Combination Comprising a Menin-MLL Inhibitor and a BCL-2 Inhibitor

Abstract

Disclosed is a combination comprising a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a therapeutically effective amount of a BCL-2 inhibitor, and optionally a therapeutically effective amount of at least one other anti-neoplastic agent. Also disclosed is a method of treating a subject diagnosed with a hematopoietic disorder using such a combination. The compound is represented by formula (I) as follows, where the variables are defined herein: [Formula 1] TIFF2025540762000257.tif60128

Description

[Technical Field]

[0001] The present invention relates to a novel combination comprising a therapeutically effective amount of a menin-MLL (mixed-lineage leukemia) inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor, and optionally a therapeutically effective amount of at least one other anti-neoplastic agent, and to a method for treating a subject diagnosed with a hematopoietic disorder. [Background technology]

[0002] Of the 10 million cancer deaths recorded by GLOBOCAN in 2020, 7.1% were attributable to hematopoietic disorders. Therefore, there is an urgent need for new therapies for hematopoietic disorders, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), as further detailed below.

[0003] AML is a common hematologic malignancy with an incidence rate ranging from 3:100,000 in young adults to over 20:100,000 in older adults. Overall survival (OS) is 40–50% in patients under 60 years of age, but only 5% in those over 60 years of age. The majority of newly diagnosed AML patients are over 60 years of age. In this patient population, standard induction chemotherapy is often not an option due to increased treatment-related mortality as a result of age and comorbidities. For AML patients ineligible for combination chemotherapy, standard treatment is treatment with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine. Despite these state-of-the-art treatments, the median OS is only approximately 10 months. In all types of AML, disease relapse is common despite initial treatment response and is the most common reason for death. Standard chemotherapy and allogeneic stem cell transplantation (when used) often fail to eradicate all tumor-propagating cells and select for chemotherapy-resistant leukemic subclones. Patients who are refractory to salvage therapy are treated palliatively because current treatment options are extremely limited. The median survival time for these patients is 2 months. Furthermore, patients with newly diagnosed intermediate- or higher-risk MDS and those who relapse after standard care have a poor prognosis and a high risk of progression to AML. Therefore, new therapies are urgently needed for relapsed / refractory (R / R) AML and MDS patients, newly diagnosed AML patients who are ineligible for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate-, high-, and very high-risk MDS patients.

[0004] ALL is a hematological malignancy propagated by impaired differentiation, proliferation, and accumulation of lymphoid progenitor cells in the bone marrow and / or extramedullary sites. ALL represents 12% of all leukemia cases and is the most common childhood acute leukemia, with a predicted worldwide incidence of 1–4.75 cases per 100,000. ALL accounts for approximately 20% of adult leukemias. Despite high complete remission (CR) rates (80%–90%) with current therapies, the majority of adult patients with ALL relapse. The 5-year overall survival rate is approximately 30–40% in adult and elderly patients. Therefore, new therapies are urgently needed, especially for relapsed / refractory ALL in adults and especially elderly patients. Summary of the Invention

[0005] An embodiment of the present invention relates to a novel combination of a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent.

[0006] Embodiments of the present invention relate to the use of a menin-MLL inhibitor as described herein in combination with a BCL-2 inhibitor and, optionally, at least one other anti-neoplastic agent to treat a subject diagnosed with a hematopoietic disorder, such as, but not limited to, a hematological cancer.

[0007] Embodiments of the present invention relate to novel methods for treating a subject diagnosed with a hematopoietic disorder using such combinations. Embodiments of the novel method comprise administering to the subject a therapeutically effective amount of a menin-MLL inhibitor described herein, a therapeutically effective amount of a BCL-2 inhibitor, and optionally a therapeutically effective amount of at least one other anti-neoplastic agent, wherein the menin-MLL inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0008] Embodiments of the present invention relate to novel methods for treating a subject diagnosed with a hematopoietic disorder using such combinations. Embodiments of the novel method comprise administering to the subject a therapeutically effective amount of a menin-MLL inhibitor described herein, a therapeutically effective amount of a BCL-2 inhibitor, and a therapeutically effective amount of at least one other anti-neoplastic agent, wherein the menin-MLL inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0009] In some embodiments, the present invention relates to a method of treating a subject diagnosed with a hematopoietic disorder, comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a therapeutically effective amount of venetoclax or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the present invention relates to a method of treating a subject diagnosed with a hematopoietic disorder, comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a therapeutically effective amount of venetoclax or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt or solvate thereof, wherein the venetoclax or the pharmaceutically acceptable salt or solvate thereof is administered to the subject before, simultaneously with, or after administration of the menin-MLL inhibitor, and the azacitidine or a pharmaceutically acceptable salt or solvate thereof is administered to the subject before, simultaneously with, or after administration of the menin-MLL inhibitor.

[0011] In embodiments, the menin-MLL inhibitor of formula (I) is

[0012] [ka] and tautomeric and stereoisomeric forms thereof, wherein Q is -CHR y-, -O-, -C(=O)-, -NR q - or -CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-OC 1~4 Alkyl-NR 22a R 22b , -C(=O)-OC 1~4 Alkyl,

[0013] [ka] represents R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R 19 together to form -(CH2)3-, -(CH2)4-, or -(CH2)5-, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 O, S, or N atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are each independently hydrogen, Het 3 ;C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and C 1~6 Alkyl is -OH, -OC1~4 Alkyl, -C 1~4 Alkyl-OH, Halo, CF3, C 3~6 Cycloalkyl, Het 3 , and NR 11c R 11d C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, cyano, and halo and OR 23 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, cyano, and halo and OR 23 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 1~4forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 23 is hydrogen or C optionally substituted with 1, 2, or 3 halo 1~4 represents alkyl, R 1b is hydrogen, F, Cl, or -OC 1~4 represents alkyl, R 2 But, Halo, C 3~6 Cycloalkyl, C 1~4 Alkyl, -OC 1~4 C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0014] [ka] represents n1 is selected from 1 and 2; n2 is selected from 1, 2, 3, and 4; R y But hydrogen, -OH, C 1~4 Alkyl, -C 1~4 Alkyl-OH or -C 1~4 Alkyl-OC 1~4 represents alkyl, R q is hydrogen or C 1~4 represents alkyl, R 5 But hydrogen, C 1~4 Alkyl or C3~6 represents cycloalkyl, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ;C 1~8 Alkyl; and -C(=O)-NR 10a R 10b , -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , Ar 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~8 is selected from the group consisting of alkyl, R xc But Cy 1 , Het 5 , -C 1~6 Alkyl-Cy 1 , -C 1~6 Alkyl-Het 3 , -C 1~6 Alkyl-Het 4 , or -C 1~6 represents alkyl-phenyl, R xd But hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano 1~4 represents alkyl, or R xc and R xdtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl-S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl;-(C=O)-C 1~4 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl1~6 is selected from the group consisting of alkyl, Ar 1 Optionally, C 1~4 Alkyl, halo, -OC 1~4 Alkyl, -CF3, -OH, -S(=O)2-C 1~4 Alkyl, and -C(=O)-NR 10a R 10b represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl, which optionally has on one nitrogen atom R 6a may be substituted with R 6 and R 6a However, each independently, Het 3 ;Het4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-C(=O)-Het 6a ;-C(=O)-NR 10d R 10e ; -C(=O)-OC 1~4 Alkyl; -S(=O)2-C 1~4 alkyl; Optionally, Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-N(C 1~4 alkyl)2, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and Optionally, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-N(C 1~4 alkyl)2, -NH-S(=O)2-C 1~4 Alkyl, and optionally OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 C substituted with one substituent selected from the group consisting of alkyl 1~4 C substituted by 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; R 8 But hydrogen, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4Alkyl, halo, cyano, -NR 11a R 11b , -S(=O)2-C 1~4 Alkyl, Het 3a , and Het 6a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 , Het 3a , Het 5 , and Het 5a each independently represent a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo, and the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 Alkyl or -(C=O)-C 1~4 is substituted with alkyl, Het 4 and Het 7 each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 Alkyl or -(C=O)-OC 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 , and -C(=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a , Het 8 , and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl may optionally be substituted on one or two carbon atoms with a halo, —OH, oxo, —NH—C(═O)—C 1~4 Alkyl, -NH-C(=O)-Cy 3 , -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, and -(C=O)-NR 10a R 10b and is substituted with a substituent selected from the group consisting of Het 6b and Het 8b each independently represent a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4 Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 9represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C 1~4 and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl, Cy 1 optionally, -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl, -OC 1~4 Alkyl, cyano,

[0015] [ka] and Het 3a , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 But C 3~7 represents cycloalkyl, 3~7 cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 1~4 is selected from the group consisting of alkyl, R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , R 17b , R 20a , R 20b , R 22a , and R 22b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 11c and R 11d are each independently hydrogen, C 1~6 Alkyl, and -C(=O)-C 1~4 is selected from the group consisting of alkyl, R 10a , R 10b , and R 10c are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl; R 10d and R 10e However, each independently, C 1~4 Alkyl, -OC 1~4 Alkyl, and C 3~6 cycloalkyl; R 14 But, Het 5a ;Het 7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 represents alkyl, R 16 is -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 , or Het 8 represents], and pharmaceutically acceptable salts and solvates thereof.

[0016] The substituent R in formula (I) 21 and -YR3 It should be clear that the groups may be attached to any carbon or nitrogen atom of the ring to which they are attached, thereby replacing a hydrogen on the same atom or replacing a hydrogen atom on a different atom (including the N atom) in the moiety. Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

[0017] Additional embodiments, features, and advantages of the invention will become apparent from the following detailed description, as well as through practice of the invention. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of Compound 51 as the crystalline free base form. [Figure 2] 1 is a powder X-ray diffraction (XRPD) pattern of compound 51a as the crystalline HCl salt form. [Figure 3] 1 is a dynamic vapor sorption (DVS) isotherm plot of compound 51a as the crystalline HCl salt form. [Figure 4] Dynamic vapor sorption (DVS) change in mass plot of compound 51a as the crystalline HCl salt form. [Figure 5-1] Figure 5A is a contour plot of maxR showing the effect of compound 51 in combination with decitabine and venetoclax on the proliferation of MOLM-13 cells in vitro. Figure 5B is a contour plot of maxR showing the effect of compound 51 in combination with decitabine and venetoclax on the proliferation of MV4-11 cells in vitro. Figure 5C is a contour plot of maxR showing the effect of compound 51 in combination with decitabine and venetoclax on the proliferation of OCI-AML3 cells in vitro. [Figure 5-2]Figure 5D is a contour plot of maxR showing the effect of compound 51 in combination with venetoclax on the proliferation of MOLM-13 cells in vitro. [Figure 5-3] Figure 5E is a contour plot of maxR showing the effect of compound 51 in combination with venetoclax and azacitidine on the proliferation of MOLM-13 cells in vitro. [Figure 6] Figure 1 shows a comparison of percent survival as a function of time in mice bearing established MOLM-13 tumors after treatment with vehicle, either venetoclax, azacitidine, or Compound 51 monotherapy, either dual combinations of venetoclax and azacitidine or Compound 51 and venetoclax, or triple combinations of Compound 51, venetoclax, and azacitidine. DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0020] As used herein, the prefix "C x~y " (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1~6 An alkyl group contains 1 to 6 carbon atoms, and so on.

[0021] As used herein, "C" as a group or part of a group 1~4 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, and the like.

[0022] Similarly, as used herein, "C" as a group or part of a group 1~6The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0023] Similarly, as used herein, "C" as a group or part of a group 1~8 The term "alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-octyl,

[0024] [ka] represents a linear or branched saturated hydrocarbon radical having 1 to 8 carbon atoms, such as

[0025] As used herein, "C" as a group or part of a group 3~6 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] As used herein, "C" as a group or part of a group 3~7 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0027] It will be apparent to those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0028] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0029] Those skilled in the art will recognize that groups such as -NR

[0030] [ka] It will be clear that an example of such a group is -NR q -It is.

[0031] Non-limiting examples of "monocyclic 5- or 6-membered aromatic rings containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety" include, but are not limited to, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or 1,2-dihydro-2-oxo-4-pyridinyl.

[0032] Those skilled in the art will recognize that the term "aromatic ring" includes, but is not limited to, a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and a carbonyl moiety.

[0033] [ka] will understand that this includes

[0034] The term "monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N" defines a fully or partially saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing at least one nitrogen atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which is attached to the remainder of the molecule of formula (I) via a nitrogen atom. Examples are N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked 1,4-diazepanyl, N-linked piperidinyl, and N-linked 1,2,3,6-tetrahydro-pyridinyl. Two R groups that, taken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and, optionally, one additional heteroatom selected from O, S, and N, are similarly defined.

[0035] The term "monocyclic C-linked 4- to 7-membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N" defines a fully or partially saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, such as C-linked azetidinyl, C-linked pyrrolidinyl, C-linked morpholinyl, C-linked tetrahydrofuranyl, C-linked thiolanyl, C-linked oxetanyl, C-linked thietanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked piperidinyl, C-linked azepanyl, C-linked 1,3-dioxolanyl, and C-linked 1,2,3,6-tetrahydro-pyridinyl.

[0036] For clarity, a 4- to 7-membered fully or partially saturated heterocyclyl has 4 to 7 ring members, including the heteroatom.

[0037] Non-limiting examples of "monocyclic C-linked 5- or 6-membered aromatic rings containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N" include, but are not limited to, C-linked pyrazolyl, C-linked imidazolyl, C-linked pyridinyl, C-linked triazolyl, C-linked pyridazinyl, C-linked pyrimidinyl, C-linked oxazolyl, C-linked furanyl, C-linked isothiazolyl, C-linked thiazolyl, C-linked thiadiazolyl, C-linked oxadiazolyl, or C-linked pyrazinyl.

[0038] Within the context of this invention, bicyclic 6-11 membered fully or partially saturated heterocyclyl groups include fused, spiro and bridged bicyclic rings.

[0039] A fused bicyclic group is two rings that share two atoms and a bond between those atoms.

[0040] A spiro bicyclic group is two rings joined at a single atom.

[0041] A bridged bicyclic group is two rings that have three or more atoms in common.

[0042] Examples of bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyls containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N include:

[0043] [ka] These include, but are not limited to:

[0044] Examples of bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyls containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N include:

[0045] [ka]

[0046] [ka] These include, but are not limited to:

[0047] Two R groups that, taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and, optionally, one additional heteroatom selected from O, S, and N, are similarly defined.

[0048] Examples of fused bicyclic C-linked 9- or 10-membered aromatic rings containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N include:

[0049] [ka] These include, but are not limited to:

[0050] As used herein, "5-12 membered saturated carbobicyclic" systems define saturated fused, spiro, and bridged bicyclic hydrocarbon systems having 5 to 12 carbon atoms. Examples of 5-12 membered saturated carbobicyclic systems include:

[0051] [ka] These include, but are not limited to:

[0052] The substituents may be, for example,

[0053] [ka] Whenever represented by a chemical structure such as "----" represents the bond to the remainder of the molecule of formula (I).

[0054] When any variable occurs more than one time in any constituent, each definition is independent.

[0055] When any variable occurs more than one time in any formula (eg, formula (I)), each definition is independent.

[0056] It will be apparent to one of skill in the art that when a moiety (e.g., a heterocyclyl or a monocyclic 5- or 6-membered aromatic ring) is substituted with two or more substituents (e.g., 1, 2, or 3 substituents) selected from a group, each substituent may be independently selected from that group, even if not explicitly stated.

[0057] Generally, whenever the term "substituted" is used herein, unless otherwise specified or clear from the context, it means that one or more hydrogens, specifically 1 to 4 hydrogens, more specifically 1 to 3 hydrogens, preferably 1 or 2 hydrogens, and more preferably 1 hydrogen, on the atom or radical designated in the expression "substituted" are replaced with a selection from the designated group, provided that the normal valences are not exceeded, and that the replacement results in a chemically stable compound, i.e., a compound that is sufficiently robust to withstand isolation to a useful degree of purity from the reaction mixture (post-reaction isolation, for example, purification by silica gel chromatography). In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is 1.

[0058] Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. "Stable compound," in this context, is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (post-reaction isolation, e.g., purification by silica gel chromatography).

[0059] Those skilled in the art will understand that the term "optionally substituted" means that the atom or radical designated in the expression using "optionally substituted" may be substituted or unsubstituted (which means substituted or unsubstituted, respectively).

[0060] When two or more substituents are present on a moiety, they may replace hydrogen atoms on the same atom, or they may replace hydrogen atoms on different atoms in the moiety, unless otherwise stated or apparent from the context.

[0061] In the context of the present invention, "saturated" means "fully saturated" unless otherwise specified.

