SUBSTITUTED BICYCLIC HETEROCYCLEANS AS MALT-1 INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Indian Provisional Patent Application No. 202241002859, filed on January 18, 2022. The entire contents of this provisional application are incorporated herein by reference.

Abstract

The present invention is directed to compounds of formula (I) or pharma- ceutically acceptable salts or stereoisomers or tautomers thereof useful as MALT-1 inhibitors for the treatment of MALT-1 dependent diseases or disorders. The present invention also relates to methods for preparing the compounds of the invention and pharmaceutical compositions comprising said compounds. [Formula 1] TIFF2025503727000129.tif32142

Description

[Technical field]

[0001] The present invention relates to compounds of formula (I) or pharma- ceutically acceptable salts or stereoisomers or tautomers thereof, useful as MALT-1 inhibitors and in the treatment of MALT-1 dependent diseases or disorders. The present invention also relates to processes for the preparation of compounds of formula (I), pharmaceutical compositions containing them, and their use as therapeutic agents for the treatment of diseases, particularly cancer and autoimmune diseases. [Background technology]

[0002] MALT-1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular signaling protein known from innate immune cells (natural killer cells NK, dendritic cells DC, and mast cells) and adaptive immune cells (T cells and B cells). In association with BCL10 and CARD11, MALT-1 functions as a scaffolding protein for activating the inhibitor of IκB kinase (IKK) complex. The function of MALT-1 is best known in the context of T cell receptor (TCR) signaling, where it mediates nuclear factor kappa-beta (NF-κB) signaling to control lymphocyte activation, survival, and differentiation (S. Hailfinger et al., Immunol. Rev., 232 (2009), pp. 334-347, M. Thome, Nat. Rev. Immunol., 8 (2008), pp. 495-500). In addition to its scaffolding function, MALT-1 is the only gene encoding a paracaspase belonging to the caspase (cysteine-aspartic acid protease) family of proteases that shows high homology to mammalian caspases and plant and fungal metacaspases (AGUren et al., Mol. Cell, 6 (2000), pp. 961-967). Paracaspase MALT-1 plays a key role in the activation of immune cells by certain subtypes of immune receptors, which induces nuclear translocation of NF-κB transcription factor complexes leading to activation of the NF-κB signaling pathway (M. Jaworski et al., Cell Mol. Life Science 2016, 73, 459-473). NF-κB target genes include cytokines and anti-apoptotic proteins that together trigger the receptor to promote the activation, proliferation and survival of activated immune cells, thereby enabling efficient generation of immune responses.

[0003] Studies of BCL10 and MALT1-deficient mice seem to suggest that they play an important role in the signaling cascade from antigen receptors to the transcription factor NF-kB. Furthermore, chromosomal translocations leading to overexpression of BCL10 and MALT-1 or generating the constitutively active fusion protein API2-MALT-1 appear to activate NF-kB in an uncontrolled and stimulus-independent manner. Inhibitors of the proteolytic activity of MALT-1 have been described to have activity in preclinical lymphoma models (M. Vincendeau et al. Int. J. Hematol. Oncol. 2013, 2, 409-417). Furthermore, several publications seem to suggest that MALT-1 and its proteolytic function play an important role in signaling cascades triggered by innate cell receptors such as the dectin receptor, and by G protein-coupled receptors in many cell types.

[0004] International Applications Nos. 2015181747, 2017081641, 2018020474, 2018119036, 2018141749, 2018165385, 2018226150, 2020010252, 2020111087, 2021000855 and 2020208222 report several small molecule compounds and their derivatives that can target MALT-1 and thereby inhibit its activity. However, there is a demand for the development of small molecule MALT-1 inhibitors that could attenuate NF-kB signaling in various proliferative and autoimmune diseases. Summary of the Invention [Means for solving the problem]

[0005] Provided herein are compounds of formula (I) or pharma- ceutically acceptable salts or stereoisomers or tautomers thereof, and pharmaceutical compositions comprising compounds of formula (I) or pharma- ceutically acceptable salts or stereoisomers or tautomers thereof, useful as MALT-1 inhibitors and for the treatment of diseases or disorders that are MALT-1 dependent or mediated by MALT-1. The invention also provides for the preparation of compounds of formula (I) or pharma- ceutically acceptable salts or stereoisomers or tautomers thereof.

[0006] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein X represents N or C; R x and R y together with the atoms to which they are attached form a fused 5-membered heteroaryl substituted with 1 or 2 occurrences of R6; R t and R z each independently represents hydrogen or alkyl; R1 is hydrogen, halogen, cyano, hydroxy, amino, alkoxy, alkyl or haloalkyl; R2 is hydrogen, halogen, alkyl or haloalkyl; R3 is an aryl, cycloalkyl, heterocyclyl or a group of the formula -CHR a R b wherein aryl, cycloalkyl and heterocyclyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy, haloalkyl and alkyl; R a and R b independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, haloalkyl, or cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, form a fused 5-membered heteroaryl substituted with R5 occurring 1 or 2 times; R5, at each occurrence, is independently hydrogen, alkyl, halogen, haloalkyl, cyano, alkoxy, haloalkoxy, amino, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R6, at each occurrence, is independently hydrogen, halogen, hydroxy, cyano, alkoxy, alkyl, or cycloalkyl; where alkyl is optionally substituted with 1 to 3 substituents independently selected from hydroxy, oxo, halogen, alkylamino, alkoxy, and heterocycloalkyl; n is 1, 2 or 3.

[0007] In another aspect, the present invention provides the preparation of a compound of formula (I) or a pharma- ceutically acceptable salt, or stereoisomer or tautomer thereof.

[0008] In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt, or stereoisomer, or tautomer, thereof, and at least one pharma- ceutically acceptable excipient, such as a pharma- ceutically acceptable carrier or diluent.

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use as a medicament.

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use in the treatment or prevention of a disease or disorder mediated by MALT-1.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for the treatment of a disease or disorder associated with MALT-1, including mutations and overexpression of MALT-1.

[0012] In another aspect, the present invention provides a method for treating a disease or disorder mediated by inhibition of MALT-1 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof. The MALT-1 dependent disease or disorder is cancer.

[0013] In another aspect, the invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by MALT-1, such as cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention provides substituted heterobicyclic compounds, referred to as compounds of formula (I), useful as MALT-1 inhibitors and for the treatment of diseases or disorders that are MALT-1 dependent or mediated by MALT-1. The present invention further provides pharmaceutical compositions comprising said compounds or stereoisomers or tautomers thereof.

[0015] Each embodiment is intended to illustrate the invention and is not intended to limit the invention in any way. Indeed, it will be apparent to one skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be applied to another embodiment to obtain yet further embodiments. Thus, the present invention is intended to include such modifications and variations and their equivalents. Other objects, features, and aspects of the present invention are disclosed in or are apparent from the following detailed description. Those skilled in the art will appreciate that this description is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the invention.

[0016] In one embodiment, the present invention provides a method for the preparation of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof; X represents N or C; R x and R y together with the atoms to which they are attached form a fused 5-membered heteroaryl substituted with 1 or 2 occurrences of R6; R t and R z each independently represents hydrogen or alkyl; R1 is hydrogen, halogen, cyano, hydroxy, amino, alkoxy, alkyl or haloalkyl; R2 is hydrogen, halogen, alkyl or haloalkyl; R3 is an aryl, cycloalkyl, heterocyclyl or a group of the formula -CHR a R b wherein aryl, cycloalkyl and heterocyclyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy, haloalkyl and alkyl; Ra and R b independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, haloalkyl, or cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, form a fused 5-membered heteroaryl substituted with R5 occurring 1 or 2 times; R5, at each occurrence, is independently hydrogen, alkyl, halogen, haloalkyl, cyano, alkoxy, haloalkoxy, amino, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R6, at each occurrence, is independently hydrogen, halogen, hydroxy, cyano, alkoxy, alkyl, or cycloalkyl; where alkyl is optionally substituted with 1 to 3 substituents independently selected from hydroxy, oxo, halogen, alkylamino, alkoxy, and heterocycloalkyl; n is 1, 2 or 3.

