Combination comprising multiple endocrine cancer protein-MLL inhibitor and BCL-2 inhibitor

Abstract

Disclosed are combinations comprising a therapeutically effective amount of a multiple endocrine cancer protein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a BCL-2 inhibitor; and optionally, a therapeutically effective amount of at least one other antitumor agent. Also disclosed are methods for treating a subject that has been diagnosed with hematopoietic dysfunction using such combinations. Compounds are represented by the following formula (I): # imgabs0 # wherein the variables are as defined herein.

Description

Technical Field

[0001] The present invention relates to novel combinations comprising a therapeutically effective amount of a menin-mixed lineage leukemia 1 (menin-MLL) inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and 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-tumor agent; and also to methods for treating a subject diagnosed with a hematopoietic disorder. Background Art

[0002] Of the ten million cancer deaths recorded by GLOBOCAN in 2020, 7.1% were attributed to hematopoietic disorders. Thus, there is an urgent need for new forms of treatment for hematopoietic disorders, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and acute lymphoblastic leukemia (ALL), as further detailed below.

[0003] AML is a common blood malignancy, with its incidence rising from 3:100,000 in young people to greater than 20:100,000 in the elderly. For patients <60 years of age, the overall survival (OS) is 40% to 50%, but for patients >60 years of age it is only 5%. The majority of newly diagnosed AML patients are 60 years of age or older. In this patient population, standard induction chemotherapy is generally not an option due to increased treatment-related mortality due to age and comorbidities. The standard of care for AML patients not suitable for combination chemotherapy is treatment with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine. Despite these frontline treatments, the median OS is also only about 10 months. In all types of AML, disease relapse is common despite an initial treatment response and is the most common cause of death. Standard chemotherapy and allogeneic stem cell transplantation (when used) generally cannot eradicate all tumor-propagating cells and select for chemotherapy-resistant leukemia-propagating subclones. Patients refractory to salvage therapy are treated palliatively because current treatment options are very limited. These patients have a median survival of 2 months. In addition, patients with newly diagnosed moderate or higher-risk MDS and those who relapse after standard of care have poor prognoses and a high risk of progression to AML. Thus, there is an urgent need for new forms of treatment for relapsed / refractory (R / R) AML and MDS patients, newly diagnosed AML patients not suitable for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate / high / very high-risk MDS patients.

[0004] ALL is a hematologic malignancy that spreads through 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 acute leukemia in children, with an estimated worldwide incidence of 1 to 4.75 cases per 100,000 people. ALL represents approximately 20% of adult leukemias. Despite the high complete remission (CR) rate of current therapies (80% to 90%), most adult patients with ALL relapse. The 5-year overall survival rate for adult and elderly patients is approximately 30% to 40%. Thus, there is an urgent need for new treatment modalities for relapsed / refractory ALL, particularly in adults and especially in elderly patients. SUMMARY OF THE INVENTION

[0005] Embodiments of the invention relate to novel combinations of the following: a multiple endocrine neoplasia protein-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and a BCL-2 inhibitor; and optionally in combination with at least one other anti-tumor agent.

[0006] Embodiments of the invention relate to the use of such combinations for treating a subject diagnosed with a hematopoietic disorder (including but not limited to blood cancers) using a combination of a multiple endocrine neoplasia protein-MLL inhibitor as described herein, a BCL-2 inhibitor, and optionally at least one other anti-tumor agent.

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

[0008] Embodiments of the invention relate to a novel method for treating a subject diagnosed with a hematopoietic disorder using such combinations. Embodiments of the novel method include administering to the subject a therapeutically effective amount of a multiple endocrine neoplasia protein-MLL inhibitor as described herein; and a therapeutically effective amount of a BCL-2 inhibitor and a therapeutically effective amount of at least one other anti-tumor agent; wherein the multiple endocrine neoplasia protein-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 for treating a subject diagnosed with a hematopoietic disorder, the method comprising administering to the subject a therapeutically effective amount of a multiple endocrine neoplasia protein-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and 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 for treating a subject diagnosed with a hematopoietic disorder, the method comprising administering to the subject a therapeutically effective amount of a multiple endocrine neoplasia protein-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 a pharmaceutically acceptable salt or solvate thereof is administered to the subject before, simultaneously with, or after administering the multiple endocrine neoplasia protein-MLL inhibitor; and wherein the azacitidine or a pharmaceutically acceptable salt or solvate thereof is administered to the subject before, simultaneously with, or after administering the multiple endocrine neoplasia protein-MLL inhibitor.

[0011] In an embodiment, the multiple endocrine neoplasia protein-MLL inhibitor of formula (I) is:

[0012]

[0013] and its tautomeric and stereoisomeric forms, wherein

[0014] Q represents -CHR y -, -O-, -C(=O)-, -NR q - or -CR y =; in the case where Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0015] R 1a represents 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)O-C 1-4 alkyl,

[0016]

[0017] R 18 represents C 1-6alkyl or C 3-6 cycloalkyl;

[0018] R 19 represents hydrogen or C 1-6 alkyl;

[0019] or R 18 and R 19 together form -(CH2)3-, -(CH2)4- or -(CH2)5-;

[0020] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three O atoms, S atoms or N atoms and optionally a carbonyl moiety; wherein the monocyclic 5- or 6-membered aromatic ring is optionally substituted by one, two or three substituents selected from the group consisting of: C 1-4 alkyl, C 3-6 cycloalkyl or cyano;

[0021] R xa and R xb are each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted by one, two or three substituents selected from the group consisting of: -OH, -OC 1-4 alkyl, -C 1-4 alkyl-OH, halo, CF3, C 3-6 cycloalkyl, Het 3 and NR 11c R 11d ;

[0022] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: halo and OR 23 ;

[0023] or R xa and R xbTogether with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: halo and OR 23 ;

[0024] R 23 represents hydrogen or C 1-4 alkyl optionally substituted by one, two, or three halo groups;

[0025] R 1b represents hydrogen, F, Cl, or -O-C 1-4 alkyl;

[0026] R 2 represents halo, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C 1-4 alkyl substituted by one, two, or three halo substituents;

[0027] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a then one of -Y a -R 3a and -Y-R 3 is attached to the nitrogen atom of the ring;

[0028] Y and Y a each independently represent a covalent bond or

[0029]

[0030] n1 is selected from 1 and 2;

[0031] n2 is selected from 1, 2, 3, and 4;

[0032] R y represents hydrogen, -OH, C 1-4 alkyl, -C 1-4 alkyl-OH, or -C1-4 alkyl - O - C 1-4 alkyl;

[0033] R q represents hydrogen or C 1-4 alkyl;

[0034] R 5 represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

[0035] R 3 , R 3a and R 4 each independently selected from the group consisting of: Het 1 ; Het 2 ; Cy 2 ; C 1-8 alkyl; and C 1-8 alkyl substituted by one, two, three or four substituents each independently selected from the group consisting of: -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, -O-C 1-4 alkyl, Het 1 , Het 2 , Ar 1 and Cy 2 ;

[0036] R xc represents 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 alkyl - phenyl;

[0037] R xd represents hydrogen; C 1-4 alkyl; or C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of:Alkyl: halo group, -OH, -O-C 1-4 alkyl and cyano group;

[0038] Or R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo group, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and cyano group;

[0039] Or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo group, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl -S(=O)2-C 1-4 alkyl and cyano group;

[0040] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -(C=O)-C 1-4 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: -OH, cyano group, halo group, -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 alkyl;

[0041] Ar 1 represents a phenyl group optionally substituted by one, two, or three substituents each independently selected from the group consisting of: C 1-4 alkyl, halo group, -O-C 1-4alkyl, -CF3, -OH, -S(=O)2-C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0042] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of: halo group, R 6 , Het 6a , Het 6b , C 1-4 alkyl, oxo group, -NR 9a R 9b and -OH;

[0043] Het 2 represents a C-linked pyrazolyl, 1,2,4- diazolyl, pyridazinyl or triazolyl; the group can be optionally substituted on one nitrogen atom with R 6a ;

[0044] R 6 and R 6a are each independently selected from the group consisting of:

[0045] 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;

[0046] Optionally substituted by one or two substituents each independently selected from the group consisting of: C 1-6 alkyl: Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN, -OH, -O-C 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 alkyl; and

[0047] Optionally substituted by one or two substituents each independently selected from the group consisting of: C 3-6 cycloalkyl: -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 substituted by one substituent selected from the group consisting of: C 1-4 alkyl: -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl;

[0048] R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or substituted by one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, halo, cyano, -NR 11a R 11b 、-S(=O)2-C 1-4 alkyl, Het 3a and Het 6a of C 1-6 alkyl;

[0049] Het 3 、Het 3a 、Het 5 and Het 5aEach independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0050] wherein the heterocyclic group is optionally substituted at one carbon atom by C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; wherein the heterocyclic group is optionally substituted at one nitrogen atom by C 1-4 alkyl or -(C=O)-C 1-4 alkyl;

[0051] Het 4 and Het 7 Each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms independently selected from O, S and N; wherein the aromatic ring is optionally substituted at one nitrogen atom by C 1-4 alkyl or -(C=O)-O-C 1-4 alkyl; and wherein the aromatic ring is optionally substituted at one or two carbon atoms by a total of one or two substituents independently selected from the group consisting of: -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)-O-C 1-4 alkyl, -NH-S(=O)2-C 1-4 alkyl, Het 8a 、-C 1-4 alkyl-Het 8a 、Het 8b 、Het9 and -C(=O)-NR 10a R 10b ;

[0052] Het 6a 、Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four substituents each independently selected from the group consisting of: 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 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ;

[0053] Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: 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 -O-C1-4 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -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 alkyl;

[0054] Het 9 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted on one nitrogen atom with C 1-4 alkyl; and wherein said aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -OH, halo and C 1-4 alkyl;

[0055] Cy 1 represents C 3-6 cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of: -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 -0-C 1-4 alkyl;

[0056] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system;

[0057] wherein said C 3-7 cycloalkyl or said carbobicyclic system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 、-C(=O)-Het 6a 、Het 6a 、Het 6b 、-NR 9a R 9b 、-OH、C 1-4 alkyl, -O-C1-4 alkyl, cyano,

[0058]

[0059] C substituted by one or two substituents each independently selected from the group consisting of: 1-4 alkyl: Het 3a 、Het 6a 、Het 6b and -NR 9a R 9b ;

[0060] Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7 cycloalkyl is optionally substituted by one, two or three halo substituents;

[0061] R 9a and R 9b are each independently selected from the group consisting of: 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 ;

[0062] C 3-6 cycloalkyl substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and

[0063] C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano;

[0064] R 11a 、R 11b 、R 13a 、R 13b 、R 15a 、R15b , R 17a , R 17b , R 20a , R 20b , R 22a and R 22b each independently selects from the group consisting of: hydrogen and C 1-4 alkyl;

[0065] R 11c and R 11d each independently selects from the group consisting of: hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl;

[0066] R 10a , R 10b and R 10c each independently selects from the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0067] R 10d and R 10e each independently selects from the group consisting of: C 1-4 alkyl, -O-C 1-4 alkyl and C 3-6 cycloalkyl;

[0068] R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C 3-6 cycloalkyl substituted by one, two or three substituents selected from the group consisting of: -O-C 1-4 alkyl and halo; or C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ;

[0069] R 16 represents -C(=O)-NR 17a R 17b , -S(=O)2-C 1-4 alkyl, Het 5 , Het 7 or Het8 ; and their pharmaceutically acceptable salts and solvates.

[0070] It should be clear that the substituent R in formula (I) 21 and -Y-R 3 can be attached to any carbon or nitrogen atom of the ring to which they are attached, thus replacing the hydrogen atom on the same atom, or they can replace the hydrogen atoms on different atoms (including N atoms) in this moiety. The line drawn from the substituent to the ring system indicates that the bond can be attached to any suitable ring atom.

[0071] From the following detailed description and by practicing the present invention, additional embodiments, features, and advantages of the present invention will become apparent. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 is an X-ray powder diffraction (XRPD) pattern of compound 51 in crystalline free base form.

[0073] Figure 2 is an X-ray powder diffraction (XRPD) pattern of compound 51a in crystalline HCl salt form.

[0074] Figure 3 is a dynamic vapor sorption (DVS) isotherm plot of compound 51a in crystalline HCl salt form.

[0075] Figure 4 is a dynamic vapor sorption (DVS) mass change plot of compound 51a in crystalline HCl salt form.

[0076] Figure 5 A is a contour plot of maxR, which shows the effect of the combination of compound 51 with decitabine and venetoclax on the in vitro proliferation of MOLM-13 cells.

[0077] Figure 5 B is a contour plot of maxR, which shows the effect of the combination of compound 51 with decitabine and venetoclax on the in vitro proliferation of MV4-11 cells.

[0078] Figure 5 C is a contour plot of maxR, which shows the effect of the combination of compound 51 with decitabine and venetoclax on the in vitro proliferation of OCI-AML 3 cells.

[0079] Figure 5D is a contour plot of maxR, which shows the effect of the combination of compound 51 with venetoclax on the in vitro proliferation of MOLM-13 cells.

[0080] Figure 5EIt is an isocontour map of maxR, which shows the effect of the combination of compound 51 with venetoclax and azacytidine on the in vitro proliferation of MOLM-13 cells.

[0081] Figure 6 Depicts a comparison of the percentage of survival of mice bearing established MOLM-13 tumors as a function of time after treatment with vehicle, single therapies with venetoclax, azacytidine or compound 51, dual combinations with venetoclax and azacytidine or compound 51 and venetoclax, or triple combinations with compound 51, venetoclax and azacytidine. Detailed Description

[0082] As used herein, the term "halo group" or "halogen" means fluorine, chlorine, bromine and iodine.

[0083] 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 alkyl groups contain from 1 to 6 carbon atoms, and so on.

[0084] As used herein as a group or part of a group, the term "C 1-4 alkyl" means a straight or branched chain saturated hydrocarbon group having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.

[0085] Similarly, as used herein as a group or part of a group, the term "C 1-6 alkyl" means a straight or branched chain fully saturated hydrocarbon group having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

[0086] Similarly, as used herein as a group or part of a group, the term "C 1-8 alkyl" means a straight or branched chain fully saturated hydrocarbon group having from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl and the like.

[0087] As used herein as a group or part of a group, the term "C 3-6 cycloalkyl" is defined as a saturated cyclic hydrocarbon group having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0088] As used herein as a group or part of a group, the term "C 3-7 cycloalkyl" is defined as a saturated cyclic hydrocarbon group having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0089] It is understood by those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0090] It is understood by those skilled in the art that CO or C(=O) represents a carbonyl moiety.

[0091] Those skilled in the art will understand that groups such as -NR- represent Examples of such groups are -NR q -.

[0092] Non-limiting examples of "a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety" include, but are not limited to, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1,2-dihydro-2-oxo-4-pyridyl.

[0093] Those skilled in the art will understand that a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and a carbonyl moiety includes, but is not limited to

[0094] The term "a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N" is defined as a fully saturated or partially saturated cyclic hydrocarbon group having 4 to 7 ring members and containing at least 1 nitrogen atom and optionally one or two additional heteroatoms each independently selected from O, S and N, which is linked to the remainder of the molecule of formula (I) through 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-tetrahydropyridinyl. The definition of two R groups which, together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N is similar.

[0095] The term "monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N" is defined as a fully saturated or partially saturated cyclic hydrocarbon group having 4 to 7 ring members and containing one, two or three 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 and C-linked piperidinyl, C-linked azepanyl, C-linked 1,3-dioxolanyl and C-linked 1,2,3,6-tetrahydro-pyridinyl.

[0096] For clarity, the 4- to 7-membered fully saturated or partially saturated heterocyclic group has 4 to 7 ring members, including heteroatoms.

[0097] Non-limiting examples of "monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O atom, S atom and N atom" include but are not limited to C-linked pyrazolyl, C-linked imidazolyl, C-linked pyridyl, C-linked triazolyl, C-linked pyridazinyl, C-linked pyrimidinyl, C-linked oxazolyl, C-linked furyl, C-linked isothiazolyl, C-linked thiazolyl, C-linked thiadiazolyl, C-linked diazolyl or C-linked pyrazinyl.

[0098] In the context of the present invention, bicyclic 6- to 11-membered fully saturated or partially saturated heterocyclic groups include fused bicyclics, spiro bicyclics and bridged bicyclics.

[0099] A fused bicyclic group is two rings sharing two atoms and the bonds between these atoms.

[0100] A spiro bicyclic group is two rings joined at a single atom.

[0101] A bridged bicyclic group is two rings sharing more than two atoms.

[0102] Examples of bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic groups containing one, two or three heteroatoms each independently selected from O, S and N include but are not limited to

[0103]

[0104] etc.

[0105] Examples of bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic groups containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N include, but are not limited to

[0106]

[0107]

[0108] and the like.

[0109] The definition of the two R groups, which together with the N atom to which they are attached form a 6- to 11-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, is similar.

[0110] Examples of fused bicyclic C-linked 9- or 10-membered aromatic rings containing one, two, three, or four heteroatoms each independently selected from O, S, and N include, but are not limited to

[0111]

[0112] and the like.

[0113] As used herein, "5- to 12-membered saturated carbobicyclic" means a saturated fused, spiro, and bridged bicyclic hydrocarbon system having 5 to 12 carbon atoms. Examples of 5- to 12-membered saturated carbobicyclic systems include, but are not limited to

[0114]

[0115] and the like.

[0116] Whenever a substituent is represented by a chemical structure, e.g.,

[0117] "----" represents the bond connecting to the remainder of the molecule of formula (I).

[0118] When any variable occurs more than once in any component, each definition is independent.

[0119] When any variable occurs more than once in any formula (e.g., formula (I)), each definition is independent.

[0120] It will be clear to those skilled in the art that when a moiety (e.g., a heterocyclic group or a monocyclic 5- or 6-membered aromatic ring) is substituted by two or more substituents selected from a group (e.g., one, two, or three substituents), each substituent can be independently selected from the group, even if not explicitly mentioned.

[0121] Generally, unless otherwise specified or clear from the context, whenever the term "substituted" is used in the present invention, it means that one or more hydrogens, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen on the atom or group indicated in the expression using "substituted" are replaced by a selection from the indicated groups, provided that the normal valency is not exceeded and the substitution results in a chemically stable compound, i.e., a compound stable enough to withstand isolation from the reaction mixture to a useful purity (isolated after the reaction, e.g., purified by silica gel chromatography). In a specific embodiment, when the number of substituents is not explicitly specified, the number of substituents is one.

[0122] Combinations of substituents and / or variables are only permitted if such combinations result in a chemically stable compound. A "stable compound" in this context means a compound stable enough to withstand isolation from the reaction mixture to a useful purity (isolated after the reaction, e.g., purified by silica gel chromatography).

[0123] One skilled in the art will understand that the term "optionally substituted" means that the atom or group indicated in the expression using "optionally substituted" may or may not be substituted (which means substituted or unsubstituted, respectively).

