SPPL2a inhibitors

Abstract

This disclosure relates to tricyclic compounds comprising a diazoxide moiety that effectively inhibit SPPL2a (signal peptidase-like protease 2a), to pharmaceutical compositions containing such inhibitors, and to methods of using such inhibitors and compositions.

Description

[0001] Cross-reference to related applications

[0002] This application relates to U.S. Provisional Application No. 63 / 553,929, filed February 15, 2024; U.S. Provisional Application No. 63 / 555,660 (filed February 20, 2024); and U.S. Provisional Application No. 63 / 632,768 (filed April 11, 2024), the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to tricyclic compounds comprising a diazoxide moiety (which effectively inhibit signal peptidase-like proteinase 2a (SPPL2a)), to pharmaceutical compositions containing such compounds, to methods for synthesizing such compounds, and to methods for using such compounds and pharmaceutical compositions. Background Technology

[0004] The signal peptidase-like 2A (SPPL2a) protein (an intramembrane aspartic protease) appears to play a role in innate and adaptive immunity by cleaving specific transmembrane anchoring proteins and thereby affecting the function of a variety of immune cells.

[0005] SPPL2a was initially described as a protease that cleaves the transmembrane portion of TNF-α in vitro, thereby controlling the release of IL-12 from dendritic cells (E. Friedmann et al., SPPL2a and SPPL2b promote intramembraneproteolysis of TNFα in activated dendritic cells to trigger IL-12 production, Nat. Cell Biol., Vol. 8 (2006), pp. 843-848). SPPL2a has also been shown to play a role in the development and function of antigen-presenting cells such as B cells and dendritic cells. This is achieved through proteolytic processing of CD74 (also known as the invariant chain of the major histocompatibility class II complex (MCHII)) (D. Beisner et al., “The intramembrane protease SPPL2a is required for B cell and dendritic cell (DC) development and survival via cleavage of the invariant chain” J. Exp. Med. 210, pp. 23-39, 2013). Antigen presentation via MCHII molecules enables the differentiation between foreign antigens and self-antigens. When the immune system loses its ability to distinguish between "self" and "non-self," it may develop into an autoimmune disease.

[0006] As a molecular chaperone for the MHCII complex, CD74 prevents premature binding of peptides to the complex. To enable antigen-derived peptides to bind to MHCII, CD74 is degraded by various proteases. Processing of full-length CD74 results in the generation of an N-terminal 8 kDa CD74 (CD74-p8) transmembrane fragment, which is subsequently further processed by SPPL2a.

[0007] Inhibition of SPPL2a leads to the accumulation of the N-terminal CD74 fragment (CD74-p8) in intracellular compartments, thereby inducing the death of CD74-expressing B cells and myeloid dendritic cells, which may impair humoral immune responses (J. Schneppenheim et al., The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain, J. Exp. Med., Vol. 210 (2013), pp. 41–58). Accumulation of unprocessed CD74 appears to impair T cell-dependent antibody responses in mice (D. Beisner et al. 2013).

[0008] Inhibition of SPPL2a protease, and the corresponding reduction in the immune system's antigen-presenting capacity, may be associated with the suppression of harmful, uncontrolled immune responses, such as pathological conditions driven by the presentation of autoantigens.

[0009] SPPL2a inhibition may also affect the proliferation of B-cell lymphomas, which appears to be associated with high levels of CD74 expression (Zhao et al., J Pathol Clin Res. 2019, 5(1): 12–24). Furthermore, chemical library screening for SPPL2a inhibitors identified selective SPPL2a inhibition as having immunomodulatory effects (Zhang, X, et al. Identification of SPPL2a Inhibitors by Multiparametric Analysis of a High-Content Ultra-High-Throughput Screen. SLAS Discov. (2017) Oct; 22(9): pp. 1106–1119).

[0010] Therefore, there is a need for new, effective, and often selective SPPL2a inhibitors to treat diseases and / or conditions, especially diseases and / or conditions of the immune system. Summary of the Invention

[0011] On the one hand, this article provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] (I)

[0013] in:

[0014] Y is CH2 or C=O;

[0015] R1 is H, C1-C6 alkyl, or halogenated;

[0016] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0017] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0018] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0019] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0020] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0021] i) Halogenation;

[0022] ii) Amino;

[0023] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0024] iv) C3-C6 cycloalkenyl groups;

[0025] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0026] vi) C1-C6 haloalkyl groups;

[0027] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0028] viii)-NHC(=O)-C1-C6 haloalkyl;

[0029] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0030] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0031] xi)-C(=O)NH-C1-C6 haloalkyl;

[0032] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0033] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0034] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0035] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0036] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0037] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0038] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0039] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0040] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0041] xxi)-C(=O)NH2;

[0042] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; and

[0043] R 11 It is H, C1-C6 alkyl or halogenated; or

[0044] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0045] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0046] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a7 R c7 and R d7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0047] Or any R connected to the same N atom c7 and R d7 Together with the N atoms they are attached to, they form 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R atoms. 7A Substituent substitution;

[0048] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0049] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0050] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2Rb71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. M Substituent substitution;

[0051] Each R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)ORa71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0052] Each R a71 R c71 and R d71 Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a71 R c71 and R d71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0053] Or any R connected to the same N atom c71 and R d71 Together with the N atoms they are attached to, they form 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups, wherein the 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3 or 4 independently selected R atoms. M Substituent substitution;

[0054] Each R b71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0055] Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0056] Each R M Independently selected from H, OH, halogenated, oxo-substituted, CN, C(O)OH, NH2, NO2, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene.

[0057] On the other hand, this article provides a compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0058] (Ia)

[0059] in:

[0060] Y is CH2 or C=O;

[0061] R1 is H, C1-C6 alkyl, or halogenated;

[0062] R2 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0063] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0064] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0065] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0066] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0067] i) Halogenation;

[0068] ii) Amino;

[0069] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0070] iv) C3-C6 cycloalkenyl groups;

[0071] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0072] vi) C1-C6 haloalkyl groups;

[0073] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0074] viii)-NHC(=O)-C1-C6 haloalkyl;

[0075] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0076] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0077] xi)-C(=O)NH-C1-C6 haloalkyl;

[0078] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0079] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0080] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0081] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0082] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0083] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0084] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0085] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0086] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0087] xxi)-C(=O)NH2;

[0088] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; and

[0089] R 11 It is H, C1-C6 alkyl or halogenated; or

[0090] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0091] R 7 For H.

[0092] On another front, this article provides a method for treating conditions selected from hidradenitis suppurativa, arthritis, cutaneous lupus, pemphigus, ANCA vasculitis, diabetes, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity in subjects in need, the method comprising administering a therapeutically effective amount of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0093] On the other hand, this article provides a pharmaceutical composition comprising a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0094] On the other hand, this article provides a method for treating a disease or condition mediated by the activity of signal peptidase-like proteinase 2a (SPPL2a), wherein the method comprises administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0095] On the other hand, this article provides a method for treating an autoimmune disease in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0096] On the other hand, this document provides for the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating diseases or conditions related to or mediated by the activity of signal peptidase-like proteinase 2a (SPPL2a).

[0097] On the other hand, this document provides for the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of autoimmune diseases.

[0098] On the other hand, this document provides for the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof in the treatment of diseases or conditions related to or mediated by the activity of signal peptidase-like proteinase 2a (SPPL2a).

[0099] On the other hand, this document provides the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof in the treatment of autoimmune diseases.

[0100] On the other hand, this document provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with or mediated by the activity of signal peptidase-like protease 2a (SPPL2a).

[0101] On the other hand, this document provides the compounds disclosed herein or pharmaceutically acceptable salts thereof for the treatment of lymphoma. Attached Figure Description

[0102] Figure 1A , Figure 1B and Figure 1C The reduction in in vivo epimerization in rat, monkey, and canine models is shown in Example 1 compared to Example A.

[0103] Figure 2 The inhibitory effects of selective SPPL2a inhibitors Example 1 and Example A on TNFα-eGFP nuclear translocation are shown.

[0104] Figure 3 The inhibition of SPPL2a activity in SPPL2a-U2OS reporter cells by Examples 1 and A is shown.

[0105] Figure 4 The effects of Examples 1 and A on dendritic cell maturation are shown.

[0106] Figure 5 The efficacy of Example A in an experimental autoimmune encephalomyelitis (EAE) mouse model is demonstrated.

[0107] Figure 6 The efficacy of Example A in a systemic lupus erythematosus (SLE) disease model (renal pathology) is demonstrated.

[0108] Figure 7 The results show that treatment with Examples 1 and A significantly reduced the clinical signs of collagen-induced arthritis (CIA). Detailed Implementation

[0109] This article provides compounds of formula I or pharmaceutically acceptable salts thereof for use as inhibitors of signal peptidase-like proteinase 2a (SPPL2a). Therefore, these SPPL2a inhibitors can be used to treat a variety of diseases and conditions associated with SPPL2a activity.

[0110] SPPL2a is a protease that cleaves the transmembrane portion of TNF-α. Since TNF-α is an inflammatory cytokine, targeting SPPL2a could treat inflammation (C. Spitz et al., Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix. iScience. (2020) Nov 5;23(12):101775). SPPL2a- / - mice exhibit impaired B cell maturation. Given the role of B cells in several autoimmune diseases (such as rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, and pemphigus vulgaris), it is suggested that inhibiting SPPL2a activity should be evaluated as a potential therapeutic strategy for autoimmune diseases (J. Schneppenheim et al., 2013). B-cell depletion has been shown to be beneficial in a variety of autoimmune diseases, including pemphigus vulgaris, Sjögren's syndrome, systemic lupus erythematosus (SLE), arthritis, lupus nephritis, neuroautoimmune diseases, autoantibody-mediated encephalitis syndrome, NMDAR encephalitis, neuromyelitis optica spectrum disorder (NMOSD), myelin-oligodendrocyte glycoprotein (MOG) spectrum disorder (MOGSD), multiple sclerosis, pemphigus foliaceus, myasthenia gravis, cardiomyopathy, arthritis, rheumatoid arthritis, idiopathic thrombocytopenic purpura, spondyloarthritis (SpA), vasculitis, and multiple myeloma (Mentrup T et al. A Cell-Based Assay Reveals Nuclear Translocation of Intracellular Domains Released by SPPL Proteases. Traffic. 2015 Aug;16(8):871-92 and Lee, DSW et al. B-cell depletion therapies in autoimmune disease: advances and (Mechanical Insights. Nat Rev Drug Discov (2021) 20, pp. 179–199). For example, SPPL2a inhibition in dendritic cells (DCs) disrupts TNFα cleavage, leading to suppression of IL12 and downstream IFNγ responses. Furthermore, CD74 accumulation in DCs may also impair their function, particularly in providing homologous aid to pathogenic T cells.

[0111] A genome-wide association study of psoriasis and psoriatic arthritis identified a disease locus containing the SPPL2a gene, suggesting a new drug target for these diseases (Liu Y, et al., A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoSGenet. 2008, March 28). SPPL2a expression was also found to be high in a transcriptomic study of samples from patients with systemic juvenile idiopathic arthritis (Cepika AM, et al., A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med. (2017) November 6; 214(11): 3449-3466).

[0112] Given the role of SPPL2a in adaptive immunity and its cross-presentation in regulating dendritic cells (DCs), DC-regulating cytokines such as TNFα and IL-12, B cell function, and autoantibody production, SPPL2a inhibition could have therapeutic benefits in treating a variety of other inflammatory conditions in which antigen presentation and autoantibody production are crucial, while innate immune cells (APCs) and B cells make important contributions to disease pathology. Such diseases include hidradenitis suppurativa (Lowe et al., JCI Insight. 2020 Oct 2; Byrd et al., Sci Transl Med. 4019 Sep; Thomi et al., Br JDermatol. 2017 Nov; 177(5): 1358-1366), pemphigus (Wang et al., J InvestDermatol. 2024 Oct; Ramadan et al., Ann Dermatol. 2019 Aug; 31(4): 454-457; Mashikilleyson et al., Acta Derm Venereol. 1989; 69(5): 424-8; Ettinger et al., Autoimmunity. 2017 Feb; 50(1): 25-36), and ANCA vasculitis indications (Wilde et al., Nephrol DialTransplant. July 2009; 24(7); Wilde et al. Kidney Int. March 2011; 79(6): 599-612; Braudeau C et al., Immunol. February 9, 2017; 8: 102), metabolic diseases (such as diabetes (Guerder et al., Curr Opin Immunol. December 2013; 25(6): 670-5; Soedono et al., Int J Mol Sci. August 12, 2021; 22(16): 8666; Hotta-Iwamura et al., J Leukoc Biol. July 2016; 100(1): 65-80), insulin resistance (Bertola A. et al., Immunol. February 9, 2017; 8: 102), fatty liver disease (Deczkowska et al., Nat Med. June 2021; Zhou et al., Front Immunol. August 10, 2022), gallstone disease (Maurer KJ et al., Gastroenterology. February 2009;136(2):425-40); and obesity (Sundara R. et al., Immunology).December 2016; 149(4):353-361, Kae Won Cho et al., J Immunol November 1, 2016; 197 (9): 3650–3661), temporal arteritis (Reitsema RD, et al., FrontImmunol. August 2, 2023; 14; Graver et al., Front Immunol. January 29, 2019; 10:83), alopecia areata (Ito T. et al., Allergol Int. January 2020; 69(1):121-131; Raghunandan et al., Genomics, Vol. 96, No. 3, 2010), primary biliary cirrhosis (Taylor S. et al., Semin Liver Dis. November 2019; 39(4):422-431; Bjorkland et al., J Immunol. September 15, 1994; 153 (6): 2750–2757), autoimmune hemolytic anemia (Watanabe N., et al., 2002; Efremov D et al., Leuk Lymphoma. January 1998; 28(3-4):285-93; Richards A, et al., Transfusion. January 2021; 61(1):225-235), hyperlipidemia (Ito et al., Immunity. 2016), hypertension (Guzik et al., Nat RevCardiol. June 2024; 21(6):396-416; Dixon K et al., Am J Physiol Heart Circ Physiol. March 1, 2017; 312(3)), and stroke (Gelderblom et al., Stroke. January 2018; Hammond M et al., Transl Stroke). Res. July 2012; 3; Reichmann G et al., J Neuroimmunol. August 2002).

[0113] Therefore, SPPL2a is a promising target for the treatment of a variety of conditions.

[0114] definition

[0115] Throughout this specification, certain characteristics of the compounds are disclosed by groups or ranges. The specific intent is that this disclosure encompasses every individual sub-combination of members of such groups and ranges. For example, the term "C" 1-6 The term "alkyl" specifically refers to (but is not limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0116] The term "n-membered" (where n is an integer) typically describes the number of cyclic atoms in a portion, where the number of cyclic atoms is n. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cyclic alkyl group.

[0117] Variables defining divalent linking groups may be described in different locations within this specification. These groups may be explicitly described using hyphens or implicitly described based on the properties of this disclosure (e.g., C...). 6-10 Aryl-C 1-6 (alkylene). Where the structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", then "alkyl" or "aryl" should be understood to represent the linking alkylene group or arylene group, respectively.

[0118] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. Unless otherwise stated, the term "substituted" refers to any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substituted, where such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. It should be understood that substitution at a given atom produces a chemically stable molecule. The phrase "optionally substituted" refers to either unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., oxo) can substitute for two hydrogen atoms. The phrase "replaced by one or more..." is understood to mean that only as many substituents as the valence allows are permitted. In one embodiment, "one or more" means 1 to 6 substituents, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 or 2 substituents, or 1 substituent.

[0119] Term "C" n-m The indicator includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-4 C 1-6 wait.

[0120] As used herein, the term "alkyl" refers to a fully saturated branched or straight-chain hydrocarbon having up to 20 carbon atoms. In some embodiments, the alkyl group is "C1-C2 alkyl", "C1-C3 alkyl", "C1-C4 alkyl", "C1-C5 alkyl", "C1-C6 alkyl", "C1-C7 alkyl", "C1-C8 alkyl", "C1-C9 alkyl" or "C1-C 10 Alkyl", including the terms "C1-C2 alkyl", "C1-C3 alkyl", "C1-C4 alkyl", "C1-C5 alkyl", "C1-C6 alkyl", "C1-C7 alkyl", "C1-C8 alkyl", "C1-C9 alkyl" and "C1-C 10 "alkyl" refers to an alkyl group containing at least one and at most two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0121] The term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. The alkenyl group formally corresponds to an alkene, where one CH bond is replaced by the alkenyl group at the junction with the rest of the compound. The term "C..." n-m "Alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0122] The term "alkynyl" (used alone or in combination with other terms) refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. The alkynyl group formally corresponds to an alkyne, where one CH bond is replaced by an alkyl group at the junction with the rest of the compound. The term "C..." n-m "Alynyl" refers to an alkynyl group having n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-yl, prop-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0123] The term "alkylene" used alone or in combination with other terms refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane in which two CH bonds are replaced by the alkylene group at the junction with the rest of the compound. The term "C n-m"alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethyl-1,2-diyl, ethyl-1,1-diyl, propion-1,3-diyl, propion-1,2-diyl, propion-1,1-diyl, bution-1,4-diyl, bution-1,3-diyl, bution-1,2-diyl, 2-methyl-propion-1,3-diyl, etc.

[0124] As used herein, the term "alkoxy" refers to -O-alkyl or -alkyl-O-, where "alkyl" is as defined herein. In some embodiments, the alkoxy group is "C1-C2 alkoxy", "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy" or "C1-C 10 "Alkoxy", including the terms "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy" and "C1-C" as used herein. 10 "Alkoxy" refers to -O-C1-C2 alkyl, -O-C1-C3 alkyl, -O-C1-C4 alkyl, -O-C1-C5 alkyl, -O-C1-C6 alkyl, -O-C1-C7 alkyl, -O-C1-C8 alkyl, -O-C1-C9 alkyl, or –O-C1-C 10 Alkyl groups. Non-limiting examples of "alkoxy" groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.