[0017] In one embodiment, the present invention provides a method for the preparation of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof; X represents N or C; R x and R y together with the atoms to which they are attached form a fused 5-membered heteroaryl substituted with 1 or 2 occurrences of R6; R t and R z independently represent hydrogen or (C1-C6) alkyl; R1 is hydrogen, halogen, cyano, hydroxy, amino, (C1-C6)alkoxy, (C1-C6)alkyl or halo(C1-C6)alkyl; R2 is hydrogen, halogen, (C1-C6)alkyl or halo(C1-C6)alkyl; R3 is (C6-C 10 )aryl, (C3-C8)cycloalkyl, 5-10 membered heterocyclyl or the formula -CHR a R b wherein the aryl, cycloalkyl and heterocyclyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy, halo(C1-C6)alkyl and (C1-C6)alkyl; R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl, halo(C1-C6)alkyl or (C3-C8)cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy or (C3-C8)cycloalkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, form a fused 5-membered heteroaryl substituted with R5 occurring 1 or 2 times; R5, in each occurrence, is independently hydrogen, (C1-C6)alkyl, halogen, haloC1-C6)alkyl, cyano, (C1-C6)alkoxy, halo(C1-C6)alkoxy, amino, (C6-C 10 )aryl, (C3-C8)cycloalkyl, 5-10 membered heterocycloalkyl or 5-10 membered heteroaryl; R6, at each occurrence, is independently hydrogen, halogen, hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkyl, or (C3-C8)cycloalkyl; where alkyl is optionally substituted with 1 to 3 substituents independently selected from hydroxy, oxo, halogen, (C1-C6)alkylamino, (C1-C6)alkoxy, and 5 to 10 membered heterocycloalkyl; n is 1, 2 or 3.

[0018] In one embodiment, X represents N.

[0019] In one embodiment, X represents C.

[0020] In one embodiment, R1 represents hydrogen, halogen, cyano, alkoxy or haloalkyl.In one embodiment, R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl.

[0021] In one embodiment, R2 represents hydrogen or alkyl.In one embodiment, R2 represents hydrogen.

[0022] In one embodiment, R3 is a cycloalkyl, heteroaryl, heterocycloalkyl, or a group of the formula -CHR a R b wherein the cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from halogen, haloalkyl, and alkyl.

[0023] In one embodiment, R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, or a group of the formula -CHR a R b wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two substituents independently selected from halogen, haloalkyl, and alkyl.

[0024] In one embodiment, R a and R b independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, haloalkyl, or cycloalkyl. a and R b independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, or 3- to 10-membered cycloalkyl.

[0025] In one embodiment, R x and R ytogether with the atom to which they are attached form a fused 5-membered heteroaryl substituted with one or two occurrences of R6.

[0026] In one embodiment, R x and R y together with the atoms to which they are attached, [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents the point of fusion; each ring is substituted with one or two occurrences of R6.

[0027] In one embodiment, R4, at each occurrence, is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, or cycloalkyl. In one embodiment, R4, at each occurrence, is independently hydrogen, halogen, or alkyl.

[0028] In one embodiment, any two adjacent R4 groups together with the atoms to which they are attached form a fused 5-membered heteroaryl substituted with one or two occurrences of R5.

[0029] In one embodiment, any two adjacent R groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point, and each ring is substituted with one or two occurrences of R5.

[0030] In one embodiment, R5 at each occurrence is independently hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, cyano, or cycloalkyl.

[0031] In one embodiment, R5 is hydrogen or halogen.

[0032] In one embodiment, R5 is halogen.

[0033] In one embodiment, R6, at each occurrence, is independently hydrogen, halogen, alkyl, alkyl-OH, alkyl-N(alkyl), alkoxy-alkyl, haloalkyl, -C(=O)-(5- to 6-membered heterocycloalkyl), or 3- to 10-membered cycloalkyl.

[0034] In one embodiment, the present invention provides a compound of formula (I), wherein X represents N or C; R1 represents hydrogen, halogen, cyano, alkoxy or haloalkyl; R2 represents hydrogen or alkyl; R x and R y together with the atoms to which they are attached form a fused 5-membered heteroaryl substituted with 1 or 2 occurrences of R6; R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, or a group of the formula -CHR a R b wherein cycloalkyl and heterocycloalkyl are optionally substituted with haloalkyl; R a and R b independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, or 3 to 10 membered cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, or alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, form a fused 5-membered heteroaryl substituted with R5 occurring 1 or 2 times; R5, at each occurrence, is independently hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, cyano, or cycloalkyl; R6, at each occurrence, is independently hydrogen, halogen, alkyl, alkyl-OH, alkyl-N(alkyl)2, alkoxy-alkyl, haloalkyl, -C(=O)-(5- to 6-membered heterocycloalkyl), or 3- to 10-membered cycloalkyl; n is 1 or 2.

[0035] In one embodiment, the present invention provides a compound of formula (I), wherein X represents N or C; R1 represents hydrogen, halogen, cyano, alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; R x and R y together with the atoms to which they are attached, [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point, each ring being substituted with one or two occurrences of R6; R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, or a group of the formula -CHR a R b wherein the cycloalkyl and heterocycloalkyl are optionally substituted with halo(C1-C6)alkyl; R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl or 3- to 10-membered cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point; each ring is optionally substituted with one or two occurrences of R5; R5, at each occurrence, is independently hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6, at each occurrence, is independently hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N(C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl; n is 1 or 2.

[0036] In one embodiment, the present invention provides a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; wherein R1, R2, R3, R4, R6, X, and n are as defined in the compound of formula (I).

[0037] In one embodiment of formula (IA), X represents N.

[0038] In one embodiment of formula (IA), R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl.

[0039] In one embodiment of formula (IA), R1 represents hydrogen, halogen, cyano, alkoxy or halo(C1-C6)alkyl.

[0040] In one embodiment of formula (IA), R2 represents hydrogen or (C1-C6)alkyl.

[0041] In one embodiment of formula (IA), R2 represents hydrogen.

[0042] In one embodiment of formula (IA), R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0043] In one embodiment of formula (IA), R6 is hydrogen.

[0044] In one embodiment of formula (IA), R6 is (C1-C6) alkyl.

[0045] In one embodiment of formula (IA), R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, or a group of the formula -CHR a R b wherein the cycloalkyl and heterocycloalkyl are optionally substituted with halo(C1-C6)alkyl.

[0046] In one embodiment of formula (IA), R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl or 3- to 10-membered cycloalkyl.

[0047] In one embodiment of formula (IA), R4, at each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, form a fused 5-membered heteroaryl substituted with R5 occurring once or twice.

[0048] In one embodiment of formula (IA), any two adjacent R groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point, and each ring is optionally substituted with one or two occurrences of R5.

[0049] In one embodiment of formula (IA), R5 represents hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl.

[0050] In one embodiment, the present invention provides a compound of formula (IA), wherein X represents N or C; R1 represents hydrogen, halogen, cyano, alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, or a group of the formula -CHR a R b wherein the cycloalkyl and heterocycloalkyl are optionally substituted with halo(C1-C6)alkyl; R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl or 3- to 10-membered cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point; each ring is optionally substituted with one or two occurrences of R5; R5, at each occurrence, is independently hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl)2, (C1-C6)alkoxy-(C1-C6)alkyl, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl; n is 1 or 2.