[0124] When there are two or more substituents on a moiety, where possible and unless otherwise specified or clear from the context, they may replace hydrogens on the same atom, or they may replace hydrogen atoms on different atoms in the moiety.

[0125] In the context of the present invention, if not otherwise stated, "saturated" means "fully saturated".

[0126] Unless otherwise specified or clear from the context, aromatic ring and heterocyclic group moieties can be attached to the remainder of the molecule of formula (I) through any available ring carbon atom (C - linked) or nitrogen atom (N - linked).

[0127] Unless otherwise specified or clear from the context, aromatic ring and heterocyclic group moieties can optionally be substituted on carbon and / or nitrogen atoms where possible according to the embodiment. One skilled in the art will understand that in such cases, the hydrogens on the carbon atom and / or nitrogen atom are replaced by such substituents.

[0128] Unless otherwise stated or clear from the context, the variable R 21 and -Y - R 3 can be attached to any carbon or nitrogen atom of the ring to which they are attached, provided that when R 21 represents -Y a -R 3a , -Ya -R 3a and -Y-R 3 One of them is connected to the nitrogen atom of the ring.

[0129] For example, when R 21 represents hydrogen and -Y-R 3 is connected to the nitrogen atom of the ring in formula (I), a compound of sub-formula (I-x) is obtained:

[0130]

[0131] When Y represents a covalent bond in formula (I), a compound of sub-formula (I-y) is obtained:

[0132]

[0133] When Y represents in formula (I), a compound of sub-formula (I-z) is obtained:

[0134]

[0135] As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., a cat, dog, primate, or human), and more preferably a human who is or has been the subject of treatment, observation, or experiment.

[0136] As used herein, the term "therapeutically effective amount" means the amount of an active compound or agent that elicits the biological or pharmaceutical response (including alleviation or reversal of the symptoms of the disease or disorder being treated) that a researcher, veterinarian, physician, or other clinician is seeking in a tissue system, animal, or human body.

[0137] The term "composition" is intended to cover a product containing specified amounts of specified ingredients, as well as any product directly or indirectly obtained by combining specified amounts of the specified ingredients.

[0138] As used herein, the term "treatment" is intended to refer to all processes in which there may be a slowing, interruption, arrest, or stoppage of the progression of a disease, but not necessarily to the complete elimination of all symptoms.

[0139] As used herein, the term "compounds of the present invention" or "compounds according to the present invention" means compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

[0140] The compounds of formula (I) are multiple endocrine neoplasia protein-MLL inhibitors of formula (I).

[0141] As used herein, any chemical formula having only bonds shown as solid lines and not shown as solid wedges or hash wedges or otherwise represented as having a specific configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0142] In the foregoing and the following, the term "compound of formula (I)" is meant to include its tautomers and its stereoisomeric forms.

[0143] The terms "stereoisomer", "stereoisomeric form" or "stereochemical isomeric form" may be used interchangeably in the foregoing or the following.

[0144] The present invention includes all stereoisomers of the compounds of the present invention as pure stereoisomers or as mixtures of two or more stereoisomers.

[0145] 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.

[0146] Atropisomers (or atropoisomers) are stereoisomers having a specific spatial configuration that results in restricted rotation about a single bond due to large steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0147] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related to a mirror image. If a compound contains a double bond, the substituents may be in the E or Z configuration.

[0148] Substituents on a divalent cyclic saturated or partially saturated group may have a cis or trans configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

[0149] Accordingly, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0150] The meaning of all those terms, namely enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, is known to the person skilled in the art.

[0151] The absolute configuration is assigned according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is assigned as R or S. A resolved stereoisomer of unknown absolute configuration may be assigned as (+) or (-), depending on the direction in which it rotates plane-polarized light. For example, a resolved enantiomer of unknown absolute configuration may be assigned as (+) or (-) according to the direction in which it rotates plane-polarized light.

[0152] When identifying a specific stereoisomer, 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 designated as (R), for example, this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated as E, for example, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is designated as cis, for example, this means that the compound is substantially free of the trans isomer.

[0153] Some compounds according to formula (I) may also exist in their tautomeric forms. Although not explicitly indicated in formula (I) above, these forms are intended to be included within the scope of the present invention as long as they may exist. It can be seen therefrom that a single compound may exist in the form of stereoisomers and tautomers.

[0154] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional methods, for example by reacting the free acid or 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, followed by removal of the solvent or the medium using standard techniques (e.g., vacuum, by lyophilization or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the invention in salt form with another counterion, for example using a suitable ion exchange resin.

[0155] The pharmaceutically acceptable salts mentioned above or below refer to the non-toxic acid and non-toxic base salt forms of the therapeutically active compounds of formula (I) and their solvates that can be formed.

[0156] Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic acid, propionic acid, glycolic 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 and the like. Conversely, the salt form can be converted into the free base form by treatment with a suitable base.

[0157] Compounds of formula (I) containing acidic protons and their solvates can also be converted into their non-toxic metal or amine salt forms by treatment with suitable organic and inorganic bases.

[0158] Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts (such as lithium, sodium, potassium, cesium, magnesium, calcium salts, etc.), salts with organic bases, such organic bases as primary, secondary and tertiary aliphatic and aromatic amines, such as 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-D-glucamine, hydrabamine salts, and salts with amino acids (such as, for example, arginine, lysine, etc.). Conversely, the salt form can be converted into the free acid form by treatment with an acid.

[0159] The term "prodrug" includes any compound that is metabolized in vivo to the (more) active form in an experimentally detectable amount within a predetermined time (e.g., within a dosing interval between 0.5 hours and 24 hours, or e.g., within a dosing interval between 6 hours and 24 hours (i.e., one to four times a day)) after oral or parenteral administration (especially oral administration). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, especially intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.

[0160] Prodrugs can be prepared by modifying the functional groups present on the compound such that the modification is cleaved in vivo when such prodrug is administered to a mammalian subject. These modifications are generally achieved by synthesizing the parent compound with a prodrug substituent. Generally, prodrugs include compounds in which a hydroxyl, amino, mercapto, carboxyl or carbonyl group is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, mercapto, carboxyl or carbonyl group, respectively.

[0161] Examples of prodrugs include, but are not limited to, esters and carbamates of the hydroxyl functional group, ester groups of the carboxyl functional group, N-acyl derivatives and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" pages l - 92, Elesevier, New York - Oxford (1985).

[0162] The term solvate includes the solvent addition forms and their salts that the compounds of formula (I) are capable of forming. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc.

[0163] The compounds of the present invention prepared by the following methods may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, which mixtures may be separated from one another by resolution methods known in the art. The separation of the enantiomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates involves the use of liquid chromatography on a chiral stationary phase. The pure stereochemical isomer forms may also be derived from the corresponding pure stereochemical isomer forms of the appropriate starting materials, provided that the reactions occur stereospecifically. Preferably, if a specific stereoisomer is required, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously employ optically pure starting materials.

[0164] As used herein, the term "optically pure" means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In the most preferred embodiment, the term "optically pure" means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the other enantiomer.

[0165] The present invention also encompasses isotopically labeled compounds of the present invention which are identical to those described herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant atomic mass or mass number found in nature).

[0166] All isotopes and mixtures of isotopes of any specific atom or element designated herein are contemplated within the scope of the compounds of the present invention, whether naturally occurring or synthetically produced, whether in natural abundance or in isotopically enriched form. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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 82Br. Preferably, the isotopes are selected from 2 H, 3 H, 11 C, 13 C and 18 F. Preferably, the isotopes are selected from 2 H, 3 H, 11 C and 18 F. More preferably, the isotope is 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, deuterated compounds and compounds enriched in 13 C 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.

[0167] Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3 H and 14 C) can be used, for example, in substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages (e.g., extended in vivo half-life or reduced required dose) due to greater metabolic stability and can therefore be preferred in some cases. Positron-emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies. PET imaging in cancer can be used to help localize and identify tumors, stage the disease, and determine appropriate treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind to such receptors or proteins on tumor cells with high affinity and specificity have great potential for diagnostic imaging and targeted radionuclide therapy. In addition, target-specific PET radiotracers can be used as biomarkers to examine and evaluate pathology by, for example, measuring target expression and treatment response.

[0168] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, at least one other therapeutic agent as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0169] For further example, a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a BCL-2 inhibitor and optionally at least one other anti-tumor agent as active ingredients can be prepared by mixing these compounds with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and / or a pharmaceutically acceptable excipient.

[0170] As used herein, the term "multiple endocrine neoplasia protein-MLL inhibitor" refers to an inhibitor of the protein-protein interaction between multiple endocrine neoplasia protein and mixed lineage leukemia 1 (MLL1) (also known as histone-lysine N-methyltransferase 2A (KMT2A) protein) (UniProt accession #Q03164) in the scientific field, which inhibits or reduces multiple endocrine neoplasia protein-MLL1 activity. The multiple endocrine neoplasia protein-MLL inhibitors described herein are disclosed in PCT / CN2022 / 095901, which is incorporated herein by reference in its entirety, and the corresponding synthesis schemes and analytical characterizations are also disclosed.

[0171] As used herein, the term "BCL-2 inhibitor" may refer to an agent that inhibits or reduces BCL-2 activity.

[0172] As used herein, the term "anti-tumor agent" refers to any agent for treating cancer.

[0173] As used herein, the term "hypomethylating agent" refers to an agent that inhibits or reduces DNA methylation.

[0174] 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's tyrosine kinase (BTK), Abelson tyrosine kinase 1 (ABL), Aurora serine / tyrosine kinase).

[0175] As used herein, the term "FLT-3 inhibitor" refers to a tyrosine kinase inhibitor (TKI) classified as a first-generation and next-generation inhibitor based on its potency and specificity for fms-like receptor tyrosine kinase 3 (FLT3) and its related downstream targets.

[0176] As used herein, the term "CD20 inhibitor" refers to any agent that reduces CD20 activity.

[0177] 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.

[0178] As used herein, the term "immunomodulatory anti-tumor agent" refers to any agent that enhances the activity of anti-tumor immune cells.

[0179] As used herein, the term "programmed cell death protein 1 (PD-1) inhibitor" refers to any agent that inhibits or reduces the activity of PD-1.

[0180] As used herein, the term "dihydroorotate dehydrogenase (DHODH) inhibitor" refers to any agent that inhibits or reduces the activity of dihydroorotate dehydrogenase.

[0181] Unless otherwise specified, as used herein, the term "affect" or "affected" (when referring to a disease, disorder, or medical condition that is affected by inhibition or alteration of multiple endocrine neoplasia protein-MLL activity) includes a decrease in the frequency and / or severity of one or more symptoms or clinical manifestations of the hematopoietic disorder; and / or includes prevention of the development of the hematopoietic disorder or the development of one or more symptoms or clinical manifestations of the hematopoietic disorder.

[0182] As used herein, the term "hematopoietic disorder" refers to any disorder related to the production of cellular components in blood and plasma, including but not limited to blood cancers.

[0183] According to one embodiment, the present invention provides the combination as described herein.

[0184] According to one embodiment, the present invention provides the combination as described herein for use as a medicament.

[0185] According to one embodiment, the present invention provides the combination as described herein for use in the preparation of a medicament.

[0186] According to one embodiment, the present invention provides the combination as described herein for use in the preparation of a medicament for treating or preventing any one of the disease conditions mentioned herein.

[0187] According to one embodiment, the present invention provides the combination as described herein for use in the prevention or treatment of the disease as described herein, particularly for the treatment of the disease as described herein.

[0188] According to one embodiment, the present invention provides the combination as described herein for use in the prevention or treatment of a hematopoietic disorder (including but not limited to blood cancers, including but not limited to lymphoma, myeloma, and leukemia), particularly for the treatment of a hematopoietic disorder.

[0189] According to one embodiment, the present invention provides the combination as described herein for use in the prevention or treatment of a hematopoietic disorder, particularly for the treatment of a hematopoietic disorder.

[0190] According to one embodiment, the hematopoietic disorder is selected from, but not limited to, lymphoma, myeloma, myelodysplasia, and leukemia.

[0191] According to one embodiment, the hematopoietic disorder is lymphoma, which is selected from Hodgkin's lymphoma and non-Hodgkin lymphoma.

[0192] According to one embodiment, the lymphoma is non-Hodgkin disease, which is Burkitt lymphoma, anaplastic large cell lymphoma, splenic marginal zone lymphoma, hepatosplenic T-cell lymphoma, or angioimmunoblastic T-cell lymphoma (AILT).

[0193] According to one embodiment, the hematopoietic disorder is myeloma. According to one embodiment, the hematopoietic disorder is multiple myeloma, Waldenström macroglobulinemia, or plasmacytoma.

[0194] According to one embodiment, the hematopoietic disorder is myelodysplasia, including but not limited to myelodysplastic syndromes (MDS).

[0195] According to one embodiment, the hematopoietic disorder is leukemia.

[0196] According to one embodiment, the hematopoietic disorder is leukemia, which is selected from acute leukemia and chronic leukemia. According to one embodiment, the leukemia is acute leukemia. According to one embodiment, the leukemia is chronic leukemia.

[0197] According to one embodiment, the hematopoietic disorder is myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia. According to one embodiment, the hematopoietic disorder is leukemia, which is selected from, but not limited to, acute lymphoblastic 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 (HCL), T-cell large granular lymphocyte leukemia (T-LGL), and aggressive NK-cell leukemia. According to one embodiment, AML is acute megakaryoblastic leukemia (AMKL).

[0198] According to one embodiment, the leukemia is MDS, CLL, SLL, ALL or AML. According to one embodiment, the leukemia is CLL, SLL or AML. According to one embodiment, the leukemia is CLL or SLL. In some embodiments, CLL or SLL is a cancer that expresses CD20. According to one embodiment, the leukemia is ALL or AML. According to one embodiment, the leukemia is ALL. According to one embodiment, the leukemia is AML. According to one embodiment, the hematopoietic disorder is Waldenström macroglobulinemia.

[0199] 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 that exhibits an elevated HOX / MEIS1 gene expression signature.

[0200] According to one embodiment, the leukemia is MLL-rearranged leukemia and / or nucleophosmin 1 (NPM1)-mutated leukemia. According to one embodiment, the hematopoietic disorder is MLL-rearranged leukemia.

[0201] According to one embodiment, the hematopoietic disorder is nucleophosmin 1 (NPM1)-mutated leukemia (e.g., NPM1c).

[0202] According to one embodiment, the present invention provides a method for treating a hematopoietic disorder that is myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), the method 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, and a BCL-2 inhibitor and optionally at least one other anti-tumor agent.

[0203] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0204] According to one embodiment, the hematopoietic disorder is acute lymphoblastic leukemia (ALL).

[0205] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0206] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

[0207] According to one embodiment, the hematopoietic disorder is SLL or CLL, wherein SLL or CLL is a cancer that expresses CD20.

[0208] According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS).

[0209] According to one embodiment, the hematopoietic disorder is myeloproliferative neoplasm (MPN).

[0210] According to one embodiment, the hematopoietic disorder is NPM1-mutated leukemia with FLT3 mutation.

[0211] According to one embodiment, the hematopoietic disorder is FLT3-dependent leukemia.

[0212] According to one embodiment, the hematopoietic disorder has one or more MLL1 (KMT2A) rearrangements or alterations (e.g., duplications or amplifications) and / or NPM1 mutations.

[0213] According to one embodiment, the hematopoietic disorder has (i) one or more MLL1 (KMT2A) rearrangements or alterations (e.g., duplications or amplifications) and / or NPM1 mutations plus (ii) FLT3 mutations.

[0214] According to one embodiment, the hematopoietic disorder is MLL-rearranged leukemia.

[0215] According to one embodiment, the hematopoietic disorder is acute myeloid leukemia (AML).

[0216] According to one embodiment, the hematopoietic disorder is small lymphocytic lymphoma (SLL).

[0217] According to one embodiment, the hematopoietic disorder is chronic lymphocytic leukemia (CLL).

[0218] 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.

[0219] According to one embodiment, the hematopoietic disorder is AML, particularly nucleophosmin (NPM1)-mutated AML (i.e., NPM1 mut AML), more particularly abstract NPM1-mutated AML.

[0220] According to one embodiment, the hematopoietic disorder is MLL-rearranged leukemia, particularly MLL-rearranged AML or ALL.

[0221] According to one embodiment, the hematopoietic disorder comprises an MLL gene alteration, particularly the hematopoietic disorder is AML or ALL with an MLL gene alteration. In certain embodiments, the MLL gene alteration is a duplication. In certain embodiments, the MLL gene alteration is an amplification.

[0222] According to one embodiment, the hematopoietic disorder comprises an NPM1 gene mutation and / or an MLL1 (also known as KMT2A) gene mutation.

[0223] According to one embodiment, the MLL1 gene mutation comprises, but is not limited to, an MLL1 gene rearrangement, duplication or amplification.

[0224] According to one embodiment, the hematopoietic disorder is mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, leukemia associated with MLL, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0225] All embodiments of the methods for treating a hematopoietic disorder described herein are also applicable for use in treating said hematopoietic disorder.

[0226] All embodiments of the compositions for use in treating a hematopoietic disorder described herein are also applicable for the methods of treating said hematopoietic disorder.

[0227] All embodiments of the methods for treating a hematopoietic disorder described herein are also applicable for use in the methods for treating said hematopoietic disorder.

[0228] All embodiments of the compositions for use in the methods for treating a hematopoietic disorder described herein are also applicable for the methods of treating said hematopoietic disorder.

[0229] In one embodiment, the present invention relates to a novel combination comprising:

[0230] A therapeutically effective amount of a multiple endocrine neoplasia protein-MLL inhibitor of formula (I), or a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof;

[0231] A therapeutically effective amount of a BCL-2 inhibitor; and

[0232] Optionally, a therapeutically effective amount of at least one other anti-tumor agent.

