Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy
Pettersson, Martin; Johnson, Douglas S.; Rankic, Danica A.; Kauffman, Gregory W.; am Ende, Christopher W.; Butler, Todd W.; Boscoe, Brian; Evrard, Edelweiss; Helal, Christopher J.; Humphrey, John M.; Stepan, Antonia F.; Stiff, Cory M.; Yang, Eddie; Xie, Longfei; Bales, Kelly R.; Hajos-Korcsok, Eva; Jenkinson, Stephen; Pettersen, Betty; Pustilnik, Leslie R.; Ramirez, David S.; Steyn, Stefanus J.; Wood, Kathleen M.; Verhoest, Patrick R.; Med. Chem. Commun. 8 (2017) 730–; doi:10.1039/C6MD00406G

data_7119190
_publ_section_title
;
 Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione
 \g-secretase modulators with robust central efficacy
;
_journal_issue                   4
_journal_name_full               'Med. Chem. Commun.'
_journal_page_first              730
_journal_paper_doi               10.1039/C6MD00406G
_journal_volume                  8
_journal_year                    2017
_chemical_absolute_configuration ad
_chemical_formula_sum            'C26 H25 F3 N4 O3'
_chemical_formula_weight         498.50
_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'
_symmetry_space_group_name_Hall  'P 2ac 2ab'
_symmetry_space_group_name_H-M   'P 21 21 21'
_atom_sites_solution_hydrogens   geom
_audit_creation_method           SHELXL-2014/7
_audit_update_record
;
2016-02-10 deposited with the CCDC.
2016-11-02 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   6.1848(2)
_cell_length_b                   13.6417(3)
_cell_length_c                   27.9922(7)
_cell_measurement_reflns_used    8882
_cell_measurement_temperature    296(2)
_cell_measurement_theta_max      67.66
_cell_measurement_theta_min      3.16
_cell_volume                     2361.74(11)
_computing_cell_refinement       'Bruker SAINT'
_computing_data_collection       'Bruker APEX2'
_computing_data_reduction        'Bruker SAINT'
_computing_molecular_graphics    'Bruker SHELXTL'
_computing_publication_material  'Bruker SHELXTL'
_computing_structure_refinement  'SHELXL-2014/7 (Sheldrick, 2014)'
_computing_structure_solution    'SHELXS-97 (Sheldrick, 2008)'
_diffrn_ambient_temperature      296(2)
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.998
_diffrn_measurement_device_type  'Bruker D8 QUEST diffractometer'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_source         'fine-focus sealed tube'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0637
_diffrn_reflns_av_unetI/netI     0.0379
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.998
_diffrn_reflns_limit_h_max       6
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       16
_diffrn_reflns_limit_k_min       -16
_diffrn_reflns_limit_l_max       33
_diffrn_reflns_limit_l_min       -33
_diffrn_reflns_number            28648
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.994
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         68.456
_diffrn_reflns_theta_min         3.157
_exptl_absorpt_coefficient_mu    0.923
_exptl_absorpt_correction_T_max  1.0
_exptl_absorpt_correction_T_min  0.700
_exptl_absorpt_correction_type   empirical
_exptl_absorpt_process_details   SADABS
_exptl_crystal_density_diffrn    1.402
_exptl_crystal_description       tabular
_exptl_crystal_F_000             1040
_exptl_crystal_recrystallization_method 'Re-crystallisation from solvent: '
_refine_diff_density_max         0.273
_refine_diff_density_min         -0.255
_refine_diff_density_rms         0.040
_refine_ls_abs_structure_details
; 
 Flack x determined using 1608 quotients [(I+)-(I-)]/[(I+)+(I-)] 
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259). 
;
_refine_ls_abs_structure_Flack   0.01(7)
_refine_ls_extinction_coef       0.0011(3)
_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   1.068
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     402
_refine_ls_number_reflns         4322
_refine_ls_number_restraints     7
_refine_ls_restrained_S_all      1.082
_refine_ls_R_factor_all          0.0476
_refine_ls_R_factor_gt           0.0444
_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^)+(0.0380P)^2^+1.0638P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1073
_refine_ls_wR_factor_ref         0.1101
_reflns_Friedel_coverage         0.714
_reflns_Friedel_fraction_full    0.998
_reflns_Friedel_fraction_max     0.988
_reflns_number_gt                4042
_reflns_number_total             4322
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            c6md00406g2.cif
_cod_data_source_block           z357
_cod_depositor_comments          'Adding full bibliography for 7119190.cif.'
_cod_database_code               7119190
_shelx_res_checksum              63971