[0125] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having two fused rings). The term "C..." n-m "Aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, etc. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0126] As used herein, the term "cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having a carbon atom as a ring member. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, as used herein, the term "C3-C6 cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 6 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0127] As used herein, the term "carbocyclic" refers to a saturated or partially saturated hydrocarbon ring. Non-limiting examples of such carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0128] As used in this article, the term "cycloalkenyl" refers to a partially saturated (but non-aromatic) monocyclic hydrocarbon ring system with carbon atoms as ring members.

[0129] As used herein, the term "C1-C6 alkyl-phenyl" refers to a C1-C6 alkyl group as defined above, substituted with a phenyl group. A non-limiting example of C1-C6 alkyl-phenyl is a benzyl group.

[0130] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom of the alkyl group is replaced by a halogenated group (as defined herein). The haloalkyl group can be a monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl (including perhaloalkyl). A monohaloalkyl group may have an iodide, bromine, chlorine, or fluorine atom within the alkyl group. Dihaloalkyl and polyhaloalkyl groups may have two or more identical halogen atoms or combinations of different halogenated groups within the alkyl group. Typically, the polyhaloalkyl group contains up to six, four, three, or two halogenated groups. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group is an alkyl group having all hydrogen atoms replaced by halogen atoms, for example, trifluoromethyl. Unless otherwise stated, preferred haloalkyl groups include monofluoro, difluoro, and trifluoro substituted methyl and ethyl groups, such as CF3, CHF2, CH2F, CH2CHF2, and CH2CF3.

[0131] As used herein, the term "C1-C6 haloalkyl" refers to the corresponding "C1-C6 alkyl" as defined herein, wherein at least one hydrogen atom of the "C1-C6 alkyl" is replaced by a halogroup (as defined herein). The C1-C6 haloalkyl group can be a mono-C1-C6 haloalkyl group, wherein such a C1-C6 haloalkyl group has one iodinated, one brominated, one chlorinated, or one fluorinated atom. Alternatively, the C1-C6 haloalkyl group can be a di-C1-C6 haloalkyl group, wherein such a C1-C6 haloalkyl group may have two halogen atoms independently selected from iodinated, brominated, chlorinated, or fluorinated atoms. Furthermore, the C1-C6 haloalkyl group can be a poly-C1-C6 haloalkyl group, wherein such a C1-C6 haloalkyl group may have two or more identical halogen atoms or a combination of two or more different halogen atoms. Such poly-C1-C6 haloalkyl groups can be fully haloalkyl groups, wherein all hydrogen atoms of the corresponding C1-C6 alkyl group have been replaced by halogen atoms, and these halogen atoms can be the same or a combination of different halogen atoms. Non-limiting examples of “C1-C6 haloalkyl” groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0132] As used herein, the term "haloalkoxy" refers to an –O-haloalkyl group in which at least one hydrogen atom of the alkyl group of the alkoxy group is replaced by a halogenated group (as defined herein). The haloalkoxy group can be a monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, or polyhaloalkoxy (including perhaloalkoxy). A monohaloalkoxy group may have an iodide, bromine, chlorine, or fluorine atom within the alkyl group. Dihaloalkoxy and polyhaloalkoxy groups may have two or more identical halogen atoms or combinations of different halogenated groups within the alkyl group. Typically, the polyhaloalkoxy group contains up to six, four, three, or two halogenated groups. Non-limiting examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy. A perhaloalkoxy group is an alkoxy group having all hydrogen atoms replaced by halogen atoms, such as a trifluoromethoxy group. Unless otherwise specified, preferred haloalkoxy groups include monofluoro-, difluoro-, and trifluoro-substituted methoxy and ethoxy groups, such as -OCF3, -OCHF2, -OCH2F, -OCH2CHF2, and -OCH2CF3.

[0133] As used herein, the term "C1-C6 haloalkoxy" refers to the group –O-C1-C6 haloalkyl, wherein at least one hydrogen atom of the “C1-C6 alkyl” of the “C1-C6 alkoxy” is replaced by a halogroup (as defined herein). The C1-C6 haloalkoxy group can be a mono-C1-C6 haloalkoxy group, wherein such a C1-C6 haloalkoxy group has one iodinated, one brominated, one chlorinated, or one fluorinated atom. Alternatively, the C1-C6 haloalkoxy group can be a di-C1-C6 haloalkoxy group, wherein such a C1-C6 haloalkoxy group may have two halogen atoms independently selected from iodinated, brominated, chlorinated, or fluorinated atoms. Furthermore, the C1-C6 haloalkoxy group can be a poly-C1-C6 haloalkoxy group, wherein such a C1-C6 haloalkoxy group may have two or more identical halogen atoms or a combination of two or more different halogen atoms. Such polyC1-C6 haloalkoxy groups can be perhaloC1-C6 haloalkoxy groups, wherein all hydrogen atoms of the corresponding C1-C6 alkoxy group have been replaced by halogen atoms, and these halogen atoms can be the same or a combination of different halogen atoms. Non-limiting examples of “C1-C6 haloalkoxy” groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0134] As used herein, the terms “halogen” or “halogenated” refer to fluorinated (F), chlorinated (Cl), brominated (Br), and iodinated (I).

[0135] As used in this article, the term "heteroatom" refers to a nitrogen (N), oxygen (O), or sulfur (S) atom.

[0136] As used herein, the term "heteroaryl" refers to an aromatic ring system containing one or more heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups can be monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings have 5 to 6 ring atoms. Bicyclic heteroaryl rings have 7 to 12 ring member atoms. Bicyclic heteroaryl rings include those ring systems in which the heteroaryl ring is fused to a phenyl ring. Non-limiting examples of heteroaryl groups as used herein include benzofuranyl, benzo[c]thiophenyl, benzothiophenyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, cenylyl, furazolyl, furanyl, imidazolyl, indoleyl, indoleazinyl, indazoleyl, isoindoleyl, isoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxindoleyl, oxadiazolyl (including 1,3,4-oxadiazolyl) (Azolyl and 1,2,4-oxadiazolyl), purine, pyrazolyl, pyrroleyl, phthalazinyl, pyridinyl (including 2-, 3- and 4-pyridinyl), pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, tetrazinyl, tetrazolyl, tetrazono[1,5-a]pyridinyl, thiazolyl, thiadiazolyl (including 1,3,4-thiadiazolyl), thienyl, triazinyl and triazolyl.

[0137] As used herein, the term "5-membered heteroaryl" refers to an aromatic 5-membered monocyclic ring system having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such 5-membered heteroaryl groups as used herein include furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrroleyl, pyrazolyl, thiadiazolyl, thiazolyl, thiopheneyl, and triazolyl. In some embodiments, as used herein, "5-membered heteroaryl" refers to an aromatic 5-membered monocyclic ring system having one or two heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such 5-membered heteroaryl groups as used herein include furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrroleyl, pyrazolyl, thiadiazolyl, thiazolyl, thiopheneyl, and triazolyl.

[0138] As used herein, the term "6-membered heteroaryl" refers to an aromatic 6-membered monocyclic ring system having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such 6-membered heteroaryl groups as used herein include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl. In some embodiments, as used herein, the term "6-membered heteroaryl" refers to an aromatic 6-membered monocyclic ring system having one or two heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such 6-membered heteroaryl groups as used herein include pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl.

[0139] As used herein, the term "9- or 10-membered bicyclic heteroaryl" refers to a 9- or 10-membered fused bicyclic aromatic ring system having 1, 2, 3, or 4 heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such bicyclic heteroaryl groups as used herein include indolyl, quinolinyl, isoquinolinyl, indazolyl, purine, phthalazinyl, naphthidyl, quinazolinyl, cenolinyl, thieno[2,3-b]furanyl, 1H-pyrazolo[4,3-d]oxazolyl, imidazo[2,1-b]thiazolyl, pyrazolo[2,3-d]pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, benzoxazolyl, benzimidazolyl, imidazopyridyl, and benzothiazolyl. In some embodiments, such bicyclic heteroaryl groups are 1H-benzo[d]imidazolyl or 1H-imidazo[4,5-c]pyridyl.

[0140] As used in this article, "heterocyclic group" refers to a group containing one or two independently selected from N, NH, NR. A In saturated or partially saturated hydrocarbon rings where the heteroatoms of O or S are ring members, R AIt is H, C1-C6 alkyl, or C3-C8 cycloalkyl. This heterocyclic group may be attached to another group at the nitrogen or carbon atom. Non-limiting examples of heterocyclic alkyl groups as used herein include azirrobutane, azirrobutane-1-yl, azirrobutane-2-yl, azirrobutane-3-yl, oxacyclobutane, oxacyclobutane-2-yl, oxacyclobutane-3-yl, oxacyclobutane-4-yl, thiohexacyclobutane, thiohexacyclobutane-2-yl, thiohexacyclobutane-3-yl, thiohexacyclobutane-4-yl, pyrrolyl, pyrrolyl-1-yl, pyrrolyl-2-yl, pyrrolyl-3-yl, pyrrolyl-4-yl, pyrrolyl-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, Tetrahydrofuran-5-yl, tetrahydrothiopheneyl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, tetrahydrothiophene-4-yl, tetrahydrothiophene-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopheneyl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, tetrahydrothiophene-4-yl, tetrahydrothiophene-5-yl, tetrahydrothiophene-6-yl, piperazinyl, piperazin-1-yl, piperazinyl Azin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxothiohexane-2-yl, oxothiohexane-3-yl, oxothiohexane-5-yl, oxothiohexane-6-yl, dithiohexane-2-yl, dithiohexane-3-yl, dithiohexane-5-yl Dithiocyclohexane-6-yl, dioxolane-6-yl, dioxolane-2-yl, dioxolane-4-yl, dioxolane-5-yl, thiooxolane-6-yl, thiooxolane-6-yl, thiooxolane-6-yl, thiooxolane-6-yl, thiooxolane-6-yl, thiooxolane-6-yl, dioxolane-6-yl, dioxolane-2-yl, dioxolane-4-yl, dioxolane-5-yl, pyrazolyl, pyrazolidine-1-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, pyrazolidine-4-yl, pyrazolidine-5-yl, 2-azabicyclo[4.2.0]octyl, octahydro-1H-cyclopentano[b]pyridine, and decahydroquinoline.

[0141] As used herein, the term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. Similarly, as used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that can exist for a given compound of this disclosure, and include geometric isomers. It should be understood that substituents may be attached to the chiral center of a carbon atom. The term "chiral" refers to a molecule having the property of non-overlapping mirror-couples, while the term "chiral" refers to a molecule that can overlap its mirror-couple. Therefore, this disclosure includes enantiomers, diastereomers, or racemates of the compound. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used where appropriate to refer to a racemic mixture. A "diastereomer" is a stereoisomer having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configurations can be specified as (+) or (-) based on the direction (dextrorotatory or levorotatory) of their plane-polarized light at the sodium D line wavelength. Some compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-.

[0142] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

[0143] The phrase "therapeuticly effective amount" for compounds of this disclosure refers to an amount of the compound of this disclosure that will elicit a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease. In a non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of this disclosure that, when administered to a subject, effectively achieves the following objectives: (1) at least partially relieves, inhibits, prevents, and / or improves (i) symptoms, disorders, or diseases mediated by SPPL2a, or (ii) symptoms associated with or mediated by SPPL2a activity, or (iii) symptoms, disorders, or diseases characterized by (normal or abnormal) activity of SPPL2a; or (2) reduces or inhibits the activity of SPPL2a; or (3) reduces or inhibits the expression of SPPL2a. In another non-limiting embodiment, the term "therapeutic effective amount" refers to the amount of the compound of this disclosure that, when applied to cells, or tissues, or non-cellular biological materials, or culture media, effectively achieves the following objectives: at least partially reducing or inhibiting the activity of SPPL2a; or at least partially reducing or inhibiting the expression of SPPL2a.

[0144] As used herein, the term "subject" can refer to an animal. The animal can be a mammal. "Subject" also refers to, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0145] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given condition, symptom, or disorder, or a significant decrease in the baseline activity of a biological activity or process.

[0146] As used herein, in one embodiment, the term "treatment" for any disease or condition means alleviating said disease or condition (i.e., slowing or halting or reducing the development of at least one symptom of the disease or its clinical symptoms). In another embodiment, "treatment" means alleviating or improving at least one physical parameter, including physical parameters that the patient may not be able to discern. In yet another embodiment, "treatment" means regulating a disease or condition physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing physical parameters), or both.

[0147] As used in this article, the term "prevention" refers to delaying the onset, development, or progression of the disease or condition.

[0148] As used in this article, a subject “needs” treatment if he or she will derive biological, medical, or quality-of-life benefits from it.

[0149] As used herein, “a / an”, “the”, and similar terms used in the context of this disclosure (especially in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context.

[0150] This document describes various enumerated embodiments of the present disclosure. It will be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0151] compound

[0152] This article provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0153] (I)

[0154] in:

[0155] Y is CH2 or C=O;

[0156] R1 is H, C1-C6 alkyl, or halogenated;

[0157] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0158] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0159] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0160] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0161] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0162] i) Halogenation;

[0163] ii) Amino;

[0164] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0165] iv) C3-C6 cycloalkenyl groups;

[0166] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0167] vi) C1-C6 haloalkyl groups;

[0168] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0169] viii)-NHC(=O)-C1-C6 haloalkyl;

[0170] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0171] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0172] xi)-C(=O)NH-C1-C6 haloalkyl;

[0173] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0174] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0175] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0176] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0177] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0178] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0179] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0180] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0181] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0182] xxi)-C(=O)NH2;

[0183] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; and

[0184] R 11 It is H, C1-C6 alkyl or halogenated; or

[0185] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0186] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (ORa7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0187] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a7 R c7 and R d7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0188] Or any R connected to the same N atom c7 and R d7 Together with the N atoms they are attached to, they form 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R atoms. 7A Substituent substitution;

[0189] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0190] Each Re7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0191] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 Rd71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. M Substituent substitution;

[0192] Each R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0193] Each R a71 R c71 and R d71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a71 R c71 and R d71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0194] Or any R connected to the same N atom c71 and R d71 Together with the N atoms they are attached to, they form 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups, wherein the 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3 or 4 independently selected R atoms. M Substituent substitution;

[0195] Each R b71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0196] Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6Alkylene; and

[0197] Each R M Independently selected from H, OH, halogenated, oxo-substituted, CN, C(O)OH, NH2, NO2, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene.

[0198] In an embodiment,

[0199] Y is CH2 or C=O;

[0200] R1 is H, C1-C6 alkyl, or halogenated;

[0201] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0202] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0203] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0204] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0205] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0206] i) Halogenation;

[0207] ii) Amino;

[0208] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0209] iv) C3-C6 cycloalkenyl groups;

[0210] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0211] vi) C1-C6 haloalkyl groups;

[0212] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0213] viii)-NHC(=O)-C1-C6 haloalkyl;

[0214] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0215] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0216] xi)-C(=O)NH-C1-C6 haloalkyl;

[0217] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0218] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0219] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0220] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0221] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0222] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0223] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0224] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0225] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0226] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0227] R 11 It is H, C1-C6 alkyl or halogenated; or

[0228] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0229] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0230] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a7 R c7 and R d7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0231] Or any R connected to the same N atom c7 and R d7 Together with the N atoms they are attached to, they form 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R atoms. 7A Substituent substitution;

[0232] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0233] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0234] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NRc71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. M Substituent substitution;

[0235] Each R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 Rd71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0236] Each R a71 R c71 and R d71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a71 R c71 and R d71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0237] Or any R connected to the same N atom c71 and R d71Together with the N atoms they are attached to, they form 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups, wherein the 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3 or 4 independently selected R atoms. M Substituent substitution;

[0238] Each R b71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0239] Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and

[0240] Each R MIndependently selected from H, OH, halogenated, oxo-substituted, CN, C(O)OH, NH2, NO2, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene.

[0241] On the other hand, this article provides a compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0242] (Ia)

[0243] in:

[0244] Y is CH2 or C=O;

[0245] R1 is H, C1-C6 alkyl, or halogenated;

[0246] R2 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0247] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0248] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0249] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0250] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0251] i) Halogenation;

[0252] ii) Amino;

[0253] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0254] iv) C3-C6 cycloalkenyl groups;

[0255] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0256] vi) C1-C6 haloalkyl groups;

[0257] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0258] viii)-NHC(=O)-C1-C6 haloalkyl;

[0259] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0260] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0261] xi)-C(=O)NH-C1-C6 haloalkyl;

[0262] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0263] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0264] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0265] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0266] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0267] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0268] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0269] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0270] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0271] xxi)-C(=O)NH2;

[0272] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0273] R 11 It is H, C1-C6 alkyl or halogenated; or

[0274] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; and

[0275] R 7 For H.

[0276] In one embodiment, R2 is a C1-C6 alkyl group. In another embodiment, R2 is a C1-C6 haloalkyl group. In yet another embodiment, R2 is a C1-C6 alkoxy group. In still another embodiment, R2 is a C1-C6 haloalkoxy group.

[0277] This document describes various embodiments of the compounds of this disclosure. It will be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments. The embodiments listed below are representative of compounds of formula (I) of this disclosure.

[0278] Example 1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof,

[0279] (I)

[0280] in:

[0281] Y is CH2 or C=O;

[0282] R1 is H, C1-C6 alkyl, or halogenated;

[0283] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0284] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0285] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0286] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0287] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0288] i) Halogenation;

[0289] ii) Amino;

[0290] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0291] iv) C3-C6 cycloalkenyl groups;

[0292] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0293] vi) C1-C6 haloalkyl groups;

[0294] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0295] viii)-NHC(=O)-C1-C6 haloalkyl;

[0296] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0297] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0298] xi)-C(=O)NH-C1-C6 haloalkyl;

[0299] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0300] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0301] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0302] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0303] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0304] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0305] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0306] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0307] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0308] xxi)-C(=O)NH2;

[0309] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0310] R 11 It is H, C1-C6 alkyl or halogenated; or

[0311] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0312] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0313] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a7 R c7 and R d7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0314] Or any R connected to the same N atom c7 and R d7 Together with the N atoms they are attached to, they form 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R atoms. 7A Substituent substitution;

[0315] Each R b7 Independently selected from H and C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0316] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0317] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 Rd71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. M Substituent substitution;

[0318] Each R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0319] Each R a71 R c71 and R d71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a71 R c71 and R d71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0320] Or any R connected to the same N atom c71 and R d71 Together with the N atoms they are attached to, they form 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups, wherein the 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3 or 4 independently selected R atoms. M Substituent substitution;

[0321] Each R b71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein Rb71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0322] Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and

[0323] Each R M Independently selected from H, OH, halogenated, oxo-substituted, CN, C(O)OH, NH2, NO2, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene.