[0233] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0234] Q represents -CHR y - or -CR y =; in the case where Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0235] R 1a represents hydrogen, a halo group, -C(=O)-NR xa R xb -, -S(=O)2-R 18 -, -C(=O)-O-C 1-4 alkyl or

[0236]

[0237] R 18 represents C 1-6 alkyl;

[0238] R 19 represents hydrogen or C 1-6 alkyl;

[0239] Or R 18 and R 19 together form -(CH2)3-, -(CH2)4- or -(CH2)5-;

[0240] R xa and R xb are each independently selected from the group consisting of hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted by one, two or three substituents selected from the group consisting of: -OH, -OC 1-4 alkyl and -C 1-4 alkyl-OH;

[0241] Or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, -OH, -O-C 1-4alkyl, and C alkyl substituted by one, two or three OR 23 alkyl; 1-4 alkyl;

[0242] or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three -OH substituents;

[0243] R 23 represents hydrogen or C 1-4 alkyl;

[0244] R 1b represents F or -O-C 1-4 alkyl;

[0245] R 2 represents a halogenated group, C 1-4 alkyl, or C 1-4 alkyl substituted by one, two or three halogenated group substituents;

[0246] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a then one of -Y a -R 3a and -Y-R 3 is attached to the nitrogen atom of the ring;

[0247] Y and Y a each independently represents a covalent bond or

[0248]

[0249] R 5 represents hydrogen;

[0250] n1 is selected from 1 and 2;

[0251] n2 is selected from 1, 2, and 3;

[0252] R y represents hydrogen;

[0253] R 3 , R 3a and R 4 are each independently selected from the group consisting of Het 1; C 1-8 alkyl; and C substituted with one, two, three or four substituents each independently selected from the group consisting of 1-8 alkyl: -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, -O-C 1-4 alkyl, Het 1 , Het 2 , Ar 1 and Cy 2 ;

[0254] R xc and R xd , together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0255] Or R xc and R xd , together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0256] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -(C=O)-C 1-4 alkyl; and C substituted with one, two or three -O-C 1-4 alkyl 1-6 ;

[0257] Ar 1phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0258] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of halo, R 6 , C 1-4 alkyl, oxo and -OH;

[0259] Het 2 represents a C-linked pyrazolyl, 1,2,4- diazolyl, pyridazinyl or triazolyl;

[0260] R 6 is selected from the group consisting of 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; C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het 6a , Het 6b and -OH;

[0261] R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6alkyl; or C substituted by one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, cyano, -S(=O)2-C 1-4 alkyl and Het 3a ; 1-6 alkyl;

[0262] Het 3 and Het 3a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen atom by -(C=O)-C 1-4 alkyl;

[0263] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted at one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0264] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one or two carbon atoms by a total of one, two, three or four substituents each independently selected from the group consisting of: halo and -S(=O)2-C 1-4 alkyl; and wherein the heterocyclic group is optionally substituted at one nitrogen by a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0265] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by -C(=O)-C 1-4 alkyl;

[0266] Cy1 represents a C optionally substituted with one, two or three -OH 3-6 cycloalkyl;

[0267] Cy 2 represents a C 3-7 cycloalkyl or a 5- to 12-membered saturated carbocyclic ring system;

[0268] wherein said C 3-7 cycloalkyl or carbocyclic ring system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH and C 1-4 alkyl;

[0269] R 9a and R 9b are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -C(=O)-R 14 ;

[0270] R 10a , R 10b and R 10c are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0271] R 10d and R 10e are each independently selected from the group consisting of: C 1-4 alkyl and -O-C 1-4 alkyl;

[0272] R 14 represents -O-C 1-4 alkyl;

[0273] and their pharmaceutically acceptable salts and solvates.

[0274] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0275] Q represents -CHR y -;

[0276] R 1a represents -C(=O)-NR xa Rxb 、 -S(=O)₂-R 18 、 -C(=O)-O-C 1-4 alkyl or

[0277]

[0278] R 18 represents C 1-6 alkyl;

[0279] R 19 represents hydrogen or C 1-6 alkyl;

[0280] or R 18 and R 19 together form -(CH₂)₃-, -(CH₂)₄- or -(CH₂)₅-;

[0281] R xa and R xb are each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted with one, two or three substituents selected from the group consisting of: -OH, -OC 1-4 alkyl and -C 1-4 alkyl-OH;

[0282] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)₂; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, -OH, -O-C 1-4 alkyl, and C 23 alkyl substituted with one, two or three OR 1-4 alkyl;

[0283] or R xa and R xbTogether with the N atom to which they are attached, they form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three -OH substituents;

[0284] R 23 represents hydrogen or C 1-4 alkyl;

[0285] R 1b represents F or -O-C 1-4 alkyl;

[0286] R 2 represents a halogenated group, C 1-4 alkyl, or C 1-4 alkyl substituted by one, two, or three halogenated group substituents;

[0287] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a , one of -Y a -R 3a and -Y-R 3 is connected to the nitrogen atom of the ring;

[0288] Y and Y a represent a covalent bond;

[0289] n1 is selected from 1 and 2;

[0290] n2 is selected from 1, 2, and 3;

[0291] R y represents hydrogen;

[0292] R 3 and R 3a are each independently selected from the group consisting of Het 1 , C 1-8 alkyl, and C 1-8 alkyl substituted by one, two, three, or four substituents each independently selected from the group consisting of: -C(=O)-Het 6a , -C(=O)-Het 6b , -NR 10c -C(=O)-C 1-4 alkyl, -NR xc R xd , -NR 8a R8b , -CF3, halogenated group, -OH, -O-C 1-4 alkyl group, Het 1 , Het 2 , Ar 1 and Cy 2 ;

[0293] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl group and -S(=O)2-C 1-4 alkyl group;

[0294] or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl group and -S(=O)2-C 1-4 alkyl group;

[0295] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl group; -(C=O)-C 1-4 alkyl group; and C 1-4 alkyl group substituted by one, two, or three -O-C 1-6 alkyl group;

[0296] Ar 1 represents a phenyl group optionally substituted by one, two, or three substituents each independently selected from the group consisting of: C 1-4 alkyl group and -C(=O)-NR 10a R 10b ;

[0297] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a substituent selected from the group consisting of: halo, R 6 , C 1-4 alkyl, oxo and -OH;

[0298] Het 2 represents a C-linked pyrazolyl, 1,2,4- diazolyl, pyridazinyl or triazolyl;

[0299] R 6 is selected from the group consisting of: 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; C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of: Het 6a , Het 6b and -OH;

[0300] R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-4 alkyl substituted with one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, cyano, -S(=O)2-C 3a alkyl and Het 1-6 ;

[0301] Het 3 and Het3a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen atom by -(C=O)-C 1-4 alkyl substituted;

[0302] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted at one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0303] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one or two carbon atoms by a total of one, two, three or four substituents each independently selected from the group consisting of halo and -S(=O)2-C 1-4 alkyl; and wherein the heterocyclic group is optionally substituted at one nitrogen by a substituent selected from the group consisting of -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0304] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by -C(=O)-C 1-4 alkyl substituted;

[0305] Cy 1 represents a C 3-6 cycloalkyl optionally substituted by one, two or three -OH;

[0306] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbocyclic ring system;

[0307] wherein the C3-7 The cycloalkyl or bicyclic ring system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH and C 1-4 alkyl;

[0308] R 9a and R 9b are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -C(=O)-R 14 ;

[0309] R 10a , R 10b and R 10c are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0310] R 10d and R 10e are each independently selected from the group consisting of: C 1-4 alkyl and -O-C 1-4 alkyl;

[0311] R 14 represents -O-C 1-4 alkyl;

[0312] and their pharmaceutically acceptable salts and solvates.

[0313] According to one embodiment, the compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0314] Q represents -CHR y -;

[0315] R 1a represents -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-O-C 1-4 alkyl, or

[0316]

[0317] R 18 represents C1-6 alkyl;

[0318] R 19 represents hydrogen or C 1-6 alkyl;

[0319] or R 18 and R 19 together form -(CH2)3-;

[0320] R xa and R xb are each independently selected from the group consisting of hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted by one, two or three substituents selected from the group consisting of: -OH, -OC 1-4 alkyl and -C 1-4 alkyl-OH;

[0321] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, -OH, -O-C 1-4 alkyl, and C 23 alkyl substituted by one, two or three OR 1-4 alkyl;

[0322] or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three -OH substituents;

[0323] R 23 represents hydrogen or C 1-4 alkyl;

[0324] R 1b represents F or -O-C 1-4 alkyl;

[0325] R2 represents a halogen group, C 1-4 alkyl, or C 1-4 alkyl substituted by one, two or three halogen group substituents;

[0326] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a , -Y a -R 3a and -Y-R 3 one of which is connected to the nitrogen atom of the ring;

[0327] Y and Y a each independently represents a covalent bond;

[0328] n1 is selected from 1 and 2;

[0329] n2 is selected from 1, 2 and 3;

[0330] R y represents hydrogen;

[0331] R 3 and R 3a each independently is selected from the group consisting of: Het 1 , C 1-8 alkyl, and C 1-8 alkyl substituted by one, two, three or four substituents each independently selected from the group consisting of: -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, halogen group, -OH, -O-C 1-4 alkyl, Het 1 , Het 2 , Ar 1 and Cy 2 ;

[0332] R xc and R xdTogether with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0333] Or R xc and R xd Together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one O atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three (C=O)-C 1-4 alkyl;

[0334] R 8a and R 8b Each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -(C=O)-C 1-4 alkyl; and C 1-4 alkyl substituted by one, two, or three -O-C 1-6 alkyl;

[0335] Ar 1 represents a phenyl group optionally substituted by one, two, or three -C(=O)-NR 10a R 10b ;

[0336] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of R 6 , -C(=O)-Cy 1 and -C(=O)-R 8; and wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of: halo, C 1-4 alkyl, oxo and -OH;

[0337] Het 2 represents a C-linked pyrazolyl, 1,2,4 diazolyl or pyridazinyl;

[0338] R 6 is selected from the group consisting of: 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; C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of: Het 6a , Het 6b and -OH;

[0339] R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-6 alkyl substituted with one, two or three substituents each independently selected from the group consisting of: -OH, -O-C 1-4 alkyl, cyano and Het 3a ;

[0340] Het 3 and Het 3a each independently represent a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one nitrogen atom with -(C=O)-C 1-4 alkyl;

[0341] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two -C(=O)-NR 10aR 10b Substituted;

[0342] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four halogenated groups; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0343] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl substituted;

[0344] Cy 1 represents a C 3-6 cycloalkyl optionally substituted with one, two, or three -OH;

[0345] Cy 2 represents a C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system;

[0346] wherein the C 3-7 cycloalkyl or carbobicyclic system is optionally substituted with one, two, three, or four substituents each independently selected from the group consisting of halogenated groups, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1-4 alkyl;

[0347] R 9a and R 9b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl, and -C(=O)-R 14 ;

[0348] R 10a , R 10b and R 10c are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0349] R 10d and R 10e Each independently selected from the group consisting of: C 1-4 Alkyl and -OC 1-4 alkyl;

[0350] R 14 Indicates-OC 1-4 alkyl;

[0351] and pharmaceutically acceptable salts and solvates thereof.

[0352] According to one embodiment, the compound of formula (I) is as defined herein, and its tautomers and stereoisomeric forms, wherein

[0353] Q stands for -CHR y -;

[0354] R 1a Represents -C(=O)-NR xa R xb ;

[0355] R xa Represents C 1-6 alkyl;

[0356] R xb Represents C 1-6 alkyl;

[0357] R 1b Indicates F;

[0358] R 2 Represents C 1-4 alkyl;

[0359] R 21 represents hydrogen;

[0360] Y represents a covalent bond;

[0361] n1 is 1;

[0362] n2 is selected from 1 and 2;

[0363] R y represents hydrogen;

[0364] R 3 Het 1 ; or C substituted by a substituent selected from the group consisting of 1-8Alkyl: -C(=O)-Het 6a , Het 1 , Ar 1 and Cy 2 ;

[0365] Ar 1 represents phenyl optionally substituted by one -C(=O)NR 10a R 10b substituent;

[0366] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one, two, three or four substituents each independently selected from the group consisting of: halo group, C 1-4 alkyl, oxo group and -OH;

[0367] R 6 is selected from the group consisting of: -C(=O)-NH-R 8 ; -C(=O)-O-C 1-4 alkyl; -S(=O)2-C 1-4 alkyl and C 1-6 alkyl;

[0368] R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-6 alkyl substituted by a substituent selected from the following: -OH, -O-C 1-4 alkyl, cyano group and Het 3a ;

[0369] Het 3arepresents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one carbon atom with -(C=O)-C 1-4 alkyl substituted;

[0370] Het 6a represents a monocyclic N-linked 4- to 7-membered fully or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0371] Cy 1 represents C 3-6 cycloalkyl;

[0372] Cy 2 represents C 3-7 cycloalkyl; wherein the C 3-7 cycloalkyl is optionally substituted with one or two substituents each independently selected from the group consisting of: R 6 and -NR 9a R 9b ;

[0373] R 9a and R 9b are each independently selected from the group consisting of: hydrogen and -C(=O)-R 14 ;

[0374] R 10a and R 10b are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0375] R 14 represents -O-C 1-4 alkyl;

[0376] and their pharmaceutically acceptable salts and solvates.

[0377] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0378] Q represents -CHR y - or -CR y =; in the case where Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0379] R 1a represents hydrogen, halo, -C(=O)-NRxa R xb 、 -S(=O)₂-R 18 、 -C(=O)-O-C 1-4 alkyl

[0380]

[0381] R 18 represents C 1-6 alkyl;

[0382] R 19 represents hydrogen or C 1-6 alkyl;

[0383] or R 18 and R 19 together form -(CH₂)₃-;

[0384] R xa and R xb are each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, said C 3-6 cycloalkyl and C 1-6 alkyl are substituted by one, two or three substituents each independently selected from the group consisting of: -OH, -OC 1-4 alkyl and -C 1-4 alkyl-OH;

[0385] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and additional heteroatoms optionally selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)₂, and wherein said heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, and C 23 alkyl substituted by one, two or three substituents selected from the group consisting of OR 1-4 ;

[0386] or R xa and R xbTogether with the N atom to which they are attached, they form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two, or three -OH substituents;

[0387] R 23 represents hydrogen or C 1-4 alkyl;

[0388] R 1b represents F;

[0389] R 2 represents a halo group, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two, or three halo group substituents;

[0390] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a then one of -Y a -R 3a and -Y-R 3 is attached to the nitrogen atom of the ring;

[0391] Y and Y a each independently represents a covalent bond or

[0392]

[0393] n1 is selected from 1 and 2;

[0394] n2 is selected from 1, 2, and 3;

[0395] R y represents hydrogen;

[0396] R 5 represents hydrogen;

[0397] R 3 , R 3a and R 4 are each independently selected from the group consisting of Het 1 ; Het 2 ; Cy 2 ; C 1-8 alkyl; and C 1-8 alkyl substituted with one, two, three, or four substituents each independently selected from the group consisting of: -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, -O-C 1-4 alkyl, Het 1 , Het 2 , Ar 1 and Cy 2 ;

[0398] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0399] or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0400] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; and C 1-4 alkyl substituted by -O-C 1-6 alkyl;

[0401] Ar 1 represents a phenyl group optionally substituted by one, two, or three substituents each independently selected from the group consisting of: C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0402] Het1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents selected from the group consisting of: halo, R 6 , C 1-4 alkyl, oxo and -OH;

[0403] Het 2 represents a C-linked pyrazolyl, 1,2,4- diazolyl, pyridazinyl or triazolyl;

[0404] R 6 is selected from the group consisting of: 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; C 1-6 alkyl optionally substituted with one or two -OH substituents; and C 3-6 cycloalkyl;

[0405] R 8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-4 alkyl substituted with one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, cyano, -S(=O)2-C 3a alkyl and Het 1-6 alkyl;

[0406] Het 3 and Het3a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with an oxo group on one carbon atom; and wherein the heterocyclic group is optionally substituted on one nitrogen atom with -(C=O)-C 1-4 alkyl substituted;

[0407] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0408] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of halo and -S(=O)2-C 1-4 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0409] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl substituted;

[0410] Cy 1 represents a C 3-6 cycloalkyl optionally substituted with one, two or three -OH;

[0411] Cy2 represents C 3-7 a cycloalkyl group or a 5- to 12-membered saturated carbocyclic ring system;

[0412] wherein said C 3-7 the cycloalkyl group or the carbocyclic ring system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH and C 1-4 alkyl;

[0413] R 9a and R 9b each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -C(=O)-R 14 ;

[0414] R 10a , R 10b and R 10c each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0415] R 10d and R 10e each independently selected from the group consisting of: C 1-4 alkyl and -O-C 1-4 alkyl;

[0416] R 14 represents -O-C 1-4 alkyl;

[0417] and their pharmaceutically acceptable salts and solvates.

[0418] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0419] Q represents -CHR y -, -O-, -C(=O)-, -NR q - or -CR y =; in the case where Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0420] R 1arepresents hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0421]

[0422] R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl;

[0423] R 19 represents hydrogen or C 1-6 alkyl;

[0424] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the monocyclic 5- or 6-membered aromatic ring is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl or cyano;

[0425] R xa and R xb are each independently selected from the group consisting of hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted by one, two or three substituents selected from the group consisting of -OH, -OC 1-4 alkyl and NR 11c R 11d ;

[0426] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, -C 1-4 alkyl-O-C 1-4 alkyl and cyano;

[0427] or R xa and R xbTogether with the N atoms to which they are attached, form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom can be substituted to form S(=O) or S(=O)2; where the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, -C 1-4 alkyl-O-C 1-4 alkyl and cyano;

[0428] R 1b represents hydrogen, F, or Cl;

[0429] R 2 represents halo, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C 1-4 alkyl substituted by one, two, or three halo substituents;

[0430] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a then one of -Y a -R 3a and -Y-R 3 is attached to the nitrogen atom of the ring;

[0431] Y and Y a each independently represent a covalent bond or

[0432]

[0433] n1 and n2 each independently selected from 1 and 2;

[0434] R y represents hydrogen, -OH, C 1-4 alkyl, -C 1-4 alkyl-OH or -C 1-4 alkyl-O-C 1-4 alkyl;

[0435] R q represents hydrogen or C 1-4 alkyl;

[0436] R 5 represents hydrogen, C 1-4 alkyl or C 3-6Cycloalkyl;

[0437] R 3 , R 3a and R 4 Each independently selected from the group consisting of: Het 1 ;Het 2 ;Cy 2 ; C 1-6 Alkyl; and C substituted by one, two, three or four substituents each independently selected from the group consisting of 1-6 Alkyl: -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、halogen、-OH、-OC 1-4 Alkyl, Het 1 、Het 2 and Cy 2 ;

[0438] R xc 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 Alkyl-phenyl;

[0439] R xd represents hydrogen; C 1-4 Alkyl; or C substituted by one, two or three substituents selected from the group consisting of 1-4 Alkyl: halo, -OH, -OC 1-4 Alkyl and cyano groups;

[0440] or R xc and R xd Together with the N atom to which they are attached, they form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group, the heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -OC1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and cyano;

[0441] or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl-S(=O)2-C 1-4 alkyl and cyano;

[0442] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: -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 alkyl;

[0443] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted at one or two carbon atoms by a substituent selected from the group consisting of: halo, R 6 , Het 6a , Het6b , C 1-4 alkyl, oxo group, -NR 9a R 9b and -OH;

[0444] Het 2 represents a C-linked pyrazolyl or triazolyl group; said group can be optionally substituted on one nitrogen atom by R 6a substituted;

[0445] R 6 and R 6a each independently selected from the group consisting of:

[0446] Het 3 ; Het 4 ; -C(=O)-NH-Cy 1 ; -C(=O)-NH-R 8 ; -S(=O)2-C 1-4 alkyl;

