Exploring structural effects in a new class of NRF2 inhibitors
Hou, Zhilin; Lockwood, Lizbeth; Zhang, Di; Occhiuto, Christopher J.; Mo, Linqing; Aldrich, Kelly E.; Stoub, Hayden E.; Gallo, Kathleen A.; Liby, Karen T.; Odom, Aaron L.; RSC Medicinal Chemistry  (2022) –; doi:10.1039/D2MD00211F

data_7245848
_publ_section_title
;
 Exploring structural effects in a new class of NRF2 inhibitors
;
_journal_name_full               'RSC Medicinal Chemistry'
_journal_paper_doi               10.1039/D2MD00211F
_journal_year                    2022
_chemical_formula_moiety         'C18 H14 N4, 0.25(C H2 Cl2)'
_chemical_formula_sum            'C18.25 H14.5 Cl0.5 N4'
_chemical_formula_weight         307.56
_space_group_crystal_system      triclinic
_space_group_IT_number           2
_space_group_name_Hall           '-P 1'
_space_group_name_H-M_alt        'P -1'
_atom_sites_solution_hydrogens   mixed
_audit_creation_date             2021-05-05
_audit_creation_method
;
Olex2 1.3-ac4
(compiled 2020.11.27 svn.r5f609507 for Rigaku Oxford Diffraction, GUI svn.r6214)
;
_audit_update_record
;
2021-06-22 deposited with the CCDC.	2022-10-12 downloaded from the CCDC.
;
_cell_angle_alpha                67.463(2)
_cell_angle_beta                 77.461(3)
_cell_angle_gamma                81.987(2)
_cell_formula_units_Z            4
_cell_length_a                   9.0603(3)
_cell_length_b                   12.4451(3)
_cell_length_c                   14.3291(5)
_cell_measurement_reflns_used    6716
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      77.5540
_cell_measurement_theta_min      3.8380
_cell_volume                     1453.88(8)
_computing_cell_refinement       'CrysAlisPro 1.171.41.90a (Rigaku OD, 2020)'
_computing_data_collection       'CrysAlisPro 1.171.41.90a (Rigaku OD, 2020)'
_computing_data_reduction        'CrysAlisPro 1.171.41.90a (Rigaku OD, 2020)'
_computing_molecular_graphics    'Olex2 1.3-ac4 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3-ac4 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution
'SHELXT (Sheldrick, G.M. (2015). Acta Cryst. A71, 3-8)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.00(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.998
_diffrn_measured_fraction_theta_max 0.971
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
  1  \w    -22.00  21.00   0.50    3.08    --   47.45 -68.00 -25.00   86
  2  \w     23.00  59.00   0.50    3.08    --   47.45 -68.00 -25.00   72
  3  \w     47.00  73.00   0.50   12.32    --  107.75 -68.00 -25.00   52
  4  \w     79.00 104.00   0.50   12.32    --  107.75 -77.00 -60.00   50
  5  \w     63.00 102.00   0.50   12.32    --  107.75 -94.00 -30.00   78
  6  \w     68.00 105.00   0.50   12.32    --  107.75-105.00  33.01   74
  7  \w     76.00 102.00   0.50   12.32    --  107.75 -94.00  60.00   52
  8  \w     59.00 104.00   0.50   12.32    --  107.75-101.00 141.87   90
  9  \w     51.00  78.00   0.50   12.32    --  107.75 -77.00 150.00   54
 10  \w     36.00 101.00   0.50   12.32    --  107.75 -94.00  90.00  130
 11  \w     37.00  68.00   0.50   12.32    --  107.75 -61.00 120.00   62
 12  \w     41.00  70.00   0.50   12.32    --  107.75 -94.00 120.00   58
 13  \w     36.00  63.00   0.50   12.32    --  107.75 -94.00  60.00   54
 14  \w     35.00  65.00   0.50   12.32    --  107.75 -61.00  30.00   60
 15  \w     36.00  61.00   0.50   12.32    --  107.75 -94.00   0.00   50
 16  \w     53.00 104.00   0.50   12.32    --  107.75 -94.00 -60.00  102
 17  \w     80.00 106.00   0.50   12.32    --  107.75-125.00-120.00   52
 18  \w     74.00 104.00   0.50   12.32    --  107.75 -94.00-180.00   60
 19  \w     72.00  98.00   0.50   12.32    --  107.75 -94.00-150.00   52
 20  \w     42.00  89.00   0.50   12.32    --  107.75 -94.00 -90.00   94
 21  \w     51.00  77.00   0.50   12.32    --  107.75-125.00-120.00   52
 22  \w     36.00 108.00   0.50   12.32    --  107.75-125.00-150.00  144
 23  \w     38.00 103.00   0.50   12.32    --  107.75 -94.00-120.00  130
 24  \w     36.00  69.00   0.50   12.32    --  107.75 -61.00 -90.00   66
 25  \w     38.00  68.00   0.50   12.32    --  107.75 -61.00 -60.00   60
 26  \w     37.00  90.00   0.50   12.32    --  107.75 -94.00  30.00  106
 27  \w    123.00 176.00   0.50   12.32    --  107.75  45.00 -60.00  106
 28  \w    132.00 158.00   0.50   12.32    --  107.75  61.00 -30.00   52
 29  \w    127.00 157.00   0.50   12.32    --  107.75  61.00 -90.00   60
 30  \w    122.00 171.00   0.50   12.32    --  107.75  45.00-120.00   98
 31  \w    124.00 167.00   0.50   12.32    --  107.75  45.00-180.00   86
 32  \w    108.00 135.00   0.50   12.32    --  107.75 125.00-180.00   54
 33  \w    110.00 159.00   0.50   12.32    --  107.75 125.00 -30.00   98
 34  \w    126.00 166.00   0.50   12.32    --  107.75  77.00  30.00   80
 35  \w    122.00 159.00   0.50   12.32    --  107.75  45.00  30.00   74
 36  \w    122.00 173.00   0.50   12.32    --  107.75  45.00  90.00  102