[0324] Example 1A: The compound according to Example 1 or its pharmaceutically acceptable salt or stereoisomer, wherein

[0325] Y is CH2 or C=O;

[0326] R1 is H, C1-C6 alkyl, or halogenated;

[0327] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0328] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0329] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0330] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0331] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0332] i) Halogenation;

[0333] ii) Amino;

[0334] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0335] iv) C3-C6 cycloalkenyl groups;

[0336] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0337] vi) C1-C6 haloalkyl groups;

[0338] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0339] viii)-NHC(=O)-C1-C6 haloalkyl;

[0340] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0341] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0342] xi)-C(=O)NH-C1-C6 haloalkyl;

[0343] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0344] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0345] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0346] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0347] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0348] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0349] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0350] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0351] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0352] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0353] R 11 It is H, C1-C6 alkyl or halogenated; or

[0354] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0355] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups.7A Substituent substitution;

[0356] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a7 R c7 and R d7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0357] Or any R connected to the same N atom c7 and R d7 Together with the N atoms they are attached to, they form 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R atoms. 7A Substituent substitution;

[0358] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution;

[0359] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0360] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NRc71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. M Substituent substitution;

[0361] Each R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NRc71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0362] Each R a71 R c71 and R d71 Independently selected from H and C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a71 R c71 and R d71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0363] Or any R connected to the same N atom c71 and R d71 Together with the N atoms they are attached to, they form 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups, wherein the 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3 or 4 independently selected R atoms. M Substituent substitution;

[0364] Each R b71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b71 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution;

[0365] Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and

[0366] Each R M Independently selected from H, OH, halogenated, oxo-substituted, CN, C(O)OH, NH2, NO2, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene.

[0367] Example 2. The compound according to Example 1 or its pharmaceutically acceptable salt or stereoisomer, wherein

[0368] Y is CH2;

[0369] R1 is H, C1-C6 alkyl, or halogenated;

[0370] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0371] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0372] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0373] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0374] R5 is a 5-membered heteroaryl group having 1, 2 or 3 heteroatoms, each independently selected from N, O and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl and -NHC(=O)C1-C6 alkyl.

[0375] R 11 For H; and

[0376] R 7 It is a D, CD3, or C1-C6 alkyl group.

[0377] Example 3. The compound according to Example 1 or its pharmaceutically acceptable salt or stereoisomer, wherein

[0378] Y is CH2;

[0379] R1 is H, C1-C6 alkyl, or halogenated;

[0380] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0381] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0382] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0383] R 10It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0384] R5 is:

[0385] , or ;

[0386] in

[0387] R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halo;

[0388] R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; wherein each C1-C6 alkyl is optionally substituted with one or more D;

[0389] R 5c It is a 5- or 6-membered ring heteroaryl group, which is optionally substituted with a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl;

[0390] R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0391] R 11 For H; and

[0392] R 7 It is a D, CD3, or C1-C6 alkyl group.

[0393] In one embodiment, R 5b It can be -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0394] Example 3A. The compound according to Example 3 or its pharmaceutically acceptable salt or stereoisomer, wherein

[0395] R5 is:

[0396] , or ;

[0397] in

[0398] R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halo;

[0399] R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; wherein each C1-C6 alkyl group is optionally substituted with one or more D;

[0400] R 5c It is a 5- or 6-membered ring heteroaryl group, optionally substituted with a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C6 cycloalkyl; and

[0401] R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl.

[0402] In one embodiment, R 5b It can be -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0403] Example 4. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0404] Y is CH2;

[0405] R1 is H, C1-C6 alkyl, or halogenated;

[0406] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0407] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0408] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0409] R 10It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0410] R5 is:

[0411] ;

[0412] R 11 For H; and

[0413] R 7 It is a D, CD3, or C1-C6 alkyl group.

[0414] Example 5. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0415] Y is CH2;

[0416] R1 is H;

[0417] R2 is H;

[0418] R3 is a C1-C6 alkyl group;

[0419] R4 is H;

[0420] R 10 It is -NHC(=O)R5;

[0421] R5 is a 5-membered heteroaryl group, which is optionally substituted by one or more substituents independently selected from C1-C6 alkyl, -C(=O)NH-C1-C6 alkyl and -NHC(=O)C1-C6 alkyl;

[0422] R 11 For H; and

[0423] R 7 It is either D or methyl.

[0424] Example 6. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 It is -NHC(=O)R5.

[0425] Example 7. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 It is -C(=O)NHR5.

[0426] Example 8. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10It is a 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the bicyclic heteroaryl group is unsubstituted or is substituted by one or more R6.

[0427] Example 9. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 for

[0428] or ,

[0429] R6 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halogenated.

[0430] Example 10. The compound according to any one of Examples 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is H.

[0431] Example 11. The compound according to any one of Examples 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is a C1-C6 alkyl group.

[0432] Example 12. The compound according to any one of Examples 1 to 5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is a C1-C6 alkyl-phenyl.

[0433] Example 13. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (II).

[0434] (II).

[0435] Example 14. The compound according to Example 13 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0436] Y is CH2 or C=O;

[0437] R1 is H, C1-C6 alkyl, or halogenated;

[0438] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0439] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0440] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0441] i) Halogenation;

[0442] ii) Amino;

[0443] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0444] iv) C3-C6 cycloalkenyl groups;

[0445] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0446] vi) C1-C6 haloalkyl groups;

[0447] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0448] viii)-NHC(=O)-C1-C6 haloalkyl;

[0449] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0450] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0451] xi)-C(=O)NH-C1-C6 haloalkyl;

[0452] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0453] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0454] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0455] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0456] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0457] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0458] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0459] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0460] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0461] xxi)-C(=O)NH2;

[0462] R 11 It is H, C1-C6 alkyl or halogenated; or

[0463] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0464] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution;

[0465] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0466] Each R b7 Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0467] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0468] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and

[0469] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0470] Example 14A. The compound according to Example 13 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0471] Y is CH2 or C=O;

[0472] R1 is H, C1-C6 alkyl, or halogenated;

[0473] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0474] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0475] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0476] i) Halogenation;

[0477] ii) Amino;

[0478] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0479] iv) C3-C6 cycloalkenyl groups;

[0480] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0481] vi) C1-C6 haloalkyl groups;

[0482] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0483] viii)-NHC(=O)-C1-C6 haloalkyl;

[0484] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0485] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0486] xi)-C(=O)NH-C1-C6 haloalkyl;

[0487] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0488] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0489] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0490] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0491] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0492] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0493] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0494] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0495] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0496] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0497] R 11 It is H, C1-C6 alkyl or halogenated; or

[0498] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0499] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 ;where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution;

[0500] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0501] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0502] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene;

[0503] R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and

[0504] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0505] Example 15. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (III).

[0506] (III).

[0507] Example 16. The compound according to Example 15, or a pharmaceutically acceptable salt or stereoisomer thereof,

[0508] in

[0509] Y is CH2 or C=O;

[0510] R1 is H, C1-C6 alkyl, or halogenated;

[0511] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0512] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0513] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0514] i) Halogenation;

[0515] ii) Amino;

[0516] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0517] iv) C3-C6 cycloalkenyl groups;

[0518] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0519] vi) C1-C6 haloalkyl groups;

[0520] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0521] viii)-NHC(=O)-C1-C6 haloalkyl;

[0522] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0523] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0524] xi)-C(=O)NH-C1-C6 haloalkyl;

[0525] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0526] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0527] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0528] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0529] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0530] xvii)phenyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0531] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0532] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0533] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0534] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0535] R 11 It is H, C1-C6 alkyl or halogenated; or

[0536] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0537] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 ;where R 7 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution;

[0538] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0539] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0540] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl; and

[0541] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0542] Example 17. The compound according to Example 1, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IV):

[0543] (IV)

[0544] in

[0545] X is CH or N;

[0546] R1 is H, C1-C6 alkyl, or halogenated;

[0547] R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0548] Y is CH2 or C(O);

[0549] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0550] X is CH or N;

[0551] R6 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halogenated;

[0552] R 11 It is H, C1-C6 alkyl or halogenated; or

[0553] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings;

[0554] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, CN, C(O)Rb7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 ;where R 7 The C 6-10 Aryl-C 1-6 Alkylene and (5-10-membered heteroaryl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution;

[0555] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0556] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0557] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10Cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl; and

[0558] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0559] Example 18. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is H.

[0560] Example 19. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is a C1-C6 alkyl group.

[0561] Example 20. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is halogenated.

[0562] Example 21. The compound according to any one of Examples 1 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 For H.

[0563] Example 22. The compound according to any one of Examples 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 It is a C1-C6 alkyl group.

[0564] Example 23. The compound according to any one of Examples 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 It is a halogenated product.

[0565] Example 24. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 and R 11 Together with the carbon atoms they are attached to, they form 3 to 6-membered carbon rings.

[0566] Example 25. The compound according to any one of Examples 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 and R 11 Together with the carbon atoms they are attached to, they form a cyclopropyl ring.

[0567] Example 26. The compound according to any one of Examples 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is H.

[0568] Example 27. The compound according to any one of Examples 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is halogenated.

[0569] Example 28. The compound according to any one of Examples 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is F.

[0570] Example 29. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIA):

[0571] (IIA).

[0572] Example 30. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIB):

[0573] (IIB).

[0574] Example 31. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIC):

[0575] (IIC).

[0576] Example 32. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IID):

[0577] (IID).

[0578] Example 33. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having a structure of formula (IIA), (IIB), (IIC), or (IID):

[0579]

[0580]

[0581] Example 34. The compound or its pharmaceutically acceptable salt or stereoisomer according to Example 33,

[0582] in

[0583] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0584] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0585] i) Halogenation;

[0586] ii) Amino;

[0587] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0588] iv) C3-C6 cycloalkenyl groups;

[0589] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0590] vi) C1-C6 haloalkyl groups;

[0591] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0592] viii)-NHC(=O)-C1-C6 haloalkyl;

[0593] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0594] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0595] xi)-C(=O)NH-C1-C6 haloalkyl;

[0596] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0597] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0598] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0599] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0600] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0601] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0602] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0603] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0604] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0605] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7and S(O)2NR c7 R d7 , where R 7 The C 6-10 Aryl-C 1-6 Alkylene and (5-10-membered heteroaryl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution;

[0606] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0607] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0608] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl; and

[0609] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0610] Example 35. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIIA):

[0611] (IIIA).

[0612] Example 36. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIIB):

[0613] (IIIB)

[0614] Example 37. The compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIIC):

[0615] (IIIC).

[0616] Example 38. A compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (IIID):

[0617] (IIID).

[0618] Example 39. A compound according to any one of Examples 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having a structure of formula (IIIA), (IIIB), (IIIC) or (IIID):

[0619]

[0620] Example 40. The compound according to Example 39, wherein

[0621] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0622] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0623] i) Halogenation;

[0624] ii) Amino;

[0625] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0626] iv) C3-C6 cycloalkenyl groups;

[0627] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0628] vi) C1-C6 haloalkyl groups;

[0629] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0630] viii)-NHC(=O)-C1-C6 haloalkyl;

[0631] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0632] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0633] xi)-C(=O)NH-C1-C6 haloalkyl;

[0634] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0635] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0636] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0637] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0638] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0639] xvii)phenyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0640] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0641] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0642] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0643] xxi)-C(=O)NH2;

[0644] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 6-10 Aryl-C 1-6 Alkylene and (5-10-membered heteroaryl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups.7A Substituent substitution;

[0645] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0646] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0647] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl; and

[0648] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0649] Example 40A. The compound according to Example 39, wherein

[0650] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0651] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0652] i) Halogenation;

[0653] ii) Amino;

[0654] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0655] iv) C3-C6 cycloalkenyl groups;

[0656] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0657] vi) C1-C6 haloalkyl groups;

[0658] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0659] viii)-NHC(=O)-C1-C6 haloalkyl;

[0660] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0661] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0662] xi)-C(=O)NH-C1-C6 haloalkyl;

[0663] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0664] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0665] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0666] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0667] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0668] xvii)phenyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0669] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0670] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0671] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0672] R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C 6-10 Aryl-C 1-6 Alkylene and (5-10-membered heteroaryl)-C1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution;

[0673] Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0674] Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl;

[0675] Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl; and

[0676] Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0677] Example 41. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is H.

[0678] Example 42. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 alkyl group.

[0679] Example 43. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of Examples 1 to 40, wherein R3 is methyl, ethyl, propyl or isopropyl.

[0680] Example 44. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 haloalkyl group.

[0681] Example 45. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is CF3.

[0682] Example 46. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 alkyl-phenyl.

[0683] Example 47. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is -CH2-phenyl.

[0684] Example 48. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C3-C6 cycloalkyl group.

[0685] Example 49. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is cyclopropyl or cyclobutyl.

[0686] Example 50. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 alkyl group substituted with a C1-C6 alkoxy group.

[0687] Example 51. The compound according to any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is -CH2CH2OCH3.

[0688] Example 52. The compound according to any one of Examples 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (V):

[0689] (V).

[0690] Example 53. The compound according to Example 52, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (VA):

[0691] (VA).

[0692] Example 54. The compound according to Example 52, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (VB):

[0693] (VB).

[0694] Example 55. The compound or its pharmaceutically acceptable salt or stereoisomer according to any one of Examples 1 to 54, wherein R5 is a 5-membered heteroaryl group having 1, 2 or 3 heteroatoms each independently selected from N, O and S as ring members, wherein the 5-membered heteroaryl group is unsubstituted.

[0695] Example 56. A compound according to any one of Examples 1 to 54, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from:

[0696] i) Halogenation;

[0697] ii) Amino;

[0698] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0699] iv) C3-C6 cycloalkenyl groups;

[0700] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0701] vi) C1-C6 haloalkyl groups;

[0702] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0703] viii)-NHC(=O)-C1-C6 haloalkyl;

[0704] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0705] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0706] xi)-C(=O)NH-C1-C6 haloalkyl;

[0707] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0708] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0709] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0710] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0711] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0712] xvii)phenyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0713] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0714] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0715] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0716] xxi)-C(=O)NH2.

[0717] Example 56A. A compound according to any one of Examples 1 to 53, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from:

[0718] i) Halogenation;

[0719] ii) Amino;

[0720] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0721] iv) C3-C6 cycloalkenyl groups;

[0722] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0723] vi) C1-C6 haloalkyl groups;

[0724] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0725] viii)-NHC(=O)-C1-C6 haloalkyl;

[0726] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0727] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0728] xi)-C(=O)NH-C1-C6 haloalkyl;

[0729] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0730] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0731] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0732] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0733] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0734] xvii)phenyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0735] xviii) optional 4- to 6-membered heterocyclic groups substituted with oxo, –C(=O)OC1-C6 alkyl, or –C(=O)OC1-C6 cycloalkyl groups; and

[0736] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0737] (xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy.

[0738] Example 57. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 56, wherein R5 is:

[0739] , or ;

[0740] in

[0741] R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halo;

[0742] R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4- to 6-membered heterocyclic, 5- or 6-membered heteroaryl; wherein the heteroaryl group is optionally replaced by... The heterocyclic group is optionally substituted with an oxo, -C(O)O-C1-C6 alkyl, or –C(O)O-C3-C6 cycloalkyl group; the –C(O)NHphenyl group is optionally substituted with a oxo or C1-C6 alkyl group; and each C1-C6 alkyl group is optionally substituted with one or more D groups.

[0743] R 5cIt is a 5- or 6-membered ring heteroaryl group, optionally substituted with a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C6 cycloalkyl; and

[0744] R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl.

[0745] In one embodiment, R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4 to 6-membered heterocyclic, 5 or 6-membered cycloheteroaryl; wherein the heteroaryl is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl; and wherein the heterocyclic is optionally substituted with oxo, -C(O)O-C1-C6 alkyl or –C(O)O-C3-C6 cycloalkyl; and wherein –C(O)NHphenyl is optionally substituted with halogen or C1-C6 alkyl.

[0746] Example 57A. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 56, wherein R5 is:

[0747] , or ;

[0748] in

[0749] R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halo;

[0750] R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4 to 6-membered heterocyclic, 5 or 6-membered cycloheteroaryl; wherein the heteroaryl is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl; the heterocyclic is optionally substituted with oxo, -C(O)O-C1-C6 alkyl or –C(O)O-C3-C6 cycloalkyl; –C(O)NHphenyl is optionally substituted with halogen or C1-C6 alkyl; and each C1-C6 alkyl is optionally substituted with one or more D.

[0751] R 5c It is a 5- or 6-membered ring heteroaryl group, optionally substituted with a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C6 cycloalkyl; and

[0752] R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl.

[0753] In one embodiment, R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4 to 6-membered heterocyclic, 5 or 6-membered cycloheteroaryl; wherein the heteroaryl is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl; and wherein the heterocyclic is optionally substituted with oxo, -C(O)O-C1-C6 alkyl or –C(O)O-C3-C6 cycloalkyl; and wherein –C(O)NHphenyl is optionally substituted with halogen or C1-C6 alkyl.

[0754] Example 58. The compound according to any one of Examples 1 to 56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0755] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0756] Example 58A. The compound according to any one of Examples 1 to 56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0757] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0758] Example 59. The compound according to any one of Examples 1 to 56, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0759] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or .

[0760] Example 60. The compound according to any one of Examples 1 to 59, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0761] .