[0447] optionally substituted by one or two substituents each independently selected from the group consisting of C 1-6 alkyl: Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN, -OH, -0-C 1-4 、-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 alkyl; and

[0448] optionally substituted by one or two substituents each independently selected from the group consisting of C 3-6 cycloalkyl: -CN, -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl, -NH-S(=O)2-C 1-4 alkyl and optionally substituted by one substituent selected from the group consisting of C 1-4 alkyl: -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl;

[0449] R8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-4 alkyl substituted by one, two or three substituents each independently selected from -OH, -O-C 11a R 11b , Het 3a and Het 6a ; and C 1-6 alkyl substituted by Het

[0450] Het 3 , Het 3a , Het 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0451] wherein the heterocyclic group is optionally substituted at one carbon atom by C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; and wherein the heterocyclic group is optionally substituted at one nitrogen atom by C 1-4 alkyl;

[0452] Het 4 and Het 7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted at one nitrogen atom by C 1-4 alkyl or -(C=O)-O-C 1-4 alkyl; and wherein the aromatic ring is optionally substituted at one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 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 ;

[0453] Het 6a , Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four substituents each independently selected from the group consisting of: 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 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ;

[0454] Het 6b and Het 8bEach independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of C 1-4 alkyl, -OH, oxo group, -(C=O)-NR 10a R 10b 、-NH-C(=O)-C 1-4 alkyl, -NH-C(=O)-Cy 3 and -O-C 1-4 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -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 alkyl;

[0455] Het 9 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two, or three heteroatoms each independently selected from O, S, and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, or three heteroatoms each independently selected from O, S, and N; wherein the aromatic ring is optionally substituted on one nitrogen atom with C 1-4 alkyl; and wherein the aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of -OH, halo group, and C 1-4 alkyl;

[0456] Cy 1 represents C 3-6 cycloalkyl optionally substituted with one, two, or three substituents selected from the group consisting of -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 -0-C 1-4 alkyl;

[0457] Cy2 represents C 3-7 a cycloalkyl group or a 5- to 12-membered saturated carbocyclic ring system;

[0458] wherein said C 3-7 the cycloalkyl group or the carbocyclic ring system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: a halogenated group, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1-4 alkyl,

[0459] and C 1-4 alkyl substituted with one or two substituents each independently selected from the group consisting of: Het 3a , Het 6a , Het 6b and -NR 9a R 9b ;

[0461] Cy 3 represents C 3-7 a cycloalkyl group; wherein said C 3-7 the cycloalkyl group is optionally substituted with one, two or three halogenated substituents;

[0462] R 9a and R 9b are each independently selected from the group consisting of: 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 ;

[0463] a C 3-6 cycloalkyl group substituted with one, two or three substituents selected from the group consisting of: a halogenated group, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and a cyano group; and

[0464] C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano;

[0465] R 11a 、R 11b 、R 13a 、R 13b 、R 15a 、R 15b 、R 17a 、R 17b 、R 20a and R 20b each independently selected from the group consisting of hydrogen and C 1-4 alkyl;

[0466] R 11c and R 11d each independently selected from the group consisting of hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl;

[0467] R 10a and R 10b each independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0468] R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C 3-6 cycloalkyl substituted by one, two or three substituents selected from the group consisting of: -O-C 1-4 alkyl and halo; or C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: -O-C 1-4 alkyl, -NR 13a R 13b 、halo, cyano, -OH, Het 8a and Cy 1 ;

[0469] R 16 represents -C(=O)-NR 17a R 17b、 -S(=O)2-C 1-4 alkyl, Het 5 、Het 7 or Het 8 ;

[0470] and pharmaceutically acceptable salts and solvates thereof.

[0471] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0472] Q represents -CHR y -, -O-, -C(=O)-, -NR q - or -CR y =; when Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0473] R 1a represents hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb 、 -S(=O)2-R 18 、

[0474]

[0475] R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl;

[0476] R 19 represents hydrogen or C 1-6 alkyl;

[0477] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and an optional carbonyl moiety; wherein the monocyclic 5- or 6-membered aromatic ring is optionally substituted with one, two or three substituents selected from the group consisting of: C 1-4 alkyl, C 3-6 cycloalkyl or cyano;

[0478] R xa and R xb are each independently selected from the group consisting of: hydrogen, Het 3 、C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted with one, two or three substituents selected from the group consisting of: -OH, -OC 1-4 alkyl and NR 11c R11d ;

[0479] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, -C 1-4 alkyl-O-C 1-4 alkyl and cyano;

[0480] or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, -C 1-4 alkyl-O-C 1-4 alkyl and cyano;

[0481] R 1b represents hydrogen, F, or Cl;

[0482] R 2 represents halo, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C 1-4 alkyl substituted by one, two, or three halo substituents;

[0483] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a then one of -Y a -R 3a and -Y-R 3 is attached to the nitrogen atom of the ring;

[0484] Y and Y aeach independently represents a covalent bond or

[0485]

[0486] n1 and n2 each independently are selected from 1 and 2;

[0487] R y represents hydrogen, -OH, C 1-4 alkyl, -C 1-4 alkyl-OH or -C 1-4 alkyl-O-C 1-4 alkyl;

[0488] R q represents hydrogen or C 1-4 alkyl;

[0489] R 5 represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

[0490] R 3 、R 3a and R 4 each independently are selected from the group consisting of: Het 1 ; Het 2 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -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, -O-C 1-4 alkyl, Het 1 、Het 2 and Cy 2 ;

[0491] R xc represents 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 alkyl-phenyl;

[0492] Rxd represents hydrogen; C 1-4 alkyl; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: halo, -OH, -O-C 1-4 alkyl and cyano;

[0493] or R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and cyano;

[0494] or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl -S(=O)2-C 1-4 alkyl and cyano;

[0495] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; and C substituted by one, two or three substituents each independently selected from the group consisting of 1-6 alkyl: -OH, cyano, halo, -S(=O)2-C 1-4 alkyl, -O-C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0496] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms by 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;

[0497] Het 2 represents a C-linked pyrazolyl or triazolyl group; the group can be optionally substituted on one nitrogen atom by R 6a ;

[0498] R 6 and R 6a are each independently selected from the group consisting of:

[0499] Het 3 ; Het 4 ; -C(=O)-NH-Cy 1 ; -C(=O)-NH-R 8 ; -S(=O)2-C 1-4 alkyl;

[0500] C 1-6 alkyl substituted by one or two substituents each independently selected from the group consisting of: Het 3 , Het 4 , Het 6a , Het 6b , Cy 1 , -CN, -OH, -O-C 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 R11b and -NH-S(=O)2-C 1-4 alkyl; and

[0501] C optionally substituted with one or two substituents each independently selected from the group consisting of 3-6 cycloalkyl: -CN, -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl, -NH-S(=O)2-C 1-4 alkyl and C optionally substituted with a substituent selected from the group consisting of 1-4 alkyl: -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl;

[0502] R 8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or C substituted with one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, halo, cyano, -NR 11a R 11b , Het 3a and Het 6a and C substituted with a substituent of 1-6 alkyl;

[0503] Het 3 、Het 3a 、Het 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0504] wherein the heterocyclic group is optionally substituted on a carbon atom with C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; and wherein the heterocyclic group is optionally substituted on a nitrogen atom with C 1-4 alkyl;

[0505] Het 4 and Het7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted at one nitrogen atom with C 1-4 alkyl or -(C═O)-O-C 1-4 alkyl; and wherein said aromatic ring is optionally substituted at one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 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 ;

[0506] Het 6a , Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(═O) or S(═O)2; wherein said heterocyclic group is optionally substituted at one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of: halo, -OH, oxo, -NH-C(═O)-C 1-4 alkyl, -NH-C(═O)-Cy 3 , -(C═O)-NR 10a R 10b , -O-C3-6 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 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ;

[0507] Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: 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 -O-C 1-4 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -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 alkyl;

[0508] Het 9represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted at one nitrogen atom with C 1-4 alkyl; and wherein said aromatic ring is optionally substituted at one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -OH, halo, and C 1-4 alkyl;

[0509] Cy 1 represents C 3-6 cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of: -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 -0-C 1-4 alkyl;

[0510] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system;

[0511] wherein said C 3-7 cycloalkyl or carbobicyclic system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b , -NR 9a R 9b , -OH, C 1-4 alkyl,

[0512] and C 1-4 alkyl substituted with one or two substituents each independently selected from the group consisting of: Het 3a , Het 6a , Het 6b and -NR 9a R 9b ;

[0514] Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7 cycloalkyl is optionally substituted with one, two or three halo substituents;

[0515] R 9a and R 9b each independently is selected from the group consisting of: 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 ;

[0516] C 3-6 cycloalkyl which is substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and

[0517] C 1-4 alkyl which is substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano;

[0518] R 11a 、R 11b 、R 13a 、R 13b 、R 15a 、R 15b 、R 17a 、R 17b 、R 20a and R 20b each independently is selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0519] R 11c and R 11d each independently is selected from the group consisting of: hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl;

[0520] R 10a and R 10b each independently is selected from the group consisting of: hydrogen, C 1-4 alkyl and C 3-6Cycloalkyl;

[0521] R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -O-C 1-4 alkyl and halo; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ;

[0522] R 16 represents -C(=O)-NR 17a R 17b , -S(=O)2-C 1-4 alkyl, Het 5 , Het 7 or Het 8 ;

[0523] and pharmaceutically acceptable salts and solvates thereof.

[0524] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0525] Q represents -CHR y -, -O-, -C(=O)-, -NR q - or -CR y =; when Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0526] R 1a represents hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0527]

[0528] R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl;

[0529] R 19 represents hydrogen or C 1-6 alkyl;

[0530] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said monocyclic 5- or 6-membered aromatic ring is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl or cyano;

[0531] R xa and R xb are each independently selected from the group consisting of hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, said C 3-6 cycloalkyl and C 1-6 alkyl are substituted by one, two or three substituents each independently selected from the group consisting of -OH, -OC 1-4 alkyl and NR 11c R 11d ;

[0532] Or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, -C 1-4 alkyl-O-C 1-4 alkyl and cyano;

[0533] Or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, -C 1-4 alkyl-O-C1-4 Alkyl and cyano group;

[0534] R 1b represents hydrogen, F or Cl;

[0535] R 2 represents a halogenated group, C 3-6 cycloalkyl group, C 1-4 alkyl group, -O-C 1-4 alkyl group, cyano group, or C 1-4 alkyl group substituted by one, two or three halogenated group substituents;

[0536] R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a at this time, -Y a -R 3a and -Y-R 3 one of them is connected to the nitrogen atom of the ring;

[0537] Y and Y a each independently represents a covalent bond or

[0538]

[0539] n1 and n2 each independently selected from 1 and 2;

[0540] R y represents hydrogen, -OH, C 1-4 alkyl group, -C 1-4 alkyl group -OH or -C 1-4 alkyl group -O-C 1-4 alkyl group;

[0541] R q represents hydrogen or C 1-4 alkyl group;

[0542] R 5 represents hydrogen, C 1-4 alkyl group or C 3-6 cycloalkyl group;

[0543] R 3 、R 3a and R 4 each independently selected from the group consisting of: Het 1 ; Het 2 ; Cy 2 ; C 1-6 alkyl group; and C 1-6Alkyl: -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, -O-C 1-4 alkyl, Het 1 、Het 2 and Cy 2 ;

[0544] R xc represents 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 alkyl-phenyl;

[0545] R xd represents hydrogen; C 1-4 alkyl; or C 1-4 alkyl substituted with one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl and cyano;

[0546] Or R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and cyano;

[0547] Or R xc and R xdTogether with the N atom to which they are attached, they form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl-S(=O)2-C 1-4 alkyl and cyano;

[0548] R 8a and R 8b each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: -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 alkyl;

[0549] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one, two, three, or four substituents each independently selected from the group consisting of: halo, R 6 , Het 6a , Het 6b , C 1-4 alkyl, oxo, -NR 9a R 9b and -OH;

[0550] Het 2 represents a C-linked pyrazolyl or triazolyl group; the group can be optionally substituted on one nitrogen atom by R 6a ;

[0551] R 6and R 6a each independently selected from the group consisting of:

[0552] Het 3 ; Het 4 ; -C(=O)-NH-Cy 1 ; -C(=O)-NH-R 8 ; -S(=O)2-C 1-4 alkyl;

[0553] C alkyl substituted with one or two substituents each independently selected from the group consisting of: 1-6 Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN, -OH, -O-C 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 alkyl; and

[0554] C cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of: 3-6 -CN, -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl, -NH-S(=O)2-C 1-4 alkyl and C alkyl optionally substituted with a substituent selected from the group consisting of: 1-4 -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl;

[0555] R 8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or C alkyl substituted with one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, halo, cyano, -NR 11a R 11b 、Het 3a and Het 6a ; 1-6 alkyl;

[0556] Het 3 、Het 3a 、Het 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0557] wherein said heterocyclic group is optionally substituted at one carbon atom with C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; and wherein said heterocyclic group is optionally substituted at one nitrogen atom with C 1-4 alkyl;

[0558] Het 4 and Het 7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted at one nitrogen atom with C 1-4 alkyl or -(C=O)-O-C 1-4 alkyl; and wherein said aromatic ring is optionally substituted at one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 1-4 alkyl, -NH-S(=O)2-C 1-4 alkyl, Het 8a 、-C1-4 alkyl-Het 8a 、Het 8b 、Het 9 and -C(=O)-NR 10a R 10b ;

[0559] Het 6a 、Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four substituents each independently selected from the group consisting of: 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 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ;

[0560] Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: 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 -O-C 1-4 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: -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 alkyl;

[0561] Het 9 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted on one nitrogen atom by C 1-4 alkyl; and wherein said aromatic ring is optionally substituted on one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: -OH, halo and C 1-4 alkyl;

[0562] Cy 1 represents a C 3-6 cycloalkyl optionally substituted by one, two or three substituents selected from the group consisting of: -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 -0-C 1-4 alkyl;

[0563] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system;

[0564] wherein said C 3-7 cycloalkyl or carbobicyclic system is optionally substituted by one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 , -C(=O)-Het 6a , Het 6a , Het 6b, -NR 9a R 9b , -OH, C 1-4 alkyl,

[0565] and C substituted by one or two substituents each independently selected from the group consisting of: 1-4 alkyl: Het 3a , Het 6a , Het 6b and -NR 9a R 9b ;

[0567] Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7 cycloalkyl is optionally substituted by one, two or three halo substituents;

[0568] R 9a and R 9b are each independently selected from the group consisting of: 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 ;

[0569] C 3-6 cycloalkyl substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and

[0570] C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano;

[0571] R 11a , R 11b , R 13a , R 13b , R15a , R 15b , R 17a , R 17b , R 20a and R 20b each independently is selected from the group consisting of hydrogen and C 1-4 alkyl;

[0572] R 11c and R 11d each independently is selected from the group consisting of hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl;

[0573] R 10a and R 10b each independently is selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0574] R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C 3-6 cycloalkyl substituted with one, two or three substituents selected from the group consisting of: -O-C 1-4 alkyl and halo; or C 1-4 alkyl substituted with one, two or three substituents selected from the group consisting of: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ;

[0575] R 16 represents -C(=O)-NR 17a R 17b , -S(=O)2-C 1-4 alkyl, Het 5 , Het 7 or Het 8 ;

[0576] and their pharmaceutically acceptable salts and solvates.

[0577] According to one embodiment, the compounds of formula (I) as defined herein, and their tautomeric and stereoisomeric forms, wherein

[0578] Q represents -CHRy -, -O-, -C(=O)-, -NR q - or -CR y =; where Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0579] R 1a represents hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0580]

[0581] R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl;

[0582] R 19 represents hydrogen or C 1-6 alkyl;

[0583] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and an optional carbonyl moiety; wherein the monocyclic 5- or 6-membered aromatic ring is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl or cyano;

[0584] R xa and R xb each independently selected from the group consisting of hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, the C 3-6 cycloalkyl and C 1-6 alkyl are each independently substituted with one, two or three substituents selected from the group consisting of -OH, -OC 1-4 alkyl and NR 11c R 11d ;

[0585] Or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and an optional additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4Alkyl, halo, -OH, -O-C 1-4 Alkyl, -C 1-4 Alkyl-O-C 1-4 Alkyl and cyano;

[0586] Or R xa And R xb Together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 Alkyl, halo, -OH, -O-C 1-4 Alkyl, -C 1-4 Alkyl-O-C 1-4 Alkyl and cyano;

[0587] R 1b Represents hydrogen, F, or Cl;

[0588] R 2 Represents C 1-4 Alkyl; in particular R 2 Represents methyl;

[0589] R 21 Represents hydrogen or -Y a -R 3a ; provided that when R 21 Represents -Y a -R 3a Then, one of -Y a -R 3a And -Y-R 3 Is attached to the nitrogen atom of the ring;

[0590] Y and Y a Each independently represents a covalent bond or

[0591]

[0592] n1 and n2 each independently selected from 1 and 2;

[0593] R y Represents hydrogen, -OH, C 1-4 Alkyl, -C 1-4 Alkyl-OH or -C 1-4 Alkyl-O-C 1-4 Alkyl;

[0594] R q Represents hydrogen or C 1-4 Alkyl;

[0595] R 5 represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

[0596] R 3 , R 3a and R 4 are each independently selected from the group consisting of: Het 1 ; Het 2 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, three or four substituents each independently selected from the group consisting of: -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, -O-C 1-4 alkyl, Het 1 ; Het 2 and Cy 2 ;

[0597] R xc represents 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 alkyl-phenyl;

[0598] R xd represents hydrogen; C 1-4 alkyl; or C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl and cyano;

[0599] Or R xc and R xdTogether with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl, and cyano;

[0600] Or R xc and R xd Together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl -S(=O)2-C 1-4 alkyl, and cyano;

[0601] R 8a and R 8b Each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: -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 alkyl;

[0602] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 、-C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group 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;

[0603] Het 2 represents a C-linked pyrazolyl or triazolyl group; the group can be optionally substituted on one nitrogen atom with R 6a ;

[0604] R 6 and R 6a are each independently selected from the group consisting of:

[0605] Het 3 ; Het 4 ; -C(=O)-NH-Cy 1 ; -C(=O)-NH-R 8 ; -S(=O)2-C 1-4 alkyl;

[0606] C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of: Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN、-OH、-O-C 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 R11b and -NH-S(=O)2-C 1-4 alkyl; and

[0607] C optionally substituted with one or two substituents each independently selected from the group consisting of 3-6 cycloalkyl: -CN, -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl, -NH-S(=O)2-C 1-4 alkyl and C optionally substituted with a substituent selected from the group consisting of 1-4 alkyl: -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl;

[0608] R 8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or is substituted with one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, halo, cyano, -NR 11a R 11b , Het 3a and Het 6a of C substituted with a substituent 1-6 alkyl;

[0609] Het 3 , Het 3a , Het 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0610] wherein the heterocyclic group is optionally substituted at a carbon atom with C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; and wherein the heterocyclic group is optionally substituted at a nitrogen atom with C 1-4 alkyl;

[0611] Het 4 and Het7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted at one nitrogen atom with C 1-4 alkyl or -(C═O)-O-C 1-4 alkyl; and wherein said aromatic ring is optionally substituted at one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 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 ;

[0612] Het 6a , Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(═O) or S(═O)2; wherein said heterocyclic group is optionally substituted at one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of: halo, -OH, oxo, -NH-C(═O)-C 1-4 alkyl, -NH-C(═O)-Cy 3 , -(C═O)-NR 10a R 10b , -O-C3-6 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 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ;

[0613] Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of 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 -O-C 1-4 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -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 alkyl;

[0614] Het 9represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted at one nitrogen atom by C 1-4 alkyl; and wherein said aromatic ring is optionally substituted at one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: -OH, halo and C 1-4 alkyl;

[0615] Cy 1 represents C 3-6 cycloalkyl optionally substituted by one, two or three substituents selected from the group consisting of: -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 -0-C 1-4 alkyl;

[0616] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system;

[0617] wherein said C 3-7 cycloalkyl or carbobicyclic system is optionally substituted by one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 、-C(=O)-Het 6a 、Het 6a 、Het 6b 、-NR 9a R 9b 、-OH、C 1-4 alkyl,

[0618]

[0619] C 1-4 alkyl substituted by one or two substituents each independently selected from the group consisting of: Het 3a 、Het 6a 、Het 6b and -NR 9a R 9b ;

[0620] Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7The cycloalkyl group is optionally substituted with one, two or three halogen substituents;

[0621] R 9a and R 9b are each independently selected from the group consisting of: 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 ;

[0622] The C 3-6 cycloalkyl substituted with one, two or three substituents selected from the group consisting of: halogen substituents, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and

[0623] The C 1-4 alkyl substituted with one, two or three substituents selected from the group consisting of: halogen substituents, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano;

[0624] R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , R 17b , R 20a and R 20b are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0625] R 11c and R 11d are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl;

[0626] R 10a and R 10b are each independently selected from the group consisting of: hydrogen, C1-4 Alkyl and C 3-6 cycloalkyl;

[0627] R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -O-C 1-4 alkyl and halo; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ;

[0628] R 16 represents -C(=O)-NR 17a R 17b , -S(=O)2-C 1-4 alkyl, Het 5 , Het 7 or Het 8 ;

[0629] and their pharmaceutically acceptable salts and solvates.