[0062] Unless otherwise specified or apparent from the context, aromatic rings and heterocyclyl groups may be attached to the remainder of the molecule of formula (I) through any available ring carbon atom (C-bonded) or nitrogen atom (N-bonded).

[0063] Unless otherwise specified or apparent from the context, aromatic rings and heterocyclyl groups may be optionally substituted on carbon and / or nitrogen atoms where possible, according to embodiments, and one skilled in the art will understand that in such cases, hydrogen on the carbon and / or nitrogen atoms is replaced by such substituents.

[0064] Unless otherwise specified or clear from the context, the variable R 21 and -YR 3 can be attached to any carbon or nitrogen atom of the ring to which they are attached, provided that R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring.

[0065] For example, R 21 represents hydrogen, and -YR 3 When is attached to a nitrogen atom of the ring in formula (I), compounds of sub-formula (Ix) are obtained.

[0066] [ka]

[0067] When Y in formula (I) represents a covalent bond, compounds of sub-formula (Iy) are obtained.

[0068] [ka] Y is, In formula (I),

[0069] [ka] represents, compounds of sub-formula (Iz) are obtained.

[0070] [ka]

[0071] As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., a cat, dog, primate, or human), more preferably a human, who is or has been the object of treatment, observation, or experiment.

[0072] As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including alleviation or reversal of the symptoms of the disease or disorder being treated.

[0073] The term "composition" is intended to encompass a product containing specified ingredients in specified amounts, and any product that results directly or indirectly from combining specified ingredients in specified amounts.

[0074] As used herein, the term "treatment" is intended to refer to any process that can slow, hinder, inhibit, or halt the progression of a disease, although it does not necessarily indicate complete elimination of all symptoms.

[0075] As used herein, the term "compounds of the invention" or "compounds according to the invention" is meant to include compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

[0076] The compounds of formula (I) are menin-MLL inhibitors of formula (I).

[0077] As used herein, any chemical formula with bonds shown only as solid lines and not as solid or hashed wedge bonds, or otherwise shown as having a particular configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0078] Above and below, the term "compounds of formula (I)" is meant to include its tautomers and its stereoisomeric forms.

[0079] Above and below the terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably.

[0080] The present invention includes all stereoisomers of the compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0081] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0082] Atropisomers (or atropoisomers) are stereoisomers with specific spatial configurations resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0083] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If the compound contains double bonds, the substituents may be in either the E or Z configuration.

[0084] Substituents on a divalent cyclic saturated or partially saturated radical can have either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents can be in either the cis or trans configuration.

[0085] Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0086] The meanings of all terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to those skilled in the art.

[0087] Absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane-polarized light. For example, resolved enantiomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane-polarized light.

[0088] When a particular stereoisomer is specified, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other stereoisomers. Thus, when a compound of formula (I) is specified, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is specified, for example, as E, this means that the compound is substantially free of the Z isomer; and when a compound of formula (I) is specified, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0089] Some of the compounds according to formula (I) may also exist in their tautomeric forms. Such forms, to the extent possible, are intended to be included within the scope of the present disclosure, although not explicitly shown in formula (I) above. Thus, a single compound may exist in both stereoisomeric and tautomeric forms.

[0090] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting a free acid form or a free base form with one or more equivalents of a suitable base or acid, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, in vacuo, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present disclosure in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0091] The pharmaceutically acceptable salts referred to above or below are meant to include the therapeutically active non-toxic acid and base salt forms that the compounds of formula (I) and their solvates are able to form.

[0092] Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc. Conversely, the salt forms can be converted to the free base form by treatment with an appropriate base.

[0093] Compounds of formula (I) or solvates thereof containing acidic protons may be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0094] Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, cesium, magnesium, calcium salts, and the like, salts with organic bases such as primary, secondary, and tertiary aliphatic amines and aromatic amines, for example, methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline; benzathine, N-methyl-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, base forms can be converted to the free base forms by treatment with acid.

[0095] The term "prodrug" includes any compound that, following oral or parenteral administration, especially oral administration, is metabolized in vivo to a more active(er) form in an experimentally detectable amount and within a predetermined time period (e.g., within a 0.5 to 24 hour dosing interval, or, for example, within a 6 to 24 hour dosing interval (i.e., 1 to 4 times daily)). For the avoidance of doubt, the term "parenteral" administration includes all modes of administration other than oral administration, in particular intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.

[0096] Prodrugs can be prepared by modifying functional groups present on a compound such that the modification is cleaved in vivo when the prodrug is administered to a mammalian subject. The modification is typically accomplished by synthesizing the parent compound with a prodrug substituent. In general, prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group, respectively.

[0097] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, ester groups of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985).

[0098] The term solvates comprises the solvent addition forms, as well as the salts thereof, which the compounds of formula (I) are able to form. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc.

[0099] The compounds of the present invention prepared by the processes described below may be synthesized in the form of a mixture of enantiomers, particularly a racemic mixture of enantiomers, which can be separated from one another according to art-known resolution procedures. A method for separating the enantiomeric forms of the compound of formula (I) and its pharmaceutically acceptable salts and solvates includes liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparation methods. These methods will advantageously employ enantiomerically pure starting materials.

[0100] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and no more than 20% by weight of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and no more than 10% by weight of the other enantiomer. In the most preferred embodiment, the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and no more than 1% of the other enantiomer.

[0101] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to those enumerated herein, but due to the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant atom found in nature).

[0102] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring or synthetically produced, at natural abundance or in isotopically enriched form, are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br and other isotopes of iodine. Preferably, the isotope is 2 H, 3H, 11 C. 13 C, and 18 Preferably, the isotope is selected from the group 2 H, 3 H, 11 C, and 18 F. More preferably, the isotope is selected from the group 2 H, 3 H, or 13 C. More preferably, the isotope is 2 H or 13 C. More preferably, the isotope is 2 H. In particular, deuterium compounds and 13 C-enriched compounds are intended to be included within the scope of the present invention. In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0103] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) can be useful, for example, in substrate tissue distribution assays. 3 H) and carbon-l4( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 Substitutions such as with hydroxypropyl methyl ... 15 O. 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping to localize and identify tumors, stage disease, and determine appropriate treatments. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy. In addition, target-specific PET radiotracers can be used as biomarkers to investigate and evaluate pathologies, for example, by measuring target expression and treatment response.

[0104] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, at least one other therapeutic agent as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0105] As a further example, a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent as active ingredients can be prepared by mixing the compound with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and / or a pharmaceutically acceptable excipient.

[0106] As used herein, the term "menin-MLL inhibitor" refers to an inhibitor of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) (also known in the scientific community as histone-lysine N-methyltransferase 2A (KMT2A) protein (UniProt Accession No. Q03164)), which inhibits or reduces menin-MLL1 activity. The menin-MLL inhibitors described herein are disclosed in International Application No. CN2022 / 095901, which is incorporated herein by reference in its entirety, and which also discloses corresponding synthetic schemes and analytical characterization.

[0107] As used herein, the term "BCL-2 inhibitor" refers to an agent that inhibits or reduces BCL-2 activity.

[0108] As used herein, the term "anti-neoplastic agent" refers to any agent that treats cancer.

[0109] As used herein, the term "hypomethylating agent" refers to an agent that inhibits or reduces DNA methylation.

[0110] As used herein, the term "kinase inhibitor" refers to an agent that inhibits or reduces the activity of at least one kinase (e.g., tyrosine and / or serine kinases such as fms-like receptor tyrosine kinase-3 (FLT3), Bruton tyrosine kinase (BTK), Abelson tyrosine kinase 1 (ABL), Auroracerine / tyrosine kinase, etc.).

[0111] As used herein, the term "FLT-3 inhibitor" refers to tyrosine kinase inhibitors (TKIs) that are classified into first-generation and next-generation inhibitors based on their potency and specificity for fms-like receptor tyrosine kinase-3 (FLT3) and its associated downstream targets.

[0112] As used herein, the term "CD20 inhibitor" refers to any agent that reduces the activity of CD20.

[0113] As used herein, the term "isocitrate dehydrogenase (IDH) inhibitor" refers to any agent that interferes with the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle.

[0114] As used herein, the term "immunomodulatory anti-neoplastic agent" refers to any agent that enhances anti-tumor immune cell activity.

[0115] As used herein, the term "programmed cell death protein 1 (PD-1) inhibitor" refers to any agent that inhibits or reduces PD-1 activity.

[0116] As used herein, the term "dihydroorotate dehydrogenase (DHODH) inhibitor" refers to any agent that inhibits or reduces dihydroorotate dehydrogenase activity.

[0117] As used herein, unless otherwise specified, the terms "affected" or "affected" (when referring to a disease, disorder, or medical condition affected by inhibition or alteration of menin-MLL activity) include a reduction in the frequency and / or severity of one or more symptoms or signs of said hematopoietic disorder and / or include prevention of the onset of one or more symptoms or signs of said hematopoietic disorder or prevention of the onset of a hematopoietic disorder.

[0118] As used herein, the term "hematopoietic disorder" refers to any disorder associated with the production of the cellular components of blood and plasma, including, but not limited to, blood cancers.

[0119] According to one embodiment, the present invention provides a combination as described herein.

[0120] According to one embodiment, the present invention provides a combination as described herein for use as a medicament.

[0121] According to one embodiment, the present invention provides a combination as described herein for the manufacture of a medicament.

[0122] According to one embodiment, the present invention provides a combination as described herein for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned herein.

[0123] According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment, in particular the treatment, of a disease as described herein.

[0124] According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment, particularly the treatment, of a hematopoietic disorder, such as but not limited to, a blood cancer, such as but not limited to, lymphoma, myeloma, and leukemia.

[0125] According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment, in particular the treatment, of a hematopoietic disorder.

[0126] According to one embodiment, the hematopoietic disorder is selected from, but not limited to, lymphoma, myeloma, myelodysplasia, and leukemia.

[0127] According to one embodiment, the hematopoietic disorder is a lymphoma selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0128] According to one embodiment, the lymphoma is a non-Hodgkin's lymphoma that is Burkitt's lymphoma, anaplastic large cell lymphoma, splenic marginal zone lymphoma, hepatosplenic T-cell lymphoma, or angioimmunoblastic T-cell lymphoma (AILT).

[0129] In one embodiment, the hematopoietic disorder is myeloma. In one embodiment, the hematopoietic disorder is multiple myeloma, Waldenstrom's macroglobulinemia, or plasmacytoma.

[0130] According to one embodiment, the hematopoietic disorder is myelodysplasia, including but not limited to myelodysplastic syndromes (MDS).

[0131] According to one embodiment, the hematopoietic disorder is leukemia.

[0132] In one embodiment, the hematopoietic disorder is a leukemia selected from acute leukemia and chronic leukemia. In one embodiment, the leukemia is acute leukemia. In one embodiment, the leukemia is chronic leukemia.

[0133] According to one embodiment, the hematopoietic disorder is myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, or lymphocytic leukemia. According to one embodiment, the hematopoietic disorder is acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), acute myeloid leukemia (AML), chronic idiopathic myelofibrosis (MF), chronic myelogenous leukemia (CML), T-cell prolymphocytic leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), chronic neutrophilic leukemia (CNL), Hairy cell leukemia (CNL), leukemia, HCL), T-cell large granular lymphocyte leukemia The leukemia is selected from, but not limited to, acute myeloid leukemia (T-LGL), and aggressive NK-cell leukemia. According to one embodiment, the AML is acute megakaryoblastic leukemia (AMKL).

[0134] In one embodiment, the leukemia is MDS, CLL, SLL, ALL, or AML. In one embodiment, the leukemia is CLL, SLL, or AML. In one embodiment, the leukemia is CLL or SLL. In some embodiments, the CLL or SLL is a CD20-expressing cancer. In one embodiment, the leukemia is ALL or AML. In one embodiment, the leukemia is ALL. In one embodiment, the leukemia is AML. In one embodiment, the hematopoietic disorder is Waldenstrom's macroglobulinemia.

[0135] According to one embodiment, the hematopoietic disorder is MLL-rearranged leukemia, MLL partial tandem duplication (PTD) leukemia, MLL-amplified leukemia, MLL-positive leukemia, or leukemia exhibiting an elevated HOX / MEIS1 gene expression signature.

[0136] According to one embodiment, the leukemia is an MLL-rearranged leukemia and / or nucleophosmin 1 (NPM1)-mutated leukemia. According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia.

[0137] According to one embodiment, the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia (eg, NPM1c).

[0138] According to one embodiment, the present invention provides a method of treating a hematopoietic disorder, which is myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent.

[0139] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0140] According to one embodiment, the hematopoietic disorder is acute lymphoblastic leukemia (ALL).

[0141] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0142] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

[0143] According to one embodiment, the hematopoietic disorder is SLL or CLL, wherein the SLL or CLL is a CD20-expressing cancer.

[0144] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS).

[0145] According to one embodiment, the hematopoietic disorder is a myeloproliferative neoplasm (MPN).

[0146] According to one embodiment, the hematopoietic disorder is NPM1 mutant leukemia with a FLT3 mutation.

[0147] According to one embodiment, the hematopoietic disorder is FLT3-dependent leukemia.

[0148] According to one embodiment, the hematopoietic disorder has one or more MLL1 (KMT2A) gene rearrangements or alterations (eg, duplications or amplifications) and / or NPM1 mutations.

[0149] According to one embodiment, the hematopoietic disorder has (i) one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplifications) and / or NPM1 mutations in addition to (ii) a FLT3 mutation.

[0150] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia.

[0151] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0152] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL).

[0153] According to one embodiment, the hematopoietic disorder is chronic lymphocytic leukemia (CLL).

[0154] According to one embodiment, the hematopoietic disorder is acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, or leukemia exhibiting an elevated HOX / MEIS1 gene expression signature.

[0155] According to one embodiment, the hematopoietic disorder is AML, specifically nucleophosmin (NPM1)-mutated AML (i.e., NPM1 mut AML), more specifically abstract NPM1-mutated AML.

[0156] According to one embodiment, the hematopoietic disorder is an MLL-rearranged leukemia, in particular, MLL-rearranged AML or ALL.

[0157] According to one embodiment, the hematopoietic disorder comprises an MLL gene alteration, and in particular the hematopoietic disorder is AML or ALL with an MLL gene alteration. In a particular embodiment, the MLL gene alteration is a duplication. In a particular embodiment, the MLL gene alteration is an amplification.

[0158] According to one embodiment, the hematopoietic disorder comprises an NPM1 gene mutation and / or an MLL1 (also known as KMT2A) gene mutation.

[0159] According to one embodiment, the MLL1 gene mutation includes, but is not limited to, an MLL1 gene rearrangement, duplication, or amplification.

[0160] According to one embodiment, the hematopoietic disorder is mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, MLL-associated leukemia, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN).

[0161] All embodiments described herein with respect to methods for treating hematopoietic disorders are also applicable for use in treating said hematopoietic disorders.

[0162] All embodiments described herein for use in treating hematopoietic disorders are also applicable to methods for treating said hematopoietic disorders.

[0163] All embodiments described herein with respect to methods for treating hematopoietic disorders are also applicable for use in the methods for treating hematopoietic disorders.

[0164] All embodiments described herein for use in a method for treating a hematopoietic disorder are also applicable to the method for treating the hematopoietic disorder.

[0165] In one embodiment, the present invention provides a therapeutically effective amount of a menin-MLL inhibitor of formula (I), or a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof; a therapeutically effective amount of a BCL-2 inhibitor; Optionally, a therapeutically effective amount of at least one other anti-neoplastic agent.