 37  \w    127.00 174.00   0.50   12.32    --  107.75  61.00 150.00   94
 38  \w    107.00 149.00   0.50   12.32    --  107.75 125.00  30.00   84
 39  \w    122.00 156.00   0.50   12.32    --  107.75  45.00   0.00   68
 40  \w     90.00 172.00   0.50   12.32    --  107.75  68.00 107.00  164
 41  \w     61.00 109.00   0.50    3.08    --   47.45  68.00 107.00   96
 42  \w    -24.00   2.00   0.50    3.08    --   47.45 -19.00  30.00   52
 43  \w    -52.00  17.00   0.50    3.08    --  -47.45  68.00 107.00  138
 44  \w    -55.00 -30.00   0.50    3.08    --  -47.45 125.00   0.00   50
 45  \w    -77.00 -25.00   0.50   12.32    --  -86.25  68.00 107.00  104
 46  \w   -113.00 -40.00   0.50    3.08    --  -47.45 -68.00 -25.00  146
 47  \w    -69.00 -28.00   0.50   12.32    --  -86.25  61.00 -90.00   82
 48  \w    -82.00 -57.00   0.50    3.08    --  -47.45 125.00-180.00   50
 49  \w    -80.00 -31.00   0.50    3.08    --  -47.45 125.00-120.00   98
 50  \w   -157.00-131.00   0.50   12.32    --  -86.25 -61.00 120.00   52
 51  \w   -159.00-134.00   0.50   12.32    --  -86.25 -61.00  30.00   50
 52  \w   -137.00-112.00   0.50   12.32    --  -86.25 -68.00 -25.00   50
 53  \w   -156.00-131.00   0.50   12.32    --  -86.25 -61.00 -90.00   50
 54  \w   -157.00-132.00   0.50   12.32    --  -86.25 -61.00 -60.00   50
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.1200848000
_diffrn_orient_matrix_UB_12      0.0288938000
_diffrn_orient_matrix_UB_13      -0.0689108000
_diffrn_orient_matrix_UB_21      0.0967000000
_diffrn_orient_matrix_UB_22      -0.0719520000
_diffrn_orient_matrix_UB_23      -0.0606959000
_diffrn_orient_matrix_UB_31      -0.0817863000
_diffrn_orient_matrix_UB_32      -0.1096396000
_diffrn_orient_matrix_UB_33      0.0745960000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0374
_diffrn_reflns_av_unetI/netI     0.0398
_diffrn_reflns_Laue_measured_fraction_full 0.998
_diffrn_reflns_Laue_measured_fraction_max 0.971
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -11
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       17
_diffrn_reflns_limit_l_min       -18
_diffrn_reflns_number            20746
_diffrn_reflns_point_group_measured_fraction_full 0.998
_diffrn_reflns_point_group_measured_fraction_max 0.971
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.752
_diffrn_reflns_theta_min         3.394
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_current           1
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_diffrn_source_voltage           50
_exptl_absorpt_coefficient_mu    1.503
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.70708
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.41.90a (Rigaku Oxford Diffraction, 2020)
Empirical absorption correction using spherical harmonics,
implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            yellow
_exptl_crystal_colour_primary    yellow
_exptl_crystal_density_diffrn    1.405
_exptl_crystal_description       block
_exptl_crystal_F_000             642
_exptl_crystal_size_max          0.152
_exptl_crystal_size_mid          0.096
_exptl_crystal_size_min          0.055
_refine_diff_density_max         0.288
_refine_diff_density_min         -0.396
_refine_diff_density_rms         0.055
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.058
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     432
_refine_ls_number_reflns         6019
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.058
_refine_ls_R_factor_all          0.0608
_refine_ls_R_factor_gt           0.0520
_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^)+(0.0768P)^2^+0.5743P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1373
_refine_ls_wR_factor_ref         0.1434
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5252
_reflns_number_total             6019
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d2md00211f2.cif
_cod_data_source_block           zh-iii-71
_cod_original_cell_volume        1453.89(8)
_cod_original_formula_sum        'C18.25 H14.50 Cl0.50 N4'
_cod_database_code               7245848
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         C18H14N4
_reflns_odcompleteness_completeness 99.19
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     74.33
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2. Others
 Fixed Sof: Cl1(0.5) Cl2(0.5) C36(0.5) H36A(0.5) H36B(0.5)
3.a Secondary CH2 refined with riding coordinates:
 C36(H36A,H36B)
3.b Aromatic/amide H refined with riding coordinates:
 C1(H1), C3(H3), C6(H6), C7(H7), C9(H9), C13(H13), C14(H14), C15(H15),
 C16(H16), C17(H17), C19(H19), C21(H21), C24(H24), C25(H25), C27(H27), C30(H30),
  C31(H31), C32(H32), C33(H33), C34(H34)
3.c Idealised Me refined as rotating group:
 C18(H18A,H18B,H18C), C35(H35A,H35B,H35C)
;
_shelx_res_checksum              74769
_olex2_diffrn_ambient_temperature_device 'Oxford Cryosystems'
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.450
_oxdiff_exptl_absorpt_empirical_full_min 0.618