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_7251307
_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_formula_moiety         'C17 H20 N6 O'
_chemical_formula_sum            'C17 H20 N6 O'
_chemical_formula_weight         324.39
_space_group_IT_number           14
_space_group_name_Hall           '-P 2yn'
_space_group_name_H-M_alt        'P 1 21/n 1'
_symmetry_cell_setting           monoclinic
_symmetry_Int_Tables_number      14
_symmetry_space_group_name_Hall  '-P 2yn'
_symmetry_space_group_name_H-M   'P 1 21/n 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2023-02-07T16:58:13-00:00
_audit_update_record
;
2025-08-22 deposited with the CCDC.	2025-11-13 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 93.184(2)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   8.2112(2)
_cell_length_b                   18.3624(5)
_cell_length_c                   10.9157(3)
_cell_measurement_reflns_used    13619
_cell_measurement_temperature    173.01(10)
_cell_measurement_theta_max      78.692
_cell_measurement_theta_min      4.69
_cell_volume                     1643.30(8)
_computing_cell_refinement       'CrysAlisPro 1.171.42.73a (Rigaku OD, 2022)'
_computing_data_collection       'CrysAlisPro 1.171.42.73a (Rigaku OD, 2022)'
_computing_data_reduction        'CrysAlisPro 1.171.42.73a (Rigaku OD, 2022)'
_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      173.01(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10
_diffrn_detector_type            HyPix
_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    -52.00  43.00   0.50    1.30    --  -23.00  90.00 -66.00  190
  2  \w    -20.00  76.00   0.50    1.30    --   47.42 -90.00 179.00  192
  3  \w    101.00 177.00   0.50   10.00    --  113.25  90.00 -66.00  152
  4  \w     42.00 105.00   0.50   10.00    --  113.25 -90.00 179.00  126
  5  \w    -46.00  50.00   0.50    1.30    --  -23.00  77.00   0.00  192
  6  \w    -95.00 -10.00   0.50    1.30    --  -23.00 -45.00-150.00  170
  7  \w    -68.00 -12.00   0.50    1.30    --  -23.00 125.00  90.00  112
  8  \w    -27.00  23.00   0.50    1.30    --   47.42 -19.00-180.00  100
  9  \w     33.00 119.00   0.50    1.30    --   47.42  57.00   0.00  172
 10  \w    -25.00  40.00   0.50    1.30    --   47.42 -38.00-120.00  130
 11  \w    -27.00  23.00   0.50    1.30    --   47.42 -19.00   0.00  100
 12  \w    -25.00  40.00   0.50    1.30    --   47.42 -38.00-180.00  130
 13  \w     42.00 106.00   0.50   10.00    --  113.25 -94.00 -90.00  128
 14  \w    101.00 177.00   0.50   10.00    --  113.25  30.00-150.00  152
 15  \w    101.00 177.00   0.50   10.00    --  113.25  45.00 -90.00  152
 16  \w     42.00 102.00   0.50   10.00    --  113.25 -77.00-180.00  120
 17  \w    101.00 177.00   0.50   10.00    --  113.25  45.00 -30.00  152
 18  \w    101.00 177.00   0.50   10.00    --  113.25  30.00  60.00  152
 19  \w     42.00  68.00   0.50   10.00    --  113.25 -61.00 -60.00   52
 20  \w     91.00 177.00   0.50   10.00    --  113.25  77.00 -90.00  172
 21  \w     42.00 102.00   0.50   10.00    --  113.25 -77.00  90.00  120
 22  \w     42.00  68.00   0.50   10.00    --  113.25 -61.00 120.00   52
 23  \w     42.00 106.00   0.50   10.00    --  113.25 -94.00 120.00  128
 24  \w     42.00  68.00   0.50   10.00    --  113.25 -61.00-180.00   52