[0166] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -or-CR y= and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, halo, -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-OC 1~4 alkyl, or

[0167] [ka] represents R 18 But C 1~6 represents alkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R 19 together to form -(CH2)3-, -(CH2)4-, or -(CH2)5-, R xa and R xb are each independently hydrogen, Het 3 , C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl, and -C 1~4 substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl-OH, 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xbtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, -OC 1~4 alkyl and 1, 2, or 3 OR 23 C replaced with 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally substituted by 1, 2, or 3 -OH substituents; R 23 is hydrogen or C 1~4 represents alkyl, R 1b But F or -OC 1~4 represents alkyl, R 2 But, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0168] [ka] represents R 5 represents hydrogen, n1 is selected from 1 and 2; n2 is selected from 1, 2, and 3; R y represents hydrogen, R 3 , R 3a , and R 4 However, each independently, Het 1 ;C 1~8 Alkyl; and -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , Ar 1 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~8 is selected from the group consisting of alkyl, R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl;-(C=O)-C 1~4 alkyl; and 1, 2, or 3 -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, Ar 1 Optionally, C 1~4 Alkyl and -C(=O)-NR 10a R 10b represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het 1represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , C 1~4 substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, oxo, and —OH; Het 2 represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl; R 6 But, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-C(=O)-Het 6a ;-C(=O)-NR 10d R 10e ;-C(=O)-OC 1~4 Alkyl; -S(=O)2-C 1~4 alkyl; Optionally, Het 6a , Het 6b C substituted with 1 or 2 substituents each independently selected from the group consisting of - 1~6 is selected from the group consisting of alkyl, R 8 But hydrogen, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC1~4 Alkyl, cyano, -S(=O)2-C 1~4 Alkyl and Het 3a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 and Het 3a represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a -(C=O)-C bond on one nitrogen atom; 1~4 is substituted with alkyl, Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally having, on 1 or 2 carbon atoms, a C 1~4 Alkyl and -(C=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, each independently, halo and -S(═O)2-C 1~4 alkyl, and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl and -S(=O)2-C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 6brepresents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C 1~4 is substituted with alkyl, Cy 1 C optionally substituted with 1, 2, or 3 -OH 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; -C(=O)-C 1~4 Alkyl; -S(=O)2-C 1~4 Alkyl, and -C(=O)-R 14 is selected from the group consisting of R 10a , R 10b , and R 10c are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 10d and R 10e However, each independently, C 1~4 Alkyl and -OC 1~4 is selected from the group consisting of alkyl, R 14 But, -OC 1~4represents alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0169] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents -S(=O)2-R 18 , -C(=O)-OC 1~4 alkyl; or

[0170] [ka] represents R 18 But C 1~6 represents alkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R 19 together to form -(CH2)3-, -(CH2)4-, or -(CH2)5-, R xa and R xb are each independently hydrogen, Het 3 ;C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl, and -C 1~4 substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl-OH, 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xbtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, -OC 1~4 alkyl and 1, 2, or 3 OR 23 C replaced with 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally substituted by 1, 2, or 3 -OH substituents; R 23 is hydrogen or C 1~4 represents alkyl, R 1b But F or -OC 1~4 represents alkyl, R 2 But, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3is attached to a nitrogen atom of the ring, Y and Y a represents a covalent bond, n1 is selected from 1 and 2; n2 is selected from 1, 2, and 3; R y represents hydrogen, R 3 and R 3a However, each independently, Het 1 ;C 1~8 Alkyl; and -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , Ar 1 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~8 is selected from the group consisting of alkyl, R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xdtaken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl;-(C=O)-C 1~4 alkyl; and 1, 2, or 3 -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, Ar 1 Optionally, C 1~4 Alkyl and -C(=O)-NR 10a R 10b represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , C 1~4 substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, oxo, and —OH; Het 2 represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl; R 6 But, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-C(=O)-Het 6a ;-C(=O)-NR 10d R 10e ;-C(=O)-OC 1~4 Alkyl; -S(=O)2-C 1~4 Alkyl; optionally, Het 6a , Het 6b C substituted with 1 or 2 substituents each independently selected from the group consisting of - 1~6 is selected from the group consisting of alkyl, R 8 But hydrogen, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, cyano, -S(=O)2-C 1~4 Alkyl and Het 3a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 and Het 3a represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a -(C=O)-C bond on one nitrogen atom; 1~4 is substituted with alkyl, Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally having, on 1 or 2 carbon atoms, a C 1~4 Alkyl and -(C=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, each independently, halo and -S(═O)2-C 1~4 alkyl, and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl and -S(=O)2-C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 6b represents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C 1~4 is substituted with alkyl, Cy 1 C optionally substituted with 1, 2, or 3 -OH 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; -C(=O)-C 1~4 Alkyl; -S(=O)2-C 1~4 Alkyl, and -C(=O)-R 14 is selected from the group consisting of R 10a , R 10b , and R 10c are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 10d and R 10e However, each independently, C 1~4 Alkyl and -OC 1~4 is selected from the group consisting of alkyl, R 14 But, -OC 1~4 represents alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0171] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents -S(=O)2-R 18 , -C(=O)-OC 1~4 alkyl, or

[0172] [ka] represents R 18 But C 1~6 represents alkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R 19 together to form -(CH2)3-, R xa and R xb are each independently hydrogen, Het 3 ;C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl, and -C 1~4 substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl-OH, 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, -OC 1~4 alkyl and 1, 2, or 3 OR 23 C replaced with 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xbtogether with the N atom to which they are attached form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally substituted by 1, 2, or 3 -OH substituents; R 23 is hydrogen or C 1~4 represents alkyl, R 1b But F or -OC 1~4 represents alkyl, R 2 But, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a each independently represents a covalent bond; n1 is selected from 1 and 2; n2 is selected from 1, 2, and 3; R y represents hydrogen, R 3 and R 3a However, each independently, Het 1 ;C 1~8 Alkyl; and -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1~4 Alkyl, -NR xc R xd, -NR 8a R 8b , -CF3, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , Ar 1 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~8 is selected from the group consisting of alkyl, R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with alkyl; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl;-(C=O)-C 1~4 alkyl; and 1, 2, or 3 -OC 1~4 Alkyl-substituted C 1~6is selected from the group consisting of alkyl, Ar 1 optionally 1, 2, or 3 -C(=O)-NR 10a R 10b represents a phenyl substituted with Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on 1 or 2 carbon atoms with substituents selected from the group consisting of halo, C 1~4 substituted with a total of 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, oxo, and —OH; Het 2 represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, or pyridazinyl; R 6 But, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-C(=O)-Het 6a ;-C(=O)-NR 10d R 10e ;-C(=O)-OC 1~4 Alkyl; -S(=O)2-C 1~4 alkyl; Optionally, Het 6a , Het 6bC substituted with 1 or 2 substituents each independently selected from the group consisting of - 1~6 is selected from the group consisting of alkyl, R 8 But hydrogen, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, Cyano, and Het 3a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 and Het 3a represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a -(C=O)-C bond on one nitrogen atom; 1~4 is substituted with alkyl, Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, said aromatic ring optionally containing a total of 1 or 2 -(C=O)-NR 10a R 10b is replaced by Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(═O) or S(═O)2, said heterocyclyl being optionally substituted on one or two carbon atoms with a total of one, two, three, or four halo; and said heterocyclyl optionally being substituted on one nitrogen with -C(═O)-C 1~4 Alkyl and -S(=O)2-C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het6b represents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C 1~4 is substituted with alkyl, Cy 1 C optionally substituted with 1, 2, or 3 -OH 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; -C(=O)-C 1~4 Alkyl; -S(=O)2-C 1~4 Alkyl; and -C(=O)-R 14 is selected from the group consisting of R 10a , R 10b , and R 10c are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 10d and R 10e However, each independently, C 1~4 Alkyl and -OC 1~4 is selected from the group consisting of alkyl, R 14 But, -OC1~4 represents alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0173] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa But C 1~6 represents alkyl, R xb But C 1~6 represents alkyl, R 1b represents F, R 2 But C 1~4 represents alkyl, R 21 represents hydrogen, Y represents a covalent bond; n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 But, Het 1 , or -C(=O)-Het 6a , Het 1 , Ar 1 , and Cy 2 C substituted with one substituent selected from the group consisting of 1~8 represents alkyl, Ar 1 optionally one -C(=O)-NR 10a R 10b represents a phenyl substituted with Het 1represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on 1 or 2 carbon atoms with substituents selected from the group consisting of halo, C 1~4 substituted with a total of 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, oxo, and —OH; R 6 -C(=O)-NH-R 8 , -C(=O)-OC 1~4 alkyl; -S(=O)2-C 1~4 Alkyl; and C 1~6 is selected from the group consisting of alkyl, R 8 But hydrogen, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, Cyano, and Het 3a C substituted with one substituent each independently selected from 1~6 represents alkyl, Het 3a represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a -(C=O)-C bond on one nitrogen atom;1~4 is substituted with alkyl, Het 6a represents a monocyclic N-linked 4-7 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2; Cy 1 But C 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents cycloalkyl, 3~7 Cycloalkyl is optionally R 6 and -NR 9a R 9b and is substituted with one or two substituents each independently selected from the group consisting of: R 9a and R 9b each independently represents hydrogen and —C(═O)—R 14 is selected from the group consisting of R 10a and R 10b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 14 But, -OC 1~4 represents alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0174] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -or-CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, halo, -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-OC 1~4 alkyl;

[0175] [ka] represents R 18 But C 1~6 represents alkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R 19 together to form -(CH2)3-, R xa and R xb are each independently hydrogen, Het 3 ;C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl, and -C 1~4 substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl-OH, 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl and OR 23 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally substituted by 1, 2, or 3 -OH substituents; R 23 is hydrogen or C 1~4 represents alkyl, R 1b represents F, R 2 But, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0176] [ka] represents n1 is selected from 1 and 2; n2 is selected from 1, 2, and 3; R y represents hydrogen, R 5represents hydrogen, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ;C 1~8 alkyl; and each independently -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , Ar 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents selected from the group consisting of 1~8 is selected from the group consisting of alkyl, R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xdtaken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 8a and R 8b are each independently hydrogen; C 1~6 alkyl; and one -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, Ar 1 Optionally, C 1~4 Alkyl and -C(=O)-NR 10a R 10b represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8and the heterocyclyl is optionally substituted on 1 or 2 carbon atoms with a substituent selected from the group consisting of halo, R 6 , C 1~4 substituted with a total of 1, 2, 3, or 4 substituents selected from the group consisting of alkyl, oxo, and —OH; Het 2 represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl; R 6 But, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-C(=O)-Het 6a ;-C(=O)-NR 10d R 10e ;-C(=O)-OC 1~4 Alkyl; -S(=O)2-C 1~4 alkyl; C optionally substituted with one or two -OH substituents 1~6 alkyl; and C 3~6 cycloalkyl; R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, cyano, -S(=O)2-C 1~4 Alkyl and Het 3a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 and Het 3arepresents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, the heterocyclyl optionally being substituted on one carbon atom with oxo, the heterocyclyl optionally being substituted on one nitrogen atom with -(C=O)-C 1~4 is substituted with alkyl, Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally having, on one or two carbon atoms, a C 1~4 Alkyl and -(C=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, each independently, halo and -S(═O)2-C 1~4 alkyl, and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl and -S(=O)2-C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 6brepresents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C 1~4 is substituted with alkyl, Cy 1 C optionally substituted with 1, 2, or 3 -OH 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; -C(=O)-C 1~4 Alkyl; -S(=O)2-C 1~4 Alkyl; and -C(=O)-R 14 is selected from the group consisting of R 10a , R 10b , and R 10c are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 10d and R 10e However, each independently, C 1~4 Alkyl and -OC 1~4 is selected from the group consisting of alkyl, R 14 But, -OC 1~4represents alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0177] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -, -O-, -C(=O)-, -NR q - or -CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0178] [ka] represents R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally selected from the group consisting of C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are each independently hydrogen, Het 3 ;C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4Alkyl and NR 11c R 11d C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 1b represents hydrogen, F, or Cl; R 2 But, Halo, C 3~6 Cycloalkyl, C 1~4Alkyl, -OC 1~4 C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0179] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y But hydrogen, -OH, C 1~4 Alkyl, -C 1~4 Alkyl-OH or -C 1~4 Alkyl-OC 1~4 represents alkyl, R q is hydrogen or C 1~4 represents alkyl, R 5 But hydrogen, C 1~4 Alkyl or C 3~6 represents cycloalkyl, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ; C 1~6 Alkyl; and -C(=O)-NR 10a R 10b , -NR 10c -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -NR xc R xd, -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R xc But Cy 1 , Het 5 , -C 1~6 Alkyl-Cy 1 , -C 1~6 Alkyl-Het 3 , -C 1~6 Alkyl-Het 4 , or -C 1~6 represents alkyl-phenyl, and R xd But hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano 1~4 represents alkyl, or R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xc and R xdtaken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl-S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~6 is selected from the group consisting of alkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl or triazolyl, which optionally has on one nitrogen atom R 6a may be substituted with R 6 and R 6a However, each independently, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-S(=O)2-C 1~4 Alkyl; optionally, Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and Optionally, OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 optionally substituted with one substituent selected from the group consisting of alkyl, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4Alkyl, -NH-S(=O)2-C 1~4 Alkyl, and C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, halo, cyano, -NR 11a R 11b , Het 3a , and Het 6a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 , Het 3a , Het 5 , and Het 5a each independently represent a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo, and the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 is substituted with alkyl, Het 4 and Het 7each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 Alkyl or -(C=O)-OC 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 , and -C(=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a , Het 8 , and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl may optionally be substituted on one or two carbon atoms with a halo, —OH, oxo, —NH—C(═O)—C1~4 Alkyl, -NH-C(=O)-Cy 3 , -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, and -(C=O)-NR 10a R 10b and is substituted with a substituent selected from the group consisting of Het 6b and Het 8b each independently represent a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 9 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C 1~4 and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl, Cy 1 optionally, -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl,

[0180] [ka] and Het 3a, Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 But C 3~7 represents cycloalkyl, 3~7 cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 1~4 is selected from the group consisting of alkyl, R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , R 17b , R20a , and R 20b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 11c and R 11d are each independently hydrogen, C 1~6 Alkyl, and -C(=O)-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl; R 14 But, Het 5a ;Het 7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 represents alkyl, R 16 -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 , or Het 8 represents], and pharmaceutically acceptable salts and solvates thereof.

[0181] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y-, -O-, -C(=O)-, -NR q - or -CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0182] [ka] represents R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally selected from the group consisting of C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are each independently hydrogen, Het 3 , C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl and NR 11c R 11d C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xbtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 1b represents hydrogen, F, or Cl; R 2 But, Halo, C 3~6 Cycloalkyl, C 1~4 Alkyl, -OC 1~4 C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Ya -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0183] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y But hydrogen, -OH, C 1~4 Alkyl, -C 1~4 Alkyl-OH or -C 1~4 Alkyl-OC 1~4 represents alkyl, R q is hydrogen or C 1~4 represents alkyl, R 5 But hydrogen, C 1~4 Alkyl or C 3~6 represents cycloalkyl, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ; C 1~6 Alkyl; and -C(=O)-NR 10a R 10b , -S(=O)2-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, Rxc But Cy 1 , Het 5 ;-C 1~6 Alkyl-Cy 1 , -C 1~6 Alkyl-Het 3 , -C 1~6 Alkyl-Het 4 , or -C 1~6 represents alkyl-phenyl, R xd But hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano 1~4 represents alkyl, or R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4Alkyl-S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2represents a C-linked pyrazolyl or triazolyl, which optionally has on one nitrogen atom R 6a may be substituted with R 6 and R 6a However, each independently, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-S(=O)2-C 1~4 alkyl; Optionally, Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and Optionally, OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 optionally substituted with one substituent selected from the group consisting of alkyl, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, and C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, halo, cyano, -NR11a R 11b , Het 3a , and Het 6a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 , Het 3a , Het 5 , and Het 5a each independently represent a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo, and the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 is substituted with alkyl, Het 4 and Het 7 each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 Alkyl or -(C=O)-OC 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 , and -C(=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a , Het 8 , and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl may optionally be substituted on one or two carbon atoms with a halo, —OH, oxo, —NH—C(═O)—C 1~4 Alkyl, -NH-C(=O)-Cy 3 , -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, and -(C=O)-NR 10a R 10b and is substituted with a substituent selected from the group consisting of Het 6b and Het 8b each independently represent a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4 Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 9represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C 1~4 and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl, Cy 1 optionally, -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl,

[0184] [ka] and Het 3a , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~4substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 But C 3~7 represents cycloalkyl, 3~7 cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 1~4 is selected from the group consisting of alkyl, R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , R 17b , R 20a , and R 20b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 11c and R 11dare each independently hydrogen, C 1~6 Alkyl, and -C(=O)-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl; R 14 But, Het 5a ;Het 7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 represents alkyl, R 16 -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 , or Het 8 represents], and pharmaceutically acceptable salts and solvates thereof.