[0630] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0631] Q represents -CHR y - or -CR y =; when Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0632] R 1a represents hydrogen, halo, -C(=O)-NR xa R xb or

[0633]

[0634] R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl;

[0635] R 19represents hydrogen or C 1-6 alkyl;

[0636] R xa and R xb each independently selected from the group consisting of hydrogen, Het 3 and C 1-6 alkyl; wherein optionally said C 1-6 alkyl is substituted with one, two or three substituents each independently selected from the group consisting of OH and -OC 1-4 alkyl;

[0637] or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein said S atom may be substituted to form S(=O) or S(=O)2, and wherein said heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, -OH and -O-C 1-4 alkyl;

[0638] or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; and wherein said heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, -OH and -O-C 1-4 alkyl;

[0639] R 1b represents F;

[0640] R 2 represents a halogen group, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two or three halogen group substituents;

[0641] R 21 represents hydrogen;

[0642] Y represents a covalent bond or

[0643]

[0644] n1 and n2 each independently selected from 1 and 2;

[0645] Ry represents hydrogen;

[0646] R 5 represents hydrogen;

[0647] R 3 and R 4 each independently selected from the group consisting of: Het 1 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted by one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd , -NR 8a R 8b , -CF3, -OH, Het 1 and Cy 2 ;

[0648] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0649] Or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0650] R 8a and R 8b each independently selected from the group consisting of: C 1-6 alkyl; and C 1-4 alkyl substituted by one -O-C 1-6 alkyl;

[0651] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: oxo group and -NR 9a R 9b ;

[0652] R 6 represents Het 4 ; -C(=O)-NH-R 8 ; -S(=O)2-C 1-4 alkyl; or C 1-6 alkyl;

[0653] R 8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-4 alkyl substituted by one, two or three substituents each independently selected from -O-C 1-6 alkyl and cyano;

[0654] Het 3 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N;

[0655] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted on one or two carbon atoms by a total of one or two -C(=O)-NR 10a R 10b substituents;

[0656] Het 6arepresents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two -S(=O)2-C 1-4 alkyl substituents; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0657] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl substituents;

[0658] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbocyclic ring system;

[0659] wherein the C 3-7 cycloalkyl or carbocyclic ring system is optionally substituted with one, two, three, or four substituents each independently selected from the group consisting of: R 6 、-C(=O)-Het 6a 、Het 6a 、Het 6b 、-NR 9a R 9b 、

[0660]

[0661] R 9a and R 9b each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0662] R 10a and R 10b each independently selected from the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0663] and their pharmaceutically acceptable salts and solvates.

[0664] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0665] Q represents -CHR y - or -CR y =; in the case where Q represents -CR y =, the dashed line is an optional additional bond forming a double bond;

[0666] R 1a represents hydrogen, a halogenated group or -C(=O)-NR xa R xb ;

[0667] R xa and R xb each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

[0668] R 1b represents F;

[0669] R 2 represents a halogenated group, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two or three halogenated group substituents;

[0670] R 21 represents hydrogen;

[0671] Y represents a covalent bond or

[0672]

[0673] n1 and n2 are each independently selected from 1 and 2;

[0674] R y represents hydrogen;

[0675] R 5 represents hydrogen;

[0676] R 3 and R 4 each independently selected from the group consisting of Het 1 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd 、-NR 8a R 8b 、Het 1 and Cy2 ;

[0677] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0678] or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0679] R 8a and R 8b are each independently selected from the group consisting of: C 1-6 alkyl; and C 1-4 alkyl substituted by one -O-C 1-6 alkyl;

[0680] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 and -C(=O)-R 8 ;

[0681] R 6 represents Het 4 , -C(=O)-NH-R 8 or -S(=O)2-C 1-4 alkyl;

[0682] R 8 represents -O-C 1-6 alkyl, C 1-6 alkyl; or is substituted by one, two, or three substituents each independently selected from -O-C1-4 C substituted with substituents of alkyl and cyano 1-6 alkyl;

[0683] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two -C(=O)-NR 10a R 10b substituted;

[0684] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two -S(=O)2-C 1-4 alkyl substituted; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0685] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl substituted;

[0686] Cy 2 represents C 3-7 cycloalkyl, said cycloalkyl being optionally substituted with one, two, three or four substituents each independently selected from the group consisting of R 6 , Het 6a , Het 6b and -NR 9a R 9b ;

[0687] R 9a and R 9b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, -C(=O)-C 1-4 alkyl and -S(=O)2-C1-4 alkyl;

[0688] R 10a and R 10b each independently selected from hydrogen and C 1-4 alkyl;

[0689] and pharmaceutically acceptable salts and solvates thereof.

[0690] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0691] Q represents -CHR y -;

[0692] R 1a represents -C(=O)-NR xa R xb ;

[0693] R xa and R xb represent C 1-6 alkyl;

[0694] R 1b represents F;

[0695] R 2 represents a halogenated group or C 1-4 alkyl;

[0696] R 21 represents hydrogen;

[0697] Y represents a covalent bond or

[0698]

[0699] n1 and n2 each independently selected from 1 and 2;

[0700] R y represents hydrogen;

[0701] R 5 represents hydrogen;

[0702] R 3 is selected from the group consisting of Het 1 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd , Het 1 and Cy 2 ;

[0703] R 4 represents C 1-6 alkyl; especially isopropyl;

[0704] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted by one, two, or three -(C=O)-C 1-4 alkyl substituents;

[0705] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of R 6 and -C(=O)-R 8 ;

[0706] R 6 represents Het 4 or -C(=O)-NH-R 8 ;

[0707] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted by one, two, or three substituents each independently selected from -O-C 1-6 alkyl and cyano;

[0708] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two, or three heteroatoms each independently selected from O, S, and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three, or four heteroatoms each independently selected from O, S, and N; wherein the aromatic ring is optionally substituted on one or two carbon atoms by a total of one or two -C(=O)-NR 10a R 10b substituents;

[0709] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by -C(=O)-C 1-4 alkyl substituents;

[0710] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen with -C(=O)-C 1-4 alkyl;

[0711] Cy 2 represents C 3-7 cycloalkyl, wherein the cycloalkyl is optionally substituted with one, two, three, or four substituents each independently selected from the group consisting of: R 6 , Het 6a , Het 6b and -NR 9a R 9b ;

[0712] R 9a and R 9b are each independently selected from the group consisting of: hydrogen and -S(=O)2-C 1-4 alkyl;

[0713] R 10a and R 10b are each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0714] and pharmaceutically acceptable salts and solvates thereof.

[0715] According to one embodiment, a compound of formula (I) as defined herein, and its tautomeric and stereoisomeric forms, wherein

[0716] Q represents -CHR y -;

[0717] R 1a represents -C(=O)-NR xa R xb ;

[0718] R xa and R xb represent C 1-6 alkyl;

[0719] R 1b represents F;

[0720] R 2 represents C 1-4 alkyl;

[0721] R 21 represents hydrogen;

[0722] Y represents a covalent bond or

[0723]

[0724] n1 and n2 are each independently selected from 1 and 2;

[0725] R y represents hydrogen;

[0726] R 5 represents hydrogen;

[0727] R 3 is selected from the group consisting of: Cy 2 ; and C 1-6 alkyl substituted by one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd , Het 1 and Cy 2 ;

[0728] R 4 represents C 1-6 alkyl; in particular isopropyl;

[0729] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N; wherein said heterocyclic group is optionally substituted by one, two or three -(C=O)-C 1-4 alkyl;

[0730] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N; wherein said heterocyclic group is optionally substituted at one nitrogen by -C(=O)-R 8 ;

[0731] R 6 represents -C(=O)-NH-R 8 ;

[0732] R 8 represents C 1-6 alkyl;

[0733] Het 6arepresents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen with -C(=O)-C 1-4 alkyl substituted;

[0734] Cy 2 represents C 3-7 cycloalkyl, which cycloalkyl is optionally substituted with one, two, three, or four substituents each independently selected from the group consisting of: R 6 and Het 6a ;

[0735] and their pharmaceutically acceptable salts and solvates.

[0736] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0737] Q represents -CHR y -;

[0738] R 1a represents -C(=O)-NR xa R xb ;

[0739] R xa and R xb are C 1-6 alkyl optionally substituted with 1, 2, or 3 -OH;

[0740] R 1b represents F;

[0741] R 2 represents methyl;

[0742] R 21 represents hydrogen or methyl;

[0743] Y represents a covalent bond;

[0744] n1 is 1;

[0745] n2 is selected from 1 and 2;

[0746] R y represents hydrogen;

[0747] R 3 is selected from C 1-8 alkyl substituted with one, two, three, or four substituents each independently selected from the group consisting of: -NR xcR xd , Het 1 and Cy 2 ;

[0748] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted by one, two, or three -(C=O)-C 1-4 alkyl groups;

[0749] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on a nitrogen by -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on a carbon atom by an oxo group;

[0750] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted by one, two, or three substituents each independently selected from -OH, -O-C 1-6 alkyl, and cyano;

[0751] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on a nitrogen by -C(=O)-C 1-4 alkyl;

[0752] Cy 2 represents C 6a cycloalkyl optionally substituted by one Het 3-7 ;

[0753] and their pharmaceutically acceptable salts and solvates.

[0754] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Q represents -CHR y - or -CR y =; the dashed line is an optional additional bond that forms a double bond when Q represents -CR y =.

[0755] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Q represents -CHR y -.

[0756] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0757] R 1a represents hydrogen, Het, -C(=O)-NR xa R xb -, -S(=O)2-R 18 ,

[0758]

[0759] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0760] R 1a represents Het; -C(=O)-NR xa R xb -, -S(=O)2-R 18 ,

[0761]

[0762] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0763] R 1a represents -C(=O)-NR xa R xb -, -S(=O)2-R 18 or

[0764]

[0765] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0766] R 1a represents -C(=O)-NR xa R xb or

[0767]

[0768] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0769] R 1a represents -C(=O)-NR xa R xb .

[0770] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 18 represents C 1-6 alkyl.

[0771] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xa and R xb represent hydrogen or C 1-6 alkyl.

[0772] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xa and R xb are each independently selected from the group consisting of: hydrogen, Het 3 and C 1-6 alkyl; wherein optionally said C 1-6 alkyl is substituted with one, two or three substituents each independently selected from the group consisting of: OH and -OC 1-4 alkyl;

[0773] Or R xa and R xbTogether with the N atom to which they are attached, they form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, -OH, and -O-C 1-4 alkyl;

[0774] Or R xa and R xb Together with the N atom to which they are attached, they form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; and wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, -OH, and -O-C 1-4 alkyl.

[0775] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xa and R xb are each independently selected from the group consisting of hydrogen, Het 3 and C 1-6 alkyl; wherein optionally the C 1-6 alkyl is substituted by 1, 2, or 3 substituents each independently selected from the group consisting of OH and -OC 1-4 alkyl.

[0776] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xa and R xb represent C 1-6 alkyl.

[0777] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xa together with R xb forms a group.

[0778] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Rxa not combined with R xb not combined together.

[0779] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 1b represents F or Cl.

[0780] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 1b represents F.

[0781] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 2 represents a halo group, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two or three halo group substituents.

[0782] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 2 represents a halo group or C 1-4 alkyl.

[0783] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 2 represents C 1-4 alkyl.

[0784] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 2 represents methyl.

[0785] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0786] R 2 represents methyl; and R 1a represents -C(=O)-NR xa R xb .

[0787] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Y and Y a represent a covalent bond.

[0788] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 21 represents hydrogen.

[0789] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 21 represents hydrogen or methyl.

[0790] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0791] R 21 represents hydrogen; and

[0792] Y represents a covalent bond.

[0793] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0794] R 21 represents hydrogen or methyl; and

[0795] Y represents a covalent bond.

[0796] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 21 represents -Y a -R 3a .

[0797] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 21 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkyl substituted with 1 substituent selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -C(=O)-NR 10a R10b 、 -NR 10c -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl.

[0798] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 21 represents C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkyl substituted with a substituent selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -C(=O)-NR 10a R 10b 、 -NR 10c -C(=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl.

[0799] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 10c is selected from the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl.

[0800] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0801] R 3 、 R 3a and R 4 are each independently selected from the group consisting of: Het 1 ; Het 2 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -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, -O-C 1-4 alkyl, Het 1, Het 2 and Cy 2 ;

[0802] R 8a and R 8b are each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two or three substituents each independently selected from the group consisting of: -OH, cyano, halo, -S(=O)2-C 1-4 alkyl, -O-C 1-4 alkyl and -C(=O)-NR 10a R 10b .

[0803] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0804] R 3 , R 3a and R 4 are not C 10c alkyl substituted with -NR 1-4 -C(=O)-C 1-6 alkyl;

[0805] R 8a and R 8b are not C 10c alkyl substituted with -NR 1-4 -C(=O)-C 1-6 alkyl.

[0806] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Y represents a covalent bond.

[0807] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Y a represents a covalent bond.

[0808] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Y represents

[0809]

[0810] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Y a represents

[0811]

[0812] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein n1 represents 1 and n2 represents 2.

[0813] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0814] R 4 represents C 1-6 alkyl; oxetanyl; tetrahydropyranyl;

[0815]

[0816] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R y represents hydrogen.

[0817] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0818] R 4 represents C 1-6 alkyl; oxetanyl; tetrahydropyranyl;

[0819]

[0820] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 4 represents C 1-6 alkyl.

[0821] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 4 represents isopropyl.

[0822] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 4 represents C 1-8 alkyl.

[0823] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 4 represents C 1-4 alkyl.

[0824] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 5 represents hydrogen.

[0825] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0826] R 3 and R 4 are each independently selected from the group consisting of: Het 1 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd ; -NR 8a R 8b ; Het 1 ; and Cy 2 .

[0827] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0828] R 3 is selected from the group consisting of: Het 1 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of:

[0829] -NR xc R xd ; Het 1 ; and Cy2 ; and

[0830] R 4 represents C 1-6 alkyl; especially isopropyl.

[0831] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0832] R 3 is selected from the group consisting of Cy 2 ; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd Het 1 and Cy 2 ; and

[0833] R 4 represents C 1-6 alkyl; especially isopropyl.

[0834] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0835] R 3 is selected from the group consisting of Het 1 ; Cy 2 ; C 1-6 alkyl; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of:

[0836] -NR xc R xd Het 1 and Cy 2 .

[0837] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0838] R 3 is selected from the group consisting of Cy 2 ; and C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd Het1 and Cy 2 。

[0839] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and a pharmaceutically acceptable salt and solvate thereof, or any subgroup thereof, wherein Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system; wherein said C 3-7 cycloalkyl or said carbobicyclic system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: halo, R 6 , -NR 9a R 9b and -OH.

[0840] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and a pharmaceutically acceptable salt and solvate thereof, or any subgroup thereof, wherein

[0841] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of:

[0842] -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl;

[0843] Or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of: -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl.

[0844] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and a pharmaceutically acceptable salt and solvate thereof, or any subgroup thereof, wherein

[0845] R xcand R xd Together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of:

[0846] -(C=O)-C 1-4 alkyl and -S(=O)2-C 1-4 alkyl.

[0847] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xc together with R xd forms a group.

[0848] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xc does not form a group together with R xd forms a group.

[0849] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the fully saturated or partially saturated heterocyclic group is limited to a fully saturated heterocyclic group.

[0850] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0851] Q represents -CHR y -;

[0852] R 1a represents -C(=O)-NR xa R xb ;

[0853] R 1b represents F;

[0854] R 2 represents methyl.

[0855] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0856] R8a and R 8b are each independently selected from the group consisting of: C 1-6 alkyl; and C 1-4 alkyl substituted with one -O-C 1-6 alkyl.

[0857] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0858] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: oxo group and -NR 9a R 9b .

[0859] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 6 represents Het 4 or -C(=O)-NH-R 8 .

[0860] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted with one, two or three substituents each independently selected from -O-C 1-6 alkyl and cyano.

[0861] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 8 represents C1-6 Alkyl

[0862] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 8 represents methyl

[0863] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0864] Het 4 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two -C(=O)-NR 10a R 10b substituents

[0865] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0866] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl

[0867] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0868] Het 6b represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl

[0869] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0870] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system;

[0871] wherein said C 3-7 cycloalkyl or carbobicyclic system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: R 6 、-C(=O)-Het 6a 、Het 6a 、Het 6b 、-NR 9a R 9b 、

[0872]

[0873] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0874] Cy 2 represents C 3-7 cycloalkyl, which cycloalkyl is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: R 6 、Het 6a 、Het 6b 、-NR 9a R 9b 、

[0875]

[0876] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0877] Cy 2 represents C 3-7 cycloalkyl, which cycloalkyl is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of R 6 、Het 6a 、Het 6b and -NR 9a R 9b .

