Diversifying the Triquinazine Scaffold of a Janus Kinase Inhibitor
Mulliri, Kleni; Meier, Kris; Feuchter, Johanna-Dorothea; Javor, Sacha; Andrade Meirelles, Matheus; Reymond, Jean-Louis; RSC Medicinal Chemistry  (2025) –; doi:10.1039/D5MD00921A

data_7251309
_publ_section_title
;
 Diversifying the Triquinazine Scaffold of a Janus Kinase Inhibitor
;
_journal_name_full               'RSC Medicinal Chemistry'
_journal_paper_doi               10.1039/D5MD00921A
_journal_year                    2025
_chemical_absolute_configuration ad
_chemical_formula_moiety         'Cl, C17 H21 N6 O'
_chemical_formula_sum            'C17 H21 Cl N6 O'
_chemical_formula_weight         360.85
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_symmetry_cell_setting           triclinic
_symmetry_Int_Tables_number      1
_symmetry_space_group_name_Hall  'P 1'
_symmetry_space_group_name_H-M   'P 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2023-09-01T14:22:47-00:00
_audit_update_record
;
2025-08-22 deposited with the CCDC.	2025-11-13 downloaded from the CCDC.
;
_cell_angle_alpha                117.9068(15)
_cell_angle_beta                 91.6054(13)
_cell_angle_gamma                92.5887(12)
_cell_formula_units_Z            2
_cell_length_a                   9.50207(14)
_cell_length_b                   9.90958(14)
_cell_length_c                   10.51714(17)
_cell_measurement_reflns_used    22651
_cell_measurement_temperature    173.00(10)
_cell_measurement_theta_max      33.57
_cell_measurement_theta_min      2.183
_cell_volume                     872.90(3)
_computing_cell_refinement       'CrysAlisPro 1.171.42.89a (Rigaku OD, 2023)'
_computing_data_collection       'CrysAlisPro 1.171.42.89a (Rigaku OD, 2023)'
_computing_data_reduction        'CrysAlisPro 1.171.42.89a (Rigaku OD, 2023)'
_computing_molecular_graphics    'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT  (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      173.00(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10
_diffrn_detector_type            'HyPix-Arc 100'
_diffrn_measured_fraction_theta_full 1
_diffrn_measured_fraction_theta_max 1
_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    -11.00  94.00   0.50    7.00    --   13.07  31.00 -62.00  210
  2  \w    -68.00  37.00   0.50    7.00    --   13.07 -31.00 137.00  210
  3  \w    -35.00  68.00   0.50    7.00    --  -13.54  31.00 -62.00  206
  4  \w    -95.00  10.00   0.50    7.00    --  -13.54 -31.00 137.00  210
  5  \w     -7.00  94.00   0.50    7.00    --   13.07  38.00  90.00  202
  6  \w    -80.00 -21.00   0.50    7.00    --  -13.54 139.00  74.39  118
  7  \w    -83.00 -24.00   0.50    7.00    --  -13.54 144.00  -1.65  118
  8  \w    -19.00  29.00   0.50    7.00    --  -13.54 -99.00-120.00   96
  9  \w    -74.00 -17.00   0.50    7.00    --  -13.54 131.00 150.90  114
 10  \w    -74.00 -17.00   0.50    7.00    --  -13.54 130.00 -94.84  114
 11  \w    -19.00  29.00   0.50    7.00    --  -13.54 -99.00  60.00   96
 12  \w    -19.00  29.00   0.50    7.00    --  -13.54 -99.00 -60.00   96
 13  \w    -62.00  88.00   0.50    7.00    --   13.07   0.00-150.00  300
 14  \w    -62.00  88.00   0.50    7.00    --   13.07   0.00-180.00  300
 15  \w    -25.00  94.00   0.50    7.00    --   13.07  19.00  30.00  238
 16  \w    -62.00  38.00   0.50    7.00    --   13.07   0.00-120.00  200
 17  \w    -88.00 -27.00   0.50    7.00    --  -13.54 151.00  95.40  122
 18  \w    -82.00 -23.00   0.50    7.00    --  -13.54 142.00 171.11  118
 19  \w    -89.00 -28.00   0.50    7.00    --  -13.54 153.00 177.22  122
 20  \w    -84.00 -25.00   0.50    7.00    --  -13.54 146.00-140.24  118
 21  \w    -86.00 -26.00   0.50    7.00    --  -13.54 148.00 -51.20  120
 22  \w    -19.00  29.00   0.50    7.00    --  -13.54 -99.00 120.00   96
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy R, HyPix-Arc 100'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0238621
_diffrn_orient_matrix_UB_12      0.0701611
_diffrn_orient_matrix_UB_13      0.0078651
_diffrn_orient_matrix_UB_21      -0.0182028
_diffrn_orient_matrix_UB_22      -0.0350272
_diffrn_orient_matrix_UB_23      -0.0749909
_diffrn_orient_matrix_UB_31      -0.0685578
_diffrn_orient_matrix_UB_32      -0.020966
_diffrn_orient_matrix_UB_33      0.0125274
