Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3<i>H</i>)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.
Huestis, Malcolm P.; Dela Cruz, Darlene; DiPasquale, Antonio G.; Durk, Matthew R.; Eigenbrot, Charles; Gibbons, Paul; Gobbi, Alberto; Hunsaker, Thomas L.; La, Hank; Leung, Dennis H.; Liu, Wendy; Malek, Shiva; Merchant, Mark; Moffat, John G.; Muli, Christine S.; Orr, Christine J.; Parr, Brendan T.; Shanahan, Frances; Sneeringer, Christopher J.; Wang, Weiru; Yen, Ivana; Yin, Jianping; Siu, Michael; Rudolph, Joachim; Journal of medicinal chemistry  (2021) –; doi:10.1021/acs.jmedchem.0c02085

data_1561376
_publ_section_title
;
 Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a
 5-Fluoro-4-(3<i>H</i>)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.
;
_journal_name_full               'Journal of medicinal chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.0c02085
_journal_year                    2021
_chemical_absolute_configuration ad
_chemical_formula_sum            'C23 H27 F2 N5 O2'
_chemical_formula_weight         443.49
_chemical_name_common            'Compound 7'
_chemical_name_systematic        'Compound 7'
_space_group.centring_type       C-centered
_space_group_crystal_system      monoclinic
_space_group_IT_number           5
_space_group_name_Hall           'C 2y'
_space_group_name_H-M_alt        'C 1 2 1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     iterative
_atom_sites_solution_secondary   difmap
_audit_creation_method           SHELXL-2014/7
_cell_angle_alpha                90
_cell_angle_beta                 98.333(7)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   36.459(4)
_cell_length_b                   8.6753(8)
_cell_length_c                   13.8617(10)
_cell_measurement_reflns_used    7599
_cell_measurement_temperature    100(2)
_cell_measurement_theta_max      50.34
_cell_measurement_theta_min      2.45
_cell_volume                     4338.1(7)
_computing_cell_refinement       'Bruker SAINT'
_computing_data_collection       'Bruker APEX2'
_computing_data_reduction        'Bruker SAINT'
_computing_molecular_graphics    ORTEP-32
_computing_publication_material  WinGX
_computing_structure_refinement  SHELXL-2014
_computing_structure_solution    SHELXT-2014
_diffrn_ambient_temperature      100(2)
_diffrn_detector_area_resol_mean 8.366
_diffrn_measured_fraction_theta_full 0.995
_diffrn_measured_fraction_theta_max 0.986
_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  0.0818
_diffrn_reflns_av_unetI/netI     0.0755
_diffrn_reflns_Laue_measured_fraction_full 0.995
_diffrn_reflns_Laue_measured_fraction_max 0.986
_diffrn_refln_scan_rate          30
_diffrn_refln_scan_width         2.0
_diffrn_reflns_limit_h_max       36
_diffrn_reflns_limit_h_min       -36
_diffrn_reflns_limit_k_max       8
_diffrn_reflns_limit_k_min       -8
_diffrn_reflns_limit_l_max       13
_diffrn_reflns_limit_l_min       -10
_diffrn_reflns_number            15275
_diffrn_reflns_point_group_measured_fraction_full 0.971
_diffrn_reflns_point_group_measured_fraction_max 0.960
_diffrn_reflns_theta_full        50.000
_diffrn_reflns_theta_max         50.465
_diffrn_reflns_theta_min         2.450
_diffrn_source                   'microfocus rotating anode'
_exptl_absorpt_coefficient_mu    0.840
_exptl_absorpt_correction_T_max  0.983
_exptl_absorpt_correction_T_min  0.967
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details   SADABS
_exptl_crystal_colour            colorless
_exptl_crystal_density_diffrn    1.358
_exptl_crystal_description       plate
_exptl_crystal_F_000             1872
_exptl_crystal_size_max          0.040
_exptl_crystal_size_mid          0.040
_exptl_crystal_size_min          0.020
_refine_diff_density_max         1.380
_refine_diff_density_min         -0.719
_refine_diff_density_rms         0.181
_refine_ls_abs_structure_details
; 
 Flack x determined using 1363 quotients [(I+)-(I-)]/[(I+)+(I-)] 
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259). 
;
_refine_ls_abs_structure_Flack   -0.01(14)
_refine_ls_extinction_coef       0.0015(4)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2014/7 (Sheldrick 2014'
_refine_ls_goodness_of_fit_ref   1.091
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     269
_refine_ls_number_reflns         4379
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.091
_refine_ls_R_factor_all          0.1733
_refine_ls_R_factor_gt           0.1629
_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^)+(0.1502P)^2^+173.7439P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.3854
_refine_ls_wR_factor_ref         0.3938
_reflns_Friedel_coverage         0.792
_reflns_Friedel_fraction_full    0.941
_reflns_Friedel_fraction_max     0.928
_reflns_number_gt                3927
_reflns_number_total             4379
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c02085_si_003.cif
_cod_data_source_block           cpd7
_cod_original_sg_symbol_H-M      'C 2'
_cod_database_code               1561376
_shelx_shelxl_version_number     2014/7
_shelx_estimated_absorpt_t_min   0.967
_shelx_estimated_absorpt_t_max   0.983
_shelx_res_checksum              59052
_shelx_hkl_checksum              43513