[0878] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 9a and R 9b are each independently selected from the group consisting of hydrogen and -S(=O)2-C 1-4 alkyl.

[0879] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R 10a and R 10b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl.

[0880] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xa and R xb together form a monocyclic heterocyclic group, which represents 1-pyrrolidinyl or 1-piperidinyl, each optionally substituted as defined in any other embodiment.

[0881] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein when R xa and R xb together form a bicyclic heterocyclic group, they represent each optionally substituted as defined in any other embodiment.

[0882] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein R xc and R xd together form a monocyclic heterocyclic group, which represents 1-pyrrolidinyl, 1-piperidinyl or 1-piperazinyl, each optionally substituted as defined in any other embodiment.

[0883] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein when R xc and R xd together form a bicyclic heterocyclic group, they represent optionally substituted as defined in any other embodiment.

[0884] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 represents

[0885]

[0886]

[0887] optionally substituted as defined in any other embodiment.

[0888] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 represents

[0889]

[0890] optionally substituted on the nitrogen atom by -C(=O)-C 1-4 alkyl.

[0891] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 represents

[0892]

[0893] substituted on the nitrogen atom by -C(=O)-C 1-4 alkyl.

[0894] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0895] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a fused or spiro bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R8 ; and wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of: a halogen group, R 6 , Het 6a , Het 6b , C 1-4 alkyl, oxo, -NR 9a R 9b and -OH.

[0896] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0897] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; or represents a fused or spiro bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 and -C(=O)-R 8 ; and wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of oxo and -NR 9a R 9b .

[0898] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0899] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of a halogen group, R 6, Het 6a , Het 6b , C 1-4 alkyl, oxo group, -NR 9a R 9b and substituents of the group consisting of -OH.

[0900] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0901] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of R 6 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of an oxo group and -NR 9a R 9b .

[0902] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 3 represents

[0903]

[0904] optionally substituted as defined in any other embodiment.

[0905] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 4 represents a C-linked pyrazinyl group optionally substituted as defined in any other embodiment.

[0906] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 6a represents

[0907]

[0908] optionally substituted as defined in any other embodiment.

[0909] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 6a represents

[0910]

[0911] optionally substituted as defined in any other embodiment.

[0912] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 6a represents

[0913]

[0914] substituted on the nitrogen atom by -C(=O)-C 1-4 alkyl.

[0915] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 6b represents

[0916]

[0917] optionally substituted as defined in any other embodiment.

[0918] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Het 6b represents

[0919]

[0920] substituted on the nitrogen atom by -C(=O)-C 1-4 alkyl.

[0921] In one embodiment, the present invention comprises a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein Cy 2 represents C 3-7 alkyl,

[0922]

[0923] optionally substituted as defined in any other embodiment.

[0924] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein C 1-8 alkyl is limited to C 1-6 alkyl, especially wherein C 1-8 alkyl is limited to C 1-4 alkyl.

[0925] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein -Y-R 3 is attached to the nitrogen atom of the ring.

[0926] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein

[0927] R 21 is hydrogen, and wherein -Y-R 3 is attached to the nitrogen atom of the ring.

[0928] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compound of formula (I) is limited to the compound of formula (I-x):

[0929]

[0930] wherein the variables are defined as for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[0931] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compound of formula (I) is limited to the compound of formula (I-x1):

[0932]

[0933] wherein the variables are defined as for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[0934] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compound of formula (I) is limited to the compound of formula (I-x2):

[0935]

[0936] wherein Q represents -CHR y -, -O-, -C(=O)- or -NR q -; and wherein the other variables are as defined for the compounds of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[0937] In one embodiment, the present invention particularly includes compounds of formula (I-x2) as defined herein, as well as their tautomeric and stereoisomeric forms, wherein

[0938] Q represents -CHR y -, -O-, -C(=O)- or -NR q -;

[0939] R 1a represents 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)-O-C 1-4 alkyl,

[0940]

[0941] R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl;

[0942] R 19 represents hydrogen or C 1-6 alkyl;

[0943] Or R 18 and R 19 together form -(CH2)3-, -(CH2)4- or -(CH2)5-;

[0944] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three O atoms, S atoms or N atoms and optionally a carbonyl moiety; wherein the monocyclic 5- or 6-membered aromatic ring is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl or cyano;

[0945] R xa and R xb are each independently selected from the group consisting of hydrogen, Het 3 , C 3-6Naphthenyl and C 1-6 alkyl; optionally, the C 3-6 naphthenyl and C 1-6 alkyl are substituted by one, two or three substituents each independently selected from the group consisting of: -OH, -OC 1-4 alkyl, -C 1-4 alkyl-OH, halo, CF3, C 3-6 naphthenyl, Het 3 and NR 11c R 11d ;

[0946] Or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two or three substituents selected from the group consisting of: halo and OR 23 ;

[0947] Or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two or three substituents each independently selected from the group consisting of: halo and OR 23 ;

[0948] R 23 represents hydrogen or C 1-4 alkyl optionally substituted by one, two or three halo;

[0949] R 1b represents hydrogen, F, Cl or -O-C 1-4 alkyl;

[0950] R 2 represents a halogenated group, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C 1-4 alkyl substituted with one, two or three halogenated group substituents;

[0951] R 21 represents hydrogen or -Y a -R 3a ;

[0952] Y and Y a each independently represents a covalent bond or

[0953]

[0954] n1 is selected from 1 and 2;

[0955] n2 is selected from 1, 2, 3 and 4;

[0956] R y represents hydrogen, -OH, C 1-4 alkyl, -C 1-4 alkyl-OH or -C 1-4 alkyl-O-C 1-4 alkyl;

[0957] R q represents hydrogen or C 1-4 alkyl;

[0958] R 5 represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

[0959] R 3 、R 3a and R 4 each independently selected from the group consisting of: Het 1 ; Het 2 ; Cy 2 ; C 1-8 alkyl; and C 1-8 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -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 Rxd 、 -NR 8a R 8b 、 -CF3, cyano, halo, -OH, -O-C 1-4 alkyl, Het 1 、 Het 2 、 Ar 1 and Cy 2 ;

[0960] R xc represents 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 alkyl-phenyl;

[0961] R xd represents hydrogen; C 1-4 alkyl; or C 1-4 alkyl substituted with one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl and cyano;

[0962] Or R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and cyano;

[0963] Or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4alkyl-S(=O)2-C 1-4 alkyl and cyano group;

[0964] R 8a and R 8b each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -(C=O)-C 1-4 alkyl; and C 1-6 alkyl substituted by one, two or three substituents each independently selected from the group consisting of: -OH, cyano group, halo group, -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 alkyl;

[0965] Ar 1 represents a phenyl group optionally substituted by one, two or three substituents each independently selected from the group consisting of: C 1-4 alkyl, halo group, -O-C 1-4 alkyl, -CF3, -OH, -S(=O)2-C 1-4 alkyl and -C(=O)-NR 10a R 10b ;

[0966] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a substituent selected from the group consisting of: halo group, R 6 , Het 6a , Het 6b , C 1-4 alkyl, oxo group, -NR 9a R 9b and -OH;

[0967] Het2 represents a C-linked pyrazolyl, 1,2,4- diazolyl, pyridazinyl or triazolyl; said group being optionally substituted on one nitrogen atom by R 6a substituted;

[0968] R 6 and R 6a each independently selected from the group consisting of:

[0969] 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;

[0970] C optionally substituted by one or two substituents each independently selected from the group consisting of: 1-6 alkyl: Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN, -OH, -O-C 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 alkyl; and

[0971] C optionally substituted by one or two substituents each independently selected from the group consisting of: 3-6 cycloalkyl: -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 C optionally substituted by a substituent selected from the group consisting of: 1-4 alkyl: -OH, -O-C 1-4 alkyl, -C(=O)-NH-C1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl;

[0972] R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or C alkyl substituted by one, two or three substituents each independently selected from -OH, -O-C 1-4 alkyl, halo, cyano, -NR 11a R 11b , -S(=O)2-C 1-4 alkyl, Het 3a and Het 6a and C alkyl substituted by Het 1-6 alkyl;

[0973] Het 3 Het, 3a Het, 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2;

[0974] wherein the heterocyclic group is optionally substituted at one carbon atom by C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; wherein the heterocyclic group is optionally substituted at one nitrogen atom by C 1-4 alkyl or -(C=O)-C 1-4 alkyl;

[0975] Het 4 and Het 7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted at one nitrogen atom by C 1-4 alkyl or -(C=O)-O-C 1-4Alkyl substitution; and wherein said aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 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 ;

[0976] Het 6a 、Het 8 and Het 8a each independently represent a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four substituents each independently selected from the group consisting of: 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 1-4alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ;

[0977] Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of C 1-4 alkyl, -OH, oxo group, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1-4 alkyl, -NH-C(=O)-Cy 3 and -O-C 1-4 alkyl; and wherein said heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -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 alkyl;

[0978] Het 9 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two, or three heteroatoms each independently selected from O, S, and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, or three heteroatoms each independently selected from O, S, and N; wherein said aromatic ring is optionally substituted on one nitrogen atom with C 1-4 alkyl; and wherein said aromatic ring is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -OH, halo, and C 1-4 alkyl;

[0979] Cy 1C optionally substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -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 -0-C 1-4 alkyl;

[0980] Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbocyclic ring system;

[0981] wherein said C 3-7 cycloalkyl or said carbocyclic ring system is optionally substituted by one, two, three or four substituents each independently selected from the group consisting of: 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,

[0982] and C optionally substituted by one or two substituents each independently selected from the group consisting of: Het 1-4 , Het 3a , Het 6a , Het 6b and -NR 9a R 9b ;

[0984] Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7 cycloalkyl is optionally substituted by one, two or three halo substituents;

[0985] R 9a and R 9b are each independently selected from the group consisting of: 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 1-4alkyl-R 16 、-C(=O)-C 1-4 alkyl-Het 3a 、-C(=O)-R 14 ;

[0986] C substituted with one, two or three substituents selected from the group consisting of: 3-6 cycloalkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and

[0987] C substituted with one, two or three substituents selected from the group consisting of: 1-4 alkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano;

[0988] 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 each independently selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0989] R 11c and R 11d each independently selected from the group consisting of: hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl;

[0990] R 10a 、R 10b and R 10c each independently selected from the group consisting of: hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0991] R 10d and R 10e each independently selected from the group consisting of: C 1-4 alkyl, -O-C 1-4 alkyl and C 3-6 cycloalkyl;

[0992] R 14 represents Het5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -O-C 1-4 alkyl and halo; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ;

[0993] R 16 represents -C(=O)-NR 17a R 17b , -S(=O)2-C 1-4 alkyl, Het 5 , Het 7 or Het 8 ;

[0994] and its pharmaceutically acceptable salts and solvates.

[0995] In one embodiment, the present invention particularly includes compounds of formula (I-x2) as defined herein, and their tautomeric and stereoisomeric forms, wherein

[0996] Q represents -CHR y -;

[0997] R 1a represents -C(=O)-NR xa R xb ;

[0998] R xa and R xb are C 1-6 alkyl optionally substituted by 1, 2 or 3 -OH;

[0999] R 1b represents F;

[1000] R 2 represents methyl;

[1001] R 21 represents hydrogen or methyl;

[1002] Y represents a covalent bond or

[1003]

[1004] R 5 represents hydrogen;

[1005] n1 is 1;

[1006] n2 is selected from 1 and 2;

[1007] R y represents hydrogen;

[1008] R 3 and R 4 are each independently selected from Het 1 ; Cy 2 ; and C 1-8 alkyl substituted by one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd , Het 1 and Cy 2 ;

[1009] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted by one, two or three -(C=O)-C 1-4 alkyl;

[1010] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted at one carbon atom by an oxo group;

[1011] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted by one, two or three substituents each independently selected from -OH, -O-C 1-6 alkyl and cyano;

[1012] Het6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen with -C(=O)-C 1-4 alkyl;

[1013] Cy 2 represents a C 6a optionally substituted with one Het 3-7 cycloalkyl;

[1014] and pharmaceutically acceptable salts and solvates thereof.

[1015] In one embodiment, the present invention particularly includes compounds of formula (I-x2) as defined herein and their tautomeric and stereoisomeric forms, wherein

[1016] Q represents -CHR y -;

[1017] R 1a represents -C(=O)-NR xa R xb ;

[1018] R xa and R xb are C 1-6 alkyl optionally substituted with 1, 2, or 3 -OH;

[1019] R 1b represents F;

[1020] R 2 represents methyl;

[1021] R 21 represents hydrogen or methyl;

[1022] Y represents a covalent bond or

[1023]

[1024] R 5 represents hydrogen;

[1025] n1 is 1;

[1026] n2 is selected from 1 and 2;

[1027] R y represents hydrogen;

[1028] R 3 and R 4 are each independently selected from Het1 ; Cy 2 ; and a C 1-6 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd , Het 1 and Cy 2 ;

[1029] R xc and R xd , together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted with one, two or three -(C=O)-C 1-4 alkyl;

[1030] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one carbon atom with an oxo group;

[1031] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted with one, two or three substituents each independently selected from -OH, -O-C 1-6 alkyl and cyano;

[1032] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with -C(=O)-C 1-4 alkyl;

[1033] Cy 2 represents a C 6a cycloalkyl optionally substituted with one Het 3-7 ;

[1034] and pharmaceutically acceptable salts and solvates thereof.

[1035] In one embodiment, the present invention particularly includes compounds of formula (I-x2) as defined herein, and their tautomers and stereoisomeric forms, wherein

[1036] Q represents -CHR y -;

[1037] R 1a represents -C(=O)-NR xa R xb ;

[1038] R xa and R xb are C 1-6 alkyl optionally substituted with 1, 2 or 3 -OH;

[1039] R 1b represents F;

[1040] R 2 represents methyl;

[1041] R 21 represents hydrogen or methyl;

[1042] Y represents a covalent bond;

[1043] n1 is 1;

[1044] n2 is selected from 1 and 2;

[1045] R y represents hydrogen;

[1046] R 3 is selected from C 1-8 alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of: -NR xc R xd , Het 1 and Cy 2 ;

[1047] R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted with one, two or three -(C=O)-C 1-4 alkyl;

[1048] Het1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted at one carbon atom by an oxo group;

[1049] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted by one, two or three substituents each independently selected from -OH, -O-C 1-6 alkyl and cyano;

[1050] Het 6a represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by -C(=O)-C 1-4 alkyl;

[1051] Cy 2 represents C 6a cycloalkyl optionally substituted by one Het 3-7 ;

[1052] and pharmaceutically acceptable salts and solvates thereof.

[1053] In one embodiment, the present invention particularly includes compounds of formula (I-x2) as defined herein and their tautomeric and stereoisomeric forms, wherein

[1054] Q represents -CHR y -;

[1055] R 1a represents -C(=O)-NR xa R xb ;

[1056] R xa and R xb are C 1-6 alkyl;

[1057] R 1b represents F;

[1058] R 2 represents methyl;

[1059] R 21 represents hydrogen;

[1060] Y represents a covalent bond;

[1061] n1 is 1;

[1062] n2 is selected from 1 and 2;

[1063] R y represents hydrogen;

[1064] R 3 is selected from C 1-8 alkyl substituted by one substituent, and the substituent is selected from the group consisting of: -NR xc R xd , Het 1 and Cy 2 ;

[1065] R xc and R xd , together with the N atom to which they are attached, form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2, and wherein the heterocyclic group is optionally substituted by one, two, or three -(C=O)-C 1-4 alkyl;

[1066] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen by -C(=O)-R 8 ;

[1067] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted by one, two, or three substituents each independently selected from -OH, -O-C 1-6 alkyl and cyano;

[1068] Het 6arepresents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen with -C(=O)-C 1-4 alkyl substituted;

[1069] Cy 2 represents C 6a optionally substituted with one Het 3-7 cycloalkyl;

[1070] and its pharmaceutically acceptable salts and solvates.

[1071] In one embodiment, the present invention particularly includes compounds of formula (I-x2) as defined herein and their tautomeric and stereoisomeric forms, wherein

[1072] Q represents -CHR y -;

[1073] R 1a represents -C(=O)-NR xa R xb ;

[1074] R xa and R xb are C 1-6 alkyl;

[1075] R 1b represents F;

[1076] R 2 represents methyl;

[1077] R 21 represents hydrogen;

[1078] Y represents a covalent bond;

[1079] n1 is 1;

[1080] n2 is selected from 1 and 2;

[1081] R y represents hydrogen;

[1082] R 3 is selected from C 1 alkyl substituted with one Het 1-4 ;

[1083] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(═O) or S(═O)2; wherein the heterocyclic group is optionally substituted at one nitrogen with -C(═O)-R 8 substituted;

[1084] R 8 represents C 1-6 alkyl; or C 1-4 alkyl substituted with one, two or three substituents each independently selected from -OH, -O-C 1-6 alkyl and cyano;

[1085] and pharmaceutically acceptable salts and solvates thereof.

[1086] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) is limited to a compound of formula (I-y):

[1087]

[1088] wherein the variables are as defined for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[1089] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) is limited to a compound of formula (I-y1):

[1090]

[1091] wherein the variables are as defined for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[1092] In one embodiment, the invention includes a compound of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein the compound of formula (I) is limited to a compound of formula (I-z):

[1093]

[1094] wherein the variables are as defined for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[1095] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compound of formula (I) is limited to a compound of formula (I-z1):

[1096]

[1097] wherein the variables are defined as for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[1098] In one embodiment, the present invention includes a compound of formula (I) as mentioned in any other embodiment, and its pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compound of formula (I) is limited to a compound of formula (I-q):

[1099]

[1100] wherein the variables are defined as for the compound of formula (I) or any subgroup thereof as mentioned in any other embodiment.

[1101] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in the general reaction scheme.

[1102] In one embodiment, the compound of formula (I) is selected from the group consisting of: exemplary compounds,

[1103] their tautomeric and stereoisomeric forms,

[1104] and their free bases, any pharmaceutically acceptable salts and solvates.

[1105] In one embodiment, the compound of formula (I) is selected from the group consisting of: compound 43, 51, 51a, 59, 60, 115, 117a, 125, 140, 157, 159, 169a and 207.

[1106] In one embodiment, the compound of formula (I) is selected from the group consisting of: compound 43, 51, 51a, 59, 60, 115, 117a, 125, 140, 157, 159, 169a and 207;

[1107] their tautomeric and stereoisomeric forms,

[1108] and their free bases, any pharmaceutically acceptable salts and solvates.

[1109] In a particular embodiment, the solvate is a hydrate. In a particular embodiment, the pharmaceutically acceptable salt is the HCl salt. In a particular embodiment, the compound is the HCl salt hydrate.