[0762] Example 60A. The compound according to any one of Examples 1 to 59, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0763] ; ;or ;

[0764] Example 61. The compound according to any one of Examples 1 to 60, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 The options are D, CD3, and C. 1-6 Alkyl, C 6-10 Aryl-C 1-6 alkylene or (5-10-membered heteroaryl)-C 1-6 Alkylene.

[0765] Example 62. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7It is either D or methyl.

[0766] Example 63. The compound according to any one of Examples 1 to 62, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 The answer is D.

[0767] Example 64. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 It is CD3.

[0768] Example 65. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 It is a methyl group.

[0769] Example 66. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 It is an ethyl group.

[0770] Example 67. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 It is benzyl.

[0771] Example 68. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 It is a fluorobenzyl group.

[0772] Example 69. The compound according to any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 It is pyridylmethyl.

[0773] Example 70. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is

[0774] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0775] N 2 ,4-Dimethyl-N 5-((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0776] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0777] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0778] N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0779] N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0780] N 5 -((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0781] N 5-((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0782] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0783] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0784] N 5 -((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0785] N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0786] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0787] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0788] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0789] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0790] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0791] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0792] N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0793] N 5 -((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0794] N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0795] N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0796] N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide; and

[0797] N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide.

[0798] Example 71. The compound according to Example 1, wherein the compound is

[0799] N 2 ,4-Dimethyl-N 5-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0800] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0801] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0802] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0803] N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0804] N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0805] N 5-((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0806] N 5 -((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0807] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0808] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0809] N 5 -((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0810] N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0811] N2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0812] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide;

[0813] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0814] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0815] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0816] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0817] N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0818] N 5 -((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0819] N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0820] N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0821] N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide; and

[0822] N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide.

[0823] Example 72. The compound according to Example 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is

[0824] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; or

[0825] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazole-2,5-dicarboxamide.

[0826] Example 73. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is

[0827] 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0828] 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0829] 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide;

[0830] 4-Methyl-N 2 -(methyl-d3)-N 5-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0831] 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; or

[0832] 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazole-2,5-dicarboxamide.

[0833] Example 74. A compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof,

[0834] (Ia)

[0835] in:

[0836] Y is CH2 or C=O;

[0837] R1 is H, C1-C6 alkyl, or halogenated;

[0838] R2 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0839] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0840] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0841] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0842] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0843] i) Halogenation;

[0844] ii) Amino;

[0845] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0846] iv) C3-C6 cycloalkenyl groups;

[0847] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0848] vi) C1-C6 haloalkyl groups;

[0849] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0850] viii)-NHC(=O)-C1-C6 haloalkyl;

[0851] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0852] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more D or C1-C6 alkoxy groups;

[0853] xi)-C(=O)NH-C1-C6 haloalkyl;

[0854] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0855] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0856] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0857] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0858] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0859] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0860] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0861] xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of a 5 or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with –OH, C1-C6 alkoxy or optionally oxy-substituted 4 to 6-membered heterocyclic group;

[0862] xx) having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and

[0863] xxi)-C(=O)NH2;

[0864] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0865] R 11 It is H, C1-C6 alkyl or halogenated; or

[0866] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; and

[0867] R 7 For H.

[0868] Example 74A. The compound according to Example 74, wherein

[0869] Y is CH2 or C=O;

[0870] R1 is H, C1-C6 alkyl, or halogenated;

[0871] R2 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0872] R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0873] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0874] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6.

[0875] R5 is a 5-membered heteroaryl group having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from the following:

[0876] i) Halogenation;

[0877] ii) Amino;

[0878] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0879] iv) C3-C6 cycloalkenyl groups;

[0880] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0881] vi) C1-C6 haloalkyl groups;

[0882] vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0883] viii)-NHC(=O)-C1-C6 haloalkyl;

[0884] ix)-NHC(=O)-C3-C6 cycloalkyl;

[0885] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl group is optionally substituted with a C1-C6 alkoxy group;

[0886] xi)-C(=O)NH-C1-C6 haloalkyl;

[0887] xii)-C(=O)NH-C3-C6 cycloalkyl;

[0888] xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0889] xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups;

[0890] xv)C1-C6 alkoxy or C1-C6 haloalkoxy;

[0891] xvi) optionally substituted with one or more halogenated phenoxy groups;

[0892] xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0893] xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups;

[0894] xix) having one or two heteroatoms, each independently selected from N, O, and S, as ring members, of a 5- or 6-membered heteroaryl group, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy, or optionally substituted with an oxo-substituted 4- to 6-membered heterocyclic group; and

[0895] xx) having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4 to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0896] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0897] R 11 It is H, C1-C6 alkyl or halogenated; or

[0898] R1 and R11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; and

[0899] R 7 For H.

[0900] Depending on the choice of starting materials and procedures, these compounds may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. This disclosure is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0901] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, meaning that the material can be administered to an individual without causing undesirable biological effects or interacting with any component of a composition containing the material in a harmful manner.

[0902] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acid or organic acid salts of basic residues (such as amines); alkali metal salts or organic salts of acidic residues (such as carboxylic acids); and so on. Pharmaceutically acceptable salts of this disclosure include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutical acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0903] Any formulas given herein are also intended to represent both unlabeled and isotopically labeled forms of these compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of this disclosure include, for example, isotopes of hydrogen.

[0904] It will be recognized that, depending on the source of the chemical materials used in the synthesis, some variation in the natural isotopic abundance occurs in the synthesized compounds. Therefore, the preparation of the compounds disclosed herein will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution in the compounds disclosed herein. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0905] In the compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to have hydrogen in its native abundance isotopic composition. Furthermore, unless otherwise specified, when a position is explicitly designated as “D” or “deuterium”, it should be understood that the deuterium abundance at that position is at least 3000 times higher than the native abundance of deuterium (i.e., 0.015%) (i.e., at least 45% deuterium doping).

[0906] In one embodiment, any atom in the compound provided herein not designated as deuterium is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 40%, 50%, 60%, 70%, 80%, or 90%. In another embodiment, any atom in the compound provided herein not designated as deuterium is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 80%. In yet another embodiment, any atom in the compound provided herein not designated as deuterium is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 90%. In one embodiment, any atom in formula (I) provided herein not designated as deuterium is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 40%, 50%, 60%, 70%, 80%, or 90%. In another embodiment, any atom not specified as deuterium in Formula (I) provided herein is present at its natural isotopic abundance, and wherein for each site specified as deuterium, deuterium doping is at least 80%. In yet another embodiment, any atom not specified as deuterium in Formula (I) provided herein is present at its natural isotopic abundance, and wherein for each site specified as deuterium, deuterium doping is at least 90%.

[0907] In one embodiment, any atom not designated as deuterium in Example 1 provided herein is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 40%, 50%, 60%, 70%, 80%, or 90%. In another embodiment, any atom not designated as deuterium in Example 1 provided herein is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 80%. In yet another embodiment, any atom not designated as deuterium in Example 1 provided herein is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 90%.

[0908] In one embodiment, any atom not designated as deuterium in Examples 2, 29, or 30 provided herein is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 40%, 50%, 60%, 70%, 80%, or 90%. In another embodiment, any atom not designated as deuterium in Examples 2, 29, or 30 provided herein is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 80%. In yet another embodiment, any atom not designated as deuterium in Examples 2, 29, or 30 provided herein is present at its natural isotopic abundance, and wherein for each site designated as deuterium, the deuterium doping is at least 90%.

[0909] In addition, certain isotopes (especially deuterium, i.e., 2 The incorporation of H or D can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, improved therapeutic index and tolerability, and / or lower epimerization frequency. It should be understood that, in this context, deuterium is considered a substituent for the compounds disclosed herein. The concentration of deuterium can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance. If the substituent in the compounds of this disclosure is designated as deuterium, then the compound has an isotope enrichment factor of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) for each specified deuterium atom. It should be understood that the term "isotope enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0910] Other examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 3 H, 11 C 13 C 14 C 15 N、 18 F 31 P, 32 P, 35 S, 36 Cl、 123 I, 124 I, 125I. Therefore, it should be understood that this disclosure includes compounds doped with one or more of the aforementioned isotopes, including, for example, radioactive isotopes, such as 3 H and 14 C, or the presence of non-radioactive isotopes, such as 2 H and 13 Compounds of C. These isotope-labeled compounds can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays), or for use in patients undergoing radiation therapy. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples and preparations, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0911] For example, the compounds disclosed herein can exist in the following deuterated forms:

[0912] , , , , , , , and .

[0913] In one embodiment of the above-described deuterated form, R 7 For D. In another embodiment of the above deuterated form, R 7 It is a methyl group.

[0914] Pharmaceutically acceptable solvates according to this disclosure include solvates in which the crystallization solvent can be replaced by an isotope, such as D2O, d6-acetone, d6-DMSO.

[0915] The compounds of this disclosure containing groups capable of acting as hydrogen bond donors and / or acceptors can form eutectics with suitable eutectic forms. These eutectics can be prepared from the compounds of this disclosure using known eutectic formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compounds of this disclosure with the eutectic forms in solution under crystallization conditions and separating the resulting eutectic. Suitable eutectic forms include those described in WO 2004 / 078163. Therefore, this disclosure further provides eutectics comprising the compounds of this disclosure.

[0916] Furthermore, the compounds of this disclosure, including their salts, may also be obtained as hydrates or include other solvents for their crystallization. The compounds of this disclosure may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; therefore, this disclosure is intended to cover both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of this disclosure (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical industry and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0917] Any asymmetric atom (e.g., carbon, etc.) in the compounds of this disclosure may be present in a racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess in the (R)- or (S)- configuration. Substituents at atoms having unsaturated double bonds may be present, if possible, in cis-(Z)- or trans-(E)- form.

[0918] When the compounds described herein contain asymmetric carbons, the compounds can be any possible stereoisomers unless otherwise indicated. In some embodiments, the compounds provided herein have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one asymmetric carbon atom, each carbon atom in the compound may be independently (R) or (S) unless otherwise indicated. In compounds having a single asymmetric carbon, the stereochemistry of that asymmetric carbon may be (R) or (S). In compounds having two asymmetric carbon atoms, the stereochemistry of these carbon atoms may each be independently (R) or (S), and thus the configurations of these carbon atoms may be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In a compound having three asymmetric carbon atoms, the stereochemistry of these three carbon atoms can be (R) or (S) independently, so the configurations of these carbon atoms can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).

[0919] Therefore, as used herein, the compounds disclosed herein may exist in the form of one of the possible isomers, rotational isomers, blocked rotational isomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0920] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization, based on the physicochemical differences of the components.

[0921] Any racemic product or intermediate obtained can be resolved into its optical enantiomers by known methods, for example, by separating its diastereomer salt obtained with an optically active acid or base, and releasing the optically active acidic or basic compound. In particular, the basic moiety can therefore be used to resolve the compounds of this disclosure into their optical enantiomers, for example, by fractional crystallization of salts formed with optically active acids such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, diO,O'-p-toluyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral adsorbent.

[0922] Methods for preparing compounds

[0923] This document describes a general procedure for preparing the compounds of this disclosure. In the reactions described, reactive functional groups (e.g., hydroxyl, amino, imino, or carboxyl groups, where these groups are desired in the final product) are protected to prevent them from undesirably participating in the reaction. Within the scope of this document, unless the context otherwise requires, only easily removable groups that are not a component of the specific desired final product of the compounds of this disclosure are designated as “protecting groups.” Protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described, for example, in standard reference works such as JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, and TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, 3rd ed., Wiley, New York 1999.

[0924] Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all instances or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate this disclosure and does not constitute a limitation on the scope of this disclosure as otherwise claimed.

[0925] Methods for synthesizing compounds

[0926] The reagent disclosed herein can be prepared by the reaction sequence shown in the reaction scheme of the experimental section (see below).

[0927] Typically, the compounds of this disclosure can be prepared according to schemes 1 to 4 provided below. The compounds of this disclosure are prepared by the methods described herein and illustrated in the examples. Combinations of various structural units and intermediates described herein can be used to obtain the compounds of this disclosure. Non-limiting examples of synthetic schemes for preparing the compounds of this disclosure are illustrated in schemes 1 to 4. Further guidance can be found in the Examples section.

[0928] Compound (II) can be prepared as outlined in Scheme 1.

[0929] Option 1

[0930]

[0931] The amide of Int-1 with the corresponding N-protected β-amino acid (Int-2) can be achieved using various coupling reagents or conditions (E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606-631; A. El-Faham, F. Albericio, Chem. Rev. 2011, 111, 6557–6602). After removing the protecting group (TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis” 3rd ed., Wiley, New York 1999) such as Boc or Cbz from the formed amide, the released amine intermediate can be coupled with various acid structural units (Int-3) to provide the final compound of formula (II).

[0932] Similarly, compounds of formula (III) can be prepared as outlined in scheme 2.

[0933] Option 2

[0934]

[0935] Similar to the preparation of compounds of formula (II), compounds of formula (III) can be achieved via amide coupling between amines (Int-1), but in this case, various monoprotected succinates (Int-4) are used as acid pairs. The chiral succinate intermediate (Int-4) can be prepared in enantiomeric form by various methods, including asymmetric hydrogenation of α-substituted acrylic acid using a chiral catalyst (e.g., PM Donate et al., Tetrahedron: Asymmetry 2003, 14, 3253–3256) or by the Evans method utilizing a chiral oxazolidine auxiliaries (DA Evans et al., J. Org. Chem. 1999, 64, 6411−6417). Alternatively, such chiral acids can also be prepared by chiral resolution (JM Keith et al., Adv. Synth. Catal. 2001, 343, 5-26) using chiral amines or enzymes, by dynamic kinetic resolution, or by chiral separation using preparative chiral chromatography. The resulting amide ester intermediate then undergoes ester hydrolysis, and the obtained acid intermediate can be coupled with an aliphatic or aromatic amine to provide the final product of formula (III).

[0936] The required chiral amine intermediate Int-1 can be prepared as outlined in Scheme 3, where Y is CH2.

[0937] Option 3

[0938]

[0939] The tricyclic core is prepared by cyclization of 2-(2-(halomethyl)phenyl)acetate (prepared from the corresponding isochorium-3-one - US6,048,998) with pyrazolidine (EE Boros, F. Bouvier, S. Randhawa, MH Rabinowitz, J. Heterocycl. Chem. 2001, 38, 613−616). The desired primary amine can be introduced into such compounds in several ways. Such molecules can be converted into α-bromodermidates, which undergo nucleophilic substitution with an azide, which can then be reduced to the primary amine (e.g., WO 2015 / 160772). Another possibility for introducing azides is through a one-step sequence of azidation using the corresponding enol and 2,4,6-triisopropylbenzenesulfonyl azide (e.g., CVC Prasad et al., Bioorg. Med. Chem. Lett. 2007, 17, 4006–4011) or copper-catalyzed azidation (S.-E. Suh et al., J. Am. Chem. Soc. 2020, 142, 11388−11393). Alternatively, as shown in scheme 3, amines can also be introduced via oxime formation and its reduction (F. Hoffmann-Emery et al., Tet. Lett. 2009, 50, 6380–6382). Enantiomers can be obtained by chiral resolution, by forming a mixture of separable and cleavable diastereomers (F. Hoffmann-Emery, R. et al., 2009), or by preparative chiral chromatography.

[0940] Intermediate 1 (Int-1) (where Y is C(O)) can be prepared according to Scheme 4:

[0941] Option 4

[0942]

[0943] If isocyanate-1,3-dione is used instead of 2-(2-(halomethyl)phenyl)acetate in the cyclization with pyrazolidine, the oxotricyclic compound can be prepared similarly to the tricyclic synthesis described in Scheme 3. Alternatively, Int-1 from Scheme 3 can be oxidized with RuO2 (AG Schultz et al., J. Org. Chem. 1998, 63, 7795−7804) to directly provide Int-1 wherein Y is C(O). Chiral separation can also be performed as described in Scheme 3.

[0944] Application and pharmaceutical composition

[0945] For therapeutic use of the compounds of this disclosure, such compounds are administered alone or as part of a pharmaceutical composition. Therefore, in another aspect, this disclosure provides a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. In some embodiments, pharmaceutical compositions comprising compounds of this disclosure may be formulated for intramuscular, intravenous, subcutaneous, oral, pulmonary, intrathecal, topical, or intranasal administration.

[0946] The pharmaceutical compositions disclosed herein can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets can be film-coated or enteric-coated according to methods known in the art.

[0947] Compositions suitable for oral administration include the compounds of this disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically aesthetic and palatable formulation. Tablets may contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier / excipient suitable for tablet manufacturing. These carriers / excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binders, such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, delay-release materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0948] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous isotonic solutions or suspensions. These parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure. Furthermore, they may contain other therapeutically valuable substances. These compositions are typically prepared according to conventional mixing, granulation or coating methods and contain about 0.1-75% or about 1-50% of the active ingredient.

[0949] When the compounds or pharmaceutical compositions thereof disclosed herein are used in subjects (e.g., humans), they are typically administered orally or parenterally at a therapeutic dose of less than or equal to about 100 mg / kg. When administered intravenously via infusion, the dose may depend on the infusion rate at which the IV formulation is administered. Generally, the therapeutically effective dose of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, the condition or disease being treated, or its severity.

[0950] The above-described dosage characteristics can be demonstrated in in vitro and in vivo tests, and are advantageous for use in mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and their products. The compounds disclosed herein can be applied in vitro in solution form, for example, an aqueous solution, and in vivo via enteral, parenteral, or advantageously intravenous administration, for example, as a suspension or in an aqueous solution.

[0951] Certain aspects and examples of pharmaceutical compositions disclosed herein are provided below. It will be appreciated that the features specified in each example may be combined with other specified features to provide further embodiments of this disclosure.

[0952] In one respect, this document provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0953] In one embodiment, the pharmaceutical composition comprises one or more additional therapeutic agents.

[0954] Pharmacology and practicality

[0955] The compounds disclosed herein, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, such as inhibition of cellular levels of SPPL2a as indicated by in vitro tests provided herein, and are therefore indicated for therapeutic use or as research chemicals, such as, as tool compounds.