[0051] In one embodiment, the present invention provides a compound of formula (IB): [ka] or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; a , R b , R4, R6, X and n are as defined in the compounds of formula (I).

[0052] In one embodiment of the compound of formula (IB), R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl.

[0053] In one embodiment of the compound of formula (IB), R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl or 3- to 10-membered cycloalkyl.

[0054] In one embodiment of the compound of formula (IB), a compound of formula -CHR a R b teeth, [ka] where: [ka] represents a bonding point.

[0055] In one embodiment, the present invention provides a compound of formula (IB), wherein: R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl or 3- to 10-membered cycloalkyl; R4, in each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point; each ring is optionally substituted with one or two occurrences of R5; R5, at each occurrence, is independently hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0056] In one embodiment, the present invention provides a compound of formula (IB), wherein: R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; Formula-CHR a R b teeth, [ka] where: [ka] represents the attachment point; R4, in each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point; each ring is optionally substituted with one or two occurrences of R5; R5, at each occurrence, is independently hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0057] In one embodiment, the present invention provides a compound of formula (IB), wherein: R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; R a and R b independently represent hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkyl or 3- to 10-membered cycloalkyl; Formula-CHR a R b teeth, [ka] where: [ka] represents the attachment point; R4, in each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are [ka] forming a fused 5-membered heteroaryl selected from: [ka] represents a fusion point; each ring is optionally substituted with one or two occurrences of R5; R5, at each occurrence, is independently hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0058] In one embodiment, the present invention provides a compound of formula (IC): [ka] or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; a , R b , R5, R6, X and n are as defined in the compounds of formula (I).

[0059] In one embodiment of the compound of formula (IC), R a represents (C1-C6)alkoxy.

[0060] In one embodiment of a compound of formula (IC), Rb represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, or 3- to 10-membered cycloalkyl.

[0061] In one embodiment of the compound of formula (IC), R b represents (C1-C6) alkyl.

[0062] In one embodiment of the compound of formula (IC), a compound of formula -CHR a R b teeth, [ka] where: [ka] represents a bonding point.

[0063] In one embodiment, the present invention provides a compound of formula (IC), wherein R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; R a represents (C1-C6)alkoxy; Rb represents hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl or 3- to 10-membered cycloalkyl; Formula-CHR a R b teeth, [ka] where: [ka] represents the attachment point; R5 is hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0064] In one embodiment, the present invention provides a compound of formula (IC), wherein R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; Formula-CHR a R b teeth, [ka] where: [ka] represents the attachment point; R5 is hydrogen, (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, cyano, or 3- to 10-membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0065] In one embodiment, the present invention provides a compound of formula (ID): [ka] or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; b , R5 and R6 are as defined in the compounds of formula (I).

[0066] In one embodiment of a compound of formula (ID), Rb represents hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, or 3- to 10-membered cycloalkyl.

[0067] In one embodiment of the compound of formula (ID), R5 is (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, cyano, or 3- to 10-membered cycloalkyl.

[0068] In one embodiment, the present invention provides a compound of formula (ID), wherein R1 represents hydrogen, halogen, cyano, (C1-C6)alkoxy or halo(C1-C6)alkyl; R2 represents hydrogen or (C1-C6) alkyl; Rb represents hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl or 3- to 10-membered cycloalkyl; R5 is (C1-C6)alkyl, halogen, halo(C1-C6)alkyl, cyano or 3-10 membered cycloalkyl; R6 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-N((C1-C6)alkyl), (C1-C6)alkoxy-(C1-C6)alkyl-, halo(C1-C6)alkyl, -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

[0069] In one embodiment, the present invention provides a compound of formula (IE): [ka] or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; b , R4, R6 and n are as defined in the compounds of formula (I).

[0070] In one embodiment of the compound of formula (IE), R1 represents hydrogen or halogen.

[0071] In one embodiment of the compound of formula (IE), R2 represents hydrogen.

[0072] In one embodiment of the compound of formula (IE), R b represents (C1-C6) alkyl.

[0073] In one embodiment of the compound of formula (IE), R4, at each occurrence, is independently hydrogen, halogen, or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are optionally substituted with one or two occurrences of halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, cyano, or 3- to 10-membered cycloalkyl. [ka] where: [ka] represents the condensation point.

[0074] In one embodiment of the compound of formula (IE), R6 is hydrogen or (C1-C6)alkyl.

[0075] In one embodiment, the present invention provides a compound of formula (IE), wherein R1 represents hydrogen or halogen; R2 represents hydrogen; R b represents (C1-C6) alkyl; R4 is hydrogen, halogen or (C1-C6)alkyl; or any two adjacent R4 groups, together with the atoms to which they are attached, are optionally substituted with one or two occurrences of halogen or (C1-C6)alkyl; [ka] where: [ka] represents the condensation point; R6 is hydrogen or (C1-C6)alkyl; n is 1 or 2.

[0076] In one embodiment, the present invention provides a compound of formula (IF): [ka] or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; x , Ry, R a , R b , R4, X and n are as defined in the compounds of formula (I).

[0077] In one embodiment, the present invention provides a compound of formula (IG): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof; R3 is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl; R1, R x , Ry, R4, X and n are as defined in the compounds of formula (I).

[0078] In one embodiment, R3 is a 3-8 membered cycloalkyl.

[0079] In one embodiment, R3 is [ka] It is.

[0080] In one embodiment, R3 is a 5-6 membered heterocycloalkyl. [ka] It is.

[0081] In one embodiment, the invention provides a compound selected from the following, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof:

[0082] [Table 1]

[0083] [Table 2]

[0084] [Table 3]

[0085] [Table 4]

[0086] [Table 5]

[0087] [Table 6]

[0088] [Table 7]

[0089] [Table 8]

[0090] [Table 9]

[0091] Treatment method In one embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt, or stereoisomer, or tautomer thereof, for use as a medicament.

[0092] In one embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use in the treatment of a disease or disorder mediated by MALT-1.

[0093] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by MALT-1.

[0094] In one embodiment, the present invention provides a method of inhibiting MALT-1 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, or stereoisomer, or tautomer thereof.

[0095] In one embodiment, the present invention provides a method for treating a disease or disorder mediated by inhibition of MALT-1 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof.

[0096] In one embodiment, the subject is suffering from a MALT-1 dependent disease or disorder.

[0097] In one embodiment, the subject is suffering from cancer.

[0098] In one embodiment, the MALT-1 dependent disease or disorder includes cancer.

[0099] In one embodiment, the cancer is selected from prostate cancer, brain cancer, breast cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, cervical cancer, liver cancer, head / neck / pharynx cancer, skin cancer, bladder cancer, or blood cancer. In one embodiment, the cancer may include a tumor or a blood-borne cancer. The tumor may be solid. The tumor is typically malignant and may metastasize. In one embodiment, the tumor is an adenoma, adenocarcinoma, blastoma, carcinoma, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, germ cell tumor, lymphoma, leukemia, sarcoma, Wilms' tumor, lung tumor, colon tumor, lymphoid tumor, breast tumor, or melanoma.

[0100] In one embodiment, the blastoma comprises hepatoblastoma, glioblastoma, neuroblastoma, or retinoblastoma. In one embodiment, the carcinoma comprises colorectal or hepatocellular carcinoma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, cervical cancer, head and neck cancer, or adenocarcinoma. In one embodiment, the type of sarcoma comprises Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, or other soft tissue sarcomas. In one embodiment, the type of melanoma comprises lentigo maligna, lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft tissue melanoma, melanoma with small nevus-like cells, melanoma with features of Spitz nevus, and uveal melanoma. Lymphoma and leukemia types include precursor T-cell leukemia / lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia / lymphoma, MALT lymphoma, Burkitt lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma subtypes. Lung tumor types include non-small cell lung cancer (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and small cell lung cancer tumors.