[1110] In one embodiment, the compound of formula (I) is or a pharmaceutically acceptable salt or solvate thereof; particularly the HCl salt, solvate; more particularly the HCl salt, hydrate; more particularly the mono-HCl salt, hydrate; even more particularly the mono-HCl salt, trihydrate.

[1111] According to certain embodiments, the multiple endocrine neoplasia protein-MLL inhibitor is selected from the group consisting of: compound 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; its tautomeric and stereoisomeric forms, and its free base, any pharmaceutically acceptable salt and solvate.

[1112] According to certain embodiments, the multiple endocrine neoplasia protein-MLL inhibitor is selected from the group consisting of: compound 43, 51, 51a, 59, 60, 117a, 125, 169a, 207; its tautomeric and stereoisomeric forms, and its free base, any pharmaceutically acceptable salt and solvate.

[1113] According to certain embodiments, the multiple endocrine neoplasia protein-MLL inhibitor is compound 51 or a solvate thereof. According to certain embodiments, the multiple endocrine neoplasia protein-MLL inhibitor is compound 51 or a hydrate thereof. According to certain embodiments, the multiple endocrine neoplasia protein-MLL inhibitor is compound 51a.

[1114] In some embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the combination as described in any other embodiment as an active ingredient.

[1115] In some embodiments, provided is a combination therapy comprising a multiple endocrine carcinoma protein-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-tumor agent.

[1116] According to an embodiment, the multiple endocrine carcinoma protein-MLL inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[1117] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may have improved metabolic stability properties.

[1118] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may have an extended in vivo half-life (T1 / 2).

[1119] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may have improved oral bioavailability.

[1120] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may reduce tumor growth, such as tumors carrying MLL (KMT2A) gene rearrangement / alteration and / or NPM1 mutation.

[1121] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may have improved PD properties in vivo over an extended period, such as inhibition of target gene expression such as MEIS1 and upregulation of differentiation markers over a period of at least 16 hours.

[1122] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may have an improved safety profile (e.g., reduced hERG inhibition; improved cardiovascular safety).

[1123] In certain embodiments, the multiple endocrine carcinoma protein-MLL inhibitor may be suitable for Q.D. dosing (once daily).

[1124] According to an embodiment, 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.

[1125] According to a particular embodiment, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt or solvate thereof.

[1126] According to an embodiment, at least one other anti-tumor agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory anti-tumor agent or a DHODH inhibitor.

[1127] According to an embodiment, at least one other anti-tumor agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase (IDH) inhibitor.

[1128] According to an embodiment, the hypomethylating agent includes but is not limited to azacitidine, decitabine or a pharmaceutically acceptable salt or solvate thereof.

[1129] According to an embodiment, the DNA intercalating agent includes but is not limited to anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin).

[1130] According to an embodiment, the DNA intercalating agent is daunorubicin.

[1131] According to an embodiment, the DNA intercalating agent is doxorubicin.

[1132] According to an embodiment, the DNA intercalating agent is idarubicin.

[1133] According to an embodiment, the pyrimidine analogue includes but is not limited to cytarabine (ARA-C).

[1134] According to an embodiment, the purine analogue is fludarabine.

[1135] According to an embodiment, the kinase inhibitor is an FLT-3 inhibitor, a BTK inhibitor, an ABL inhibitor, an aurora inhibitor or a multi-kinase inhibitor of two or more of these kinase inhibitors.

[1136] According to an embodiment, the kinase inhibitor is a multi-kinase inhibitor of an FLT-3 inhibitor, an ABL inhibitor and an aurora inhibitor. According to an embodiment, such multi-kinase inhibitor includes but is not limited to KW-2449.

[1137] According to an embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.

[1138] According to an embodiment, the tyrosine kinase inhibitor is an FLT-3 inhibitor or a BTK inhibitor.

[1139] According to an embodiment, the FLT3 inhibitor includes but is not limited to sorafenib, sunitinib, midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), quizartinib (AC220), gilteritinib (ASP2215) and KW-2449.

[1140] According to an embodiment, the BTK inhibitor includes, but is not limited to, ibrutinib.

[1141] According to an embodiment, the CD20 inhibitor includes, but is not limited to, anti-CD20 antibodies (e.g., obinutuzumab (GA101)).

[1142] According to an embodiment, the IDH inhibitor includes, but is not limited to, ivosidenib and enasidenib.

[1143] According to an embodiment, the isocitrate dehydrogenase 1 inhibitor includes, but is not limited to, ivosidenib.

[1144] According to an embodiment, the isocitrate dehydrogenase 2 inhibitor includes, but is not limited to, enasidenib.

[1145] According to an embodiment, the immunomodulatory anti-tumor agents include, but are not limited to, PD-1 inhibitors (e.g., nivolumab, atezolizumab, and pembrolizumab), thalidomide, lenalidomide, pomalidomide, Bacillus Calmette-Guérin (BCG), and levamisole.

[1146] According to an embodiment, the PD-1 inhibitors include, but are not limited to, nivolumab, atezolizumab, and pembrolizumab.

[1147] According to an embodiment, the DHODH inhibitor includes, but is not limited to, a compound having the formula (Z) structure:

[1148]

[1149] X is CH or N;

[1150] Y is CH or N;

[1151] R 1 is selected from the group consisting of: C 1-6 alkyl; C alkyl substituted with OH or OCH3 1-6 alkyl; C 2-6 alkenyl; C 1-6 haloalkyl; C haloalkyl substituted with OH or OCH3 1-6 haloalkyl; C 2-6 haloalkenyl; N(CH3)2; C 3-6 cycloalkyl; C cycloalkyl substituted with 1-6 alkyl 3-6 cycloalkyl; and phenyl;

[1152] R 2 is wherein

[1153] R a is selected from the group consisting of: C 1-6 alkyl, C 1-6Halogenated alkyl and C 3-6 cycloalkyl;

[1154] R b is C 1-6 alkyl or C alkyl substituted by a member selected from the group consisting of: 1-6 alkyl: OH, halogenated group, CN, OC 1-6 alkyl, OC 1-6 halogenated alkyl and OC 3-6 cycloalkyl;

[1155] R 3 selected from the group consisting of: H, halogenated group, CH3 and OCH3;

[1156] R 4 selected from the group consisting of:

[1157] C 1-6 alkyl; C alkyl substituted by one or two OCH3 1-6 alkyl; C 3-6 cycloalkyl; C cycloalkyl substituted by CH3 or OCH3 3-6 cycloalkyl; CH2 - C 3-6 cycloalkyl; and

[1158]

[1159] and

[1160]

[1161] wherein

[1162] each R c is independently selected from the group consisting of: H; halogenated group; C 1-6 alkyl; C alkyl substituted by a member selected from the group consisting of: 1-6 alkyl: OH, OCH3, SCH3 and OCF3; C 1-6 halogenated alkyl; C halogenated alkyl substituted by a member selected from the group consisting of: 1-6 halogenated alkyl: OH and OCH3; NO2; OH; O - CH2CH2OH; and OC 1-6 alkyl;

[1163] R d selected from the group consisting of: H; halogenated group; C 1-6 alkyl; C alkyl substituted by a member selected from the group consisting of: 1-6 alkyl: OH, OCH3, SCH3 and OCF3; C 1-6 halogenated alkyl; C halogenated alkyl substituted by a member selected from the group consisting of:1-6 Halogenated alkyl: OH and OCH3; CN; and OC 1-6 Alkyl;

[1164] R g is selected from the group consisting of: H; C 1-6 alkyl; C substituted by a member selected from the group consisting of 1-6 alkyl: OH, OCH3, SCH3 and OCF3; C 1-6 halogenated alkyl; and C substituted by a member selected from the group consisting of 1-6 halogenated alkyl: OH and OCH3; and

[1165] n is 1 or 2;

[1166] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof;

[1167] or a compound selected from the following

[1168]

[1169]

[1170] or a pharmaceutically acceptable salt, N-oxide, solvate or stereoisomer thereof.

[1171] According to an embodiment, the DHODH inhibitor includes but is not limited to a compound having the formula (Z) structure:

[1172]

[1173] X is CH or N;

[1174] Y is CH or N;

[1175] R 1 is selected from the group consisting of C 1-6 alkyl; C substituted by OH or OCH3 1-6 alkyl; C 2-6 alkenyl; C 1-6 halogenated alkyl; C substituted by OH or OCH3 1-6 halogenated alkyl; C 2-6 halogenated alkenyl; N(CH3)2; C 3-6 cycloalkyl; C substituted by 1-6 alkyl 3-6 cycloalkyl; and phenyl;

[1176] R 2 is wherein

[1177] Ra Selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;

[1178] R b is C 1-6 alkyl or C substituted by a member selected from the group consisting of 1-6 alkyl: OH, halo, CN, OC 1-6 alkyl, OC 1-6 haloalkyl, and OC 3-6 cycloalkyl;

[1179] R 3 selected from the group consisting of: H, halo, CH3, and OCH3;

[1180] R 4 selected from the group consisting of:

[1181] C 1-6 alkyl; C alkyl substituted by one or two OCH3; 1-6 alkyl; C 3-6 cycloalkyl; C cycloalkyl substituted by CH3 or OCH3; 3-6 cycloalkyl; CH2-C 3-6 cycloalkyl; and

[1182]

[1183] and

[1184]

[1185] wherein

[1186] each R c is independently selected from the group consisting of: H; halo; C 1-6 alkyl; C alkyl substituted by a member selected from the group consisting of 1-6 alkyl: OH, OCH3, SCH3, and OCF3; C 1-6 haloalkyl; C haloalkyl substituted by a member selected from the group consisting of 1-6 haloalkyl: OH and OCH3; NO2; OH; O-CH2CH2OH; and OC 1-6 alkyl;

[1187] R d selected from the group consisting of: H; halo; C 1-6 alkyl; C alkyl substituted by a member selected from the group consisting of 1-6Alkyl: OH, OCH3, SCH3, and OCF3; C 1-6 Haloalkyl; C substituted with a member selected from the group consisting of the following items 1-6 Haloalkyl: OH and OCH3; CN; and OC 1-6 Alkyl;

[1188] R g Selected from the group consisting of: H; C 1-6 Alkyl; C substituted with a member selected from the group consisting of the following items 1-6 Alkyl: OH, OCH3, SCH3, and OCF3; C 1-6 Haloalkyl; and C substituted with a member selected from the group consisting of the following items 1-6 Haloalkyl: OH and OCH3; and

[1189] n is 1 or 2;

[1190] Or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[1191] In the context of formula (Z), the following definitions apply:

[1192] The term "alkenyl" includes an unsaturated aliphatic group having a length and possible substitution similar to the above alkyl, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.). The term alkenyl also includes an alkenyl group that includes oxygen, nitrogen, sulfur, or phosphorus atoms substituting one or more carbons of the hydrocarbon backbone. In certain embodiments, the straight-chain or branched-chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., for a straight chain it is C 2-6 , for a branched chain it is C 3-6 ).

[1193] The term "haloalkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, which is optionally substituted with halogen. As used herein, the term "C 1-6 haloalkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, which is optionally substituted with halogen. As used herein, the term "C 1-4"Halogenated alkyl" means a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, which is optionally substituted with halogen for hydrogen. Examples of "halogenated alkyl" groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that would be considered equivalent to any of the foregoing examples by those of ordinary skill in the art and the teachings provided herein.

[1194] The term "halogenated alkenyl" includes unsaturated aliphatic groups of similar length to the above alkyls and which may be substituted, but which contain at least one double bond and have 1 to 6 carbon atoms in the chain, optionally substituted with halogen for hydrogen.

[1195] The term "aryl" means a monocyclic aromatic carbocyclic ring having 6 atoms in each ring (a ring structure having all carbon ring atoms). (The carbon atoms in the aryl group are sp2 hybridized.)

[1196] The term "heteroaryl" means a monocyclic or fused bicyclic heterocyclic ring having 3 to 9 ring atoms in each heterocycle (a ring structure having ring atoms selected from carbon atoms and up to four heteroatoms, the heteroatoms being selected from nitrogen, oxygen, and sulfur). Exemplary examples of heteroaryl groups include the following entities in the form of appropriate bonding moieties:

[1197]

[1198] Those skilled in the art will recognize that the substances listed or illustrated above are not exhaustive, and other substances within the scope of these defined terms may also be selected.

[1199] The term "variable attachment point" means allowing a group to attach at more than one alternative position in a structure. The attachment always replaces a hydrogen atom on one of the ring atoms. In other words, all arrangements of the bonding are represented by a single schematic illustration, as shown in the following examples.

[1200]

[1201] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein X is CH.

[1202] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein X is N.

[1203] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is CH.

[1204] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is N.

[1205] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is C 1-4 alkyl; C alkyl substituted with OH or OCH3; 1-4 C 2-4 alkenyl; C 1-4 haloalkyl; C haloalkyl substituted with OH or OCH3; 1-4 C 2-4 haloalkenyl; N(CH3)2; cyclopropyl; cyclopropyl substituted with C 1-4 alkyl; or phenyl.

[1206] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is CH3, CH2CH3,

[1207]

[1208] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 is

[1209] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1210] R 2 is

[1211] wherein R b is C alkyl substituted with OH, halo, CN, OC 1-4 alkyl, OC 1-4 haloalkyl or OC 3-6 cycloalkyl; and 1-4 R

[1212] R a is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl.

[1213] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 2 is

[1214] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is H.

[1215] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is F.

[1216] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is CH3.

[1217] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 is OCH3.

[1218] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is

[1219]

[1220] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1221] R 4 is wherein

[1222] each R c is independently selected from the group consisting of: H; a halogen group; C 1-4 alkyl; C 1- alkyl substituted by a member selected from the group consisting of: OH, OCH3, SCH3, and OCF3; C 1-4 haloalkyl; C 1-4 haloalkyl substituted by a member selected from the group consisting of: OH and OCH3; and NO2;

[1223] R d is selected from the group consisting of: H; a halogen group; C 1-4 alkyl; C 1-4 alkyl substituted by OH, OCH3, SCH3, or OCF3; C 1-4 haloalkyl; C 1-4 haloalkyl substituted by OH or OCH3; or OC 1-4 alkyl; CN; and OC 1-6 alkyl; and

[1224] n is 1 or 2.

[1225] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1226] R 4 is

[1227] Each R c is independently selected from the group consisting of: H, a halogenated group, C 1-4 alkyl, C 1-4 haloalkyl, NO2, O-CH2CH2OH, and OC 1-4 alkyl;

[1228] R d is selected from the group consisting of: H, a halogenated group, C 1-4 alkyl, CN, and OC 1-6 alkyl; and

[1229] n is 1 or 2.

[1230] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is

[1231] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is

[1232] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1233] R 4 is

[1234] wherein

[1235] each R c is independently selected from the group consisting of: H; a halogenated group; C 1-4 alkyl; C 1- alkyl substituted by a member selected from the group consisting of: OH, OCH3, SCH3, and OCF3; C 1-4 haloalkyl; C 1-4 haloalkyl substituted by a member selected from the group consisting of: OH and OCH3; and R d is selected from the group consisting of: a halogenated group; C 1-4 alkyl; C 1-4 alkyl substituted by OH, OCH3, SCH3, or OCF3; C 1-4 haloalkyl; C 1-4 haloalkyl substituted by OH or OCH3; or OC 1-4 alkyl; CN; and OC 1-6 alkyl.

[1236] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1237] R 4 is wherein

[1238] each R c is independently selected from the group consisting of: H, halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, and OH;

[1239] R d is selected from the group consisting of: halo, C 1-4 alkyl, and OC 1-4 alkyl; and

[1240] n is 1 or 2.

[1241] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is

[1242]

[1243] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is

[1244] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1245] R 4 is wherein

[1246] R c is H; halo; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH3, SCH3, or OCF3; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with OH or OCH3; or OC 1-4 alkyl;

[1247] R d is halo; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH3, SCH3, or OCF3; C 1-4 haloalkyl; or C 1-4 haloalkyl substituted with OH or OCH3; and

[1248] R g is H; C 1-4 alkyl; C substituted by OH, OCH3, SCH3 or OCF3 1-4 alkyl; C 1-4 haloalkyl; or C substituted by OH or OCH3 1-4 haloalkyl.

[1249] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein

[1250] R 4 is wherein

[1251] R c is H or a halo group;

[1252] R d is C 1-4 alkyl; and

[1253] R g is H.

[1254] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 is

[1255] In an embodiment of the present invention, the DHODH inhibitor is a compound of formula (Z), the compound being selected from the group consisting of:

[1256] 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;

[1257] 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;

[1258] 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;

[1259] 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;

[1260] 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;

[1261] 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;

[1262] 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;

[1263] 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;

[1264] 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;

[1265] 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;

[1266] 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;

[1267] 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;

[1268] 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;

[1269] 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;

[1270] 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;

[1271] 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;

[1272] 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;

[1273] 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;

[1274] 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;

[1275] 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;

[1276] 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;

[1277] 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;

[1278] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(3-fluorophenyl)-4-(2-hydroxyprop-2-yl)isoquinolin-1(2H)-one;

[1279] 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;

[1280] 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;

[1281] 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;

[1282] 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;

[1283] 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;

[1284] 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;

[1285] 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;

[1286] 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;

[1287] 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;

[1288] (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;

[1289] (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;

[1290] 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;

[1291] 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;

[1292] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorobenzyl)-4-isopropylisoquinolin-1(2H)-one;

[1293] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorobenzyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one;

[1294] 2-(2-Chlorobenzyl)-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;

[1295] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluorophenoxy)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one;

[1296] 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;

[1297] 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;

[1298] 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;

[1299] 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;

[1300] 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;

[1301] 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;

[1302] 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;

[1303] 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;

[1304] 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;

[1305] 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;

[1306] 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;

[1307] (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;

[1308] (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;

[1309] 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;

[1310] 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;

[1311] 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;

[1312] 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;

[1313] 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;

[1314] 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-isopropylisoquinolin-1(2H)-one;

[1315] 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;

[1316] 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;

[1317] 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;

[1318] 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;

[1319] 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;

[1320] 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;

[1321] 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;

[1322] 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;

[1323] 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;

[1324] 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;

[1325] 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;

[1326] 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;

[1327] 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;

[1328] 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;

[1329] 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;

[1330] 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;

[1331] 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;

[1332] 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;

[1333] 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;

[1334] 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;

[1335] 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;

[1336] 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;

[1337] 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;

[1338] 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;

[1339] 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;

[1340] 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;

[1341] 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;

[1342] 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;

[1343] 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;

[1344] 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;

[1345] 6-(4 - ethyl - 3-(hydroxymethyl)-5 - oxo - 4,5 - dihydro - 1H - 1,2,4 - triazol - 1 - yl)-7 - fluoro - 4 - isopropyl - 2-(4 - methylpyrimidin - 5 - yl)isoquinolin - 1(2H)-one;

[1346] 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;

[1347] 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;

[1348] 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;

[1349] 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;

[1350] 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;

[1351] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro 4-isopropyl-2-(4-methylpyridazin-3-yl)isoquinolin-1(2H)-one;

[1352] (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;

[1353] (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;

[1354] 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;

[1355] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-4-isopropyl-2-(5-methylpyrimidin-4-yl)isoquinolin-1(2H)-one;

[1356] 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;

[1357] 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;

[1358] 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;

[1359] 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;

[1360] 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;

[1361] 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;

[1362] 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;

[1363] 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;

[1364] 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;

[1365] 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;

[1366] 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;

[1367] 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;

[1368] 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;

[1369] 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;

[1370] 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;

[1371] 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;

[1372] 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;

[1373] 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;

[1374] 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;

[1375] 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;

[1376] 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;

[1377] 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;

[1378] 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;

[1379] 2-(Bicyclo[2.2.1]hept-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;

[1380] 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;

[1381] 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;

[1382] 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;

[1383] 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;

[1384] 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;

[1385] 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;

[1386] 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;

[1387] 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;

[1388] 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;

[1389] 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;

[1390] 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;

[1391] 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;

[1392] 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

[1393] 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;

[1394] and optionally, one or more of their pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers.