[0956] Therefore, the compounds disclosed herein are generally intended for the treatment of indications involving, for example, cells expressing high levels of CD74 and / or cells involved in class II-dependent antigen presentation. Furthermore, the compounds disclosed herein can be used to treat autoimmune diseases and / or conditions. In particular, the compounds disclosed herein can be used to treat and / or prevent pemphigus vulgaris, pemphigus foliaceus, Sjögren's syndrome, systemic lupus erythematosus (SLE), arthritis, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpasture syndrome, multiple sclerosis (MS), or type I diabetes.

[0957] Furthermore, the compounds disclosed herein can be used to prevent rejection in clinical / surgical transplantation of solid organs, tissues, or cell populations (such as stem cells). Additionally, the compounds disclosed herein can be used to treat and / or prevent acute and chronic graft-versus-host disease (GvHD) associated with transplantation of solid organs, tissues, or cell populations. The compounds disclosed herein can be used further prophylactically, for example, as induction therapy to prepare the host prior to transplantation of solid organs, tissues, or cell populations; or the compounds disclosed herein can be further used for treatment after transplantation of solid organs, tissues, or cell populations. Non-limiting examples of transplantation are kidney transplantation, heart transplantation (acute or chronic), and bone marrow transplantation. Furthermore, the compounds disclosed herein can be used to treat donors prior to organ, tissue, or cell donation.

[0958] In addition, the compounds disclosed herein can be used to treat lymphomas, particularly lymphomas arising from modified B cells expressing high levels of CD74, such as Hodgkin lymphoma, follicular lymphoma, marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma, non-Hodgkin lymphoma (NHL), Burkitt lymphoma (BL), and multiple myeloma (MM).

[0959] Certain aspects and examples of the use of the compounds and pharmaceutical compositions of this disclosure are provided below. It will be appreciated that the features specified in each example may be combined with other specified features to provide further embodiments of this disclosure.

[0960] In one aspect, this article provides a method for treating a disease or condition associated with the activity of signal peptidase-like proteinase 2a (SPPL2a), said method comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt.

[0961] In one embodiment, the disease or condition is selected from NMDAR encephalitis, neuromyelitis optica spectrum disorder (NMOSD), and myelin-oligodendrocyte glycoprotein (MOG) spectrum disorder (MOGSD). In another embodiment, the disease or condition is a cardiomyopathy. In yet another embodiment, the disease or condition is spondylitis (SpA). In still another embodiment, the disease or condition is vasculitis.

[0962] In another embodiment, the disease or condition is lupus. In yet another embodiment, the disease or condition is cutaneous lupus.

[0963] In one embodiment of the method, the method includes treating a subject with systemic lupus erythematosus (SLE) in need, which includes administering N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0964] In one embodiment of the method, the method includes treating psoriasis in a subject in need, which includes administering N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0965] In one embodiment of the method, the method includes treating a subject with systemic lupus erythematosus (SLE) in need, which includes administering 4-methyl-N to the subject. 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0966] In one embodiment of the method, the method includes treating psoriasis in a subject in need, which includes administering 4-methyl-N to the subject. 2 -(methyl-d3)-N 5-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0967] In one embodiment of the method, the method includes treating psoriasis in a subject in need, which includes administering N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[0968] On another aspect, this article provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating diseases or conditions associated with the activity of signal peptidase-like proteinase 2a (SPPL2a).

[0969] On the other hand, this article provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the treatment of diseases or conditions associated with the activity of signal peptidase-like proteinase 2a (SPPL2a).

[0970] In one respect, this document provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with the activity of signal peptidase-like protease 2a (SPPL2a).

[0971] On the other hand, this article provides a method for treating an autoimmune disease in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0972] In another embodiment, the autoimmune disease is cutaneous lupus.

[0973] In another embodiment, the autoimmune disease is autoimmune encephalomyelitis.

[0974] In one embodiment, the autoimmune disease is Sjögren's syndrome, systemic lupus erythematosus (SLE), arthritis (such as rheumatoid arthritis and psoriatic arthritis), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpasture syndrome, or type 1 diabetes. In another embodiment, the autoimmune disease is cutaneous lupus. In one embodiment, the arthritis is juvenile arthritis.

[0975] In another embodiment, the autoimmune disease is multiple sclerosis (MS), Sjögren's syndrome, psoriasis, arthritis (such as rheumatoid arthritis and psoriatic arthritis), lupus nephritis, or systemic sclerosis. In yet another embodiment, the autoimmune disease is a neurological autoimmune disease. In one embodiment, the autoimmune disease is an autoantibody-mediated encephalitis syndrome. In one embodiment, the arthritis is juvenile arthritis. In one embodiment, the arthritis is osteoarthritis. In one embodiment, the arthritis is rheumatoid arthritis.

[0976] In yet another embodiment, the autoimmune disease is multiple sclerosis (MS).

[0977] In one embodiment, the autoimmune disease is autoimmune myositis, dermatomyositis, polymyositis, or juvenile myositis.

[0978] On the other hand, this article provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of autoimmune diseases.

[0979] On the one hand, this article provides the use of the compounds described herein or pharmaceutically acceptable salts thereof in the treatment of autoimmune diseases.

[0980] On the other hand, this document provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of autoimmune diseases.

[0981] In one embodiment, the disease or condition is pemphigus. In another embodiment, the pemphigus condition is pemphigus vulgaris, pemphigus foliaceus, or bullous pemphigoid.

[0982] In yet another embodiment, the disease or condition is diabetes. In still another embodiment, diabetes is type 1 diabetes. In yet another embodiment, diabetes is type 2 diabetes.

[0983] In one embodiment, the disease or condition is selected from Sjögren's syndrome, systemic lupus erythematosus (SLE), arthritis, lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpasture syndrome, hidradenitis suppurativa, ANCA vasculitis, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity.

[0984] In another embodiment, the disease or condition is arthritis. In yet another embodiment, the arthritis is rheumatoid arthritis (RA) or psoriatic arthritis. In one embodiment, the arthritis is juvenile arthritis.

[0985] In yet another embodiment, the disease or condition is systemic lupus erythematosus (SLE).

[0986] In one embodiment, the disease or condition is selected from hidradenitis suppurativa, pemphigus, dermatomyositis, and polymyositis. In another embodiment, the polymyositis is juvenile polymyositis.

[0987] In another embodiment, the disease or condition is selected from insulin resistance, metabolic disease, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity.

[0988] In another embodiment, the method or use relates to treating lymphoma. In another embodiment, the lymphoma is Hodgkin lymphoma, follicular lymphoma, marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or lymphoplasmacytic lymphoma.

[0989] In another aspect, this article provides a method for treating a disease associated with high levels of CD74 expression in B cells in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0990] In one respect, this article provides the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating diseases associated with high levels of CD74 expression in B cells in subjects.

[0991] On the other hand, this article provides the use of the compounds provided herein or pharmaceutically acceptable salts thereof in treating diseases associated with high levels of CD74 expression in B cells in subjects.

[0992] On another front, this document provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of diseases in subjects associated with high levels of CD74 expression in B cells.

[0993] In one embodiment, B-cell lymphomas are non-Hodgkin lymphoma (NHL), Burkitt lymphoma (BL), and multiple myeloma (MM).

[0994] On the other hand, this article provides a method for treating B-cell lymphoma in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0995] On the other hand, this article provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of B-cell lymphoma.

[0996] On another front, this article provides the use of the compounds described herein or pharmaceutically acceptable salts thereof in the treatment of B-cell lymphoma.

[0997] On the other hand, this document provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of B-cell lymphoma.

[0998] In one embodiment, B-cell lymphomas are non-Hodgkin lymphoma (NHL), Burkitt lymphoma (BL), and multiple myeloma (MM).

[0999] In one aspect, this document provides a method for treating graft-versus-host disease (GvHD) in a post-transplant subject, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, wherein the transplant is a transplant of a solid organ, tissue, or cell population. In one embodiment, treatment of graft-versus-host disease (GvHD) prevents rejection in clinical / surgical transplantation of a solid organ or cell population.

[1000] On another aspect, this article provides a method for preventing graft-versus-host disease (GvHD) in a subject after transplantation, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof prior to transplantation, wherein the transplantation is a transplantation of a solid organ, tissue, or cell population.

[1001] On the one hand, this article provides the use of the compounds described herein for the treatment of graft-versus-host disease (GvHD) in post-transplant subjects, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[1002] On the other hand, this article provides the use of the compounds provided herein in the manufacture of a medicament for treating graft-versus-host disease (GvHD) in post-transplant subjects, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[1003] On another aspect, this document provides compounds disclosed herein for the treatment of graft-versus-host disease (GvHD) in post-transplant subjects, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[1004] In one embodiment, the transplant is a solid organ transplant.

[1005] In another embodiment, the transplant is a bone marrow transplant.

[1006] In yet another embodiment, the transplant is a stem cell transplant.

[1007] In yet another embodiment, the transplant is a hematopoietic stem cell transplant.

[1008] In one embodiment, transplantation is tissue transplantation.

[1009] In another embodiment, graft-versus-host disease (GvHD) is acute graft-versus-host disease.

[1010] In yet another embodiment, graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[1011] In one respect, this article provides a method for treating conditions selected from hidradenitis suppurativa, arthritis, pemphigus, ANCA vasculitis, diabetes, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity in post-transplant subjects, wherein the method comprises administering the compound provided herein or a pharmaceutically acceptable salt thereof to the subject prior to transplantation.

[1012] In one respect, this article provides a method for treating a condition selected from hidradenitis suppurativa, arthritis, pemphigus, ANCA vasculitis, diabetes, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity in a subject in need, comprising administering to the subject the compound provided herein or a pharmaceutically acceptable salt thereof.

[1013] In one embodiment, the compound is N 2 ,4-Dimethyl-N 5-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is 4-methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1014] In one embodiment, pemphigus disease is bullous pemphigoid.

[1015] In another embodiment, diabetes is type 2 diabetes.

[1016] In yet another embodiment, polymyositis is juvenile polymyositis.

[1017] In one embodiment, the arthritis is juvenile arthritis.

[1018] In yet another embodiment, the condition is selected from hidradenitis suppurativa, pemphigus, dermatomyositis, and polymyositis.

[1019] In another embodiment, the condition is selected from insulin resistance, metabolic disease, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity.

[1020] On the other hand, this article provides a method for treating a condition selected from hidradenitis suppurativa, arthritis, lupus dermatitis, pemphigus, ANCA vasculitis, diabetes, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity in a subject in need, comprising administering a therapeutically effective amount of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1021] In one embodiment, the arthritis is juvenile arthritis or psoriatic arthritis.

[1022] In another embodiment, the condition is cutaneous lupus.

[1023] In another embodiment, the pemphigus condition is bullous pemphigoid.

[1024] In yet another embodiment, diabetes is type 2 diabetes.

[1025] In yet another embodiment, polymyositis is juvenile polymyositis.

[1026] In one embodiment, the condition is selected from hidradenitis suppurativa, pemphigus, dermatomyositis, and polymyositis. In another embodiment, the condition is selected from insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity.

[1027] In one aspect, this article provides a method for treating a condition selected from psoriasis, autoimmune encephalomyelitis, autoimmune myositis, juvenile myositis, and gallstone disease in a subject in need, comprising administering a therapeutically effective amount of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1028] In one aspect, this article provides a method for treating cancers selected from marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and lymphoplasmacytic lymphoma in a subject of need, comprising administering a therapeutically effective dose of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1029] In one aspect, this article provides a method for treating a condition selected from psoriasis, autoimmune encephalomyelitis, autoimmune myositis, juvenile myositis, and gallstone disease in a subject in need, comprising administering a therapeutically effective amount of N to the subject. 2,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1030] In one aspect, this article provides a method for treating cancers selected from marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and lymphoplasmacytic lymphoma in a subject of need, comprising administering a therapeutically effective dose of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1031] In one aspect, this article provides a method for treating a condition selected from psoriasis, autoimmune encephalomyelitis, autoimmune myositis, juvenile myositis, and gallstone disease in a subject in need, comprising administering to the subject a therapeutically effective amount of 4-methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1032] In one aspect, this article provides a method for treating a subject in need with cancers selected from marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and lymphoplasmacytic lymphoma, comprising administering to the subject a therapeutically effective amount of 4-methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazol-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

[1033] Combination therapy

[1034] In some cases, it may be advantageous to administer the compounds of this disclosure in combination with one or more other therapeutic agents. Therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that, when administered to a patient in combination with the compounds of this disclosure, have therapeutic activity or enhance therapeutic activity.

[1035] The compounds disclosed herein may be administered as the sole active ingredient, or in combination with other drugs used to combat neoplastic diseases, inflammatory conditions, in immunomodulatory regimens, or in induction therapy to prevent GvHD and transplant rejection. For example, the compounds disclosed herein may be used in combination with cyclosporine, rapamycin, or ascomycin, or their immunosuppressive analogs or derivatives (e.g., cyclosporine A, cyclosporine G, Isa tx247, FK-506, sirolimus, or everolimus); with corticosteroids (e.g., prednisone); cyclophosphamide; azathioprine; methotrexate; gold salts; sulfasalazine; antimalarial drugs; leflunomide; imidazolidinedin; mycophenolate mofetil; 15-deoxyguanidin; with S1P receptor agonists (e.g., FTY720 or its analogues); with immunosuppressive monoclonal antibodies (e.g., monoclonal antibodies against leukocyte receptors, e.g., MHC) or other immunomodulatory compounds (e.g., CTLA4Ig).

[1036] Compounds of Formula I can also be used in combination with other antiproliferative agents. These antiproliferative agents include, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule activators, alkylating agents, histone deacetylase inhibitors, farnesyltransferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platinum compounds, compounds that reduce protein kinase activity, and other antiangiogenic compounds, gonadorelin agonists, antiandrogens, bengamides, bisphosphonates, antiproliferative antibodies, and temozolomide (TEMODAL).

[1037] Example

[1038] The compounds disclosed herein can be produced as shown in the examples below. These examples are intended to illustrate the disclosure and should not be construed as limiting it. Temperatures are expressed in degrees Celsius. Unless otherwise specified, all evaporation is carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, such as trace analysis and spectroscopic characterization, such as MS, IR, and NMR. The abbreviations used are those conventional in the art.

[1039] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds disclosed herein are commercially available or can be produced by organic synthesis methods known to those skilled in the art, or by organic synthesis methods as described herein.

[1040] For illustrative purposes, the general reaction schemes described herein provide potential pathways for synthesizing the compounds disclosed herein, as well as key intermediates. More detailed descriptions of the individual reaction steps are provided in the Examples section below. Although specific starting materials and reagents are described in the schemes and discussed below, they can easily be substituted with other starting materials and reagents to provide a variety of derivatives and / or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified according to this disclosure using conventional chemical methods well known to those skilled in the art.

[1041] abbreviation:

[1042]

[1043] Analytical methods

[1044] HPLC conditions:

[1045] Method a: HPLC instrument: Agilent 1100 series; Column: Waters X-Bridge C18 2.5 μm 3*30 mm; Eluent A: Water + 0.1% TFA, Eluent B: ACN + 0.1% TFA, gradient 10% to 98% over 3 min; Flow rate: 1.4 mL / min

[1046] Method b: HPLC instrument: Agilent 1100 series; Column: Waters X-Bridge C18 2.5 μm 3*50 mm; Eluent A: Water + 0.1% TFA, Eluent B: ACN + 0.1% TFA, gradient 10% to 98% over 8.6 min; Flow rate: 1.4 mL / min

[1047] Synthesis of example compounds

[1048] The synthesis of int-A1 and Example A, and the activity of Example A against SPPL2a, have been previously disclosed in International Application No. PCT / IB2021 / 058398 (WO 2022 / 058902), which is incorporated herein by reference in its entirety.

[1049] (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza- 11-keto(int-A1) Synthesis

[1050]

[1051] Step 1: At 0°C, thionyl chloride (14.8 mL, 202 mmol) was added dropwise to a suspension of isochorium-3-one (15 g, 101 mmol) in methanol (150 mL). The resulting solution was stirred at 0°C for 2 hours, and then at room temperature for 16 hours. The reaction mixture was concentrated, the crude material was dissolved in ethyl acetate, and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give methyl 2-(2-(chloromethyl)phenyl)acetate. 1 H NMR (DMSO-d6, 400MHz): δ 7.44–7.47 (m, 1H), 7.27–7.36 (m, 3H), 4.80 (s, 2H), 3.85 (s, 2H), 3.63 (s, 3H).

[1052] Step 2: At room temperature, pyrazolidine dihydrochloride (14.2 g, 98 mmol) was added to a solution of methyl 2-(2-(chloromethyl)phenyl)acetate (19.4 g, 98 mmol) in DMF (500 mL), followed by DIPEA (85 mL, 488 mmol), sodium iodide (14.6 g, 98 mmol), and sodium acetate (32.0 g, 391 mmol). The suspension was stirred at room temperature for 16 hours. The reaction mixture was concentrated, the crude material was dissolved in ethyl acetate, and washed with saturated NaHCO3 solution. The organic phase was dried (Na2SO4), concentrated, and purified by column chromatography (10–20% ethyl acetate in toluene) to give 2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-11(1H)-one. LCMS (Method d) m / z 203.1 [M+H] + , t R = 1.35 min. 1 H NMR (DMSO-d6, 400 MHz): δ 7.14–7.26 (m, 3H), 7.03 (d, J= 7.3 Hz, 1H), 4.15 (s, 2H), 3.84 (br s, 2H), 3.48 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 6.7 Hz, 2H), 2.19 (quin, J = 7.0 Hz, 2H).

[1053] Step 3: At 0°C, a 1M LiHMDS THF solution (93 mL, 93 mmol) was added dropwise to a solution of 2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-11(1H)-one (14.0 g, 62 mmol) and isoamyl nitrite (10.8 mL, 81 mmol) in THF (750 mL), and the solution was stirred at 0°C for 2 hours. The reaction mixture was concentrated and dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried (Na2SO4), concentrated, and purified by column chromatography (10–90% ethyl acetate in toluene with 0.1% Et3N) to give a mixture of (Z) and (E)-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-11(1H)-one. LCMS (Method d) m / z 232.0 [M+H] + , t R = 0.90 & 1.06 min.