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Mo K\a'
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.0327
_diffrn_reflns_av_unetI/netI     0.0475
_diffrn_reflns_Laue_measured_fraction_full 1
_diffrn_reflns_Laue_measured_fraction_max 1
_diffrn_reflns_limit_h_max       13
_diffrn_reflns_limit_h_min       -13
_diffrn_reflns_limit_k_max       14
_diffrn_reflns_limit_k_min       -14
_diffrn_reflns_limit_l_max       15
_diffrn_reflns_limit_l_min       -15
_diffrn_reflns_number            53059
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.996
_diffrn_reflns_theta_full        25.242
_diffrn_reflns_theta_max         30.508
_diffrn_reflns_theta_min         2.149
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'Mova (Mo) X-ray Source'
_exptl_absorpt_coefficient_mu    0.238
_exptl_absorpt_correction_T_max  1
_exptl_absorpt_correction_T_min  0.528
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
        CrysAlisPro 1.171.42.89a (Rigaku Oxford Diffraction, 2023)
        Numerical absorption correction based on gaussian integration over
        a multifaceted crystal model
        Empirical absorption correction using spherical harmonics,
        implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            colourless
_exptl_crystal_density_diffrn    1.373
_exptl_crystal_description       needle
_exptl_crystal_F_000             380
_exptl_crystal_size_max          0.313
_exptl_crystal_size_mid          0.06
_exptl_crystal_size_min          0.031
_refine_diff_density_max         0.402
_refine_diff_density_min         -0.222
_refine_diff_density_rms         0.051
_refine_ls_abs_structure_details
;
 Flack x determined using 3639 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.005(14)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.027
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     607
_refine_ls_number_reflns         10595
_refine_ls_number_restraints     57
_refine_ls_restrained_S_all      1.039
_refine_ls_R_factor_all          0.0576
_refine_ls_R_factor_gt           0.0458
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0644P)^2^+0.0698P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1026
_refine_ls_wR_factor_ref         0.1069
_reflns_Friedel_coverage         0.992
_reflns_Friedel_fraction_full    0.999
_reflns_Friedel_fraction_max     0.992
_reflns_number_gt                8975
_reflns_number_total             10595
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d5md00921a2.cif
_cod_data_source_block           23JLR016_KM-174-UBE9-2
_cod_database_code               7251309
_shelx_estimated_absorpt_t_min   0.929
_shelx_estimated_absorpt_t_max   0.993
_oxdiff_exptl_absorpt_empirical_details
;
        Empirical correction (ABSPACK) includes:
        - Absorption correction using spherical harmonics
        - Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.252
_oxdiff_exptl_absorpt_empirical_full_min 0.869
_shelx_shelxl_version_number     2018/3
_olex2_refinement_description
;
        1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All C(H,H,H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups
        2. Rigid bond restraints
 N7, C18, C19
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
 N7A, C18A, C19
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
 C2, C1, N1
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
 C2, C1A, N1A
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
        3. Uiso/Uaniso restraints and constraints
        C18A \\sim C18: within 1.7A with sigma of 0.004 and sigma for terminal atoms of
        0.008 within 1.7A
        Uanis(N1A) \\sim Ueq, Uanis(N1) \\sim Ueq: with sigma of 0.01 and sigma for
        terminal atoms of 0.01
        Uanis(N7) \\sim Ueq, Uanis(C18) \\sim Ueq, Uanis(N7A) \\sim Ueq, Uanis(C18A)
        \\sim Ueq: with sigma of 0.01 and sigma for terminal atoms of 0.005
        4. Others
 Sof(H2BC)=Sof(H2BD)=Sof(N1A)=Sof(C1A)=1-FVAR(1)
 Sof(H2AA)=Sof(H2AB)=Sof(C1)=Sof(N1)=FVAR(1)
 Sof(H19C)=Sof(H19D)=Sof(N7A)=Sof(C18A)=1-FVAR(2)
 Sof(H19A)=Sof(H19B)=Sof(C18)=Sof(N7)=FVAR(2)
        5.a Secondary CH2 refined with riding coordinates:
 C2(H2AA,H2AB), C2(H2BC,H2BD), C19(H19A,H19B), C19(H19C,H19D)
;
_shelx_res_checksum              26188
_shelx_hkl_checksum              7276