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_1553254
_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         'C27 H28 Br N5 O3'
_chemical_formula_sum            'C27 H28 Br N5 O3'
_chemical_formula_weight         550.45
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2017-12-27
_audit_creation_method
;
Olex2 1.2
(compiled 2017.08.10 svn.r3458 for OlexSys, GUI svn.r5381)
;
_cell_angle_alpha                90
_cell_angle_beta                 110.084(9)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   13.774(4)
_cell_length_b                   18.775(6)
_cell_length_c                   10.658(3)
_cell_measurement_reflns_used    1157
_cell_measurement_temperature    205
_cell_measurement_theta_max      19.43
_cell_measurement_theta_min      2.31
_cell_volume                     2588.6(13)
_computing_cell_refinement       'SAINT v8.34A (Bruker, 2013)'
_computing_data_reduction        'SAINT v8.34A (Bruker, 2013)'
_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      205
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.991
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_type           MoK\a
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.0720
_diffrn_reflns_av_unetI/netI     0.1351
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.991
_diffrn_reflns_limit_h_max       17
_diffrn_reflns_limit_h_min       -16
_diffrn_reflns_limit_k_max       22
_diffrn_reflns_limit_k_min       -24
_diffrn_reflns_limit_l_max       13
_diffrn_reflns_limit_l_min       -13
_diffrn_reflns_number            23290
_diffrn_reflns_point_group_measured_fraction_full 0.946
_diffrn_reflns_point_group_measured_fraction_max 0.927
_diffrn_reflns_theta_full        25.242
_diffrn_reflns_theta_max         27.660
_diffrn_reflns_theta_min         1.574
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    1.626
_exptl_absorpt_correction_T_max  0.7456
_exptl_absorpt_correction_T_min  0.6603
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2014/5 (Bruker,2014/5) was used for absorption correction. wR2(int) was 0.0838 before and 0.0656 after correction. The Ratio of minimum to maximum transmission is 0.8856. The \l/2 correction factor is 0.00150.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.412
_exptl_crystal_description       block
_exptl_crystal_F_000             1136
_exptl_crystal_size_max          0.18
_exptl_crystal_size_mid          0.15
_exptl_crystal_size_min          0.12
_refine_diff_density_max         0.390
_refine_diff_density_min         -0.417
_refine_diff_density_rms         0.081
_refine_ls_abs_structure_details
;
 Flack x determined using 2047 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.029(9)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   0.967
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     675
_refine_ls_number_reflns         11188
_refine_ls_number_restraints     613
_refine_ls_restrained_S_all      0.979
_refine_ls_R_factor_all          0.1236
_refine_ls_R_factor_gt           0.0538
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0450P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1108
_refine_ls_wR_factor_ref         0.1366
_reflns_Friedel_coverage         0.815
_reflns_Friedel_fraction_full    0.893
_reflns_Friedel_fraction_max     0.859
_reflns_number_gt                6397
_reflns_number_total             11188
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm8b00441_si_003.cif
_cod_data_source_block           mo_20171147-11122035-1_0m
_cod_database_code               1553254
_shelx_shelxl_version_number     2014/7
_shelx_estimated_absorpt_t_max   0.829
_shelx_estimated_absorpt_t_min   0.758
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups, All N(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2. Restrained distances
 C49-C48
 1.28 with sigma of 0.02
 C48-C47 = C47-C1AA
 1.54 with sigma of 0.02
3. Uiso/Uaniso restraints and constraints
Uanis(C48) \\sim Ueq, Uanis(C49) \\sim Ueq: with sigma of 0.005 and sigma for
terminal atoms of 0.01
Uanis(C25) \\sim Ueq: with sigma of 0.005 and sigma for terminal atoms of 0.01
Uanis(O6) \\sim Ueq: with sigma of 0.005 and sigma for terminal atoms of 0.01
4. Rigid body (RIGU) restrains
 All non-hydrogen atoms
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
5. Others
 Fixed Sof: H47A(0.5) H47(0.5) C49(0.5) H49A(0.5) H49B(0.5) C48(0.5) H48(0.5)
 C1AA(0.5) H1AA(0.5) C0AA(0.5) H0AA(0.5) H0AB(0.5)
6.a Rotating group:
 N5(H5A,H5B), N6(H6A,H6B)
6.b Ternary CH refined with riding coordinates:
 C20(H20), C47(H47A), C47(H47)
6.c Secondary CH2 refined with riding coordinates:
 C46(H46A,H46B), C19(H19A,H19B)
6.d Aromatic/amide H refined with riding coordinates:
 N1(H1), C18(H18), C7(H7), C8(H8), C10(H10A), N10(H10), C36(H36), C38(H38),
 C35(H35), C11(H11), C21(H21), C30(H30), C39(H39), C1(H1A), C2(H2), C5(H5),
 C32(H32), C31(H31), C44(H44), C4(H4), C29(H29), C28(H28), C3(H3), C48(H48),
 C1AA(H1AA)
6.e X=CH2 refined with riding coordinates:
 C22(H22A,H22B), C49(H49A,H49B), C0AA(H0AA,H0AB)
6.f Idealised Me refined as rotating group:
 C26(H26A,H26B,H26C), C54(H54A,H54B,H54C), C52(H52A,H52B,H52C), C27(H27A,H27B,
 H27C), C53(H53A,H53B,H53C), C25(H25A,H25B,H25C)
;
_olex2_submission_special_instructions 'No special instructions were received'