[0101] In one embodiment, the disease or disorder mediated by MALT-1 is a cancer selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer. In one embodiment of the invention, the cancer is selected from B cell malignancies such as B cell lymphoma, e.g., diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and leukemia, e.g., chronic lymphocytic leukemia (CLL).

[0102] In one embodiment, the invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for treating or preventing a disease or disorder mediated by MALT-1.

[0103] In one embodiment, the MALT-1 dependent disease or disorder includes cancer. In one embodiment, the cancer is selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung or non-small cell lung cancer. In one embodiment of the invention, the cancer is selected from B cell malignancies such as B cell lymphoma, e.g., diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and leukemia, e.g., chronic lymphocytic leukemia (CLL).

[0104] In further particular embodiments, the MALT-1 dependent disease or disorder is bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, B cell lymphoma, e.g. diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and leukemia, e.g. chronic lymphocytic leukemia (CLL).

[0105] In further particular embodiments, the disease or disorder mediated by inhibition of MALT-1 is diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma and chronic obstructive pulmonary disease.

[0106] In one embodiment, the invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by inhibition of MALT-1.

[0107] In one embodiment, the invention provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for treating or preventing cancer mediated by inhibition of MALT-1.

[0108] In one embodiment, the cancer is selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, B cell lymphoma (diffuse large B cell lymphoma), mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma, and chronic obstructive pulmonary disease.

[0109] Pharmaceutical Compositions In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof or a stereoisomer or tautomer thereof as described herein, and at least one pharma- ceutically acceptable excipient (such as a pharma- ceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound as described herein or a pharma- ceutically acceptable salt or stereoisomer thereof. The compound described in the present invention may be associated with a pharma- ceutical acceptable excipient (such as a carrier or diluent), or may be diluted by a carrier or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.

[0110] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for use in inhibiting MALT-1 in a subject. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use as a medicament.

[0111] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use in the manufacture of a medicament for the treatment of a MALT-1 dependent disease or disorder.

[0112] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof for use in the treatment or prevention of a disease or disorder mediated by MALT-1.

[0113] In one embodiment, the disease or disorder mediated by inhibition of MALT-1 is selected from diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma and chronic obstructive pulmonary disease.

[0114] In one embodiment, the MALT-1 dependent disease or disorder is as described herein.

[0115] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain auxiliary agents, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and aromatics.

[0116] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0117] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug by subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.Here, the absorption rate of the drug depends on its dissolution rate, which may depend on the crystal size and crystalline form.Alternatively, the drug is dissolved or suspended in an oil medium to achieve delayed absorption of parenterally administered drug forms.

[0118] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present application with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound.

[0119] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0120] The active compound can also be in microencapsulated form with one or more excipients as described above.Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation technology.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch.Such dosage forms can contain additional substances other than inert diluents, as is common practice, including, but not limited to, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets and pills, dosage forms can also contain buffering agents.

[0121] Dosage forms for topical or transdermal administration of the compounds of the present application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any necessary preservatives or buffers, as required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated to be within the scope of this application.

[0122] The ointments, pastes, creams and gels may contain, in addition to the active compounds herein, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0123] Powders and sprays can contain, in addition to the compounds of the present application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0124] Transdermal patches have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispensing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compounds in a polymer matrix or gel.

[0125] Administration of the disclosed compounds and pharmaceutical compositions can be achieved by any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0126] Depending on the intended method of administration, the disclosed compounds or pharmaceutical compositions may be in solid, semi-solid or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, optionally in unit dosage amounts, consistent with conventional pharmaceutical practice. Similarly, they may be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all of which may be administered using forms well known to those of ordinary skill in the pharmaceutical arts.

[0127] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharma- ceutically acceptable carrier, such as, for example, a) diluents, such as purified water, triglyceride oils (e.g., hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oils (e.g., EPA or DHA or their esters or triglycerides or mixtures thereof), omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; and in the case of tablets; c) binders, such as aluminum silicate. magnesium, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (e.g. glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g. acacia, tragacanth or sodium alginate), waxes and / or polyvinylpyrrolidone (if required); d) disintegrants, e.g. starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt or effervescent mixtures; e) absorbents, colouring agents, flavourings and sweeteners; f) emulsifiers or dispersing agents, e.g. Tween 80, Labrasol, HPMC, DOSS, capmul 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E. TGPS or other acceptable emulsifier; and / or g) compound absorption enhancers, such as, but not limited to, cyclodextrin, hydroxypropylcyclodextrin, PEG400, PEG200.

[0128] Liquid (especially injectable) compositions can be prepared, for example, by dissolving, dispersing, etc. For example, one or more of the disclosed compounds are dissolved or mixed in a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0129] One or more disclosed compounds or compositions can be delivered by parenteral administration.Parenteral injection administration is generally used for subcutaneous, intramuscular or intravenous injection and infusion.Injection can be prepared in conventional form, as liquid solution or suspension, or as solid form suitable for dissolving in liquid before injection.

[0130] Combination therapy The compounds of the invention can be used in combination with, simultaneously with, prior to or subsequent to other anti-cancer agents, such as immunomodulatory, anti-proliferative or chemotherapeutic agents, or adjunct agents in cancer therapy, such as immunosuppressants or anti-inflammatory agents.

[0131] As used herein, terms such as "co-administration" or "administration in combination" are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which agents are not necessarily administered by the same route of administration or at the same time.

[0132] In one embodiment, the invention provides a composition comprising a MALT-1 blocking agent and one or more anti-cancer agents, where the MALT-1 blocking agent is represented by a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or any compound, salt, stereoisomer, tautomer, or composition described herein.

[0133] In one embodiment, anti-cancer agents that can be combined with the compounds of the present invention may include, but are not limited to, BTK (Bruton's tyrosine kinase) inhibitors such as ibrutinib, SYK inhibitors (such as fostamatinib, entospletinib, celduratinib, etc.), PKC inhibitors (such as ruboxistaurin, tamoxifen, etc.), PI3K pathway inhibitors (such as apitolisib, gedatolicib, buparlisib, copanlisib, duvelisib, pictilisib, taselisib, etc.), BCL family inhibitors (such as oblimersen, navitoclax, venetoclax, etc.), JAK inhibitors (such as baricitinib, tofacitinib, and upadacitinib), PIM kinase inhibitors, rituximab or other B cell antigen binding antibodies, and immune cell redirecting agents (e.g., blinatumomab or CAR T cells), and immunomodulatory agents such as daratumumab, anti-PD-1 antibodies, and anti-PD-L1 antibodies.

[0134] In one embodiment, provided herein is a method of combination therapy of a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, with one or more chemotherapeutic agents, therapeutic antibodies and / or radiation therapy to provide a synergistic or additive therapeutic effect in the treatment of diseases, disorders and conditions, such as, for example, cancer. In one embodiment, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, metabolic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0135] For example, the additional therapeutic agent may include an alkylating agent such as chlorambucil, cyclophosphamide, cisplatin, a mitotic inhibitor such as docetaxel or paclitaxel, an antimetabolite such as 5-fluorouracil, cytarabine, methotrexate or pemetrexed, an antitumor antibiotic such as daunorubicin or doxorubicin, a corticosteroid such as prednisone or methylprednisone, a BCL-2 inhibitor such as venetoclax, or an immunotherapeutic compound such as nivolumab, pembrolizumab, pidilizumab, avelumab, BMS936559 or MPDL3280A, or a combination thereof. In one embodiment, the immunotherapeutic compound comprises a chimeric antigen receptor T cell (CAR T cell).