[1395] In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), which is selected from the group consisting of:

[1396] 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;

[1397] 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;

[1398] 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;

[1399] 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;

[1400] 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;

[1401] 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;

[1402] 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;

[1403] 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;

[1404] 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;

[1405] 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;

[1406] 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;

[1407] 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;

[1408] 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;

[1409] 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;

[1410] 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;

[1411] 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;

[1412] 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;

[1413] 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;

[1414] 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;

[1415] 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;

[1416] 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;

[1417] 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;

[1418] 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;

[1419] 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;

[1420] 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;

[1421] 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;

[1422] 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;

[1423] 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;

[1424] 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;

[1425] 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;

[1426] 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;

[1427] 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;

[1428] (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;

[1429] (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;

[1430] 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;

[1431] 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;

[1432] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-tolyl)-4-isopropylisoquinolin-1(2H)-one;

[1433] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-fluoro-2-(2-fluoro-5-tolyl)-4-(prop-1-en-2-yl)isoquinolin-1(2H)-one;

[1434] 2-(2-Chloro-5-tolyl)-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;

[1435] 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;

[1436] 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;

[1437] 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;

[1438] 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;

[1439] 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;

[1440] 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;

[1441] 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;

[1442] 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;

[1443] 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;

[1444] 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;

[1445] 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;

[1446] 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;

[1447] (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;

[1448] (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;

[1449] 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;

[1450] 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;

[1451] 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;

[1452] 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;

[1453] 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;

[1454] 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-isopropylisoquinolin-1(2H)-one;

[1455] 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;

[1456] 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;

[1457] 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;

[1458] 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;

[1459] 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;

[1460] 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;

[1461] 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;

[1462] 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;

[1463] 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;

[1464] 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;

[1465] 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;

[1466] 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;

[1467] 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;

[1468] 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;

[1469] 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;

[1470] 6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-7-methyl-4-(prop-1-en-2-y...

Claims

1. A combination, comprising: A therapeutically effective amount of a multiple endocrine neoplasia protein - mixed lineage leukemia 1 (MLL) inhibitor of formula (I), or a tautomer 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; and Optionally, a therapeutically effective amount of at least one other anti - tumor agent; Wherein the multiple endocrine neoplasia protein - MLL inhibitor of formula (I) has the following structure: wherein Q represents -CHR y -, -O-, -C(=O)-, -NR q -, or -CR y =; when Q represents -CR y =, the dashed line is an optional additional bond forming a double bond; R 1a represents hydrogen, cyano group, halogenated group, 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)-O-C 1-4 alkyl, R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl; R 19 represents hydrogen or C 1-6 alkyl; or R 18 and R 19 together form -(CH2)3-, -(CH2)4- or -(CH2)5-; Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three O atoms, S atoms or N atoms and optionally a carbonyl moiety; wherein said monocyclic 5- or 6-membered aromatic ring is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl or cyano; R xa and R xb each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl, and C 1-6 alkyl; wherein optionally, said C 3-6 cycloalkyl and C 1-6 alkyl are substituted with one, two or three substituents each independently selected from the group consisting of: -OH, -OC 1-4 alkyl, -C 1-4 alkyl-OH, halo, CF3, C 3-6 cycloalkyl, Het 3 and NR 11c R 11d ; or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two, or three substituents selected from the group consisting of: halo and OR 23 ; or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: halo and OR 23 ; R 23 represents hydrogen or a C 1-4 alkyl group optionally substituted with one, two or three halogen groups; R 1b represents hydrogen, F, Cl or -O-C 1-4 alkyl; R 2 represents a halogenated group, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C substituted by one, two or three halogenated group substituents 1-4 alkyl; R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a -Y a -R 3a and one of -Y-R 3 is connected to the nitrogen atom of the ring; Y and Y a each independently represents a covalent bond or n1 is selected from 1 and 2; n2 is selected from 1, 2, 3, and 4; R y represents hydrogen, -OH, C 1-4 alkyl, -C 1-4 alkyl-OH or -C 1-4 alkyl-O-C 1-4 alkyl; R q represents hydrogen or C 1-4 alkyl; R 5 represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl; R 3 , R 3a and R 4 Each independently selected from the group consisting of: Het 1 ;Het 2 ;Cy 2 ; C 1-8 Alkyl; and C substituted by one, two, three or four substituents each independently selected from the group consisting of 1-8 Alkyl: -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、halogen、-OH、-OC 1-4 Alkyl, Het 1 、Het 2 ,Ar 1 and Cy 2 ; R xc represents 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 alkyl-phenyl; R xd represents hydrogen; C 1-4 alkyl; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: halo group, -OH, -O-C 1-4 alkyl and cyano group; or R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl, and cyano; or R xc and R xd Together with the N atom to which they are attached, form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl-S(=O)2-C 1-4 alkyl, and cyano; R 8a and R 8b each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -(C=O)-C 1-4 alkyl; and C 1-6 alkyl substituted by one, two or three substituents each independently selected from the group consisting of: -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 alkyl; Ar 1 represents a phenyl group optionally substituted by one, two or three substituents each independently selected from the group consisting of: C 1-4 alkyl, halo, -O-C 1-4 alkyl, -CF3, -OH, -S(=O)2-C 1-4 alkyl and -C(=O)-NR 10a R 10b ; Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently 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- diazolyl, pyridazinyl or triazolyl group; said group being optionally substituted by R 6a at one nitrogen atom; R 6 and R 6a each independently selected from the group consisting of: 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 substituted with one or two substituents each independently selected from the group consisting of C 1-6 alkyl: Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN, -OH, -O-C 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 alkyl; and C optionally substituted by one or two substituents each independently selected from the group consisting of 3-6 cycloalkyl: -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 C optionally substituted by a substituent selected from the group consisting of 1-4 alkyl: -OH, -O-C 1-4 alkyl, -C(=O)-NH-C 1-4 alkyl and -NH-S(=O)2-C 1-4 alkyl; R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-4 alkyl substituted by one, two or three substituents each independently selected from -OH, -O-C 11a alkyl, halo, cyano, -NR 11b R 1-4 , -S(=O)2-C 3a alkyl, Het 6a and Het 1-6 alkyl; Het 3 、Het 3a 、Het 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one carbon atom with C 1-4 alkyl, halo, -OH, -NR 11a R 11b or oxo; wherein the heterocyclic group is optionally substituted on one nitrogen atom with C 1-4 alkyl or -(C=O)-C 1-4 alkyl; Het 4 and Het 7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted on one nitrogen atom by C 1-4 alkyl or -(C═O)-O-C 1-4 alkyl; and wherein said aromatic ring is optionally substituted on one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 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 ; Het 6a 、Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four substituents each independently selected from the group consisting of: 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 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ; Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of C 1-4 alkyl, -OH, oxo group, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1-4 alkyl, -NH-C(=O)-Cy 3 and -O-C 1-4 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -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 alkyl; Het 9 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein the aromatic ring is optionally substituted at one nitrogen atom with C 1-4 alkyl; and wherein the aromatic ring is optionally substituted at one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of: -OH, halo and C 1-4 alkyl; Cy 1 represents C optionally substituted with one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -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 -0-C 1-4 alkyl; Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbocyclic ring system; Wherein said C 3-7 -cycloalkyl or said bicyclic carbocyclic system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: 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, and C substituted by one or two substituents each independently selected from the group consisting of: 1-4 alkyl: Het 3a 、Het 6a 、Het 6b and -NR 9a R 9b ; Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7 cycloalkyl is optionally substituted with one, two or three halo substituents; R 9a and R 9b each independently selected from the group consisting of: 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 and Het 7 and -C 1-4 alkyl-R 16 and -C(=O)-C 1-4 alkyl-Het 3a and -C(=O)-R 14 ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; 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 each independently selects from the group consisting of: hydrogen and C 1-4 alkyl; R 11c and R 11d each independently selected from the group consisting of: hydrogen, C 1-6 alkyl and -C(=O)-C 1-4 alkyl; R 10a 、 R 10b and R 10c each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, and C 3-6 cycloalkyl; R 10d and R 10e each independently selected from the group consisting of: C 1-4 alkyl, -O-C 1-4 alkyl and C 3-6 cycloalkyl; R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -O-C 1-4 alkyl and halo; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ; R 16 represents -C(=O)-NR 17a R 17b , -S(=O)2-C 1-4 alkyl, Het 5 Het 7 or Het 8 .

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

4. The combination according to any one of claims 1 to 3, wherein the at least one other anti - tumor 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 anti - tumor agent, or a dihydroorotate dehydrogenase inhibitor.

5. The combination according to claim 4, wherein the at least one other anti - tumor agent is a hypomethylating agent.

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

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

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

9. The combination according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7, for use in the prevention or treatment of hematopoietic dysfunction, particularly in the treatment of hematopoietic dysfunction.

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

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

12. A method for treating a subject diagnosed with hematopoietic dysfunction, comprising administering to the subject: A therapeutically effective amount of a multiple endocrine neoplasia protein - mixed lineage leukemia 1 (MLL) inhibitor of formula (I), or a tautomer or stereoisomeric form thereof, 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 - tumor agent; Wherein the multiple endocrine neoplasia protein - MLL inhibitor of formula (I) has the following structure: wherein Q represents -CHR y -, -O-, -C(=O)-, -NR q -, or -CR y =; when Q represents -CR y =, the dashed line is an optional additional bond forming a double bond; R 1a represents hydrogen, cyano group, halogenated group, 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)-O-C 1-4 alkyl, R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl; R 19 represents hydrogen or C 1-6 alkyl; or R 18 and R 19 together form -(CH2)3-, -(CH2)4- or -(CH2)5-; Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two or three O atoms, S atoms or N atoms and optionally a carbonyl moiety; wherein said monocyclic 5- or 6-membered aromatic ring is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl or cyano; R xa and R xb each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, said C 3-6 cycloalkyl and C 1-6 alkyl are substituted by one, two or three substituents each independently selected from the group consisting of: -OH, -OC 1-4 alkyl, -C 1-4 alkyl-OH, halo, CF3, C 3-6 cycloalkyl, Het 3 and NR 11c R 11d ; or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two, or three substituents selected from the group consisting of: halo and OR 23 ; or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 1-4 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of: halo and OR 23 ; R 23 represents hydrogen or a C 1-4 alkyl group optionally substituted by one, two or three halogen groups; R 1b represents hydrogen, F, Cl or -O-C 1-4 alkyl group; R 2 represents a halogenated group, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C substituted by one, two or three halogenated group substituents 1-4 alkyl; R 21 represents hydrogen or -Y a -R 3a ; provided that when R 21 represents -Y a -R 3a one of -Y a -R 3a and -Y-R 3 is connected to the nitrogen atom of the ring; Y and Y a each independently represents a covalent bond or n1 is selected from 1 and 2; n2 is selected from 1, 2, 3, and 4; R y represents hydrogen, -OH, C 1-4 alkyl, -C 1-4 alkyl-OH or -C 1-4 alkyl-O-C 1-4 alkyl; R q represents hydrogen or C 1-4 alkyl; R 5 represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl; R 3 , R 3a and R 4 Each independently selected from the group consisting of: Het 1 ;Het 2 ;Cy 2 ; C 1-8 Alkyl; and C substituted by one, two, three or four substituents each independently selected from the group consisting of 1-8 Alkyl: -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、halogen、-OH、-OC 1-4 Alkyl, Het 1 、Het 2 ,Ar 1 and Cy 2 ; R xc represents 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 alkyl - phenyl; R xd represents hydrogen; C 1-4 alkyl; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: halo, -OH, -O-C 1-4 alkyl and cyano; or R xc and R xd together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl, and cyano; or R xc and R xd together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two or three substituents selected from the group consisting of: halo, -OH, -O-C 1-4 alkyl, -(C=O)-C 1-4 alkyl-S(=O)2-C 1-4 alkyl and cyano; R 8a and R 8b each independently selected from the group consisting of: hydrogen; C 1-6 alkyl; -(C═O)-C 1-4 alkyl; and C 1-6 alkyl substituted by one, two or three substituents each independently selected from the group consisting of: -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 alkyl; Ar 1 represents phenyl optionally substituted by one, two or three substituents each independently selected from the group consisting of: C 1-4 alkyl, halo, -O-C 1-4 alkyl, -CF3, -OH, -S(=O)2-C 1-4 alkyl and -C(=O)-NR 10a R 10b ; Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by a substituent selected from the group consisting of: R 6 , -C(=O)-Cy 1 and -C(=O)-R 8 ; and wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one, two, three or four substituents each independently 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- diazolyl, pyridazinyl or triazolyl group; said group being optionally substituted on one nitrogen atom by R 6a substituted; R 6 and R 6a each independently selected from the group consisting of: 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 substituted by one or two substituents each independently selected from the group consisting of C 1-6 alkyl: Het 3 、Het 4 、Het 6a 、Het 6b 、Cy 1 、-CN, -OH, -O-C 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 alkyl; and Optionally substituted by one or two substituents each independently selected from the group consisting of C 3-6 Cycloalkyl: -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 substituted by a substituent selected from the group consisting of C 1-4 Alkyl: -OH, -O-C 1-4 Alkyl, -C(=O)-NH-C 1-4 Alkyl and -NH-S(=O)2-C 1-4 Alkyl; R 8 represents hydrogen, -O-C 1-6 alkyl, C 1-6 alkyl; or C 1-4 alkyl substituted by one, two or three substituents each independently selected from -OH, -O-C 11a alkyl, halo, cyano, -NR 11b R 1-4 , -S(=O)2-C 3a alkyl, Het 6a and Het 1-6 alkyl; Het 3 、Het 3a 、Het 5 and Het 5a each independently represents a monocyclic C-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at a carbon atom with C 1-4 alkyl, halogenated group, -OH, -NR 11a R 11b or oxo group; wherein the heterocyclic group is optionally substituted at a nitrogen atom with C 1-4 alkyl or -(C=O)-C 1-4 alkyl; Het 4 and Het 7 each independently represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted at one nitrogen atom by C 1-4 alkyl or -(C═O)-O-C 1-4 alkyl; and wherein said aromatic ring is optionally substituted at one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: -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)-O-C 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 ; Het 6a 、Het 8 and Het 8a each independently represents a monocyclic N-linked 4- to 7-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three, or four substituents each independently selected from the group consisting of: 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 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of: -C(=O)-C 1-4 alkyl, -S(=O)2-C 1-4 alkyl and -(C=O)-NR 10a R 10b ; Het 6b and Het 8b each independently represents a bicyclic N-linked 6- to 11-membered fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one or two substituents each independently selected from the group consisting of C 1-4 alkyl, -OH, oxo group, -(C=O)-NR 10a R 10b , -NH-C(=O)-C 1-4 alkyl, -NH-C(=O)-Cy 3 and -O-C 1-4 alkyl; and wherein the heterocyclic group is optionally substituted on one nitrogen with a substituent selected from the group consisting of -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 alkyl; Het 9 represents a monocyclic C-linked 5- or 6-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N, or represents a fused bicyclic C-linked 9- or 10-membered aromatic ring containing one, two or three heteroatoms each independently selected from O, S and N; wherein said aromatic ring is optionally substituted on one nitrogen atom by C 1-4 alkyl; and wherein said aromatic ring is optionally substituted on one or two carbon atoms by a total of one or two substituents each independently selected from the group consisting of: -OH, halo and C 1-4 alkyl;​​​ Cy 1 represents C optionally substituted with one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -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 -0-C 1-4 alkyl; Cy 2 represents C 3-7 cycloalkyl or a 5- to 12-membered saturated carbobicyclic system; Wherein said C 3-7 The cycloalkyl group or said bicyclic carbocyclic system is optionally substituted with one, two, three or four substituents each independently selected from the group consisting of: 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, and C substituted by a substituent or two substituents each independently selected from the group consisting of: 1-4 alkyl: Het 3a 、Het 6a 、Het 6b and -NR 9a R 9b ; Cy 3 represents C 3-7 cycloalkyl; wherein said C 3-7 cycloalkyl is optionally substituted with one, two or three halo substituents; R 9a and R 9b each independently selected from the group consisting of: 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 ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; and C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: halo, -OH, -O-C 1-4 alkyl, -NR 11a R 11b and cyano; 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 each independently selected from the group consisting of: hydrogen and C 1-4 alkyl; R 11c and R 11d each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, and - C(=O)-C 1-4 alkyl; R 10a , R 10b and R 10c are each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl; R 10d and R 10e each independently selected from the group consisting of: C 1-4 alkyl, -O-C 1-4 alkyl and C 3-6 cycloalkyl; R 14 represents Het 5a ; Het 7 ; Het 8a ; -O-C 1-4 alkyl; -C(=O)NR 15a R 15b ; C substituted by one, two or three substituents selected from the group consisting of 3-6 cycloalkyl: -O-C 1-4 alkyl and halo; or C substituted by one, two or three substituents selected from the group consisting of 1-4 alkyl: -O-C 1-4 alkyl, -NR 13a R 13b , halo, cyano, -OH, Het 8a and Cy 1 ; R 16 represents -C(=O)-NR 17a R 17b 、-S(=O)2-C 1-4 alkyl, Het 5 、Het 7 or Het 8 。 13. The method according to 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. The method according to claim 13, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt or solvate thereof.

15. The method according to any one of claims 12 to 14, wherein the at least one other anti-tumor agent is a hypomethylating agent, a DNA intercalator, a pyrimidine analogue, a purine analogue, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory anti-tumor agent, or a dihydroorotate dehydrogenase inhibitor.

16. The method according to claim 15, wherein the at least one other anti-tumor agent is a hypomethylating agent.

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

18. The method according to any one of claims 12 to 17, wherein the hematopoietic disorder is leukemia with nucleophosmin 1 (NPM1) mutation or leukemia with MLL rearrangement.

19. The method according to 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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