[0185] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -, -O-, -C(=O)-, -NR q - or -CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0186] [ka] represents R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally selected from the group consisting of C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are each independently hydrogen, Het 3 , C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl and NR 11c R 11d C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xbtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 1b represents hydrogen, F, or Cl; R 2 But, Halo, C 3~6 Cycloalkyl, C 1~4 Alkyl, -OC 1~4 C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Ya -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0187] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y But hydrogen, -OH, C 1~4 Alkyl, -C 1~4 Alkyl-OH or -C 1~4 Alkyl-OC 1~4 represents alkyl, R q is hydrogen or C 1~4 represents alkyl, R 5 But hydrogen, C 1~4 Alkyl or C 3~6 represents cycloalkyl, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ; C 1~6 Alkyl; and -C(=O)-NR 10a R 10b , -NR 10c -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of1~6 is selected from the group consisting of alkyl, R xc But Cy 1 , Het 5 ;-C 1~6 Alkyl-Cy 1 , -C 1~6 Alkyl-Het 3 , -C 1~6 Alkyl-Het 4 , or -C 1~6 represents alkyl-phenyl, R xd But hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano 1~4 represents alkyl, or R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC1~4 Alkyl, -(C=O)-C 1~4 Alkyl-S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~6 is selected from the group consisting of alkyl, Het 1 is 1, 2, or 3 heteroatoms each independently selected from O, S, and N, and the S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen atom R 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl or triazolyl, which optionally has on one nitrogen atom R 6a may be substituted with R6 and R 6a However, each independently, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-S(=O)2-C 1~4 alkyl; Optionally, Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and Optionally, OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 optionally substituted with one substituent selected from the group consisting of alkyl, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, and C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, halo, cyano, -NR 11a R 11b , Het 3a , and Het 6aC substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 , Het 3a , Het 5 , and Het 5a each independently represent a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo, and the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 is substituted with alkyl, Het 4 and Het 7 each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 Alkyl or -(C=O)-OC 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 , and -C(=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a , Het 8 , and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl may optionally be substituted on one or two carbon atoms with a halo, —OH, oxo, —NH—C(═O)—C 1~4 Alkyl, -NH-C(=O)-Cy 3 , -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -S(=O)2-C 1~4Alkyl, and -(C=O)-NR 10a R 10b and is substituted with a substituent selected from the group consisting of Het 6b and Het 8b each independently represent a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4 Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 9 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C 1~4and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl, Cy 1 optionally, -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl,

[0188] [ka] and Het 3a , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 But C 3~7 represents cycloalkyl, 3~7 cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b are each independently hydrogen; C 1~4Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 1~4 is selected from the group consisting of alkyl, R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , R 17b , R 20a , and R 20b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 11c and R 11d are each independently hydrogen, C 1~6 Alkyl, and -C(=O)-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl], R 14 But, Het 5a ;Het7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 represents alkyl, R 16 -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 , or Het 8 represents], and pharmaceutically acceptable salts and solvates thereof.

[0189] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -, -O-, -C(=O)-, -NR q - or -CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0190] [ka] represents R 18 But C 1~6Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally selected from the group consisting of C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are each independently hydrogen, Het 3 , C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl and NR 11c R 11d C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xa and Rxb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OC 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 1b represents hydrogen, F, or Cl; R 2 But C 1~4 Represents alkyl, in particular R 2 represents methyl, R 21 is hydrogen or -Y a -R 3a However, R 21 Ga-Y a -R 3a If you want to represent a -R 3a and -YR 3 is attached to a nitrogen atom of the ring, Y and Y a are each independently a covalent bond or

[0191] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y But hydrogen, -OH, C 1~4 Alkyl, -C 1~4 Alkyl-OH or -C 1~4 Alkyl-OC 1~4 represents alkyl, Rq is hydrogen or C 1~4 represents alkyl, R 5 But hydrogen, C 1~4 Alkyl or C 3~6 represents cycloalkyl, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ; C 1~6 Alkyl; and -C(=O)-NR 10a R 10b , -NR 10c -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R xc But Cy 1 , Het 5 ;-C 1~6 Alkyl-Cy 1 , -C 1~6 Alkyl-Het 3 , -C 1~6 Alkyl-Het 4 , or -C 1~6 represents alkyl-phenyl, R xd But hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano 1~4 represents alkyl, or R xc and R xdtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl-S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~6 is selected from the group consisting of alkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH; Het 2 represents a C-linked pyrazolyl or triazolyl, which optionally has on one nitrogen atom R 6a may be substituted with R 6 and R 6a However, each independently, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-S(=O)2-C 1~4 alkyl; Optionally, Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and Optionally, OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, and -NH-S(=O)2-C 1~4 optionally substituted with one substituent selected from the group consisting of alkyl, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, and C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, halo, cyano, -NR 11a R 11b , Het 3a , and Het 6a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 , Het 3a , Het 5 , and Het 5aeach independently represent a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo, and the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 is substituted with alkyl, Het 4 and Het 7 each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 Alkyl or -(C=O)-OC 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 , and -C(=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a , Het 8 , and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl may optionally be substituted on one or two carbon atoms with a halo, —OH, oxo, —NH—C(═O)—C 1~4 Alkyl, -NH-C(=O)-Cy 3 , -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, and -(C=O)-NR 10a R 10b and is substituted with a substituent selected from the group consisting of Het 6b and Het 8beach independently represent a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4 Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 9 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C 1~4 and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl, Cy 1 optionally, -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl,

[0192] [ka] and Het 3a , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 But C 3~7 represents cycloalkyl, 3~7 cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 1~4 is selected from the group consisting of alkyl, R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , R 17b , R 20a , and R 20b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 11c and R 11d are each independently hydrogen, C 1~6 Alkyl, and -C(=O)-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl; R 14 But, Het 5a ;Het 7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 represents alkyl, R 16 -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 , or Het 8 represents], and pharmaceutically acceptable salts and solvates thereof.

[0193] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -or-CR y = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, halo, -C(=O)-NR xa R xb , or

[0194] [ka] represents R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, R xa and R xb are each independently hydrogen, Het3 , and C 1~6 alkyl, optionally 1~6 The alkyl is -OH and -OC 1~4 substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, and -OC 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, and -OC 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 1b represents F, R 2 But, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 represents hydrogen, Y is a covalent bond or

[0195] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y represents hydrogen, R 5 represents hydrogen, R 3 and R 4 However, each independently, Het 1 ;Cy 2 ; C 1~6 Alkyl; and -NR xc R xd , -NR 8a R 8b , -CF3, -OH, Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xdtaken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 8a and R 8b However, each independently, C 1~6 alkyl and one -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of oxo and -NR 9a R 9b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: R 6 But, Het 4 , -C(=O)-NH-R 8 ;-S(=O)2-C1~4 Alkyl; or C 1~6 represents alkyl, R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl or -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl and cyano 1~6 represents alkyl, Het 3 represents a monocyclic C-bonded 4- to 7-membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing a total of 1 or 2 -(C=O)-NR 10a R 10b is replaced by Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and, optionally, one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally contains a total of one or two -S(═O)2-C groups on one or two carbon atoms; 1~4 and the heterocyclyl is optionally substituted on one nitrogen by -C(=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 6brepresents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C 1~4 is substituted with alkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or carbobicyclic ring system may optionally be R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b ,

[0196] [ka] and is substituted with 1, 2, 3, or 4 substituents selected from the group consisting of: R 9a and R 9b are each independently hydrogen, C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, and -S(=O)2-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0197] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y -or-CRy = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond, R 1a is hydrogen, halo, or -C(=O)-NR xa R xb represents R xa and R xb are each independently hydrogen and C 1~6 is selected from the group consisting of alkyl, R 1b represents F, R 2 But, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 represents hydrogen, Y is a covalent bond or

[0198] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y represents hydrogen, R 5 represents hydrogen, R 3 and R 4 However, each independently, Het 1 ;Cy 2 ; C 1~6 Alkyl; and -NR xc R xd , -NR 8a R 8b , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R xc and R xdtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 8a and R 8b However, each independently, C 1~6 alkyl and one -OC 1~4 Alkyl-substituted C 1~6 is selected from the group consisting of alkyl, Het 1 represents a monocyclic C-bonded 4- to 7-membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, said heterocyclyl optionally containing, on one nitrogen, R 6 and -C(=O)-R 8 and is substituted with a substituent selected from the group consisting of R 6 But, Het 4, -C(=O)-NH-R 8 ; or -S(=O)2-C 1~4 represents alkyl, R 8 But, -OC 1~6 Alkyl, C 1~6 Alkyl or -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl and cyano 1~6 represents alkyl, Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing a total of 1 or 2 -(C=O)-NR 10a R 10b is replaced by Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and, optionally, one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally contains a total of one or two -S(═O)2-C groups on one or two carbon atoms; 1~4 and the heterocyclyl is optionally substituted on one nitrogen by -C(=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 6b represents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C1~4 is substituted with alkyl, Cy 2 , but optionally, R 6 , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 3~7 represents cycloalkyl, R 9a and R 9b are each independently hydrogen, C 1~4 Alkyl, -C(=O)-C 1~4 Alkyl, and -S(=O)2-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen and C 1~4 alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0199] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb But C 1~6 represents alkyl, R 1b represents F, R 2 But halo or C 1~4 represents alkyl, R 21 represents hydrogen, Y is a covalent bond or

[0200] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y represents hydrogen, R 5 represents hydrogen, R 3 But, Het 1 ;Cy 2 ;C 1~6 Alkyl; and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R 4 But C 1~6 represents alkyl, specifically isopropyl, R xc and R xd taken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, said heterocyclyl optionally containing, on one nitrogen, R 6 and -C(=O)-R 8 and is substituted with a substituent selected from the group consisting of R 6 But, Het 4 or -C(=O)-NH-R 8 represents R 8 But C 1~6 Alkyl or -OC 1~4C substituted with 1, 2, or 3 substituents each independently selected from alkyl and cyano 1~6 represents alkyl, Het 4 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing a total of 1 or 2 -(C=O)-NR 10a R 10b is replaced by Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Het 6b represents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-C 1~4 is substituted with alkyl, Cy 2 , but optionally, R 6 , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 3~7 represents cycloalkyl, R 9a and R 9bare each independently hydrogen and -S(=O)2-C 1~4 is selected from the group consisting of alkyl, R 10a and R 10b are each independently hydrogen and C 1~4 alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0201] According to one embodiment, the compounds of formula (I) are as defined herein, as well as tautomeric and stereoisomeric forms thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb But C 1~6 represents alkyl, R 1b represents F, R 2 But C 1~4 represents alkyl, R 21 represents hydrogen, Y is a covalent bond or

[0202] [ka] represents n1 and n2 are each independently selected from 1 and 2; R y represents hydrogen, R 5 represents hydrogen, R 3 But Cy 2 , and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R4 But C 1~6 represents alkyl, specifically isopropyl, R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1 represents a monocyclic C-bonded 4- to 7-membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, said heterocyclyl optionally having on one nitrogen a -C(=O)-R 8 is replaced by R 6 -C(=O)-NH-R 8 represents R 8 But C 1~6 represents alkyl, Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Cy 2 , but optionally, R 6 and Het 6a C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 3~7 represents cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0203] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb C optionally substituted with 1, 2, or 3 -OH 1~6 is alkyl, R 1b represents F, R 2 represents methyl, R 21 represents hydrogen or methyl; Y represents a covalent bond; n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 But, -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~8 alkyl, R xc and R xd taken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-R 8 and the heterocyclyl is optionally substituted on one carbon atom with oxo; R 8 But C 1~6 Alkyl, or -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl, and cyano 1~6 represents alkyl], Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Cy 2 However, optionally one Het 6a C replaced with 3~7 represents cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0204] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Q is -CHR y or -CRy = and the dotted line indicates Q = -CR y = is an optional additional bond to form a double bond.

[0205] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Q is -CHR y Represents.

[0206] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1a is hydrogen, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0207] [ka] Represents.

[0208] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1a Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0209] [ka] Represents.

[0210] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1a is -C(=O)-NR xa R xb , -S(=O)2-R 18 , or

[0211] [ka] Represents.

[0212] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1a is -C(=O)-NR xa R xb , or

[0213] [ka] Represents.

[0214] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 1a is -C(=O)-NR xa R xb Represents.

[0215] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 18 is C 1~6 Represents alkyl.

[0216] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb is C 1~6Represents alkyl.

[0217] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb are each independently hydrogen, Het 3 , and C 1~6 alkyl, optionally 1~6 Alkyl is -OH and -OC 1~4 substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, and -OC 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, -OH, and -OC 1~4and forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl.

[0218] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb are each independently hydrogen, Het 3 , and C 1~6 alkyl, and optionally, the C 1~6 Alkyl is -OH and -OC 1~4 and substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl.

[0219] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb is C 1~6 Represents alkyl.

[0220] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb will come together.

[0221] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb But they don't go together.

[0222] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F or Cl.

[0223] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F.

[0224] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 Ha, Halo, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 Represents alkyl.

[0225] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 is halo or C 1~4 Represents alkyl.

[0226] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 is C 1~4 Represents alkyl.

[0227] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 represents methyl.

[0228] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 2 represents methyl, and R 1a is -C(=O)-NR xa R xb Represents.

[0229] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y and Y a represents a covalent bond.

[0230] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 21 represents hydrogen.

[0231] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 21 represents hydrogen or methyl.

[0232] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 21 represents hydrogen, Y represents a covalent bond.

[0233] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 21 represents hydrogen or methyl, Y represents a covalent bond.

[0234] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 21 -Y a -R 3a Represents.

[0235] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 21 is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or halo, -OH, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , -NR 10c -C(=O)-C 1~4 Alkyl, and -S(=O)2-C 1~4 C substituted with one substituent selected from the group consisting of alkyl 1~6 Represents alkyl.

[0236] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 21 is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or halo, -OH, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , -NR 10c -C(=O)-C 1~4 Alkyl, and -S(=O)2-C 1~4 C substituted with one substituent selected from the group consisting of alkyl 1~6 Represents alkyl.

[0237] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 10c is hydrogen, C 1~4 Alkyl, and C 3-6 cycloalkyl.

[0238] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 , R 3a , and R 4 are each independently 1 ;Het 2 ;Cy 2 ; C 1~6 Alkyl; and -C(=O)-NR 10a R 10b , -S(=O)2-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , and Cy 2 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R 8a and R 8b are each independently hydrogen; C 1~6 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, and -C(=O)-NR 10a R 10b C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 1~6 alkyl.

[0239] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 , R 3a , and R 4 is -NR 10c -C(=O)-C 1~4 Alkyl-substituted C 1~6 Not alkyl, R 8a and R 8b is -NR 10c -C(=O)-C 1~4 Alkyl-substituted C 1~6 Not alkyl.

[0240] In one embodiment, the invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y represents a covalent bond.

[0241] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y a represents a covalent bond.

[0242] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y is

[0243] [ka] Represents.

[0244] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y ateeth,

[0245] [ka] Represents.

[0246] In one embodiment, the invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 represents 1 and n2 represents 2.

[0247] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 4 is C 1~6 Alkyl, oxetanyl, tetrahydropyranyl,

[0248] [ka] Represents.

[0249] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R y represents hydrogen.

[0250] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 4 is C 1~6 Alkyl, oxetanyl, tetrahydropyranyl,

[0251] [ka] Represents.

[0252] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 is C 1~6 Represents alkyl.

[0253] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 represents isopropyl.

[0254] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 is C 1~8 It is alkyl.

[0255] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 is C 1~4 It is alkyl.

[0256] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5 represents hydrogen.

[0257] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 and R 4 are each independently 1 ;Cy 2 ; C 1~6Alkyl; and -NR xc R xd , -NR 8a R 8b , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 alkyl.

[0258] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 Het 1 ;Cy 2 ;C 1~6 Alkyl; and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R 4 is C 1~6 It represents alkyl, especially isopropyl.

[0259] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Cy 2 ; and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 is selected from the group consisting of alkyl, R 4 is C 1~6 It represents alkyl, especially isopropyl.

[0260] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Het 1 ;Cy 2 ;C 1~6 Alkyl; and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 alkyl.

[0261] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 3 Cy 2 ; and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 alkyl.

[0262] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Cy 2 is C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system, 3~7 The cycloalkyl or carbobicyclic ring system may optionally be R 6 , -NR 9a R 9b and -OH.

[0263] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 and forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl.

[0264] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R xc and R xdtaken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally -(C=O)-C 1~4 Alkyl and -S(=O)2-C 1~4 and forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl.

[0265] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xc and R xd will come together.

[0266] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xc and R xd But they don't go together.

[0267] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein fully or partially saturated heterocyclyl groups are limited to fully saturated heterocyclyl groups.

[0268] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Q is -CHR y - represents R 1a is -C(=O)-NR xa Rxb represents R 1b represents F, R 2 represents methyl.

[0269] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 8a and R 8b are each independently C 1~6 Alkyl and -OC 1~4 Alkyl-substituted C 1~6 alkyl.

[0270] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of oxo and -NR 9a R 9b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of:

[0271] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 6 Het 4 or -C(=O)-NH-R 8 Represents.

[0272] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 8 is C 1~6 alkyl; or each independently -OC 1~4 C substituted with 1, 2, or 3 substituents selected from alkyl and cyano 1~6 Represents alkyl.

[0273] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 8 is C 1~6 Represents alkyl.

[0274] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 8 represents methyl.

[0275] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 4represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing a total of 1 or 2 -(C=O)-NR 10a R 10b is replaced by .

[0276] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally be joined on one nitrogen by a -C(=O)-C 1~4 It is substituted with alkyl.

[0277] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 6b represents a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a -C(=O)-C bond on one nitrogen. 1~4 It is substituted with alkyl.