[1054] Step 4: At room temperature, zinc powder (10.9 g, 166 mmol) was added to a solution of (Z) and (E)-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-11(1H)-one (9.6 g, 42 mmol) in AcOH (300 mL) and 10% HCl aqueous solution (300 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give 10-amino-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-11(1H)-one, which was used in the next step without further purification.

[1055] Step 5: At room temperature, Boc₂O (9.0 g, 41 mmol) and Na₂CO₃ (13.0 g, 124 mmol) were added to a solution of 10-amino-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-11(1H)-one (29.2 g, 41 mmol) in dioxane (400 mL) and water (200 mL), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then concentrated and treated with ethyl acetate and a saturated NaHCO₃ solution. The organic layer was dried (MgSO4) and concentrated to obtain a crude product, which was purified by column chromatography (0–80% ethyl acetate in cyclohexane) to obtain racemic 11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-10-ylcarbamate tert-butyl ester.

[1056] Step 6 (Chiral Separation); Chiral HPLC (Thhar SFC-200 instrument, mobile phase: scCO2 / EtOH 85:15, column: Chiralcel OD-H, 30 x 250 mm) was performed. (mm) Separation of two enantiomers of 11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl tert-butyl carbamate yielded (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl) tert-butyl carbamate (enantiomer excess ≥99.5%) and (R)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl) tert-butyl carbamate (enantiomer excess ≥99.5%). Analytical data for (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)carbamate tert-butyl: LCMS (Method b) m / z 318.3 [M+H] + , t R = 1.03 min. 1H NMR (400 MHz, DMSO-d6) δppm 7.31 (d, J = 7.3 Hz,1H), 7.15–7.27 (m, 2H), 7.05 (d, J = 6.7 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 6.42 (d, J = 9.1 Hz, 1H), 4.22 (s, 2H), 3.42–3.60(m, 2H), 3.22–3.30 (m, 1H), 3.13–3.21 (m, 1H), 2.27–2.41 (m, 1H), 2.04–2.16(m, 1H), 1.43 (s, 9H).

[1057] Step 7: Treat (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)carbamate tert-butyl ester (17.7 g, 56 mmol) with a dioxane solution (250 mL) of 4M HCl and stir the mixture at room temperature for 1 hour. Concentrate the reaction mixture to give (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one (int-A1) as an HCl salt. LCMS (Method b) m / z 218.3 [M+H] + , t R = 0.40 min. Stereochemical analysis confirmed [α] by X-ray diffraction. 23 D -105.7 (c = 1.0, MeOH). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (br s, 3H), 7.29–7.39 (m, 2H), 7.24(d, J = 7.6 Hz, 1H), 7.16 (d, J=7.1 Hz, 1H), 5.98 (s, 1H), 4.28 (s, 2H), 3.55–3.62 (m, 2H), 3.18–3.29 (m, 2H), 2.29–2.44 (m, 1H), 2.12–2.19 (m, 1H).

[1058] 2-(Ethylcarbamoyl)-4-methylthiazolyl-5-carboxylic acid (int-EC2) Synthesis

[1059]

[1060] Step 1: Ethyl 2-amino-2-thiooxoethyl acetate (1.7 g, 12.8 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutyrate (2.46 g, 12.8 mmol) in DMF (10 mL), and the solution was stirred at 90 °C for 3 days. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by column chromatography (0-50% ethyl acetate in cyclohexane) to give 5-(tert-butyl)-2-ethyl-4-methylthiazolium-2,5-dicarboxylate. LCMS (Method e) m / z 272.1 [M+H] + , t R = 1.23 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (d, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.54 (s, 9H), 1.33 (t, J = 7.0 Hz, 3H).

[1061] Step 2: A solution of 5-(tert-butyl)-2-ethyl-4-methylthiazolium-2,5-dicarboxylate (500 mg, 1.84 mmol) in 2M ethylamine in THF (27.6 mL, 55.2 mmol) was stirred at room temperature for 16 hours. The reaction mixture was treated with ethyl acetate and washed with saturated NaHCO3 and 1N HCl. The organic phase was dried (MgSO4) and concentrated to give tert-butyl 2-(ethylcarbamoyl)-4-methylthiazolium-5-carboxylate. LCMS (Method b) m / z 271.1 [M+H] + , t R = 1.14min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (t, J = 6.1 Hz, 1H), 3.30 – 3.23 (m,2H), 2.66 (s, 3H), 1.53 (s, 9H), 1.11 (t, J = 7.3 Hz, 3H).

[1062] Step 3: A solution of tert-butyl 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylate (540 mg, 1.8 mmol) in TFA (15 mL) and CH2Cl2 (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and treated with Et2O. The precipitate was filtered, washed with cold Et2O, and dried under vacuum to give 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC2). LCMS (Method b) m / z 215.1 [M+H]+ , t R = 0.54 min. 1 ¹H NMR (400MHz, DMSO-d6) δ ppm 8.97 (t, J = 6.0 Hz, 1H), 3.30 – 3.26 (m, 2H), 2.67 (s, 3H), 1.12 (q, J = 7.4 Hz, 3H) (no acid protons observed).

[1063] 4-Methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4) Synthesis

[1064]

[1065] 4-Methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4) was obtained using a method similar to that used for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazolyl-5-carboxylic acid (int-EC2), except that in step 2, an ethanolic solution of methylamine was used instead of a THF solution of ethylamine. LCMS (Method a) m / z 201.1 M+H] + , t R = 0.45min.

[1066] Int-IN1. 2-Carbamoyl-4-methylthiazolyl-5-carboxylic acid

[1067]

[1068] This compound was prepared according to the procedure described in int-EC2, in which ammonia (7 N in MeOH, Sigma-Aldrich, 499145) was used instead of ethylamine in step 2. LC-MS retention time t r =0.543 min, LC-MS calculated value of C6H7N2O3S (M+H) + m / z = 187.0; measured value 187.1.

[1069] Int-IN2,4-Methyl-2-((methyl-d3)carbamoyl)thiazolyl-5-carboxylic acid

[1070]

[1071] This compound was prepared according to the procedure described in int-EC2, in which ethylamine was replaced by a 1:2 molar ratio of methyl-d3-amine hydrochloride (Cambridge Isotope, DLM-289-1) and potassium tert-butoxide in step 2. LC-MS retention time t r=0.668 min, LC-MS calculated value of C7H6D3N2O3S (M+H) + m / z = 204.1; Measured value 204.2.

[1072] Example A: N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide (A)

[1073]

[1074] Step 1: To a solution of (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one (int-A1) (5.0 g, 11.12 mmol) in CH3CN (50 mL), add (R)-3-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (int-L9) (2.26 g, 11.12 mmol), DIPEA (5.83 mL, 33.4 mmol), and TOTU (3.65 g, 11.12 mmol), and stir the reaction mixture at room temperature for 16 hours. The reaction mixture is then concentrated, and the crude product is dissolved in ethyl acetate, washed with 1N HCl and saturated NaHCO3, dried (MgSO4), and concentrated to give an oily substance, which is then treated with cold Et2O to crystallize the product. The precipitate was collected by filtration and dried under vacuum to give ((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)carbamate tert-butyl. LCMS (Method a) m / z 403.1 [M+H] + , t R = 0.92 min. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.21 (d, J = 8.8Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.6Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 4.0 Hz, 1H), 6.70 (d, J = 8.7Hz, 1H), 4.24 (s, 2H), 3.62 – 3.43 (m, 2H), 3.31 – 3.22 (m, 1H), 3.21 – 3.08(m, 2H), 3.00 – 2.91 (m, 1H), 2.89 – 2.79 (m, 1H), 2.42 – 2.27 (m, 1H), 2.16– 2.07 (m, 1H), 1.40 (s, 9H), 1.01 (d, J = 6.7 Hz, 3H).

[1075] Step 2: 4.92 g (11.0 mmol) of tert-butyl ((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)carbamate was dissolved in 4N HCl (50 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and then CH3CN / Et2O was added. The resulting precipitate was filtered, washed with cold Et2O, and dried under vacuum to give (R)-3-amino-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)propionamide. LCMS (Method a) m / z 303 [M+H] + , t R = 0.41 min. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.74 (d, J = 9.2 Hz, 1H), 7.79 (s, 3H), 7.31 (d, J = 7.7 Hz,1H), 7.24 (t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.0 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 9.1 Hz, 1H), 4.25 (s, 2H), 3.56 – 3.49 (m, 2H), 3.33 – 3.24(m, 1H), 3.22 – 3.14 (m, 1H), 3.11 – 2.98 (m, 2H), 2.94 – 2.79 (m, 1H), 2.43– 2.30 (m, 1H), 2.18 – 2.03 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H).

[1076] Step 3: 4-Methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4) (10 mg, 0.04 mmol) and EDC (14.71 mg, 0.077 mmol) were added to a solution of (R)-3-amino-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)propionamide (13 mg, 0.038 mmol) in pyridine (2 mL), and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with saturated NaHCO3, dried over (MgSO4), and concentrated. The crude product was purified by preparative HPLC (Waters SunFire Prep C18 OBD 5 µm, 30*100 mm, flow rate: 40 mL / min, CH3CN: 5 min to 5%, 25 min to 60%) to obtain N. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide (1). LCMS (Method b) m / z 485.2 [M+H] + , t R = 0.73 min. 1H NMR (400 MHz, DMSO-d6)δ ppm: 8.84 (q, J = 4.0 Hz, 1H), 8.40 (t, J = 5.6 Hz, 1H), 8.36 (d, J = 8.9Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.6Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.24 (s, 2H), 3.63 – 3.40 (m, 3H), 3.29 – 3.24 (m, 1H), 3.23 – 3.14 (m, 1H), 3.13 – 3.01(m, 1H), 2.80 (d, J = 4.8 Hz, 3H), 2.59 (s, 3H), 2.43 – 2.26 (m, 2H), 2.17 –2.03 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H).

[1077] Alternatively, the resulting product is ground in MTBE (or acetonitrile) and the suspension is filtered to obtain a solid. The solid is then dried under vacuum to obtain the compound of example A in crystalline form.

[1078] Examples 1 and 2.N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide (1) and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide(2)

[1079] and

[1080] To N 2 ,4-Dimethyl-N 5-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide (Example A) (100.0 mg, 0.206 mmol) was added to a mixture in methanol-d4 (5 mL, Cambridge Isotope Laboratories DLM-24-10), potassium tert-butoxide (20.0 mg, 0.179 mmol) was added, and the mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with 1% v / v acetic acid-d1 (Sigma-Aldrich 151777) solution in acetonitrile (5 mL). After stirring for 5 minutes, the reaction mixture was further diluted with water, and the diastereomer mixture was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1081] Example 1: LC-MS retention time t r = 1.76 min, LC-MS calculated value C 23 H 28 DN6O4S (M+H) + m / z = 486.2; measured value 486.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.84 (q, J = 4.7 Hz, 1H), 8.40 (t, J = 5.5 Hz, 1H), 8.36 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.4Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 4.24 (s, 2H), 3.60 – 3.43 (m, 3H), 3.33 – 3.24 (m, 2H), 3.22 – 3.14 (m, 1H), 3.12 – 3.04(m, 1H), 2.80 (d, J = 4.7 Hz, 3H), 2.59 (s, 3H), 2.41 – 2.30 (m, 1H), 2.18 –2.04 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H).

[1082] Example 2: LC-MS retention time t r = 1.84 min, LC-MS calculated value C 23 H 28 DN6O4S (M+H) + m / z = 486.2; measured value 486.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (q, J = 4.7 Hz, 1H), 8.44(t, J = 5.7 Hz, 1H), 8.40 (s, 1H), 7.28 – 7.15 (m, 3H), 7.10 – 7.04 (m, 1H),4.25 (s, 2H), 3.55 – 3.47 (m, 2H), 3.42 – 3.23 (m, 3H), 3.22 – 3.14 (m, 1H), 3.12 – 3.01 (m, 1H), 2.79 (d, J = 4.7 Hz, 3H), 2.57 (s, 3H), 2.42 – 2.29 (m,1H), 2.15 – 2.06 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H).

[1083] Examples 3 and 4.N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide

[1084] and

[1085] Step 1: 2-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)isoindoline-1,3-dione

[1086]

[1087] To a mixture of 10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one (int-A1, step 4) (993 mg, 4.57 mmol) and triethylamine (2.31 g, 22.9 mmol) in CH2Cl2 (40 mL), phthaloyl dichloro(1.02 g, 5.03 mmol) was added, and the mixture was stirred at room temperature for 30 min. The mixture was then diluted with CH2Cl2 (40 mL). ， The mixture was washed with water (50 mL) and a saturated NaCl aqueous solution. The organic layer was dried over Na₂SO₄, concentrated, and the crude residue was purified by rapid chromatography (SiO₂, EtOAc / hexane) to give the desired product (610 mg, 38% yield) as a yellow solid. LC-MS calculated C 20 H 18 N3O3 (M+H) + m / z = 348.1; measured value 348.2.

[1088] Step 2: 2-(10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)isoindoline-1,3-dione

[1089]

[1090] In a dry vial equipped with a stir bar, a mixture of 2-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)isoindoline-1,3-dione (487 mg, 1.40 mmol) in DMF (14 mL) was added, along with sodium hydride (112 mg, 2.80 mmol) (60% dispersed in mineral oil, Aldrich 452912). The mixture was stirred at room temperature for 15 min, followed by the addition of methyl iodide (398 mg, 2.80 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and a saturated aqueous NaCl solution. The organic layer was dried with Na₂SO₄, concentrated, and the crude residue was purified by rapid chromatography (SiO₂, EtOAc / hexane) to give the desired product (313 mg, 62% yield) as a grayish-white solid. LC-MS calculated Cp 21 H 20 N3O3 (M+H) +m / z = 362.2; measured value 362.2.

[1091] Step 3: 10-Amino-10-methyl-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one

[1092]

[1093] To a mixture of 2-(10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)isoindoline-1,3-dione (313 mg, 0.866 mmol) in MeOH (15 mL), a 1 mol THF solution of hydrazine (4.5 mL, 4.5 mmol, Aldrich 433632) was added, and the reaction mixture was irradiated in a microwave reactor at 120 °C for 6 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude residue was diluted with CH₂Cl₂ and 1 N NaOH, and the layers were separated. The organic layer was removed, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried with Na₂SO₄, and concentrated to give the desired compound as a colorless oil (182 mg, 91% yield). LC-MS calculated C₀ 13 H 18 N3O (M+H) + m / z = 232.1; measured value 232.2.

[1094] Step 4: ((2R)-2-methyl-3-((10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)tert-butyl carbamate

[1095]

[1096] To a mixture of 10-amino-10-methyl-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one (182 mg, 0.790 mmol) and (R)-3-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (192 mg, 0.947 mmol, Combi-Blocks QB-0994) in CH2Cl2 (7 mL) and pyridine (2.5 mL), EDC (454 mg, 2.37 mmol) was added, and the reaction mixture was stirred at 40 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude residue was purified by rapid chromatography (SiO2, EtOAc / hexane) to give the title compound (281 mg, 86% yield) as a colorless oily mixture of diastereomers. LC-MS calculated value C 22 H 33 N4O4 (M+H) + m / z = 417.3; measured value 417.3.

[1097] Step 5: (2R)-3-amino-2-methyl-N-(10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)propionamide

[1098]

[1099] To a mixture of ((2R)-2-methyl-3-((10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)carbamate tert-butyl ester (281 mg, 0.676 mmol) in CH2Cl2 (10 mL), a solution of 4 mol HCl in dioxane (3 mL, 12 mmol, Sigma-Aldrich 345547) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a crude, colorless oil containing the desired product, a mixture of diastereomers (HCl salts), which could be used without further purification. LC-MS calculated C 17 H 25 N4O2 (M+H) + m / z = 317.2; measured value 317.3.

[1100] Step 6: N 2 ,4-Dimethyl-N 5-((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide

[1101] EDC (454 mg, 2.37 mmol) was added to a mixture of (2R)-3-amino-2-methyl-N-(10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)propionamide (step 5) and 4-methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (158 mg, 0.790 mmol) in CH2Cl2 (4 mL) and pyridine (2.5 mL), and the reaction mixture was stirred at 40 °C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude residue was diluted with 40 mL of 5% v / v acetic acid in acetonitrile, and the diastereomer mixture was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1102] Example 3: LC-MS retention time t r = 0.94 min, LC-MS calculated value C 24 H 31 N6O4S (M+H) + m / z = 499.2; measured value 499.2. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (q, J = 4.7 Hz, 1H), 8.29 (t, J = 5.6 Hz, 1H), 8.19 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.4Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 4.21 (d, J =15.9 Hz, 1H), 3.99 (d, J = 15.9 Hz, 1H), 3.63 – 3.54 (m, 1H), 3.54 – 3.46 (m,1H), 3.37 – 3.27 (m, 1H), 3.27 – 3.12 (m, 3H), 2.84 – 2.67 (m, 4H), 2.59 (s,3H), 2.20 – 2.00 (m, 2H), 1.81 (s, 3H), 1.07 (d, J = 7.0 Hz, 3H).

[1103] Example 4: LC-MS retention time t r = 0.99 min, LC-MS calculated value C 24 H 31 N6O4S (M+H) + m / z = 499.2; measured value 499.2. 1H NMR (600 MHz, DMSO-d6) δ 8.83 (q, J = 4.7 Hz, 1H), 8.50 –8.36 (m, 2H), 7.51 – 7.43 (m, 1H), 7.18 – 7.12 (m, 2H), 7.04 – 6.99 (m, 1H), 4.25 (d, J = 15.8 Hz, 1H), 3.99 (d, J = 15.9 Hz, 1H), 3.66 – 3.58 (m, 1H), 3.54 – 3.44 (m, 2H), 3.26 – 3.17 (m, 2H), 3.17 – 3.08 (m, 1H), 2.79 (d, J =4.7 Hz, 3H), 2.75 – 2.67 (m, 1H), 2.62 (s, 3H), 2.23 – 2.12 (m, 1H), 2.12 –2.02 (m, 1H), 1.79 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H).