[0136] In one embodiment, the additional therapeutic agent is a hormone therapy, such as docetaxel, venetoclax, or fulvestrant. Docetaxel is a type of chemotherapy agent known as a microtubule inhibitor. Docetaxel is used to treat various cancers, such as metastatic prostate cancer. Docetaxel treatment is often administered intravenously and often includes premedication with a corticosteroid, such as prednisone. In one embodiment, the additional therapeutic agent is venetoclax, a BCL-2 inhibitor that can induce apoptosis in cancer cells. Venetoclax is typically administered orally.

[0137] In some embodiments, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein may be administered in combination with a metabolic inhibitor such as erlotinib, bortezomib, disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant, sunitinib, letrozole, imatinib mesylate, oxaliplatin, 5-FU (5-fluorouracil), rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, methotrexate; a taxoid, e.g., paclitaxel, ABRAXANE® (Cremophor Free), paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.) albumin engineered nanoparticle formulations and one or more chemotherapeutic agents, such as docetaxel / doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum analogues, such as cisplatin and carboplatin; retinoids, such as retinoic acid; and pharmacologic acceptable salts, acids, and derivatives of any of the above.

[0138] In some embodiments, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, can be used in combination with one or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immuno-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors and phosphatase inhibitors, and targeted therapies for the treatment of a disease, disorder or condition, such as cancer.

[0139] In some embodiments, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer, or composition disclosed herein, can be used in combination therapy with one or more kinase inhibitors for the treatment of cancer. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib ...crizotinib, These include rubociclib, lenvatinib, cobimetinib, abemaciclib, acalabrutinib, alectinib, binimetinib, brigatinib, encorafenib, erdafitinib, everolimus, fostamatinib, gilterinib, larotrectinib, lorlatinib, netarsudil, osimertinib, pemigatinib, pexidartinib, ribociclib, temsirolimus, XL-102, XL-092, XL-147, XL-765, XL-499, and XL-880.

[0140] In some embodiments, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, can be used in combination with an HSP90 inhibitor (e.g., XL888), a Liver X receptor (LXR) modulator, a retinoid-related orphan receptor gamma (RORγ) modulator, a checkpoint inhibitor (e.g., a CK1 inhibitor or a CK1α inhibitor), a Wnt pathway inhibitor (e.g., SST-215) or a mineralocorticoid receptor inhibitor (e.g., esaxerenone), or a poly ADP-ribose polymerase (PARP) inhibitor (e.g., olaparib, rucaparib, niraparib, talazoparib) for the treatment of cancer.

[0141] In some embodiments, for the treatment of cancer, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, may be administered in combination with one or more immune checkpoint inhibitors, such as an inhibitor of PD-1 or an inhibitor of PD-L1, such as an anti-PD-1 monoclonal antibody or an anti-PD-L1 monoclonal antibody, such as nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), amyloid β-blockerase (ALB), or gliomab (Tregs), or a combination thereof. It may be used in combination with tedolizumab, avelumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, TSR-042, AMP-224, AMP-514, PDR001, durvalumab, pidilizumab (Imfinzi®, CT-011), CK-301, BMS936559, MPDL3280A. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, pidilizumab, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1 antibody is nivolumab.

[0142] In some embodiments, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, may be used in combination with one or more PD-L1 inhibitors for the treatment of cancer. Antibodies that bind to human PD-L1 include atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, FAZ053, KN035, CS1001, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, KN035, LY3300054. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A, or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, or durvalumab.

[0143] In some embodiments, for the treatment of cancer, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, can be used in combination with one or more CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, e.g., ipilimumab (Yervoy), tremelimumab and AGEN1884; phosphatidylserine inhibitors, e.g., bavituximab (PGN401); antibodies against cytokines (e.g., IL-10, TGF-b); cemiplimab, and other anti-cancer agents. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1 and CTLA-4, such as an anti-PD-L1 / CTLA-4 bispecific antibody or an anti-PD-1 / CTLA-4 bispecific antibody. Bispecific antibodies that bind to PD-L1 and CTLA-4 include AK104.

[0144] In one embodiment, the present invention provides a composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, in combination with one or more other therapeutic agents and a pharma- ceutically acceptable excipient or carrier. A compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, can be administered in combination with one or more other therapeutic agents (preferably one or two, more preferably one) to (1) complement and / or enhance the prophylactic and / or therapeutic efficacy of the prophylactic and / or therapeutic effect of the compound of the present invention, (2) modulate the pharmacodynamics, improve absorption, or reduce the dosage of the prophylactic and / or therapeutic compound of the present invention, and / or (3) reduce or ameliorate the side effects of the prophylactic and / or therapeutic compound of the present invention. As used herein, the phrase "co-administration" refers to any form of administration of two or more different therapeutic compounds where a second compound is administered while a previously administered therapeutic compound is still effective in the body (e.g., the two compounds are effective in the patient simultaneously, which may involve a synergistic effect of the two compounds).

[0145] For example, different therapeutic compounds can be administered simultaneously, sequentially, or separately in the same formulation or in separate formulations. In one embodiment, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week of each other. Thus, an individual undergoing such treatment can benefit from the combined effect of different therapeutic compounds. Each compound can be administered by the same or different route and by the same or different method. In one embodiment, the other therapeutic compound can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week before or after administration of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), or a compound, salt, stereoisomer, tautomer, or composition disclosed herein. In one embodiment, the other therapeutic compound can be administered within 0.5 to 24 hours before or after administration of a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), or a compound, salt, stereoisomer, tautomer, or composition disclosed herein. In one embodiment, the other therapeutic compound can be administered within 0.5 to 72 hours before or after administration of a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), or a compound, salt, stereoisomer, tautomer, or composition disclosed herein. In one embodiment, the other therapeutic compound can be administered within 2 hours before or after administration of a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG), or a compound, salt, stereoisomer, tautomer, or composition disclosed herein.

[0146] The combination drug containing the compound of the present invention and another drug may be administered as a combined preparation containing both components in a single preparation, or may be administered as separate preparations. Administration by separate preparations includes simultaneous administration or administration at a certain time interval. When administered at a time interval, the compound of the present invention may be administered first, and then the other drug, or the other drug may be administered first, and then the compound of the present invention, as long as the two compounds are simultaneously active in the patient for at least part of the time during the combination therapy. The administration method of each drug may be the same or different route, and the same or different method.

[0147] The dosage of the other drug may be appropriately selected based on the dosage used clinically, or may be a reduced dosage that is effective when administered in combination with the compound of the present invention. The mixing ratio of the compound of the present invention and the other drug may be appropriately selected depending on the age and weight of the subject to be administered, the administration method, the administration time, the disease to be treated, symptoms, and combinations thereof. For example, the other drug may be used in an amount of about 0.01 to about 100 parts by mass per part by mass of the compound of the present invention. The other drug may be a combination of any two or more drugs in an appropriate ratio. The other drug that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention includes not only those already discovered based on the above mechanism, but also those to be discovered in the future.

[0148] In one embodiment, the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) of the present invention, or compounds, salts, stereoisomers, tautomers or compositions disclosed herein thereof, can be administered in combination with non-chemical cancer treatment methods. In one embodiment, the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or compounds, salts, stereoisomers, tautomers or compositions disclosed herein thereof, can be administered in combination with non-chemical cancer treatment methods. In one embodiment, the compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or compounds, salts, stereoisomers, tautomers or compositions disclosed herein thereof, can be administered in combination with radiation therapy. In one embodiment, a compound of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG), or a compound, salt, stereoisomer, tautomer or composition disclosed herein, can be administered in combination with surgery, thermal ablation therapy, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0149] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings provided to facilitate understanding of the invention.

[0150] The singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise.