[0278] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Cy 2 is C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or carbobicyclic ring system may optionally be R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b ,

[0279] [ka] and is substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of:

[0280] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Cy 2 Optionally, R 6 , Het 6a , Het 6b , -NR 9a R 9b ,

[0281] [ka] C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 3~7 represents cycloalkyl.

[0282] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Cy2 Optionally, R 6 , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 3~7 represents cycloalkyl.

[0283] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 9a and R 9b are each independently hydrogen and -S(=O)2-C 1~4 alkyl.

[0284] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 10a and R 10b are each independently hydrogen and C 1~4 alkyl.

[0285] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb When taken together to form a monocyclic heterocyclyl, they represent 1-pyrrolidinyl or 1-piperidinyl, each optionally substituted as defined in any of the other embodiments.

[0286] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xbWhen taken together to form a bicyclic heterocyclyl, they are

[0287] [ka] , each optionally substituted as defined in any of the other embodiments.

[0288] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xc and R xd When taken together to form a monocyclic heterocyclyl, they represent 1-pyrrolidinyl, 1-piperidinyl, or 1-piperazinyl, each optionally substituted as defined in any of the other embodiments.

[0289] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xc and R xd When taken together to form a bicyclic heterocyclyl, they are

[0290] [ka] , optionally substituted as defined in any of the other embodiments.

[0291] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 teeth,

[0292] [ka] , optionally substituted as defined in any of the other embodiments.

[0293] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 teeth,

[0294] [ka] and optionally on the nitrogen atom, -C(=O)-C 1~4 It is substituted with alkyl.

[0295] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 teeth,

[0296] [ka] On the nitrogen atom, -C(=O)-C 1~4 It is substituted with alkyl.

[0297] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 1represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a fused or spiro bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b and -OH.

[0298] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 1represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a fused or spiro bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen an R 6 and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of oxo and -NR 9a R 9b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of:

[0299] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 1 represents a monocyclic, C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has on one nitrogen an R 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9band -OH.

[0300] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: Het 1 represents a monocyclic, C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has on one nitrogen an R 6 and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of oxo and -NR 9a R 9b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of:

[0301] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 3 teeth,

[0302] [ka] , optionally substituted as defined in any of the other embodiments.

[0303] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 4 represents a C-linked pyrazinyl, optionally substituted as defined in any of the other embodiments.

[0304] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 6a teeth,

[0305] [ka] , optionally substituted as defined in any of the other embodiments.

[0306] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 6a teeth,

[0307] [ka] , optionally substituted as defined in any of the other embodiments.

[0308] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 6a teeth,

[0309] [ka] On the nitrogen atom, -C(=O)-C 1~4 It is substituted with alkyl.

[0310] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 6b teeth,

[0311] [ka] , optionally substituted as defined in any of the other embodiments.

[0312] In one embodiment, the present invention comprises compounds of formula (I) as mentioned in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 6b teeth,

[0313] [ka] On the nitrogen atom, -C(=O)-C 1~4 It is substituted with alkyl.

[0314] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Cy 2 is C 3~7 cycloalkyl,

[0315] [ka] Optionally, substituted as defined in any of the other embodiments.

[0316] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein 1~8 Alkyl is C 1~6 Limited to alkyl, especially C 1~8 Alkyl is C 1~4 Limited to alkyl.

[0317] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein -YR 3 is attached to the nitrogen atom of the ring.

[0318] In one embodiment, the present invention comprises compounds of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein: R 21 is hydrogen, -YR 3 is attached to the nitrogen atom of the ring.

[0319] In one embodiment, the invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (Ix):

[0320] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0321] In one embodiment, the present invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (I-x1):

[0322] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0323] In one embodiment, the present invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (I-x2):

[0324] [ka] is limited to compounds In the formula, Q is -CHR y -, -O-, -C(=O)-, or -NR q and the other variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0325] In one embodiment, the present invention relates in particular to compounds of formula (I-x2) as defined herein, and tautomers and stereoisomers thereof, wherein: Q is -CHR y -, -O-, -C(=O)-, or -NR q - represents R 1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-OC 1~4 Alkyl-NR 22a R 22b , -C(=O)-OC 1~4 Alkyl,

[0326] [ka] represents R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R19 together to form -(CH2)3-, -(CH2)4-, or -(CH2)5-, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 O, S, or N atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are each independently hydrogen, Het 3 ;C 3~6 Cycloalkyl, and C 1~6 alkyl, optionally 3~6 Cycloalkyl and C 1~6 Alkyl is -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OH, Halo, CF3, C 3~6 Cycloalkyl, Het 3 , and NR 11c R 11d C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 3~6 Cycloalkyl, and C 1~6 alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, cyano, and halo and OR 23 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb taken together with the N atom to which they are attached, a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, cyano, and halo and OR 23 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 23 is hydrogen or C optionally substituted with 1, 2, or 3 halo 1~4 represents alkyl, R 1b is hydrogen, F, Cl, or -OC 1~4 represents alkyl, R 2 But, Halo, C 3~6 Cycloalkyl, C 1~4 Alkyl, -OC 1~4 C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 21 is hydrogen or -Y a -R 3a represents, Y and Y a are each independently a covalent bond or

[0327] [ka] represents n1 is selected from 1 and 2; n2 is selected from 1, 2, 3, and 4; R y But hydrogen, -OH, C 1~4 Alkyl, -C 1~4 Alkyl-OH or -C 1~4 Alkyl-OC 1~4 represents alkyl, R q is hydrogen or C 1~4 represents alkyl, R 5 But hydrogen, C 1~4 Alkyl or C 3~6 represents cycloalkyl, R 3 , R 3a , and R 4 However, each independently, Het 1 ;Het 2 ;Cy 2 ;C 1~8 Alkyl; and -C(=O)-NR 10a R 10b , -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -NR xc R xd , -NR 8a R 8b , -CF3, cyano, halo, -OH, -OC 1~4 Alkyl, Het 1 , Het 2 , Ar 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~8 is selected from the group consisting of alkyl, R xc But Cy 1 , Het 5 ;-C 1~6 Alkyl-Cy 1 , -C 1~6 Alkyl-Het 3 , -C 1~6Alkyl-Het 4 , or -C 1~6 represents alkyl-phenyl, R xd But hydrogen; C 1~4 Alkyl; or halo, -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano 1~4 represents alkyl, or R xc and R xd taken together with the N atom to which they are attached, a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; or R xc and R xd taken together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl is optionally selected from halo, -OH, -OC 1~4 Alkyl, -(C=O)-C 1~4 Alkyl-S(=O)2-C 1~4 forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and cyano; R 8a and R 8bare each independently hydrogen; C 1~6 Alkyl;-(C=O)-C 1~4 Alkyl; and -OH, cyano, halo, -S(=O)2-C 1~4 Alkyl, -OC 1~4 Alkyl, -C(=O)-NR 10a R 10b , and -NR 10c -C(=O)-C 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~6 is selected from the group consisting of alkyl, Ar 1 Optionally, C 1~4 Alkyl, halo, -OC 1~4 Alkyl, -CF3, -OH, -S(=O)2-C 1~4 Alkyl, and -C(=O)-NR 10a R 10b represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen 6 , -C(=O)-Cy 1 , and -C(=O)-R 8 and the heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R9b and -OH; Het 2 represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl, which optionally has on one nitrogen atom R 6a may be substituted with R 6 and R 6a However, each independently, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ;-C(=O)-Het 6a ;-C(=O)-NR 10d R 10e ;-C(=O)-OC 1~4 Alkyl; -S(=O)2-C 1~4 alkyl; Optionally, Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-N(C 1~4 alkyl)2, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and Optionally, -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-N(C 1~4 alkyl)2, -NH-S(=O)2-C 1~4 Alkyl, and optionally OH, -OC 1~4 Alkyl, -C(=O)-NH-C1~4 Alkyl, and -NH-S(=O)2-C 1~4 C substituted with one substituent selected from the group consisting of alkyl 1~4 C substituted by 1 or 2 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; R 8 But hydrogen, -OC 1~6 Alkyl, C 1~6 Alkyl, or -OH, -OC 1~4 Alkyl, halo, cyano, -NR 11a R 11b , -S(=O)2-C 1~4 Alkyl, Het 3a , and Het 6a C substituted with 1, 2, or 3 substituents each independently selected from 1~6 represents alkyl, Het 3 , Het 3a , Het 5 , and Het 5a each independently represent a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be substituted to form S(=O) or S(=O)2; The heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or oxo, and the heterocyclyl is optionally substituted on one nitrogen atom by C 1~4 Alkyl or -(C=O)-C 1~4 is substituted with alkyl, Het 4 and Het 7each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 Alkyl or -(C=O)-OC 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b , -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-Cy 3 , -NH-C(=O)-NR 10a R 10b , -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a , Het 8b , Het 9 , and -C(=O)-NR 10a R 10b and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het 6a , Het 8 , and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl may optionally be substituted on one or two carbon atoms with a halo, —OH, oxo, —NH—C(═O)—C1~4 Alkyl, -NH-C(=O)-Cy 3 , -(C=O)-NR 10a R 10b , -OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, Cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, and -(C=O)-NR 10a R 10b and is substituted with a substituent selected from the group consisting of Het 6b and Het 8b each independently represent a bicyclic N-linked 6-11 membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains, on one or two carbon atoms, C 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C 1~4 Alkyl, -C(=O)-Cy 3 , -(C=O)-C 1~4 Alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 substituted with a substituent selected from the group consisting of alkyl; Het 9 represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, the aromatic ring optionally containing, on one nitrogen atom, C 1~4 alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C 1~4 and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl, Cy 1 optionally, -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl 3~6 represents cycloalkyl, Cy 2 But C 3~7 represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system; The C in question 3~7 The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1~4 Alkyl, -OC 1~4 Alkyl, cyano,

[0328] [ka] and Het 3a , Het 6a , Het 6b , and -NR 9a R 9b C substituted with 1 or 2 substituents each independently selected from the group consisting of 1~4 substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy 3 But C 3~7 represents cycloalkyl, 3~7 cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R 9a and R 9b are each independently hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)-C 1~4 Alkyl; -C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl;Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 3~6 cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, 1~4 is selected from the group consisting of alkyl, R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R17a , R 17b , R 20a , R 20b , R 22a , and R 22b are each independently hydrogen and C 1~4 is selected from the group consisting of alkyl, R 11c and R 11d are each independently hydrogen, C 1~6 Alkyl, and -C(=O)-C 1~4 is selected from the group consisting of alkyl, R 10a , R 10b , and R 10c are each independently hydrogen, C 1~4 Alkyl, and C 3~6 cycloalkyl; R 10d and R 10e However, each independently, C 1~4 Alkyl, -OC 1~4 Alkyl, and C 3~6 cycloalkyl; R 14 But, Het 5a ;Het 7 ;Het 8a ;-OC 1~4 Alkyl; -C(=O)NR 15a R 15b ;-OC 1~4 C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b , Halo, Cyano, -OH, Het 8a , and Cy 1 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 represents alkyl, R 16 -C(=O)-NR 17a R 17b , -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 , or Het8 represents], and pharmaceutically acceptable salts and solvates thereof.

[0329] In one embodiment, the present invention relates in particular to compounds of formula (I-x2) as defined herein, and tautomers and stereoisomers thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb C optionally substituted with 1, 2, or 3 -OH 1~6 is alkyl, R 1b represents F, R 2 represents methyl, R 21 represents hydrogen or methyl; Y is a covalent bond or

[0330] [ka] represents R 5 represents hydrogen, n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 and R 4 However, each independently, Het 1 , Cy 2 , and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~8 alkyl, R xc and R xdtaken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-R 8 and the heterocyclyl is optionally substituted on one carbon atom with oxo; R 8 But C 1~6 Alkyl, or -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl, and cyano 1~6 represents alkyl, Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Cy2 However, optionally one Het 6a C replaced with 3~7 represents cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0331] In one embodiment, the present invention relates in particular to compounds of formula (I-x2) as defined herein, and tautomers and stereoisomers thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb C optionally substituted with 1, 2, or 3 -OH 1~6 is alkyl, R 1b represents F, R 2 represents methyl, R 21 represents hydrogen or methyl; Y is a covalent bond or

[0332] [ka] represents R 5 represents hydrogen, n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 and R 4 However, each independently, Het 1 , Cy 2 , and -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~6 alkyl, R xc and Rxd taken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-R 8 and the heterocyclyl is optionally substituted on one carbon atom with oxo; R 8 But C 1~6 Alkyl, or -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl, and cyano 1~6 represents alkyl, Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Cy 2 However, optionally one Het 6a C replaced with 3~7 represents cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0333] In one embodiment, the present invention relates in particular to compounds of formula (I-x2) as defined herein, and tautomers and stereoisomers thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb C optionally substituted with 1, 2, or 3 -OH 1~6 is alkyl, R 1b represents F, R 2 represents methyl, R 21 represents hydrogen or methyl; Y represents a covalent bond; n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 But, -NR xc R xd , Het 1 , and Cy 2 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~8 alkyl, R xc and R xdtaken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4 forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has on one nitrogen a -C(=O)-R 8 and the heterocyclyl is optionally substituted on one carbon atom with oxo; R 8 But C 1~6 Alkyl, or -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl, and cyano 1~6 represents alkyl, Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Cy2 However, optionally one Het 6a C replaced with 3~7 represents cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0334] In one embodiment, the present invention relates in particular to compounds of formula (I-x2) as defined herein, and tautomers and stereoisomers thereof, wherein: Q is -CHR y - represents R 1a -C(=O)-NR xa R xb represents R xa and R xb But C 1~6 is alkyl, R 1b represents F, R 2 represents methyl, R 21 represents hydrogen, Y represents a covalent bond; n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 But, -NR xc R xd , Het 1 , and Cy 2 C substituted with one substituent selected from the group consisting of 1-8 alkyl, R xc and R xd taken together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, wherein the heterocyclyl optionally contains one, two, or three -(C=O)-C 1~4forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with alkyl; Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, or a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, which S atoms may be replaced to form S(=O) or S(=O)2, wherein the heterocyclyl optionally has a —C(=O)—R 8 is replaced by R 8 is C 1~6 Alkyl, or -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl, and cyano 1~6 represents alkyl, Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which S atom may be substituted to form S(═O) or S(═O)2, and the heterocyclyl optionally has on one nitrogen a —C(═O)—C 1~4 is substituted with alkyl, Cy 2 However, optionally one Het 6a C replaced with 3~7 represents cycloalkyl], and pharmaceutically acceptable salts and solvates thereof.

[0335] In one embodiment, the present invention relates in particular to compounds of formula (I-x2) as defined herein, and tautomers and stereoisomers thereof, wherein: Q is -CHR y- represents R 1a -C(=O)-NR xa R xb represents R xa and R xb But C 1~6 is alkyl, R 1b represents F, R 2 represents methyl, R 21 represents hydrogen, Y represents a covalent bond; n1 is 1, n2 is selected from 1 and 2; R y represents hydrogen, R 3 But one Het 1 C replaced with 1~4 alkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully or partially saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, where the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a —C(=O)—R 8 is replaced by R 8 But C 1~6 Alkyl, or -OH, -OC 1~4 C substituted with 1, 2, or 3 substituents each independently selected from alkyl, and cyano 1~6 represents alkyl], and pharmaceutically acceptable salts and solvates thereof.

[0336] In one embodiment, the invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (Iy):

[0337] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0338] In one embodiment, the present invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (I-y1):

[0339] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0340] In one embodiment, the invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (Iz):

[0341] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0342] In one embodiment, the present invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (I-z1):

[0343] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0344] In one embodiment, the invention comprises a compound of formula (I) as referred to in any of the other embodiments, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) has the formula (Iq):

[0345] [ka] is limited to compounds wherein the variables are as defined for the compounds of formula (I) or any subgroup thereof referred to in any of the other embodiments.

[0346] In one embodiment, the present invention relates to a subgroup of formula (I) defined in the general reaction scheme:

[0347] In one embodiment, the compound of formula (I) is an exemplified compound: its tautomeric and stereoisomeric forms, and any of the free bases, any pharmaceutically acceptable salts, and solvates thereof.

[0348] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 43, 51, 51a, 59, 60, 115, 117a, 125, 140, 157, 159, 169a, and 207.

[0349] In one embodiment, the compound of formula (I) is selected from compounds 43, 51, 51a, 59, 60, 115, 117a, 125, 140, 157, 159, 169a, and 207, its tautomers and stereoisomers, and the free base; It is selected from the group consisting of any pharmaceutically acceptable salts and solvates thereof.

[0350] In certain embodiments, the solvate is a hydrate. In certain embodiments, the pharmaceutically acceptable salt is an HCl salt. In certain embodiments, the compound is an HCl salt hydrate.