 25  \w     42.00  68.00   0.50   10.00    --  113.25 -61.00-150.00   52
 26  \w     97.00 177.00   0.50   10.00    --  113.25  61.00-120.00  160
 27  \w     91.00 177.00   0.50   10.00    --  113.25  77.00  60.00  172
 28  \w     42.00 102.00   0.50   10.00    --  113.25 -77.00-120.00  120
 29  \w     91.00 177.00   0.50   10.00    --  113.25  77.00 -30.00  172
 30  \w     91.00 177.00   0.50   10.00    --  113.25  77.00-150.00  172
 31  \w    101.00 177.00   0.50   10.00    --  113.25  31.00  16.78  152
 32  \w     42.00 102.00   0.50   10.00    --  113.25 -77.00 -60.00  120
 33  \w     42.00  68.00   0.50   10.00    --  113.25 -61.00 150.00   52
 34  \w     42.00 106.00   0.50   10.00    --  113.25 -94.00 -60.00  128
 35  \w     42.00 106.00   0.50   10.00    --  113.25 -94.00-150.00  128
 36  \w     97.00 177.00   0.50   10.00    --  113.25  61.00 120.00  160
 37  \w     42.00 102.00   0.50   10.00    --  113.25 -77.00  30.00  120
 38  \w     42.00 102.00   0.50   10.00    --  113.25 -77.00 120.00  120
 39  \w     42.00 106.00   0.50   10.00    --  113.25 -94.00-120.00  128
 40  \w    100.00 177.00   0.50   10.00    --  113.25  52.00  77.85  154
 41  \w    101.00 177.00   0.50   10.00    --  113.25  45.00  30.00  152
 42  \w     42.00  68.00   0.50   10.00    --  113.25 -61.00  60.00   52
 43  \w     74.50 119.00   0.50    1.30    --   47.42  77.00 -90.00   89
 44  \w     25.00  75.00   0.50    1.30    --   47.42  77.00  30.00  100
 45  \w     74.50 119.00   0.50    1.30    --   47.42  77.00-180.00   89
 46  \w     25.00  45.00   0.50    1.30    --   47.42  77.00  90.00   40
 47  \w     25.00  70.00   0.50    1.30    --   47.42  77.00-120.00   90
 48  \w     89.50 119.00   0.50    1.30    --   47.42  77.00 120.00   59
;
_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      -0.0900818
_diffrn_orient_matrix_UB_12      0.0426979
_diffrn_orient_matrix_UB_13      -0.1045366
_diffrn_orient_matrix_UB_21      -0.0272564
_diffrn_orient_matrix_UB_22      0.0635691
_diffrn_orient_matrix_UB_23      0.0888924
_diffrn_orient_matrix_UB_31      0.1626056
_diffrn_orient_matrix_UB_32      0.0342753
_diffrn_orient_matrix_UB_33      -0.0339943
_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  0.0432
_diffrn_reflns_av_unetI/netI     0.0544
_diffrn_reflns_Laue_measured_fraction_full 1
_diffrn_reflns_Laue_measured_fraction_max 1
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -9
_diffrn_reflns_limit_k_max       22
_diffrn_reflns_limit_k_min       -22
_diffrn_reflns_limit_l_max       13
_diffrn_reflns_limit_l_min       -13
_diffrn_reflns_number            30043
_diffrn_reflns_point_group_measured_fraction_full 1
_diffrn_reflns_point_group_measured_fraction_max 1
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.501
_diffrn_reflns_theta_min         4.718
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.702
_exptl_absorpt_correction_T_max  0.962
_exptl_absorpt_correction_T_min  0.926
_exptl_absorpt_correction_type   analytical
_exptl_absorpt_process_details
;
        CrysAlisPro 1.171.42.73a (Rigaku Oxford Diffraction, 2022)
        Analytical numeric absorption correction using a multifaceted crystal
        model based on expressions derived by R.C. Clark & J.S. Reid.