[0151] As used herein, the term "optionally" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. In other words, "optionally substituted" refers to an event or circumstance in which a substituent is present, and an event or circumstance in which a substituent is not present. For example, "optionally substituted alkyl" refers to an event or circumstance in which the alkyl may be substituted, and an event or circumstance in which the alkyl is not substituted. The term "optionally substituted alkyl" is also referred to as an "unsubstituted or substituted alkyl" group, where the substituents are as described herein.

[0152] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It is understood that "substituted" or "substituted with" includes the potential proviso that such substitution is in accordance with the permissible valences of the replacing atom and substituents, and that the substitution results in a stable compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For appropriate organic compounds, the permissible substituents can be one or more and can be the same or different. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Unless otherwise specified, the substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heteroaryl, heterocycloalkyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that the substituents themselves may be substituted where appropriate.

[0153] As used herein, the term "alkyl" refers to a saturated aliphatic group, which is a C-C 10 Straight chain alkyl group or C3-C 10It includes, but is not limited to, branched alkyl groups. Preferably, an "alkyl" group refers to a C1-C6 straight chain alkyl group or a C3-C6 branched chain alkyl group. In one embodiment, an "alkyl" group refers to a C1-C6 alkyl group. In another embodiment, an "alkyl" group refers to a C1-C4 alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, and 4-octyl. An "alkyl" group may be optionally substituted. In one embodiment, the term "optionally substituted alkyl" may also be referred to as an "unsubstituted or substituted alkyl" group, where the substituents are as described herein.

[0154] As used herein, the term "alkylamino" refers to an amino group substituted with one or two alkyl groups, where the alkyl group is as defined above. In one embodiment, "alkylamino" refers to a (C1-C6) alkylamino group. Examples of "alkylamino" include, but are not limited to, -NH(CH3), N(CH3)2, -NH(C2H5), and -NH(C2H5)2.

[0155] As used herein, the terms "halo" or "halogen," alone or in combination with other terms, mean fluorine, chlorine, bromine or iodine.

[0156] The term "haloalkyl" as used herein refers to an alkyl substituted with one or more halogen atoms, where halo and alkyl groups are as defined above. In one embodiment, haloalkyl includes halo(C1-C6)alkyl, preferably halo(C1-C4)alkyl. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0157] As used herein, the term "cycloalkyl", alone or in combination with other terms, refers to a C3-C10 saturated cyclic hydrocarbon ring. Cycloalkyls can be monocyclic or polycyclic rings, typically containing 3 to 8 carbon ring atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Alternatively, cycloalkyls may be polycyclic and may contain multiple rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls, and the like. In one embodiment, cycloalkyls are (C3-C 10 ) cycloalkyl. A cycloalkyl group can be unsubstituted or substituted with one or more substituents, where the substituents are described herein. In one embodiment, the term "optionally substituted cycloalkyl" also refers to an "unsubstituted or substituted cycloalkyl" group, where the substituents are as described herein.

[0158] As used herein, the term "aryl" refers to an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. In one embodiment, "aryl" refers to a C6-C 10 Refers to the aryl group. C6-C 14Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, fluorenyl, indanyl, biphenylenyl, acenaphthyl.Aryl groups can be unsubstituted or substituted with one or more suitable groups.The term "optionally substituted aryl" can also be referred to as "unsubstituted or substituted aryl" groups, where the substituents are as described herein.

[0159] The terms "heterocyclyl" or "heterocyclic" as used herein, alone or in combination with other terms, include both "heterocycloalkyl" and "heteroaryl" groups described herein.

[0160] The term "heterocycloalkyl" as used herein refers to a 3-15 membered, non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2 and NH, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur, unless a ring size is specifically mentioned. The term "heterocycloalkyl" also refers to a bridged bicyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2 and NH. Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, azabicyclooctanyl, diazabicyclooctanyl, azocinyl, chromanyl, isochromanyl, xanthenyl, and 2-oxa-6-azaspiro[3.3]heptanyl. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups may be optionally substituted with one or more of the aforementioned groups, and with one or more suitable groups. Preferably, "heterocycloalkyl" refers to a 5-10 membered ring (unless a ring size is specifically mentioned). More preferably, "heterocycloalkyl" refers to a 5-6 membered ring (unless a ring size is specifically mentioned). Examples of heterocycloalkyl groups include, but are not limited to, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl.All heterocycloalkyls are optionally substituted with one or more of the aforementioned groups. In one embodiment, the term "optionally substituted heterocycloalkyl" may also be referred to as an "unsubstituted or substituted heterocycloalkyl" group, where the substituents are as described herein.

[0161] As used herein, the term "heteroaryl" refers to a fully unsaturated ring system containing a total of 5-20 ring atoms, unless a ring size is specifically mentioned. At least one of the ring atoms is a heteroatom (O, N, or S), and the remaining ring atoms / groups are independently selected from C, N, O, and S. A heteroaryl may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) fused or covalently linked together. Preferably, a "heteroaryl" is a 5-10 membered ring, unless a ring size is specifically mentioned. More preferably, a "heteroaryl" is a 5-6 membered ring, unless a ring size is specifically mentioned. The ring may contain 1-4 additional heteroatoms selected from N, O, and S, where the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of "heteroaryl" include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, Examples of heteroaryl groups include, but are not limited to, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothienyl, acridinyl, and the like. Heteroaryl groups may be optionally further substituted. In one embodiment, the term "optionally substituted heteroaryl" also refers to an "unsubstituted or substituted heteroaryl" group, where the substituents are as described herein.

[0162] In one embodiment, the heteroaryl (eg, pyridine or pyridyl) can be optionally substituted with oxo to form pyridine-N-oxide or pyridyl-N-oxide, respectively.

[0163] As used herein, the term "amino" refers to the group --NH.

[0164] As used herein, the term "hydroxy", alone or in combination with other terms, means --OH.

[0165] As used herein, the term "oxo" refers to the group ═O.

[0166] As used herein, the term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined above. Exemplary C-C 10 Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, or t-butoxy. In one embodiment, an "alkoxy" group refers to a C1-C6 alkoxy group. In another embodiment, an "alkoxy" group refers to a C1-C4 alkoxy group. An alkoxy group can be optionally substituted with one or more suitable groups. In some embodiments, an alkoxy group can be unsubstituted or substituted with one or more substituents, where the substituents are described herein. As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, where the alkyl and alkoxy groups are defined above.

[0167] In one embodiment, alkoxy-alkyl refers to (C1-C6)alkoxy-(C1-C6)alkyl, preferably (C1-C4)alkoxy-(C1-C4)alkyl. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, and ethoxyethyl. In one embodiment, the point of attachment of the "alkoxyalkyl" group to the remainder of the moiety is through the alkyl group.

[0168] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e., haloC 1-8 In one embodiment, "haloalkoxy" refers to halo(C1-C6)alkoxy. Examples of "haloalkoxy" include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and 1-bromoethoxy.

[0169] The term "heteroatom" as used herein refers to a sulfur, nitrogen, or oxygen atom.

[0170] As used herein, the terms "comprises" or "comprising" are used in a general sense to include, i.e. permitting the presence of one or more features or components.

[0171] As used herein, the term "compound" includes the compounds disclosed in the present invention.

[0172] As used in this specification, the term "including" and other forms such as "include," "includes," and "included" are not limiting.

[0173] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0174] As used herein, the term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of Formula (I), as described herein, or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof; and a pharma- ceutically acceptable carrier.

[0175] The term "tautomer" refers to a compound in which a hydrogen atom is transferred to another part of the molecule, resulting in a rearrangement of the chemical bonds between the atoms of the molecule. The compounds of the present invention, both in their free form and in their salts, may exist in multiple tautomeric forms. It is understood that all tautomers, if any, are included in the present invention. For example, pyridine or pyridyl can be optionally substituted with oxo to form the respective pyridone or pyridon-yl, and also include tautomers such as the respective hydroxy-pyridine or hydroxy-pyridyl, so long as said tautomeric forms can be obtained.