[1104] Examples 5 and 6.N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1105] and

[1106] These compounds were prepared according to the procedures described in Examples 3 and 4, with (bromomethyl)benzene used instead of iodomethane in step 2. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1107] Example 5 LC-MS retention time t r=1.14 min, LC-MS calculated value C 30 H 35 N6O4S (M+H) + m / z = 575.2; measured value 575.3.

[1108] Example 6 LC-MS retention time t r =1.17 min, LC-MS calculated value C 30 H 35 N6O4S (M+H) + m / z = 575.2; measured value 575.3.

[1109] Examples 7 and 8.N 5 -((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1110] and

[1111] These compounds were prepared according to the procedures described in Examples 3 and 4, with iodoethane used instead of iodomethane in step 2. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1112] Example 7 LC-MS retention time t r =0.946 min, LC-MS calculated value C 25 H 33 N6O4S (M+H) + m / z = 513.2; measured value 513.3.

[1113] Example 8 LC-MS retention time t r =0.998 min, LC-MS calculated value C25 H 33 N6O4S (M+H) + m / z = 513.2; measured value 513.3.

[1114] Examples 9 and 10.N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide

[1115] and

[1116] These compounds were prepared according to the procedures described in Examples 3 and 4, with 3-(bromomethyl)pyridine hydrobromide (Combi-Blocks ST-7536) used instead of iodomethane in step 2. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1117] Example 9 LC-MS retention time t r =0.794 min, LC-MS calculated value C 29 H 34 N7O4S (M+H) + m / z = 576.2; measured value 576.3.

[1118] Example 10 LC-MS retention time t r =0.824 min, LC-MS calculated value C 29 H 34 N7O4S (M+H) + m / z = 576.2; measured value 576.3.

[1119] Examples 11 and 12.N 5-((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1120] and

[1121] These compounds were prepared according to the procedures described in Examples 3 and 4, with 1-bromomethyl-4-fluorobenzene used instead of iodomethane in step 2. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1122] Example 11 LC-MS retention time t r =1.26 min, LC-MS calculated value C 30 H 34 FN6O4S (M+H) + m / z = 593.2; measured value 593.3.

[1123] Example 12 LC-MS retention time t r =1.29 min, LC-MS calculated value C 30 H 34 FN6O4S (M+H) + m / z = 593.2; measured value 593.3.

[1124] Examples 13 and 14.N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide

[1125] and

[1126] These compounds were prepared according to the procedures described in Examples 3 and 4, with iodomethane-d3 (Sigma-Aldrich 176036) used instead of iodomethane in step 2. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1127] Example 13 LC-MS retention time t r =0.942 min, LC-MS calculated value C 24 H 28 D3N6O4S (M+H) + m / z = 502.2; measured value 502.2.

[1128] Example 14 LC-MS retention time t r =0.988 min, LC-MS calculated value C 24 H 28 D3N6O4S (M+H) + m / z = 502.2; measured value 502.2.

[1129] Examples 15 and 16.N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide

[1130] and

[1131] Step 1: 2-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)benzoic acid

[1132]

[1133] To a mixture of 2-bromo-5-(trifluoromethyl)benzoic acid (5.00 g, 18.6 mmol) in ethanol (50 mL), ethyl acetoacetate (4.74 mL, 37.2 mmol), CuBr (3.20 g, 22.3 mmol), and sodium ethoxide (21 wt.% in EtOH, 25 mL, Sigma-Aldrich 230553) were added. The reaction mixture was stirred under reflux for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum, and the residue was dissolved in 3M HCl aqueous solution (75 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired product (5.1 g, quantitative yield) as a yellow solid. LC-MS calculated C 12 H 12 F3O4 (M+H) + m / z = 277.2; measured value 277.2.

[1134] Step 2: Ethyl 2-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)acetate

[1135]

[1136] Triethylamine (3.55 mL, 25.5 mmol) was added to a mixture of 2-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)benzoic acid (3.52 g, 12.7 mmol) in CH₂Cl₂ (60 mL), followed by ethyl chloroformate (1.33 mL, 14.0 mmol), and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched by adding 1 N HCl aqueous solution (100 mL) and extracted with CH₂Cl₂ (2 x 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude intermediate. The crude intermediate was dissolved in 30 mL THF, and an aqueous solution of NaBH₄ (prepared by dissolving 1 g of NaBH₄ in 10 mL of water) was added at 0 °C. After stirring at 0 °C for 30 min, the reaction was quenched by adding 1 N HCl aqueous solution, and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and the crude residue was purified by rapid chromatography (SiO₂, EtOAc / hexane) to give the desired product as a colorless oil (1.30 g, 39% yield). LC-MS calculated C 12 H 12 F3O2 (M-OH) + m / z = 245.1; measured value 245.2.

[1137] Step 3: Ethyl 2-(2-(((methylsulfonyl)oxy)methyl)-4-(trifluoromethyl)phenyl)acetate

[1138]

[1139] To a mixture of ethyl 2-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)acetate (1.33 g, 5.07 mmol) in CH₂Cl₂ (30 mL), triethylamine (1.41 mL, 10.1 mmol) and methanesulfonyl chloride (0.47 mL, 6.1 mmol) were added. After stirring at room temperature for 0.5 hours, the reaction mixture was quenched by adding 1 N HCl aqueous solution and extracted with CH₂Cl₂ (2 x 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and the crude residue was purified by rapid chromatography (SiO₂, EtOAc / hexane) to give the desired product (0.94 g, 55% yield) as a colorless oil. LC-MS calculated C 13 H 19 F3NO5S (M+NH4) + m / z = 358.1; measured value 358.1.

[1140] Step 4: 7-(trifluoromethyl)-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one

[1141]

[1142] A mixture of ethyl 2-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)acetate (940 mg, 2.76 mmol), pyrazolidine dihydrochloride (400 mg, 2.76 mmol), DIPEA (1.9 mL, 11 mmol), and sodium acetate (906 mg, 11.0 mmol) in DMF (10 mL) was heated to 100 °C for 1 hour. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with water (2 x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated, and the crude residue was purified by rapid chromatography (SiO₂, EtOAc / hexane) to give the desired product (0.38 g, 51% yield) as a colorless oil. LC-MS calculated C 13 H 14 F3N2O (M+H) + m / z = 271.1; measured value 271.2.

[1143] Step 5: 10-Amino-7-(trifluoromethyl)-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one

[1144]

[1145] At 0 °C, LiHMDS (1 M in THF, 3.1 mL, 3.1 mmol, Sigma-Aldrich 225770) was added to a mixture of 7-(trifluoromethyl)-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one (0.38 g, 1.4 mmol) and isoamyl nitrite (0.28 mL, 2.1 mmol) in 14 mL of THF. After stirring at 0 °C for 2 hours, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude intermediate. The crude intermediate was dissolved in acetic acid (5 mL) and 3 N HCl aqueous solution (1 mL). Zinc powder (800 mg, 12.2 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was diluted with 10% w / w NaOH aqueous solution and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired product as a yellow oil (0.30 g, 75% yield). LC-MS calculated C 13 H 15 F3N3O (M+H) + m / z = 286.1; measured value 286.2.

[1146] Step 6: ((2R)-2-methyl-3-oxo-3-((11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)tert-butyl carbamate

[1147]

[1148] EDC (302 mg, 1.58 mmol) was added to a mixture of 10-amino-7-(trifluoromethyl)-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diaza-11-one (150 mg, 0.526 mmol) and (R)-3-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (128 mg, 0.631 mmol, Combi-Blocks QB-0994) in CH2Cl2 (5.3 mL) and pyridine (1.7 mL), and the reaction mixture was stirred at 40 °C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude residue was purified by rapid chromatography (SiO2, EtOAc / hexane) to give the title compound (195 mg, 79% yield) as a colorless oily mixture of diastereomers. LC-MS calculated Cp 22 H 30 F3N4O4 (M+H) + m / z = 471.2; measured value 471.2.

[1149] Step 7: (2R)-3-amino-2-methyl-N-(11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)propionamide

[1150]

[1151] To a mixture of ((2R)-2-methyl-3-oxo-3-((11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)carbamate tert-butyl ester (195 mg, 0.414 mmol) in CH2Cl2 (10 mL), 4 mol of dioxane solution of HCl (2 mL, 8 mmol, Sigma-Aldrich 345547) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a crude colorless oil containing the desired product, a mixture of diastereomers (HCl salt). The crude product was used directly without further purification. LC-MS calculated C 17 H 22 F3N4O2 (M+H) + m / z = 371.2; measured value 371.2.

[1152] Step 8: N 2 ,4-Dimethyl-N5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide

[1153] EDC (288 mg, 1.50 mmol) was added to a mixture of (2R)-3-amino-2-methyl-N-(11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)propionamide (step 7) and 4-methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (100 mg, 0.50 mmol) in CH2Cl2 (4 mL) and pyridine (1.6 mL), and the reaction mixture was stirred at 40 °C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude residue was diluted with 40 mL of 5% v / v acetic acid in acetonitrile, and the diastereomer mixture was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1154] Example 15 LC-MS retention time t r =1.032 min, LC-MS calculated value C 24 H 28 F3N6O4S (M+H) + m / z = 553.2; measured value 553.2.

[1155] Example 16 LC-MS retention time t r =1.093 min, LC-MS calculated value C 24 H 28 F3N6O4S (M+H) + m / z = 553.2; measured value 553.2.

[1156] Examples 17 and 18.N2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazole-2,5-dicarboxamide and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide

[1157] and

[1158] These compounds were prepared according to the procedures described in Examples 1 and 2, with Example 16 replacing Example A. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1159] Example 17 LC-MS retention time t r =1.107 min, LC-MS calculated value C 24 H 27 DF3N6O4S (M+H) + m / z = 554.2; measured value 554.2.

[1160] Example 18 LC-MS retention time t r =1.171 min, LC-MS calculated value C 24 H 27 DF3N6O4S (M+H) + m / z = 554.2; measured value 554.2.

[1161] Examples 19 and 20.N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5-((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1162] and

[1163] These compounds were prepared according to the procedures described in Examples 15 and 16, in which 2-bromo-5-methoxybenzoic acid was substituted for 2-bromo-5-(trifluoromethyl)benzoic acid in step 1. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1164] Example 19 LC-MS retention time t r =1.501 min, LC-MS calculated value C 24 H 31 N6O5S (M+H) + m / z = 515.2; measured value 515.2.

[1165] Example 20 LC-MS retention time t r =1.560 min, LC-MS calculated value C 24 H 31 N6O5S (M+H) + m / z = 515.2; measured value 515.2.

[1166] Instance B and CN 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1167] and

[1168] These compounds were prepared according to the procedures described in Examples 15 and 16, with 2-bromo-5-fluorobenzoic acid used instead of 2-bromo-5-(trifluoromethyl)benzoic acid in step 1. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1169] Example B LC-MS retention time t r =0.955 min, LC-MS calculated value C 23 H 28 FN6O4S (M+H) + m / z = 503.2; measured value 503.2.

[1170] Example C LC-MS retention time t r =1.007 min, LC-MS calculated value C 23 H 28 FN6O4S (M+H) + m / z = 503.2; measured value 503.2.

[1171] Examples 21 and 22.N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1172] and

[1173] These compounds were prepared according to the procedures described in Examples 1 and 2, with Example C replacing Example A. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1174] Example 21 LC-MS retention time t r =0.953 min, LC-MS calculated value C 23 H 27 DFN6O4S (M+H) + m / z = 504.2; measured value 504.2.

[1175] Example 22 LC-MS retention time t r =1.005 min, LC-MS calculated value C 23 H 27 DFN6O4S (M+H) + m / z = 504.2; measured value 504.2.

[1176] Examples D and EN 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1177] and

[1178] These compounds were prepared according to the procedures described in Examples 15 and 16, with 2-bromo-5-chlorobenzoic acid used instead of 2-bromo-5-(trifluoromethyl)benzoic acid in step 1. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1179] Example D LC-MS retention time t r =1.029 min, LC-MS calculated value C 23 H 28 ClN6O4S (M+H) + m / z = 519.2; measured value 519.2.

[1180] Example E LC-MS retention time t r =1.096 min, LC-MS calculated value C 23 H 28 ClN6O4S (M+H) + m / z = 519.2; measured value 519.2.

[1181] Examples 23 and 24.N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide and N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazole-2,5-dicarboxamide

[1182] and

[1183] These compounds were prepared according to the procedures described in Examples 1 and 2, with Example E replacing Example A. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1184] Example 23 LC-MS retention time t r =1.029 min, LC-MS calculated value C 23 H 28 ClN6O4S (M+H) + m / z = 520.2; measured value 520.2.

[1185] Example 24LC-MS retention time t r =1.096 min, LC-MS calculated value C 23 H 28 ClN6O4S (M+H) + m / z = 520.2; measured value 520.2.

[1186] Example 25.4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide

[1187]

[1188] This compound was prepared according to the procedure described in Example A, in which 2-carbamoyl-4-methylthiazolyl-5-carboxylic acid (int-IN1) was used instead of 4-methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4) in step 3. The crude product was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain the desired product as its TFA salt. LC-MS calculated value C 22 H 27 N6O4S (M+H) + m / z = 471.2; measured value 471.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.44 – 8.32 (m, 2H), 8.21 (s, 1H), 7.92 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.24 (s,2H), 3.60 – 3.44 (m, 3H), 3.34 – 3.25 (m, 2H), 3.22 – 3.14 (m, 1H), 3.13 –3.03 (m, 1H), 2.59 (s, 3H), 2.41 – 2.30 (m, 1H), 2.15 – 2.05 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H).

[1189] Examples 26 and 27: 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide and 4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazole-2,5-dicarboxamide

[1190] and

[1191] These compounds were prepared according to the procedures described in Examples 1 and 2, with Example 25 replacing Example A. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1192] Example 26 LC-MS retention time t r =0.849 min, LC-MS calculated value C 22 H 26 DN6O4S (M+H) + m / z = 472.2; measured value 472.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.46 – 8.32 (m, 2H), 8.22 (s,1H), 7.92 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.05(d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 4.24 (s, 2H), 3.59 – 3.43 (m,3H), 3.33 – 3.24 (m, 2H), 3.23 – 3.14 (m, 1H), 3.13 – 3.04 (m, 1H), 2.58 (s,3H), 2.41 – 2.30 (m, 1H), 2.16 – 2.06 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H).

[1193] Example 27 LC-MS retention time t r =0.909 min, LC-MS calculated value C 22 H 26 DN6O4S (M+H) + m / z = 472.2; measured value 472.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.49 – 8.37 (m, 2H), 8.19 (s,1H), 7.91 (s, 1H), 7.27 – 7.17 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 4.30 – 4.20(m, 2H), 3.57 – 3.46 (m, 2H), 3.44 – 3.23 (m, 3H), 3.22 – 3.13 (m, 1H), 3.11– 3.02 (m, 1H), 2.56 (s, 3H), 2.41 – 2.30 (m, 1H), 2.14 – 2.04 (m, 1H), 1.16(d, J = 6.9 Hz, 3H).

[1194] Example 28.4 -Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide

[1195]

[1196] The compound was prepared according to the procedure described in Example A, in which 4-methyl-2-((methyl-d3)carbamoyl)thiazolyl-5-carboxylic acid (int-IN2) was substituted for 4-methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4). The crude product was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain the desired product as its TFA salt.

[1197] Example 28 LC-MS retention time t r = 0.920 min, LC-MS calculated value C 23 H 26 D3N6O4S (M+H)+ m / z = 488.2; measured value 488.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.40 (t, J = 5.1Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.4Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8Hz, 1H), 4.24 (s, 2H), 3.61 – 3.43 (m, 3H), 3.33 – 3.23 (m, 2H), 3.22 – 3.14(m, 1H), 3.12 – 3.03 (m, 1H), 2.59 (s, 3H), 2.41 – 2.30 (m, 1H), 2.17 – 2.04(m, 1H), 1.10 (d, J = 6.9 Hz, 3H).

[1198] Examples 29 and 30: 4-methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide (29) and 4-methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide (30)

[1199] as well as

[1200] These compounds were prepared according to the procedures described in Examples 1 and 2, with Example 28 replacing Example A. The mixture of diastereomers was filtered and purified by preparative HPLC (Sunfire C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA at a flow rate of 60 mL / min) to obtain each diastereomer as its TFA salt.

[1201] Example 29 LC-MS retention time t r = 0.922 min, LC-MS calculated value C 23 H 25 D4N6O4S (M+H) + m / z = 489.2; measured value 489.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.40 (t, J = 5.6Hz, 1H), 8.37 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 4.24 (s, 2H), 3.60 – 3.43(m, 3H), 3.33 – 3.24 (m, 2H), 3.22 – 3.14 (m, 1H), 3.11 – 3.03 (m, 1H), 2.59(s, 3H), 2.42 – 2.31 (m, 1H), 2.15 – 2.05 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H).

[1202] Example 30 LC-MS retention time t r = 0.976 min, LC-MS calculated value C 23 H 25 D4N6O4S (M+H) + m / z = 489.2; measured value 489.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.44 (t, J = 5.7Hz, 1H), 8.41 (s, 1H), 7.29 – 7.16 (m, 3H), 7.06 (d, J = 7.5 Hz, 1H), 4.28 –4.20 (m, 2H), 3.56 – 3.47 (m, 2H), 3.41 – 3.24 (m, 3H), 3.22 – 3.15 (m, 1H), 3.11 – 3.03 (m, 1H), 2.57 (s, 3H), 2.40 – 2.30 (m, 1H), 2.14 – 2.05 (m, 1H),1.16 (d, J = 6.9 Hz, 3H).