[0351] In one embodiment, the compound of formula (I) is

[0352] [ka] or a pharmaceutically acceptable salt or solvate thereof; specifically, an HCl salt, solvate; more specifically, an HCl salt, hydrate; more specifically, a mono-HCl salt, hydrate; even more specifically, a mono-HCl salt, trihydrate.

[0353] According to certain embodiments, the menin-MLL inhibitor is selected from the group consisting of compounds 43, 50, 51, 51a, 59, 60, 61, 62, 63, 64, 65, 82, 83, 85, 86, 87, 91, 92, 98, 101, 104, 106, 108, 114, 117a, 120, 121, 125, 126, 135, 156, 169, 169a, 169b, 188a, 188b, 190a, 190b, 191a, 191b, 194, 196, 207, 213a, 213b, 283, 286, 287, 288, 289, 290 , 291, 292a, 292b, 293a, 293b, 294a, 294b, 295, 296, 378, 381, 382, ​​383, 384, 387, 388, 392, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 442, 448, 485, 498, 526a, 526b, 531; tautomers and stereoisomers thereof, and the free base, It is selected from the group consisting of any pharmaceutically acceptable salts and solvates thereof.

[0354] According to certain embodiments, the menin-MLL inhibitors are compounds 43, 51, 51a, 59, 60, 117a, 125, 169a, 207; tautomers and stereoisomers thereof, and the free base, It is selected from the group consisting of any pharmaceutically acceptable salts and solvates thereof.

[0355] According to certain embodiments, the menin-MLL inhibitor is compound 51 or a solvate thereof. According to certain embodiments, the menin-MLL inhibitor is compound 51 or a hydrate thereof. According to certain embodiments, the menin-MLL inhibitor is compound 51a.

[0356] In some embodiments, a pharmaceutical composition is provided that includes a pharmaceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of a combination as described in any of the other embodiments.

[0357] In some embodiments, a combination therapy is provided comprising a menin-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent.

[0358] According to an embodiment, the menin-MLL inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0359] In certain embodiments, menin-MLL inhibitors may have improved metabolic stability properties.

[0360] In certain embodiments, menin-MLL inhibitors may have an extended in vivo half-life (T1 / 2).

[0361] In certain embodiments, menin-MLL inhibitors may have improved oral bioavailability.

[0362] In certain embodiments, menin-MLL inhibitors may reduce tumor growth, for example, tumors harboring MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations.

[0363] In certain embodiments, menin-MLL inhibitors may have improved PD properties in vivo over an extended period of time, for example, inhibition of target gene expression such as MEIS1 and upregulation of differentiation markers over a period of at least 16 hours.

[0364] In certain embodiments, menin-MLL inhibitors may have an improved safety profile (e.g., reduced hERG inhibition, improved cardiovascular safety).

[0365] In certain embodiments, the menin-MLL inhibitor may be suitable for QD dosing (once daily).

[0366] According to embodiments, the BCL-2 inhibitor is selected from obatoclax, HA14-1, navitoclax, ABT-737, TW-37, AT101, sabutoclax, gambogic acid and venetoclax, or a pharmaceutically acceptable salt or solvate thereof.

[0367] According to certain embodiments, the BCL-2 inhibitor is venetoclax, or a pharmaceutically acceptable salt or solvate thereof.

[0368] According to embodiments, the at least one other antineoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory antineoplastic agent, or a DHODH inhibitor.

[0369] According to embodiments, the at least one other anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, or an isocitrate dehydrogenase (IDH) inhibitor.

[0370] According to embodiments, hypomethylating agents include, but are not limited to, azacitidine, decitabine, or pharmaceutically acceptable salts or solvates thereof.

[0371] According to embodiments, DNA intercalating agents include, but are not limited to, anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin).

[0372] According to an embodiment, the DNA intercalating agent is daunorubicin.

[0373] According to an embodiment, the DNA intercalating agent is doxorubicin.

[0374] According to an embodiment, the DNA intercalating agent is idarubicin.

[0375] According to embodiments, pyrimidine analogs include, but are not limited to, cytarabine (ARA-C).

[0376] According to an embodiment, the purine analog is fludarabine.

[0377] According to embodiments, the kinase inhibitor is a FLT-3 inhibitor, a BTK inhibitor, an ABL inhibitor, an Aurora inhibitor, or a multikinase inhibitor consisting of two or more of these kinase inhibitors.

[0378] According to embodiments, the kinase inhibitor is a multikinase inhibitor consisting of an FLT-3 inhibitor, an ABL inhibitor, and an Aurora inhibitor, including, but not limited to, KW-2449.

[0379] According to an embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.

[0380] According to an embodiment, the tyrosine kinase inhibitor is an FLT-3 inhibitor or a BTK inhibitor.

[0381] According to embodiments, FLT3 inhibitors include, but are not limited to, sorafenib, sunitinib, midostaurin (PKC412), lestaurtinib (CEP-701), tanzutinib (MLN518), quizartinib (AC220), gilteritinib (ASP2215), and KW-2449.

[0382] According to embodiments, BTK inhibitors include, but are not limited to, ibrutinib.

[0383] According to embodiments, CD20 inhibitors include, but are not limited to, anti-CD20 antibodies (e.g., obinutuzumab (GA101)).

[0384] According to embodiments, IDH inhibitors include, but are not limited to, ivosidenib and enazidenib.

[0385] According to embodiments, isocitrate dehydrogenase-1 inhibitors include, but are not limited to, ivosidenib.

[0386] According to embodiments, isocitrate dehydrogenase-2 inhibitors include but are not limited to enazidenib.

[0387] According to embodiments, immunomodulatory anti-neoplastic agents include, but are not limited to, PD-1 inhibitors (e.g., nivolumab, atezolizumab, and pembrolizumab), thalidomide, lenalidomide, pomalidomide, sterile Mycobacterium bovis (BCG), and levamisole.

[0388] According to embodiments, PD-1 inhibitors include, but are not limited to, nivolumab, atezolizumab, and pembrolizumab.

[0389] According to embodiments, the DHODH inhibitor may be selected from the group consisting of, but not limited to, the formula (Z):

[0390] [ka] A compound having the structure (Z) X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; C substituted with OH or OCH 1~6 Alkyl; C 2~6 Alkenyl; C 1~6 Haloalkyl; C substituted with OH or OCH 1~6 Haloalkyl;C 2~6 Haloalkenyl; N(CH3)2, C 3~6 Cycloalkyl; C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl, R 2 teeth,

[0391] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 cycloalkyl; R b is C 1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~6 Haloalkyl and OC 3~6 C substituted with a member selected from the group consisting of cycloalkyl 1~6 is alkyl, R 3 is selected from the group consisting of H, halo, CH3 and OCH3; R 4 teeth, C 1~6 Alkyl; C substituted with 1 or 2 OCH 1~6 Alkyl; C 3~6 Cycloalkyl; C substituted with CH3 or OCH3 3~6Cycloalkyl;CH2-C 3~6 cycloalkyl; and

[0392] [ka] is selected from the group consisting of During the ceremony, Each R c are independently H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; NO2; OH; O-CH2CH2OH; and OC 1~6 is selected from the group consisting of alkyl, R d is H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; and C substituted with a member selected from the group consisting of OH and OCH 1~6 haloalkyl; n is 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; or,

[0393] [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, or stereoisomer thereof.

[0394] According to embodiments, the DHODH inhibitor may be selected from the group consisting of, but not limited to, the formula (Z):

[0395] [ka] A compound having the structure (Z) X is CH or N; Y is CH or N; R 1 is C 1~6 Alkyl; C substituted with OH or OCH 1~6 Alkyl; C 2~6 Alkenyl; C 1~6 Haloalkyl; C substituted with OH or OCH 1~6 Haloalkyl;C 2~6 Haloalkenyl; N(CH3)2, C 3~6 Cycloalkyl; C 1~6 Alkyl-substituted C 3~6 cycloalkyl; and phenyl, R 2 teeth,

[0396] [ka] where: R a is C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 cycloalkyl; R b is C 1~6 Alkyl, or OH, halo, CN, OC 1~6 Alkyl, OC 1~6 Haloalkyl and OC 3~6 C substituted with a member selected from the group consisting of cycloalkyl 1~6 is alkyl, R 3is selected from the group consisting of H, halo, CH3 and OCH3; R 4 teeth, C 1~6 Alkyl; C substituted with 1 or 2 OCH 1~6 Alkyl; C 3~6 Cycloalkyl; C substituted with CH3 or OCH3 3~6 Cycloalkyl;CH2-C 3~6 cycloalkyl; and

[0397] [ka] is selected from the group consisting of During the ceremony, Each R c are independently H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; NO2; OH; O-CH2CH2OH; and OC 1~6 is selected from the group consisting of alkyl, R d is H; halo; C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~6 Haloalkyl; CN; and OC 1~6 is selected from the group consisting of alkyl, R g is H;C 1~6 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1~6 Alkyl; C 1~6 haloalkyl; and C substituted with a member selected from the group consisting of OH and OCH 1~6 haloalkyl; n is 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0398] In the context of formula (Z), the following definitions apply: The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to alkyl, except that they contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.). The term alkenyl also includes alkenyl groups that include oxygen, nitrogen, sulfur, or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight-chain or branched-chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C for straight chain). 2~6 , C for branched chain 3~6 ).

[0399] The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. 1~6 The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. 1~4 The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (CF(CF)), as well as groups deemed equivalent to any one of the foregoing examples given the ordinary skill in the art and the teachings provided herein.

[0400] The term "haloalkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double bond and, optionally, replacing hydrogens with halogens, having 1 to 6 carbon atoms in the chain.

[0401] The term "aryl" refers to a monocyclic aromatic carbocycle (a ring structure in which the ring atoms are all carbon) having six atoms per ring. (The carbon atoms in an aryl group are sp2 hybridized.)

[0402] The term "heteroaryl" refers to a monocyclic or fused bicyclic heterocycle (a ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 9 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities in the form of appropriately bonded moieties:

[0403] [ka]

[0404] Those skilled in the art will recognize that the above listed or exemplified species are not all inclusive and that additional species within the scope of these defined terms may also be selected.

[0405] The term "variable point of attachment" means that a group may be attached at two or more alternative positions within a structure. The bond always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bond, as shown in the diagram below, are represented by a single diagram.

[0406] [ka]

[0407] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein X is CH.

[0408] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein X is N.

[0409] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is CH.

[0410] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is N.

[0411] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is C 1~4 Alkyl; C substituted with OH or OCH 1~4 Alkyl; C 2~4 Alkenyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl;C 2~4 Haloalkenyl; N(CH3)2, cyclopropyl; C 1~4 cyclopropyl substituted with alkyl; or phenyl.

[0412] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 are CH3, CH2CH3,

[0413] [ka]

[0414] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 teeth,

[0415] [ka] is.

[0416] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 2 teeth,

[0417] [ka] and In the formula, R b OH, halo, CN, OC 1~4 Alkyl, OC 1~4 Haloalkyl or OC 3~6 Cycloalkyl-substituted C 1~4 is alkyl, R a But C 1~4 Alkyl, C 1~4 Haloalkyl, or C 3~6 It is cycloalkyl.

[0418] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 2 teeth,

[0419] [ka] is.

[0420] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is H.

[0421] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is F.

[0422] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is CH3.

[0423] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is OCH3.

[0424] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is as follows:

[0425] [ka]

[0426] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0427] [ka] where: Each R c are independently H; halo, C 1~4 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1- Alkyl; C 1~4 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~4 haloalkyl; and NO2, R d H; Halo, C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl; or OC 1~4 Alkyl; CN; and OC 1~6 is selected from the group consisting of alkyl, n is 1 or 2.

[0428] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0429] [ka] and Each R c are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl, NO2, O-CH2CH2OH, and OC 1~4 is selected from the group consisting of alkyl, R d H, halo, C 1~4 Alkyl, CN, and OC 1~6 is selected from the group consisting of alkyl, n is 1 or 2.

[0430] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is as follows:

[0431] [ka]

[0432] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0433] [ka] is.

[0434] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0435] [ka] and During the ceremony, Each R c are independently H; halo; C 1~4 alkyl; C substituted with a member selected from the group consisting of OH, OCH3, SCH3, and OCF3; 1-Alkyl; C 1~4 haloalkyl; C substituted with a member selected from the group consisting of OH and OCH 1~4 haloalkyl; R d Ha, halo;C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl; or OC 1~4 Alkyl; CN; and OC 1~6 alkyl.

[0436] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0437] [ka] where: Each R c are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 selected from the group consisting of alkyl, and OH; R d Ha, Halo, C 1~4 Alkyl and OC 1~4 is selected from the group consisting of alkyl, n is 1 or 2.

[0438] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is as follows:

[0439] [ka]

[0440] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4teeth,

[0441] [ka] is.

[0442] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0443] [ka] where: R c is H; halo; C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 Haloalkyl; C substituted with OH or OCH 1~4 Haloalkyl; or OC 1~4 is alkyl, R d Ha, halo;C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 haloalkyl; or C substituted with OH or OCH 1~4 is haloalkyl, R g is H;C 1~4 Alkyl; C substituted with OH, OCH3, SCH3, or OCF3 1~4 Alkyl; C 1~4 haloalkyl; or C substituted with OH or OCH 1~4 It is haloalkyl.

[0444] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein: R 4 teeth,

[0445] [ka] where: R c is H or halo, R d is C 1~4 is alkyl, R g is H.

[0446] In one embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 teeth,

[0447] [ka] is.

[0448] In one embodiment of the present invention, the DHODH inhibitor is 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-phenylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-oxo-4-(prop-1-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropylphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropylphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropylphthalazin-1(2H)-one; 4-ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)phthalazin-1(2H)-one; 4-ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(2-hydroxypropan-2-yl)isoquinolin-1(2H)-one; 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-en-2-yl)-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-methyl-6-(o-tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o-tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; (S)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridin-5(6H)-one; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylthiazol-5-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methoxyphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; racemic-4-(sec-butyl)-2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoroisoquinolin-1(2H)-one; 2-(3-chloro-6-methoxypyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylphthalazin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (S * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (R * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-4-methylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-(2-hydroxyethoxy)phenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-3,5-dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-3,5-dimethylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-methyl-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxyphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methoxypyridin-4-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2-ethylphenyl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxypyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-(methyl-d3)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylpyridin-5-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxyphenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-6-methoxypyridin-2-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylpyrazin-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(2-fluoro-5-methylphenyl)-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro4-isopropyl-2-(4-methylpyridazin-3-yl)isoquinolin-1(2H)-one; (S)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxypyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclohexyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclopentyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-4-methoxypyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S,2R)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(cyclopropylmethyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(1-methoxybutan-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylpyridin-2-yl)isoquinolin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((cis)-3-methoxycyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R * ,2R *)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S * ,2S * )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(pentan-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R * ,2R * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S * ,2S * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R * ,2S * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S * ,2R * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((cis)-3-methoxycyclohexyl)isoquinolin-1(2H)-one; 2-(bicyclo[2.2.1]heptan-1-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2-methoxyphenyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylisothiazol-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5-methylisothiazol-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2-(trifluoromethyl)phenyl)-1,6-naphthyridin-5(6H)-one; 2-(3,6-dimethylpyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylpyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-5-methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(2-(difluoromethyl)phenyl)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-3-methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; and 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o-D3-tolyl)-1,6-naphthyridin-5(6H)-one; and optionally one or more of a pharmaceutically acceptable salt, isotope, N-oxide, solvate, and stereoisomer thereof.