[0176] A pharmaceutical composition usually contains about 1% to 99% by weight of a compound of formula (I) or (II) or a pharma- ceutically acceptable salt thereof, for example, about 5% to 75%, or about 10% to about 30%. The amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition may be about 1 mg to about 1000 mg, or about 2.5 mg to about 500 mg, or about 5 mg to about 250 mg, or any range within the broader range of 1 mg to 1000 mg, or a range higher or lower than the above range.

[0177] As used herein, a "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surface active agent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0178] The terms "administer," "administering," or "administration," as used in this disclosure, refer to administering one or more of the disclosed compounds, or a pharma- ceutically acceptable salt of one or more of the disclosed compounds, or a composition comprising one or more of the disclosed compounds, directly to a subject, or administering to a subject an analog of the compound, or a pharma- ceutically acceptable salt of the compound, or a composition that is capable of forming an equivalent amount of the active compound in the subject's body.

[0179] The term "carrier" as used in this disclosure encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in carrying or transporting a drug from one organ or part of the body of a subject to another organ or part of the body.

[0180] As used herein, the terms "treat," "treating," and "treatment" refer to a method of alleviating or inhibiting a disease and / or its associated symptoms.

[0181] As used herein, the terms "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and / or its associated symptoms or barring a subject from contracting a disease.

[0182] As used herein, the term "subject" refers to an animal, preferably a mammal, and most preferably a human.

[0183] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof; or a composition containing a compound of formula (I) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, effective to produce a desired therapeutic response in a particular subject suffering from a disease or disorder mediated by MALT-1, particularly in a disease or disorder related to cancer. In particular, the term "therapeutically effective amount" includes an amount of a compound of formula (I) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, sufficient when administered to induce favorable alterations or changes in the disease or disorder being treated, or to effectively prevent or alleviate to some extent the onset of one or more symptoms associated with the disease or disorder being treated in the subject. With respect to the therapeutic amount of a compound, it may also be considered that the amount of the compound used to treat a subject is low enough to avoid excessive or severe side effects, within the bounds of sound medical judgment. The therapeutically effective amount of a compound or composition will vary depending on factors such as the condition of the subject being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of any concurrent therapy, the age and physical condition of the end user, the particular compound or composition used, and the particular pharma- ceutically acceptable carrier used.

[0184] "Pharmaceutically acceptable" means useful for preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those acceptable for veterinary and human pharmaceutical use.

[0185] The term "pharmaceutical acceptable salt" refers to the product obtained by reacting the compound of the present invention with a suitable acid or base. In some cases, the pharmaceutical agent can be present in the form of a pharmaceutical acceptable salt. In some examples, the pharmaceutical acceptable salt can be a salt described in Berge et al., J.Pharm.Sci, 1977. In some cases, the pharmaceutical acceptable salt can include a salt derived from an inorganic organic acid or an inorganic base. Examples of pharmaceutical acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutical acceptable salts of the present invention include non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids.

[0186] The pharma- ceutically acceptable salts of the present invention can be prepared from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid (such as an organic or inorganic acid). Such reactions are typically carried out in water or an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is preferred, where practicable. Further lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20 th ed., Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0187] In one embodiment, when such pharmaceutical compositions are for administration to humans, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to delay release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized powders for reconstitution, solutions, syrups, suppositories, injections, and the like. The composition can also be present in a transdermal delivery system, for example, a skin patch. The composition can also be present as a solution suitable for topical administration, such as eye drops.

[0188] Throughout this specification, the term "cancer" is used to refer to a cancerous or malignant neoplasm, i.e., a pathological process that results in the formation and growth of abnormal tissue that grows by cellular proliferation, often growing more rapidly than normal and continuing to grow after the stimulus that initiated the new growth has ceased. Malignant tumors are partially or completely devoid of structural organization and functional coordination with normal tissue, many of which may invade surrounding tissues, metastasize to multiple sites, recur after attempted removal, and cause the death of the patient if not treated appropriately. As used herein, the term neoplasm is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous tumors, ascites, and solid tumors. Examples of cancers that may be treated by the compounds of the invention include, but are not limited to, the following: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Head and Neck: squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cavity carcinoma, and oropharyngeal carcinoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated carcinoma, small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, non-small cell lung carcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumor, lymphoma, carcinoid, Turcot's syndrome; gastrointestinal tract: gastric cancer, gastroesophageal junction adenocarcinoma, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (tubular adenocarcinoma, insulinoma) tumour, glucagonoma, gastrinoma, carcinoid tumour, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumour, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple negative breast cancer; urinary Reproductive tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia, renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma, castration-resistant prostate carcinoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), clear cell carcinoma, clear cell renal cell carcinoma, non-clear cell renal cell carcinoma, papillary carcinoma;Liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor Chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid and giant cell tumor; thyroid: medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hürthle cell carcinoma and anaplastic thyroid carcinoma; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancer) Cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer); blood: blood (myeloid leukemia [acute and chronic], acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole Dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and adrenal gland: neuroblastoma. Thus, the term "cancer cells" as provided herein includes cells afflicted by any one of the above-identified conditions.

[0189] The term "stereoisomer" refers to any enantiomer, diastereoisomer or geometric isomer of a compound of formula (I) when the compound is chiral or has one or more double bonds. When the compounds of formula (I) and related formulae are chiral, they can exist in racemic or optically active form. It should be understood that the present invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of a compound can be prepared synthetically from commercially available starting materials containing chiral centers, or by separation, such as preparing a mixture of enantiomeric products followed by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Starting compounds with a particular stereochemistry are commercially available or can be made and separated by techniques known in the art. Additionally, the compounds of the present invention can exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0190] The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" refers to one of this pair of stereoisomers. The term "racemate" refers to a 1:1 mixture of a pair of enantiomers. The present disclosure includes enantiomers of the compounds described herein. Each compound disclosed herein includes all enantiomers that fit the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or in other forms in terms of stereochemistry. In some embodiments, the compounds are (R,S)-enantiomers.

[0191] The term "diastereomer" refers to a set of stereoisomers that are not superimposable when rotated around a single bond. For example, compounds containing cis and trans double bonds, endo and exo substitutions in bicyclic ring systems, and multiple stereocenters that differ in relative configuration are considered to be diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. The present disclosure includes diastereomers of the compounds described herein.

[0192] The compounds of the present invention can be used as single agents or as pharmaceutical compositions in which the compounds are mixed with various pharmacologically acceptable excipients.

[0193] The compounds of the present invention are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical arts and contain at least one compound of the present invention. The pharmaceutical compositions of this patent application contain one or more compounds described herein and one or more pharma-ceutically acceptable excipients. Typically, pharma-ceutically acceptable excipients are approved by regulatory agencies or generally considered safe for human or animal use. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, thickening agents, and solvents.

[0194] The pharmaceutical compositions can be administered orally, parenterally or by inhalation. Examples of parenteral administration include injection, transdermal, transmucosal, intranasal and pulmonary administration.

[0195] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, fatty acid esters and polyoxyethylene.

[0196] The pharmaceutical compositions may also include one or more pharma- ceutically acceptable adjuvants, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, coloring agents, or any combination thereof.

[0197] The pharmaceutical compositions may be in conventional forms, such as tablets, capsules, solutions, suspensions, injectables, or topical products. Additionally, the pharmaceutical compositions of the present invention may be formulated to provide a desired release profile.

[0198] The administration of the compounds of the present invention, in pure form or in a suitable pharmaceutical composition, can be carried out using any route accepted for administration of pharmaceutical compositions. The route of administration can be any route that effectively transports the active compounds of this patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular or topical.

[0199] Solid oral preparations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.