        (Clark, R. C. & Reid, J. S. (1995). Acta Cryst. A51, 887-897)
        Empirical absorption correction using spherical harmonics,
        implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            colourless
_exptl_crystal_density_diffrn    1.311
_exptl_crystal_description       block
_exptl_crystal_F_000             688
_exptl_crystal_size_max          0.124
_exptl_crystal_size_mid          0.084
_exptl_crystal_size_min          0.065
_refine_diff_density_max         0.342
_refine_diff_density_min         -0.22
_refine_diff_density_rms         0.062
_refine_ls_extinction_coef       0.0083(11)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2018/3 (Sheldrick 2018)'
_refine_ls_goodness_of_fit_ref   1.057
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     309
_refine_ls_number_reflns         3369
_refine_ls_number_restraints     43
_refine_ls_restrained_S_all      1.059
_refine_ls_R_factor_all          0.0681
_refine_ls_R_factor_gt           0.065
_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^)+(0.1019P)^2^+0.5535P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1812
_refine_ls_wR_factor_ref         0.1844
_reflns_Friedel_coverage         0
_reflns_number_gt                3058
_reflns_number_total             3369
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d5md00921a2.cif
_cod_data_source_block           22JLR022_KM-174-F1
_cod_original_cell_volume        1643.30(7)
_cod_database_code               7251307
_shelx_estimated_absorpt_t_min   0.918
_shelx_estimated_absorpt_t_max   0.956
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
- B-factor correction
;
_oxdiff_exptl_absorpt_empirical_full_max 4.557
_oxdiff_exptl_absorpt_empirical_full_min 0.411
_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
 At 1.5 times of:
  All C(H,H,H) groups
2. Rigid bond restraints
 C12, C9A
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
3. Uiso/Uaniso restraints and constraints
Uanis(C15A) \\sim Ueq, Uanis(N5A) \\sim Ueq, Uanis(O1A) \\sim Ueq: with sigma
of 0.01 and sigma for terminal atoms of 0.02
Uanis(C7A) \\sim Ueq: with sigma of 0.01 and sigma for terminal atoms of 0.01
Uanis(C8A) \\sim Ueq: with sigma of 0.02 and sigma for terminal atoms of 0.02
Uanis(C16A) \\sim Ueq: with sigma of 0.01 and sigma for terminal atoms of 0.02
Uanis(C9A) \\sim Ueq: with sigma of 0.01 and sigma for terminal atoms of 0.02
4. Others
 Sof(H10A)=Sof(H14D)=Sof(H14E)=Sof(H12C)=Sof(H12D)=Sof(H12E)=Sof(C13A)=
 Sof(H13A)=Sof(N5A)=Sof(O1A)=Sof(C15A)=Sof(C8A)=Sof(H8AA)=Sof(H8AB)=Sof(C9A)=
 Sof(C11A)=Sof(H11C)=Sof(H11D)=Sof(C7A)=Sof(H7AA)=Sof(H7AB)=Sof(C16A)=Sof(H16C)=
 Sof(H16D)=1-FVAR(1)
 Sof(N5)=Sof(O1)=Sof(H10)=Sof(C7)=Sof(H7A)=Sof(H7B)=Sof(C13)=Sof(H13)=Sof(C15)=
 Sof(H14A)=Sof(H14B)=Sof(H14C)=Sof(H12A)=Sof(H12B)=Sof(C9)=Sof(C16)=Sof(H16A)=
 Sof(H16B)=Sof(C8)=Sof(H8A)=Sof(H8B)=Sof(C11)=Sof(H11A)=Sof(H11B)=FVAR(1)
5.a Ternary CH refined with riding coordinates:
 C10(H10), C10(H10A), C13(H13), C13A(H13A)
5.b Secondary CH2 refined with riding coordinates:
 C7(H7A,H7B), C14(H14D,H14E), C12(H12A,H12B), C16(H16A,H16B), C8(H8A,H8B),
 C11(H11A,H11B), C8A(H8AA,H8AB), C11A(H11C,H11D), C7A(H7AA,H7AB), C16A(H16C,
 H16D)
5.c Me refined with riding coordinates:
 C12(H12C,H12D,H12E)
5.d Aromatic/amide H refined with riding coordinates:
 C5(H5A), C2(H2), C1(H1A)
5.e Idealised Me refined as rotating group:
 C14(H14A,H14B,H14C)
;
_shelx_res_checksum              40619
_shelx_hkl_checksum              40003