[0449] In one embodiment of the present invention, the DHODH inhibitor is 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-phenylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 2-(2,6-dichlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-4-cyclopropyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 2-(6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-oxo-4-(prop-1-en-2-yl)isoquinolin-2(1H)-yl)benzonitrile; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropylphthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-isopropylphthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-isopropylphthalazin-1(2H)-one; 4-ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)phthalazin-1(2H)-one; 4-ethyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)phthalazin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-4-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(2-hydroxypropan-2-yl)isoquinolin-1(2H)-one; 4-(Dimethylamino)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-methoxy-4-(prop-1-en-2-yl)phthalazin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-en-2-yl)-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-methyl-6-(o-tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o-tolyl)pyrido[2,3-d]pyridazin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-(prop-1-en-2-yl)-1,6-naphthyridin-5(6H)-one; 6-(2-chloro-6-fluorophenyl)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; (S)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridin-5(6H)-one; (R)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(o-tolyl)-8-(1,1,1-trifluoropropan-2-yl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylthiazol-5-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methoxyphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; racemic-4-(sec-butyl)-2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoroisoquinolin-1(2H)-one; 2-(3-chloro-6-methoxypyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylphthalazin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (S *)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; (R * )-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)phthalazin-1(2H)-one; 2-(2-chloro-6-fluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(1-methylcyclopropyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-4-methylpyridin-3-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(5-chloro-3-methyl-1H-pyrazol-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxy-5-methylpyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-(2-hydroxyethoxy)phenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxy-3,5-dimethylpyridin-4-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2,5-difluorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-6-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methylphenyl)-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(4-fluoro-2-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenyl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-3,5-dimethylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-methyl-4-(prop-1-en-2-yl)-2-(o-tolyl)isoquinolin-1(2H)-one; 2-(2-chloro-6-fluoro-3-methoxyphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-methoxyphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methoxypyridin-4-yl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-2-methylphenyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; 2-(2,5-dimethylphenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(2-ethylphenyl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxypyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(5-fluoro-2-methoxypyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-(methyl-d3)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylpyridin-5-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxyphenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(3-fluoro-6-methoxypyridin-2-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylpyrazin-2-yl)isoquinolin-1(2H)-one; 2-(2-chloro-5-methylpyridin-3-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-6-(2-fluoro-5-methylphenyl)-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro4-isopropyl-2-(4-methylpyridazin-3-yl)isoquinolin-1(2H)-one; (S)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; (R)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(o-tolyl)-4-(1,1,1-trifluoropropan-2-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(2-(difluoromethyl)phenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-2-methoxypyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclohexyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-6-methylpyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-Cyclopentyl-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(3-chloro-4-methoxypyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R,2S)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(1,3-dimethoxypropan-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4 triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S,2R)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 2-(cyclopropylmethyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(1-methoxybutan-2-yl)isoquinolin-1(2H)-one; 2-(2-chlorophenyl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylpyridin-2-yl)isoquinolin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((cis)-3-methoxycyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R * ,2R * )-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S * ,2S *)-2-methylcyclohexyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(pentan-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R * ,2R * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S * ,2S * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1R * ,2S * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((1S * ,2R * )-2-methylcyclopentyl)isoquinolin-1(2H)-one; racemic-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-((cis)-3-methoxycyclohexyl)isoquinolin-1(2H)-one; 2-(bicyclo[2.2.1]heptan-1-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methoxy-3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2-methoxyphenyl)-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylisothiazol-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5-methylisothiazol-4-yl)isoquinolin-1(2H)-one; 2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-6-(2-(trifluoromethyl)phenyl)-1,6-naphthyridin-5(6H)-one; 2-(3,6-dimethylpyridin-2-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 2-(2,5-dimethylpyridin-4-yl)-6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(4-methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(3-methylpyridin-4-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(2-methylpyridin-3-yl)isoquinolin-1(2H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-5-methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; 6-(2-(difluoromethyl)phenyl)-2-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8-isopropyl-1,6-naphthyridin-5(6H)-one; 6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-hydroxy-3-methylpyridin-4-yl)-4-isopropylisoquinolin-1(2H)-one; and 2-(4-ethyl-3...

Claims

1. It is a combination, a therapeutically effective amount of a menin-mixed lineage leukemia 1 (MLL) inhibitor of formula (I), or a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof; a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor; optionally a therapeutically effective amount of at least one other anti-neoplastic agent; The menin-MLL inhibitor of formula (I) has the structure: 【Chemistry 1】 wherein Q is -CHR ｙ -, -O-, -C(=O)-, -NR ｑ - or -CR ｙ =, and the dotted line indicates that Q is -CR ｙ is an optional additional bond to form a double bond when = is represented, R １ａ is hydrogen, cyano, halo, Het, -C(=O)-NR ｘａ R ｘｂ , -S(=O) ２ -R １８ , -C(=O)-O-C １～４ Alkyl-NR ２２ａ R ２２ｂ , -C(=O)-OC １～４ Alkyl, 【Chemistry 2】 represents R １８ But C １～６ Alkyl or C ３～６ represents cycloalkyl, R １９ is hydrogen or C １～６ represents alkyl, or R １８ and R １９ together, -(CH ２ ) ３ -, -(CH ２ ) ４ -, or -(CH ２ ) ５ - forms, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 O, S, or N atoms and, optionally, a carbonyl moiety, said monocyclic 5- or 6-membered aromatic ring optionally being selected from the group consisting of C １～４ Alkyl, C ３～６ substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R ｘａ and R ｘｂ are each independently hydrogen, Het ３ , C ３～６ Cycloalkyl, and C １～６ alkyl, optionally ３～６ Cycloalkyl and C １～６ The alkyl is —OH, —OC １～４ Alkyl, —C １～４ Alkyl-OH, Halo, CF ３ , C ３～６ Cycloalkyl, Het ３ , and N.R. １１ｃ R １１ｄ C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of ３～６ Cycloalkyl, and C １～６ alkyl; or R ｘａ and R ｘｂ together with the N atom to which they are attached, one N atom and optionally one additional heteroatom selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one additional heteroatom, which may form: １～４ Alkyl, halo, —OH, —O—C １～４ Alkyl, cyano, and halo and OR ２３ C substituted with 1, 2, or 3 substituents selected from the group consisting of １～４ forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R ｘａ and R ｘｂ taken together with the N atom to which they are attached, form one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one or two additional heteroatoms, which may form: １～４ Alkyl, halo, —OH, —O—C １～４ Alkyl, cyano, and halo and OR ２３ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of １～４ forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R ２３ is hydrogen or C optionally substituted with 1, 2, or 3 halo １～４ represents alkyl, R １ｂ is hydrogen, F, Cl, or —O—C １～４ represents alkyl, R ２ But, Halo, C ３～６ Cycloalkyl, C １～４ Alkyl, —O—C １～４ C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents １～４ represents alkyl, R ２１ is hydrogen or -Y ａ -R ３ａ where R ２１ Ga-Y ａ -R ３ａ When representing -Y ａ -R ３ａ and -Y-R ３ is attached to a nitrogen atom of the ring, Y and Y ａ are each independently a covalent bond or 【Transformation 3】 represents n1 is selected from 1 and 2; n2 is selected from 1, 2, 3, and 4; R ｙ is hydrogen, -OH, C １～４ Alkyl, —C １～４ Alkyl-OH, or -C １～４ Alkyl-O-C １～４ represents alkyl, R ｑ is hydrogen or C １～４ represents alkyl, R ５ But hydrogen, C １～４ Alkyl, or C ３～６ represents cycloalkyl, R ３ , R ３ａ , and R ４ Each independently, Het １ ;Het ２ ; Cy ２ ; C １～８ alkyl; and —C(═O)—NR １０ａ R １０ｂ , -C(=O)-Het ６ａ , -C(=O)-Het ６ｂ , -NR １０ｃ -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —NR ｘｃ R ｘｄ , -NR ８ａ R ８ｂ , -CF ３ , cyano, halo, —OH, —O—C １～４ Alkyl, Het １ , Het ２ , Ar １ , and Cy ２ C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of １～８ is selected from the group consisting of alkyl, R ｘｃ But Cy １ , Het ５ , -C １～６ Alkyl-Cy １ , -C １～６ Alkyl-Het ３ , -C １～６ Alkyl-Het ４ , Or -C １～６ represents alkyl-phenyl, R ｘｄ is hydrogen; C １～４ Alkyl; or halo, —OH, —O—C １～４ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano １～４ represents alkyl, or R ｘｃ and R ｘｄ together with the N atom to which they are attached, one N atom and optionally one additional heteroatom selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one additional heteroatom, which may form: １～４ Alkyl, —(C═O)—C １～４ Alkyl, —S(═O) ２ -C １～４ forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano; or R ｘｃ and R ｘｄ taken together with the N atom to which they are attached, form one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and 1 or 2 additional heteroatoms, which may form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl, wherein the heterocyclyl is optionally halo, —OH, —O—C １～４ Alkyl, —(C═O)—C １～４ Alkyl-S(=O) ２ -C １～４ forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano; R ８ａ and R ８ｂ are each independently hydrogen; C １～６ Alkyl; -(C=O)-C １～４ Alkyl; and -OH, cyano, halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ Alkyl, —C(═O)—NR １０ａ R １０ｂ , and -NR １０ｃ -C(=O)-C １～４ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～６ is selected from the group consisting of alkyl, Ar １ Optionally, C １～４ Alkyl, halo, —O—C １～４ Alkyl, —CF ３ , -OH, -S (=O) ２ -C １～４ Alkyl, and —C(═O)—NR １０ａ R １０ｂ represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het １ is 1, 2, or 3 heteroatoms each independently selected from O, S, and N, and the S atom is substituted to form S(=O) or S(=O) ２ or 1, 2, or 3 heteroatoms each independently selected from O, S, and N, wherein the S atom is substituted to form S(═O) or S(═O) ２ and R represents a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2 or 3 heteroatoms, which may optionally form, on one nitrogen, R ６ , -C(=O)-Cy １ and —C(═O)—R ８ and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R ６ , Het ６ａ , Het ６ｂ , C １～４ Alkyl, oxo, -NR ９ａ R ９ｂ and -OH; Het ２ represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl, which optionally has on one nitrogen atom R ６ａ may be substituted with R ６ and R ６ａ Each independently, Het ３ ;Het ４ ;-C(=O)-NH-Cy １ ;-C(=O)-NH-R ８ ;-C(=O)-Het ６ａ ;-C(=O)-NR １０ｄ R １０ｅ ; -C(=O)-O-C １～４ Alkyl; -S(=O) ２ -C １～４ Alkyl; Optionally, Het ３ , Het ４ , Het ６ａ , Het ６ｂ , Cy １ , -CN, -OH, -OC １～４ Alkyl, —C(═O)—NH—C １～４ Alkyl, —C(═O)—N(C １～４ alkyl) ２ , -C(=O)-NH-C １～４ Alkyl-C ３～６ Cycloalkyl, —C(═O)—OH, —NR １１ａ R １１ｂ , and —NH—S(═O) ２ -C １～４ C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl １～６ alkyl; and Optionally, —CN, —OH, —O—C １～４ Alkyl, —C(═O)—NH—C １～４ Alkyl, —C(═O)—N(C １～４ alkyl) ２ , -NH-S (=O) ２ -C １～４ Alkyl, and optionally OH, —O—C １～４ Alkyl, —C(═O)—NH—C １～４ Alkyl, and —NH—S(═O) ２ -C １～４ C substituted with one substituent selected from the group consisting of alkyl １～４ C substituted by 1 or 2 substituents each independently selected from the group consisting of alkyl ３～６ cycloalkyl; R ８ is hydrogen, —O—C １～６ Alkyl, C １～６ Alkyl; or —OH, —O—C １～４ Alkyl, halo, cyano, -NR １１ａ R １１ｂ , -S(=O) ２ -C １～４ Alkyl, Het ３ａ , and Het ６ａ C substituted with 1, 2, or 3 substituents each independently selected from １～６ represents alkyl, Het ３ , Het ３ａ , Het ５ , and Het ５ａ are each independently 1, 2, or 3 heteroatoms each independently selected from O, S, and N, and the S atoms are substituted to form S(=O) or S(=O) ２ or 1, 2, or 3 heteroatoms each independently selected from O, S, and N, wherein the S atom is substituted to form S(═O) or S(═O) ２ represents a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2 or 3 heteroatoms, which may form The heterocyclyl may optionally be, on one carbon atom, C １～４ Alkyl, halo, —OH, —NR １１ａ R １１ｂ or oxo, and said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ Alkyl or -(C=O)-C １～４ is substituted with alkyl, Het ４ and Het ７ each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, said aromatic ring optionally having, on one nitrogen atom, C １～４ Alkyl or -(C=O)-O-C １～４ alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C １～４ Alkyl, —O—C １～４ Alkyl, —NR １１ａ R １１ｂ , C １～４ Alkyl-NR １１ａ R １１ｂ , -NH-C(=O)-C １～４ Alkyl, cyano, —COOH, —NH—C(═O)—O—C １～４ Alkyl, —NH—C(═O)—Cy ３ , -NH-C(=O)-NR １０ａ R １０ｂ , -(C=O)-OC １～４ Alkyl, —NH—S(═O) ２ -C １～４ Alkyl, Het ８ａ , -C １～４ Alkyl-Het ８ａ , Het ８ｂ , Het ９ and —C(═O)—NR １０ａ R １０ｂ and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het ６ａ , Het ８ , and Het ８ａ each independently one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one or two additional heteroatoms, which may form, on one or two carbon atoms, a halo, —OH, oxo, —NH—C(═O)—C １～４ Alkyl, —NH—C(═O)—Cy ３ , -(C=O)-NR １０ａ R １０ｂ , —O—C ３～６ Cycloalkyl, —S(═O) ２ -C １～４ Alkyl, cyano, C １～４ Alkyl, —C １～４ Alkyl-OH, —O—C １～４ Alkyl, —O—(C═O)—NR １０ａ R １０ｂ and —O—(C═O)—C １～４ and said heterocyclyl is optionally substituted on one nitrogen with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, and —(C═O)—NR １０ａ R １０ｂ and is substituted with a substituent selected from the group consisting of Het ６ｂ and Het ８ｂ each independently one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one or two additional heteroatoms, which may form, on one or two carbon atoms, １～４ Alkyl, —OH, oxo, —(C═O)—NR １０ａ R １０ｂ , -NH-C(=O)-C １～４ Alkyl, —NH—C(═O)—Cy ３ , and -O-C １～４ and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C １～４ Alkyl, —C(═O)—Cy ３ , -(C=O)-C １～４ Alkyl-OH, —C(═O)—C １～４ Alkyl-O-C １～４ Alkyl, —C(═O)—C １～４ Alkyl-NR １１ａ R １１ｂ , and C １～４ substituted with a substituent selected from the group consisting of alkyl; Het ９ represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, said aromatic ring optionally having, on one nitrogen atom, C １～４ alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C １～４ substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl; Cy １ optionally, —OH, —NH—C(═O)—C １～４ Alkyl, C １～４ Alkyl, —NH—S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, and —O—C １～４ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl ３～６ represents cycloalkyl, Cy ２ But C ３～７ represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system, Said C ３～７ The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R ６ , -C(=O)-Het ６ａ , Het ６ａ , Het ６ｂ , -NR ９ａ R ９ｂ , -OH, C １～４ Alkyl, —O—C １～４ Alkyl, cyano, 【Chemistry 4】 and Het ３ａ , Het ６ａ , Het ６ｂ , and -NR ９ａ R ９ｂ C substituted with 1 or 2 substituents each independently selected from the group consisting of １～４ substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy ３ But C ３～７ represents cycloalkyl, ３～７ cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R ９ａ and R ９ｂ are each independently hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; —C(═O)—C １～４ Alkyl; —C(═O)—C ３～６ Cycloalkyl; -S(=O) ２ -C １～４ Alkyl; Het ５ ;Het ７ ;-C １～４ Alkyl-R １６ -C(=O)-C １～４ Alkyl-Het ３ａ -C(=O)-R １４ ; Halo, —OH, —O—C １～４ Alkyl, —NR １１ａ R １１ｂ C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, ３～６ cycloalkyl; and Halo, —OH, —O—C １～４ Alkyl, —NR １１ａ R １１ｂ C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, １～４ is selected from the group consisting of alkyl, R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １５ａ , R １５ｂ , R １７ａ , R １７ｂ , R ２０ａ , R ２０ｂ , R ２２ａ , and R ２２ｂ are each independently hydrogen and C １～４ is selected from the group consisting of alkyl, R １１ｃ and R １１ｄ are each independently hydrogen, C １～６ Alkyl, and —C(═O)—C １～４ is selected from the group consisting of alkyl, R １０ａ , R １０ｂ , and R １０ｃ are each independently hydrogen, C １～４ Alkyl, and C ３～６ cycloalkyl; R １０ｄ and R １０ｅ However, each independently, C １～４ Alkyl, —O—C １～４ Alkyl, and C ３～６ cycloalkyl; R １４ But, Het ５ａ ;Het ７ ;Het ８ａ ;-O-C １～４ Alkyl; —C(═O)NR １５ａ R １５ｂ ;-O-C １～４ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo ３～６ cycloalkyl; or —O—C １～４ Alkyl, —NR １３ａ R １３ｂ , halo, cyano, -OH, Het ８ａ , and Cy １ C substituted with 1, 2, or 3 substituents selected from the group consisting of １～４ represents alkyl, R １６ is -C(=O)-NR １７ａ R １７ｂ , -S(=O) ２ -C １～４ Alkyl, Het ５ , Het ７ , or Het ８ Represents a combination.

2. 2. The combination of claim 1, wherein the BCL-2 inhibitor is selected from obatoclax, HA14-1, navitoclax, ABT-737, TW-37, AT101, sabutoclax, gambogic acid, venetoclax, and pharmaceutically acceptable salts or solvates thereof.