[1203] Example A-1: ​​Reduced in vivo epimerization

[1204] In Example A, the chiral carbon in the 7-membered ring exhibited epimerization in vivo. The resulting diastereomer of Example A had significantly different PK profiles from that of Example A. For example, the half-life (t½) of this diastereomer was prolonged, and the formation and elimination pathways are not yet clear. These factors may lead to accumulation and potential toxicity. The effect of substitution at the chiral carbon on epimerization was tested in the following preclinical in vivo pharmacokinetic models by comparing Example A, Example 1, and Example 29: Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys.

[1205] Two groups of male Sprague Dawley rats (n=3 in each group) received a single dose of 10 mg / kg PO, either Example A or Example 1, via an aqueous solution containing 0.5% methylcellulose. Blood samples were collected at 0.25, 0.5, 1, 2, 4, and 6 hours post-administration.

[1206] Example 29: Male Sprague Dawley rats (n=3 per group) received a single 3 mg / kg PO dose via 50 mM citrate buffer (containing 0.5% methylcellulose) with 5% dimethylacetamide (DMAC). Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration.

[1207] Three groups of male cynomolgus monkeys (n=2 per group) received a single 3 mg / kg PO dose, as described in Example A, Example 1, or Example 29, via 50 mM citrate buffer (containing 0.5% methylcellulose) with 5% dimethylacetamide (DMAC). Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration.

[1208] Three groups of male beagle dogs (n=2 per group) received a single 3 mg / kg PO dose, as described in Example A, Example 1, or Example 29, via 50 mM citrate buffer (containing 0.5% methylcellulose) with 5% dimethylacetamide (DMAC). Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after administration.

[1209] All blood samples were collected using EDTA as an anticoagulant and centrifuged to obtain plasma. Blood drug concentrations of Examples A, Example 1, and their respective diastereomers were determined using standard reversed-phase LC-MS / MS bioanalytical methods under non-GLP conditions. Individual blood drug concentration-time data were used to determine the area under the curve (AUC) using GraphPad Prism (v9.3.1).

[1210] Epimerization was observed in all three models: Examples A, 1, and 29. However, substitution (e.g., deuteration) at the chiral carbon in the 7-membered ring of Example A reduced epimerization. Based on Table 1 and Figure 1A , 1B Based on the epimer / parent AUC ratios shown in 1C, epimerization in Example 1 was reduced by approximately 6, 11, and 59-fold in rats, monkeys, and dogs, respectively. Based on the epimer / parent AUC ratios, epimerization in Example 29 was reduced by approximately 4.5, 52, and 114-fold in rats, monkeys, and dogs, respectively (Table 1).

[1211] Two additional observations were made. Overall, the exposure levels and PK (excluding epimerization) of Examples 1, A, and 29 were consistent across species. Deuterium in Examples 1 and 29 was retained during epimerization in all studied species, forming Examples 2 and 30, respectively. Based on the epimer / parent AUC ratio of Example 1, deuteration reduced epimerization by approximately 6, 10, and >50-fold in rats, monkeys, and dogs, respectively. Based on the epimer / parent AUC ratio of Example 29, deuteration reduced epimerization by approximately 5, 50, and >100-fold in rats, monkeys, and dogs, respectively.

[1212] Table 1

[1213]

[1214] Example B-1: Nuclear translocation imaging determination of human SPPL2a

[1215] Nuclear translocation imaging assays of human SPPL2a were performed using the SPPL2a reporter U2OS cell line as previously described (Velcicky et al. 2018, Zhang et al. 2017). These cells stably expressed the human SPPL2a and doxycycline-inducible eGFP-TNFα (aa 1-76) NTF fusion protein (SPPL2a substrate). Examples 1 and A were added at specified concentrations, and cells were incubated for 24 hours, washed, and fixed. Cell nuclei were stained with DAPI. Images were acquired on a confocal fluorescence microscopy system LSM-800 (Carl Zeiss). Image data were analyzed using the midsection of a Z-stack image of at least 10 individual cells per sample. All data are presented as mean ± SEM. GraphPad Prism was used. TM 10. Statistical significance was calculated using the ANOVA test. Image analysis showed that Example 1 and Example A exhibited comparable and significant inhibition of TNFα-GFP nuclear translocation. Figure 2 ).

[1216] Example B-2

[1217] Western blot assays were performed to confirm TNF-α cleavage in U2OS cells expressing human SPPL2a. The same cell lines used in the imaging assays were employed; these cells constitutively expressed human SPPL2a and expressed eGFP-tagged TNFα (aa 1–76) NTF substrates under the doxycycline promoter. In the presence of SPPL2a activity, TNFα-GFP was cleaved at the NTF, producing a single 54–56 kDa band (lower molecular weight). If SPPL2a activity was inhibited, TNFα-GFP processing was abandoned, producing a higher molecular weight band (60–62 kDa; complete inhibition) and / or a combination of 54–56 kDa and 60–62 kDa bands (incomplete inhibition, diffuse appearance) on the blot. Examples 1 and A were added at the specified concentrations, and cells were incubated with the inhibitors for 24 hours. Total cell lysates were prepared in ice-cold 1X RIPA buffer containing a protease inhibitor mixture (AKR-190, Cell BioLabs). Lysates were collected, and total protein was quantified on NanoDrop using a BCA kit (23227, Thermo Scientific). Protein bands were obtained by processing the lysates using the Jess Simple protein blotting system (ProteinSimple) using a 12–230 kDa separation module. To detect cleaved and uncleaved TNFα-GFP fragments, an anti-GFP antibody (AF4240, R&D Biosystems) was used as the primary antibody according to the manufacturer's protocol, and detection was performed using an anti-goat detection module (DM-006, ProteinSimple). Data were analyzed using ProteinSimple compass software.

[1218] ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, (I) in: Y is CH2 or C=O; R1 is H, C1-C6 alkyl, or halogenated; R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl; R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6. R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from: i) Halogenation; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl groups; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii)-NHC(=O)-C1-C6 haloalkyl; ix)-NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more D or C1-C6 alkoxy groups; xi)-C(=O)NH-C1-C6 haloalkyl; xii)-C(=O)NH-C3-C6 cycloalkyl; xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xv)C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) optionally substituted with one or more halogenated phenoxy groups; xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups; xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of which the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy or optionally substituted with oxo-substituted 4- to 6-membered heterocyclic groups; xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and xxi)-C(=O)NH2; Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; R 11 It is H, C1-C6 alkyl or halogenated; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings; R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution; Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a7 R c7 and R d7 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution; Or any R connected to the same N atom c7 and R d7 Together with the N atoms they are attached to, they form 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups, wherein the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R atoms. 7A Substituent substitution; Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b7 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R groups. 7A Substituent substitution; Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. M Substituent substitution; Each R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene, (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, NO2, OR a71 SR a71 NHOR a71 C(O)R b71 C(O)NR c71 R d71 C(O)NR c71 (OR a71 ), C(O)OR a71 OC(O)R b71 OC(O)NR c71 R d71 NR c71 R d71 NR c71 NR c71 R d71 、 NR c71 C(O)R b71 NR c71 C(O)OR a71 NR c71 C(O)NR c71 R d71 C(=NR) e71 )R b71 C(=NR) e71 )NR c71 R d71 NR c71 C(=NR e71 )NR c71 R d71 NR c71 C(=NR e71 )R b71 NR c71 S(O)R b71 NR c71 S(O)NR c71 R d71 NR c71 S(O)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 S(O)R b71 S(O)NR c71 R d71 S(O)2R b71 S(O)2NR c71 R d71 OS(O)(=NR) e71 )R b71 and OS(O)2R b71 , where R 7A The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution; Each R a71 R c71 and R d71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R a71 R c71 and R d71 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution; Or any R connected to the same N atom c71 and R d71 Together with the N atoms they are attached to, they form 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups, wherein the 5-6-membered heteroaryl or 4-7-membered heterocyclic alkyl groups are optionally surrounded by 1, 2, 3 or 4 independently selected R atoms. M Substituent substitution; Each R b71 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene, wherein R b71 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkyl groups - each optionally selected by 1, 2, 3 or 4 independently chosen R M Substituent substitution; Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and Each R M Independently selected from H, OH, halogenated, oxo-substituted, CN, C(O)OH, NH2, NO2, SF5, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (II). (II) in: Y is CH2 or C=O; R1 is H, C1-C6 alkyl, or halogenated; R2 is H, halogenated, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from: i) Halogenation; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl groups; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii)-NHC(=O)-C1-C6 haloalkyl; ix)-NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more D or C1-C6 alkoxy groups; xi)-C(=O)NH-C1-C6 haloalkyl; xii)-C(=O)NH-C3-C6 cycloalkyl; xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xv)C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) optionally substituted with one or more halogenated phenoxy groups; xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups; xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of which the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy or optionally substituted with oxo-substituted 4- to 6-membered heterocyclic groups; xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and xxi)-C(=O)NH2; Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; R 11 It is H, C1-C6 alkyl or halogenated; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3 to 6-membered carbon rings; R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution; Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; R 7A Selected from halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-6 Alkylene, C 3-7 cycloalkyl-C 1-6 Alkylene, (5-6-membered heteroaryl)-C 1-6 Alkylene and (4-7 membered heterocyclic alkyl)-C 1-6 Alkylene; and Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, having a structure of formula (IIA), (IIB), (IIC), or (IID): in R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from: i) Halogenation; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl groups; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii)-NHC(=O)-C1-C6 haloalkyl; ix)-NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more D or C1-C6 alkoxy groups; xi)-C(=O)NH-C1-C6 haloalkyl; xii)-C(=O)NH-C3-C6 cycloalkyl; xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xv)C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) optionally substituted with one or more halogenated phenoxy groups; xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups; xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of which the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy or optionally substituted with oxo-substituted 4- to 6-membered heterocyclic groups; xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and xxi)-C(=O)NH2; R 7 Selected from D, CD3, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene, CN, C(O)R b7 C(O)NR c7 R d7 C(O)NR c7 (OR a7 ), C(O)OR a7 C(=NR) e7 )R b7 C(=NR) e7 )NR c7 R d7 S(O)R b7 S(O)NR c7 R d7 S(O)2R b7 and S(O)2NR c7 R d7 , where R 7 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Each alkylene group is optionally represented by one, two, three, or four independently selected R groups. 7A Substituent substitution Each R a7 R c7 and R d7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; Each R b7 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; Each R e7 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkylene, C 3-10 cycloalkyl-C 1-6 Alkylene, (5-10-membered heteroaryl)-C 1-6 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-6 Alkylene; and Each R 7A Selected from halogenated, CN, NO2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

4. A compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, (him) in: Y is CH2 or C=O; R1 is H, C1-C6 alkyl, or halogenated; R2 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. R3 is H, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl; R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9 or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6. R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from: i) Halogenation; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl groups; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii)-NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii)-NHC(=O)-C1-C6 haloalkyl; ix)-NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more D or C1-C6 alkoxy groups; xi)-C(=O)NH-C1-C6 haloalkyl; xii)-C(=O)NH-C3-C6 cycloalkyl; xiii)-NHC(=O)phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xiv)-C(=O)NHphenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogenated and C1-C6 alkyl groups; xv)C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) optionally substituted with one or more halogenated phenoxy groups; xvii) is optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) 4- to 6-membered heterocyclic groups optionally substituted with oxo, –C(=O)OC1-C6 alkyl or –C(=O)OC1-C6 cycloalkyl groups; xix) has one or two heteroatoms, each independently selected from N, O and S, as ring members, of which the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl groups optionally substituted with –OH, C1-C6 alkoxy or optionally substituted with oxo-substituted 4- to 6-membered heterocyclic groups; xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or is substituted by one or more substituents independently selected from halogenated, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic groups, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy groups; and xxi)-C(=O)NH2; Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; R 11 It is H, C1-C6 alkyl or halogenated; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; and R 7 For H.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is methyl, ethyl, propyl or isopropyl, CF3, -CH2-phenyl, cyclopropyl, cyclobutyl or -CH2CH2OCH3.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is... , or ; in R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halo; R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH2, -C(O)NH-CD3, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4- to 6-membered heterocyclic, 5- or 6-membered heteroaryl; wherein the heteroaryl group is optionally halogenated. The heterocyclic group is substituted with an alkyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a C3-C6 cycloalkyl group; wherein the heterocyclic group is optionally substituted with an oxo group, a -C(O)O-C1-C6 alkyl group, or a –C(O)O-C3-C6 cycloalkyl group; wherein the –C(O)NHphenyl group is optionally substituted with a halo group or a C1-C6 alkyl group; and each C1-C6 alkyl group is optionally substituted with one or more D groups; R 5c It is a 5- or 6-membered ring heteroaryl group, optionally substituted with a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C6 cycloalkyl; and R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

8. The compound according to any one of claims 1 to 3 and 5 to 7, wherein R 7 The options are D, CD3, and C. 1-6 Alkyl, C 6-10 Aryl-C 1-6 alkylene or (5-10-membered heteroaryl)-C 1-6 Alkylene.

9. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 The answer is D.

10. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 It is CD3.

11. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 It is a methyl group.

12. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 It is an ethyl group.

13. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 It is benzyl.

14. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 It is a fluorobenzyl group.

15. The compound according to any one of claims 1 to 3 and 5 to 8, wherein R 7 It is pyridylmethyl.

16. The compound according to any one of claims 1, 2, 5 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (V): (V)。 17. The compound according to claim 16, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (VA): (AND).

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt or stereoisomer thereof, having the structure of formula (VB): (VB)。 19. The compound according to any one of claims 16 to 18, wherein R5 is: ; ;or .

20. The compound according to claim 1, wherein the compound is selected from: N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazole-2,5-dicarboxamide; and N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide; and N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide. Or its pharmaceutically acceptable salt.

21. The compound according to claim 1, wherein the compound is selected from: N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide; and N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide.

22. A compound selected from... N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide; and N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; Or its pharmaceutically acceptable salt.

23. The compound according to claim 22, wherein the compound is selected from: N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-methyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-benzyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-ethyl-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-10-(pyridin-3-ylmethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-10-(4-fluorobenzyl)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((S)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-(((R)-10-(methyl-d3)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-3-oxopropyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-7-(trifluoromethyl)-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-methoxy-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((R)-7-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 5 -((R)-3-(((S)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide; and N 5 -((R)-3-(((R)-7-chloro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)-2-methyl-3-oxopropyl)-N 2 ,4-Dimethylthiazole-2,5-dicarboxamide.

24. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; or 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; Or its pharmaceutically acceptable salt.

25. The compound according to claim 24, wherein it is 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; 4-Methyl-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazolyl-2,5-dicarboxamide; or 4-Methyl-N 2 -(methyl-d3)-N 5 -((R)-2-methyl-3-oxo-3-(((R)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl-10-d)amino)propyl)thiazole-2,5-dicarboxamide.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

27. A combination comprising a therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one other pharmaceutical substance.

28. A method of treating a disease or condition mediated by SPPL2a activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 25; or a pharmaceutically acceptable salt or stereoisomer thereof.

29. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, used as a medicine.

30. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, for the treatment or prevention of diseases or conditions mediated by SPPL2a activity.

31. The method of claim 28 or the compound used according to claim 30, wherein the disease or condition is an autoimmune disease or condition.

32. The method or use according to claim 31, wherein the disease or condition is pemphigus.

33. The method or use according to claim 32, wherein the pemphigus condition is pemphigus vulgaris, pemphigus foliaceus, or bullous pemphigoid.

34. The method or use according to claim 31, wherein the disease or condition is diabetes.

35. The method or use according to claim 34, wherein the diabetes is type 1 diabetes.

36. The method or use according to claim 34, wherein the diabetes is type 2 diabetes.

37. The method of claim 28 or the compound used according to claim 28, wherein the disease or condition is selected from Sjögren's syndrome, systemic lupus erythematosus (SLE), arthritis, lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpasture syndrome, hidradenitis suppurativa, ANCA vasculitis, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity.

38. The method or use according to claim 37, wherein the disease or condition is arthritis.

39. The method or use according to claim 38, wherein the arthritis is rheumatoid arthritis (RA) or psoriatic arthritis.

40. The method or use according to claim 37, wherein the disease or condition is systemic lupus erythematosus (SLE).

41. The method or use according to claim 37, wherein the polymyositis is juvenile polymyositis.

42. The method or use according to claim 37, wherein the disease or condition is selected from insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity.

43. The method of claim 28 or the compound used according to claim 30, wherein the disease or condition is acute and chronic graft-versus-host disease (GvHD).

44. The method or use according to claim 43, wherein the treatment prevents rejection in clinical / surgical transplantation of solid organs or cell populations.

45. The method of claim 28 or the compound used according to claim 30, wherein the method or use relates to the treatment of lymphoma.

46. ​​A method of treating a condition selected from hidradenitis suppurativa, arthritis, cutaneous lupus, pemphigus, ANCA vasculitis, diabetes, dermatomyositis, primary biliary cirrhosis, polymyositis, temporal arteritis, alopecia areata, autoimmune hemolytic anemia, insulin resistance, metabolic diseases, fatty liver disease, hyperlipidemia, atherosclerosis, hypertension, stroke, gallbladder disease, and obesity in a subject in need, comprising administering a therapeutically effective amount of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

47. The method of claim 46, wherein the arthritis is juvenile arthritis or psoriatic arthritis.

48. The method of claim 46, wherein the condition is cutaneous lupus.

49. The method of claim 46, wherein the pemphigus condition is bullous pemphigoid.

50. The method of claim 46, wherein the diabetes is type 2 diabetes.

51. The method of claim 46, wherein the polymyositis is juvenile polymyositis.

52. A method of treating a condition selected from psoriasis, autoimmune encephalomyelitis, autoimmune myositis, juvenile myositis, and gallstone disease in a subject in need, comprising administering a therapeutically effective amount of N to the subject. 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

53. A method of treating a subject in need of cancer selected from marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and lymphoplasmacytic lymphoma, comprising administering to the subject a therapeutically effective amount of N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza-10-yl)amino)propyl)thiazole-2,5-dicarboxamide or a pharmaceutically acceptable salt thereof.

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