exptl_crystal_description       needle
_exptl_crystal_F_000             456
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.08
_exptl_crystal_size_min          0.03
_refine_diff_density_max         0.481
_refine_diff_density_min         -0.203
_refine_diff_density_rms         0.044
_refine_ls_abs_structure_details
;
 Flack x determined using 634 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.27(12)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   0.962
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     146
_refine_ls_number_reflns         1941
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      0.962
_refine_ls_R_factor_all          0.0475
_refine_ls_R_factor_gt           0.0390
_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^)+(0.1000P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1132
_refine_ls_wR_factor_ref         0.1224
_reflns_Friedel_coverage         0.679
_reflns_Friedel_fraction_full    0.992
_reflns_Friedel_fraction_max     0.985
_reflns_number_gt                1699
_reflns_number_total             1941
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm8b00441_si_004.cif
_cod_data_source_block           ta_a
_cod_database_code               1553255
_shelx_shelxl_version_number     2014/7
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups
 At 1.5 times of:
  All O(H) groups
2.a Ternary CH refined with riding coordinates:
 C9(H9)
2.b Secondary CH2 refined with riding coordinates:
 C10(H10A,H10B)
2.c Aromatic/amide H refined with riding coordinates:
 C4(H4), C1(H1), C3(H3A), C11(H11), C2(H2)
2.d X=CH2 refined with riding coordinates:
 C12(H12A,H12B)
2.e Idealised tetrahedral OH refined as rotating group:
 O3(H3)
;
_olex2_submission_special_instructions 'No special instructions were received'