3. 3. The combination of claim 2, wherein the BCL-2 inhibitor is venetoclax, or a pharmaceutically acceptable salt or solvate thereof.

4. 4. The combination of any one of claims 1 to 3, wherein the at least one other antineoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory antineoplastic agent or a dihydroorotate dehydrogenase inhibitor.

5. The combination of claim 4, wherein the at least one other anti-neoplastic agent is a hypomethylating agent.

6. 6. The combination of claim 5, wherein the hypomethylating agent is azacitidine, or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition comprising a combination according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. A combination according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for use as a medicament.

9. A combination according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for use in the prevention or treatment, in particular in the treatment, of hematopoietic disorders.

10. 10. The combination or pharmaceutical composition for use according to claim 9, wherein the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia or MLL-rearranged leukemia.

11. 10. The combination or pharmaceutical composition for use according to claim 9, wherein the hematopoietic disorder is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

12. 1. A method for treating a subject diagnosed with a hematopoietic disorder, comprising administering to said subject: a therapeutically effective amount of a menin-mixed lineage leukemia 1 (MLL) inhibitor of formula (I), or a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof; a therapeutically effective amount of a BCL-2 inhibitor; optionally, a therapeutically effective amount of at least one other anti-neoplastic agent; The menin-MLL inhibitor of formula (I) has the structure: 【Transformation 5】 wherein Q is -CHR ｙ -, -O-, -C(=O)-, -NR ｑ - or -CR ｙ =, and the dotted line indicates that Q is -CR ｙ is an optional additional bond to form a double bond when = is represented, R １ａ is hydrogen, cyano, halo, Het, -C(=O)-NR ｘａ R ｘｂ , -S(=O) ２ -R １８ , -C(=O)-O-C １～４ Alkyl-NR ２２ａ R ２２ｂ , -C(=O)-OC １～４ Alkyl; 【Transformation 6】 represents R １８ But C １～６ Alkyl or C ３～６ represents cycloalkyl, R １９ is hydrogen or C １～６ represents alkyl, or R １８ and R １９ together, -(CH ２ ) ３ -, -(CH ２ ) ４ -, or -(CH ２ ) ５ - forms, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 O, S, or N atoms and, optionally, a carbonyl moiety, said monocyclic 5- or 6-membered aromatic ring optionally being selected from the group consisting of C １～４ Alkyl, C ３～６ substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R ｘａ and R ｘｂ are each independently hydrogen, Het ３ , C ３～６ Cycloalkyl, and C １～６ alkyl, optionally ３～６ Cycloalkyl and C １～６ The alkyl is —OH, —OC １～４ Alkyl, —C １～４ Alkyl-OH, Halo, CF ３ , C ３～６ Cycloalkyl, Het ３ , and N.R. １１ｃ R １１ｄ C is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of ３～６ Cycloalkyl, and C １～６ alkyl; or R ｘａ and R ｘｂ together with the N atom to which they are attached, one N atom and optionally one additional heteroatom selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one additional heteroatom, which may form: １～４ Alkyl, halo, —OH, —O—C １～４ Alkyl, cyano, and halo and OR ２３ C substituted with 1, 2, or 3 substituents selected from the group consisting of １～４ forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R ｘａ and R ｘｂ taken together with the N atom to which they are attached, form one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one or two additional heteroatoms, which may form: １～４ Alkyl, halo, —OH, —O—C １～４ Alkyl, cyano, and halo and OR ２３ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of １～４ forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R ２３ is hydrogen or C optionally substituted with 1, 2, or 3 halo １～４ represents alkyl, R １ｂ is hydrogen, F, Cl, or —O—C １～４ represents alkyl, R ２ But, Halo, C ３～６ Cycloalkyl, C １～４ Alkyl, —O—C １～４ C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents １～４ represents alkyl, R ２１ is hydrogen or -Y ａ -R ３ａ where R ２１ Ga-Y ａ -R ３ａ When representing -Y ａ -R ３ａ and -Y-R ３ is attached to a nitrogen atom of the ring, Y and Y ａ are each independently a covalent bond or 【Transformation 7】 represents n1 is selected from 1 and 2; n2 is selected from 1, 2, 3, and 4; R ｙ is hydrogen, -OH, C １～４ Alkyl, —C １～４ Alkyl-OH, or -C １～４ Alkyl-O-C １～４ represents alkyl, R ｑ is hydrogen or C １～４ represents alkyl, R ５ But hydrogen, C １～４ Alkyl, or C ３～６ represents cycloalkyl, R ３ , R ３ａ , and R ４ Each independently, Het １ ;Het ２ ; Cy ２ ; C １～８ alkyl; and —C(═O)—NR １０ａ R １０ｂ , -C(=O)-Het ６ａ , -C(=O)-Het ６ｂ , -NR １０ｃ -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —NR ｘｃ R ｘｄ , -NR ８ａ R ８ｂ , -CF ３ , cyano, halo, —OH, —O—C １～４ Alkyl, Het １ , Het ２ , Ar １ , and Cy ２ C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of １～８ is selected from the group consisting of alkyl, R ｘｃ But Cy １ , Het ５ , -C １～６ Alkyl-Cy １ , -C １～６ Alkyl-Het ３ , -C １～６ Alkyl-Het ４ , Or -C １～６ represents alkyl-phenyl, R ｘｄ is hydrogen; C １～４ Alkyl; or halo, —OH, —O—C １～４ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano １～４ represents alkyl, or R ｘｃ and R ｘｄ together with the N atom to which they are attached, one N atom and optionally one additional heteroatom selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one additional heteroatom, which may form: １～４ Alkyl, —(C═O)—C １～４ Alkyl, —S(═O) ２ -C １～４ forming a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano; or R ｘｃ and R ｘｄ taken together with the N atom to which they are attached, form one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and 1 or 2 additional heteroatoms, which may form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl, wherein the heterocyclyl is optionally halo, —OH, —O—C １～４ Alkyl, —(C═O)—C １～４ Alkyl-S(=O) ２ -C １～４ forming a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, and cyano; R ８ａ and R ８ｂ are each independently hydrogen; C １～６ Alkyl; -(C=O)-C １～４ Alkyl; and -OH, cyano, halo, -S(=O) ２ -C １～４ Alkyl, —O—C １～４ Alkyl, —C(═O)—NR １０ａ R １０ｂ , and -NR １０ｃ -C(=O)-C １～４ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～６ is selected from the group consisting of alkyl, Ar １ Optionally, C １～４ Alkyl, halo, —O—C １～４ Alkyl, —CF ３ , -OH, -S (=O) ２ -C １～４ Alkyl, and —C(═O)—NR １０ａ R １０ｂ represents phenyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: Het １ is 1, 2, or 3 heteroatoms each independently selected from O, S, and N, and the S atom is substituted to form S(=O) or S(=O) ２ or 1, 2, or 3 heteroatoms each independently selected from O, S, and N, wherein the S atom is substituted to form S(═O) or S(═O) ２ and R represents a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2 or 3 heteroatoms, which may optionally form, on one nitrogen, R ６ , -C(=O)-Cy １ and —C(═O)—R ８ and wherein said heterocyclyl is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R ６ , Het ６ａ , Het ６ｂ , C １～４ Alkyl, oxo, -NR ９ａ R ９ｂ and -OH; Het ２ represents a C-linked pyrazolyl, 1,2,4-oxadiazolyl, pyridazinyl, or triazolyl, which optionally has on one nitrogen atom R ６ａ may be substituted with R ６ and R ６ａ Each independently, Het ３ ;Het ４ ;-C(=O)-NH-Cy １ ;-C(=O)-NH-R ８ ;-C(=O)-Het ６ａ ;-C(=O)-NR １０ｄ R １０ｅ ; -C(=O)-O-C １～４ Alkyl; -S(=O) ２ -C １～４ Alkyl; Optionally, Het ３ , Het ４ , Het ６ａ , Het ６ｂ , Cy １ , -CN, -OH, -OC １～４ Alkyl, —C(═O)—NH—C １～４ Alkyl, —C(═O)—N(C １～４ alkyl) ２ , -C(=O)-NH-C １～４ Alkyl-C ３～６ Cycloalkyl, —C(═O)—OH, —NR １１ａ R １１ｂ , and —NH—S(═O) ２ -C １～４ C substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl １～６ alkyl; and Optionally, —CN, —OH, —O—C １～４ Alkyl, —C(═O)—NH—C １～４ Alkyl, —C(═O)—N(C １～４ alkyl) ２ , -NH-S (=O) ２ -C １～４ Alkyl, and optionally OH, —O—C １～４ Alkyl, —C(═O)—NH—C １～４ Alkyl, and —NH—S(═O) ２ -C １～４ C substituted with one substituent selected from the group consisting of alkyl １～４ C substituted by 1 or 2 substituents each independently selected from the group consisting of alkyl ３～６ cycloalkyl; R ８ is hydrogen, —O—C １～６ Alkyl, C １～６ Alkyl, or —OH, —O—C １～４ Alkyl, halo, cyano, -NR １１ａ R １１ｂ , -S(=O) ２ -C １～４ Alkyl, Het ３ａ , and Het ６ａ C substituted with 1, 2, or 3 substituents each independently selected from １～６ represents alkyl, Het ３ , Het ３ａ , Het ５ , and Het ５ａ are each independently 1, 2, or 3 heteroatoms each independently selected from O, S, and N, and the S atoms are substituted to form S(=O) or S(=O) ２ or 1, 2, or 3 heteroatoms each independently selected from O, S, and N, wherein the S atom is substituted to form S(═O) or S(═O) ２ represents a bicyclic C-bonded 6-11 membered fully or partially saturated heterocyclyl containing 1, 2 or 3 heteroatoms, which may form The heterocyclyl may optionally be, on one carbon atom, C １～４ Alkyl, halo, —OH, —NR １１ａ R １１ｂ or oxo, and said heterocyclyl is optionally substituted on one nitrogen atom by C １～４ Alkyl or -(C=O)-C １～４ is substituted with alkyl, Het ４ and Het ７ each independently represent a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, and N, said aromatic ring optionally having, on one nitrogen atom, C １～４ Alkyl or -(C=O)-O-C １～４ alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, C １～４ Alkyl, —O—C １～４ Alkyl, —NR １１ａ R １１ｂ , C １～４ Alkyl-NR １１ａ R １１ｂ , -NH-C(=O)-C １～４ Alkyl, cyano, —COOH, —NH—C(═O)—O—C １～４ Alkyl, —NH—C(═O)—Cy ３ , -NH-C(=O)-NR １０ａ R １０ｂ , -(C=O)-OC １～４ Alkyl, —NH—S(═O) ２ -C １～４ Alkyl, Het ８ａ , -C １～４ Alkyl-Het ８ａ , Het ８ｂ , Het ９ and —C(═O)—NR １０ａ R １０ｂ and is substituted with a total of 1 or 2 substituents each independently selected from the group consisting of: Het ６ａ , Het ８ , and Het ８ａ each independently one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one or two additional heteroatoms, which may form, on one or two carbon atoms, a halo, —OH, oxo, —NH—C(═O)—C １～４ Alkyl, —NH—C(═O)—Cy ３ , -(C=O)-NR １０ａ R １０ｂ , —O—C ３～６ Cycloalkyl, —S(═O) ２ -C １～４ Alkyl, cyano, C １～４ Alkyl, —C １～４ Alkyl-OH, —O—C １～４ Alkyl, —O—(C═O)—NR １０ａ R １０ｂ and —O—(C═O)—C １～４ and said heterocyclyl is optionally substituted on one nitrogen with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, and —(C═O)—NR １０ａ R １０ｂ and is substituted with a substituent selected from the group consisting of Het ６ｂ and Het ８ｂ each independently one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom is replaced to form S(=O) or S(=O) ２ and one or two additional heteroatoms, which may form, on one or two carbon atoms, １～４ Alkyl, —OH, oxo, —(C═O)—NR １０ａ R １０ｂ , -NH-C(=O)-C １～４ Alkyl, —NH—C(═O)—Cy ３ , and -O-C １～４ and the heterocyclyl is optionally substituted on one nitrogen by a —C(═O)—C １～４ Alkyl, —C(═O)—Cy ３ , -(C=O)-C １～４ Alkyl-OH, —C(═O)—C １～４ Alkyl-O-C １～４ Alkyl, —C(═O)—C １～４ Alkyl-NR １１ａ R １１ｂ , and C １～４ substituted with a substituent selected from the group consisting of alkyl; Het ９ represents a monocyclic C-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or a fused bicyclic C-bonded 9- or 10-membered aromatic ring containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, said aromatic ring optionally having, on one nitrogen atom, C １～４ alkyl, and the aromatic ring is optionally substituted on one or two carbon atoms with —OH, halo, and C １～４ substituted with a total of 1 or 2 substituents each independently selected from the group consisting of alkyl; Cy １ optionally, —OH, —NH—C(═O)—C １～４ Alkyl, C １～４ Alkyl, —NH—S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, and —O—C １～４ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl ３～６ represents cycloalkyl, Cy ２ But C ３～７ represents a cycloalkyl or a 5- to 12-membered saturated carbobicyclic ring system, Said C ３～７ The cycloalkyl or said carbobicyclic ring system may optionally be selected from halo, R ６ , -C(=O)-Het ６ａ , Het ６ａ , Het ６ｂ , -NR ９ａ R ９ｂ , -OH, C １～４ Alkyl, —O—C １～４ Alkyl, cyano, 【Transformation 8】 and Het ３ａ , Het ６ａ , Het ６ｂ , and -NR ９ａ R ９ｂ C substituted with 1 or 2 substituents each independently selected from the group consisting of １～４ substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl; Cy ３ But C ３～７ represents cycloalkyl, ３～７ cycloalkyl is optionally substituted with 1, 2, or 3 halo substituents; R ９ａ and R ９ｂ are each independently hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; —C(═O)—C １～４ Alkyl; —C(═O)—C ３～６ Cycloalkyl; -S(=O) ２ -C １～４ Alkyl; Het ５ ;Het ７ ;-C １～４ Alkyl-R １６ -C(=O)-C １～４ Alkyl-Het ３ａ -C(=O)-R １４ ; Halo, —OH, —O—C １～４ Alkyl, —NR １１ａ R １１ｂ C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, ３～６ cycloalkyl; and Halo, —OH, —O—C １～４ Alkyl, —NR １１ａ R １１ｂ C substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, １～４ is selected from the group consisting of alkyl, R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １５ａ , R １５ｂ , R １７ａ , R １７ｂ , R ２０ａ , R ２０ｂ , R ２２ａ , and R ２２ｂ are each independently hydrogen and C １～４ is selected from the group consisting of alkyl, R １１ｃ and R １１ｄ are each independently hydrogen, C １～６ Alkyl, and —C(═O)—C １～４ is selected from the group consisting of alkyl, R １０ａ , R １０ｂ , and R １０ｃ are each independently hydrogen, C １～４ Alkyl, and C ３～６ cycloalkyl; R １０ｄ and R １０ｅ However, each independently, C １～４ Alkyl, —O—C １～４ Alkyl, and C ３～６ cycloalkyl; R １４ But, Het ５ａ ;Het ７ ;Het ８ａ ;-O-C １～４ Alkyl; —C(═O)NR １５ａ R １５ｂ ;-O-C １～４ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl and halo ３～６ cycloalkyl; or —O—C １～４ Alkyl, —NR １３ａ R １３ｂ , halo, cyano, -OH, Het ８ａ , and Cy １ C substituted with 1, 2, or 3 substituents selected from the group consisting of １～４ represents alkyl, R １６ is -C(=O)-NR １７ａ R １７ｂ , -S(=O) ２ -C １～４ Alkyl, Het ５ , Het ７ , or Het ８ A method of representing.

13. 13. The method of claim 12, wherein the BCL-2 inhibitor is selected from venetoclax, obatoclax, HA14-1, navitoclax, ABT-737, TW-37, AT101, sabutoclax, gambogic acid, and pharmaceutically acceptable salts or solvates thereof.

14. 14. The method of claim 13, wherein the BCL-2 inhibitor is venetoclax, or a pharmaceutically acceptable salt or solvate thereof.

15. 15. The method of any one of claims 12 to 14, wherein the at least one other antineoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory antineoplastic agent, or a dihydroorotate dehydrogenase inhibitor.

16. 16. The method of claim 15, wherein the at least one other anti-neoplastic agent is a hypomethylating agent.

17. 17. The method of claim 16, wherein the hypomethylating agent is azacitidine, or a pharmaceutically acceptable salt or solvate thereof.

18. The method of any one of claims 12 to 17, wherein the hematopoietic disorder is nucleophosmin 1 (NPM1) mutant leukemia or MLL-rearranged leukemia.

19. The method of any one of claims 12 to 17, wherein the hematopoietic disorder is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

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