[0200] Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids such as suspensions and solutions.

[0201] Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may not contain suitable conventional additives such as preservatives, solvents to aid in drug penetration, and the like.

[0202] The pharmaceutical compositions of this patent application may be prepared by conventional techniques known in the literature.

[0203] The appropriate dose of the compound for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through dose-ranging studies in humans based on preliminary evidence obtained from animal studies. The dose should be sufficient to obtain the desired therapeutic benefit without causing undesirable side effects. The mode of administration, dosage form and suitable pharmaceutical excipients can also be appropriately used and adjusted by those skilled in the art. All modifications and variations are contemplated within the scope of this patent application.

[0204] According to one embodiment, the compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more atoms that constitute such compounds.For example, the present invention also encompasses isotopically labeled variants of the present invention that are identical to those described herein, except that one or more atoms of the compound are replaced with an atom that has an atomic mass or mass number different from the predominant atomic mass or mass number that is usually found in nature for that atom.All isotopes of a particular atom or element specified are contemplated within the scope of the compounds of the present invention and their use.Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, e.g., 2 H("D"), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F,36 Cl, 123 I and 125 Isotopically labeled compounds of the invention can generally be prepared following procedures similar to those disclosed in the following schemes and / or examples, substituting an isotopically labeled reagent for a non-isotopically labeled reagent. EXAMPLES

[0205] The following abbreviations have the following definitions: DMSO-Dimethylsulfoxide;DPPA-Diphenylphosphoryl azide;DIPEA-N,N-Diisopropylethylamine;NaHCO3-Sodium bicarbonate;EtOH-Ethanol;MeOH-Methanol;THF-Tetrahydrofuran;SOCl2-Thionyl chloride;LAH-Lithium aluminum hydride;NaH-Sodium hydride;MnO2-Manganese dioxide;IPA-Isopropyl alcohol;NaBH4-Sodium borohydride;KO tBu-potassium tert-butoxide;TFA-trifluoroacetic acid;TBSOTf-tert-butyldimethylsilyl trifluoromethanesulfonate;TBAI-tetrabutylammonium iodide;K2CO3-potassium carbonate;EDCI-1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;DMAP-4-dimethylaminopyridine;PBr3-phosphorus tribromide;NH4OAc-ammonium acetate;TMSOTf-trimethylsilyl trifluoromethanesulfonate;Pd(dppf)Cl2-[1,1'-bis(diphenylphosphino)furan ferrocene]palladium(II) dichloride;Cs2CO3-cesium carbonate;OsO4-osmium tetroxide;NaIO4-sodium periodate;CBr4-carbon tetrabromide;PPh3-triphenylphosphine;Pd2(dba)3-tris(dibenzylideneacetone)dipalladium(0);dppf-1,1'-bis(diphenylphosphino)ferrocene;Zn(CN)2-zinc cyanide;CuI-copper iodide;DMEDA-N,N'-dimethylethylenediamine;HATU-1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4, 5-b]Pyridinium 3-oxide hexafluorophosphate;NH4Cl-Ammonium chloride;Al2O3-Aluminum oxide;Zn-Zinc;NBS-N-Bromosuccinimide;AIBN-Azobisisobutyronitrile;CCl4-Carbon tetrachloride;DME-Dimethoxyethane;P(Cy)3-Tricyclohexylphosphine;Pd(OAc)2-Palladium(II) acetate;K3PO4-Tripotassium phosphate;CDI-1,1'-Carbonyldiimidazole;KI-Potassium iodide;NaOEt-Sodium ethoxide;(Boc)2O-Di-tert -Butyl dicarbonate;MeI-Methyl iodide;Sphos-Dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphane;Dioxane;HCl;-Hydrogen acid in dioxane;Na2SO4-Sodium sulfate;Na2CO3-Sodium carbonate;Na2S2O3-Sodium thiosulfate;H2O-Water;br-Broad;A-Angstrom;℃-Celsius;conc-Concentrated;CHCl3-Chloroform;CDCl3 / / Chloroform-d-Deuterated chloroform;DMSO-d6-Deuterated dimethyl sulfoxide;CH2Cl2_ DCM-dichloromethane; DMF-N,N-dimethylformamide; Et2O-diethyl ether; g-grams; h-hours; 1 H-proton;HCl-hydrochloric acid;Hz-hertz;J-coupling constant;LC-MS-liquid chromatography-mass spectrometry;HPLC-high performance liquid chromatography;Chiral HPLC-chiral high performance liquid chromatography;M-molar concentration;MHz-megahertz (frequency);MS-mass spectrometry;mmol-millimole;mL-milliliter;min-minute;mol-molar;M + - molecular ion; m / z - mass to charge ratio; N - normality; NMR - nuclear magnetic resonance; Et3N / TEA - triethylamine; ppm - parts per million; rt / RT - room temperature; s - singlet; d - doublet, t - triplet; q - quartet; m - multiplet; dd - doublet of doublets; td - triplet of doublets; qd - quartet of doublets; ddd - doublet of doublets of doublets; dt - doublet of triplets; ddt - doublet of triplets of doublets; p - pentet; TLC - thin layer chromatography; THF - tetrahydrofuran; % - percentage; μ - micro; μL - microliter and δ - delta, anhydrous - anhydrous. ± - racemic mixture; SFC - supercritical fluid chromatography.

[0206] General Scheme-I [ka] The general scheme for the synthesis of the compound represented by formula (I-5) is shown in the scheme above. The compound represented by formula (I-2) can be obtained by reacting the compound represented by formula (I-1) with hydrazine in a suitable solvent at room temperature under nitrogen atmosphere. The compound represented by formula (I-2) can be reacted with an acid (R6-COOH) or its ester at high temperature to produce the compound represented by formula (I-3), which can be reduced in the presence of iron to give the compound represented by formula (I-4). Furthermore, the compound represented by formula (I-4) can be reacted with phenyl chloroformate in a suitable solvent to give the compound represented by formula (I-5).

[0207] General Scheme-II [ka] The general scheme for the synthesis of the compound of formula (B-1) is shown in the scheme above. The compounds of formula (A-1), (A-2) and (A-3) can be obtained by reacting the compound of formula (A) with the respective halogen derivatives under suitable reaction conditions. The compounds of formula (A-1), (A-2) and (A-3) can be individually subjected to reduction in the presence of a metal to produce the compound of formula (B-1). Furthermore, the compound of formula (A-3) can be brominated and further alkylated to produce the compound of formula (B-1).

[0208] General Scheme-III [ka] The general scheme for the synthesis of compounds of formula (IA) is shown in the scheme above. Compounds of formula (C-2) can be obtained from compounds of formula (C-1) by reaction with a strong base in a suitable solvent under nitrogen atmosphere. Compounds of formula (C-2) can be reacted with alkyl magnesium halides under nitrogen atmosphere to give compounds of formula (C-3), which can be methylated under nitrogen atmosphere in the presence of a base to give compounds of formula (C-4). Compounds of formula (C-4) can be reacted with benzhydrylimines to give compounds of formula (C-5). Compounds of formula (C-5) can be further treated with a suitable acid to give compounds of formula (C-6). Compounds of formula (C-6) can be further reacted with compounds of formula (I-5) in the presence of a base to give compounds of formula (I-A') as products.

[0209] General Scheme-IV [ka] The general scheme for the synthesis of compound of formula (ID') is shown in the scheme above. Compound of formula (ii) can be obtained by reacting compound of formula (i) with compound of formula (ia) in a suitable solvent at room temperature. Compound of formula (ii) can be reacted with corresponding derivatives of formula (iib) and (iia) at temperatures ranging from 80°C to 140°C to obtain compound of formula (iii), which can be further hydrolyzed in the presence of acid to obtain compound of formula (iv). Compound of formula (iv) can be under reaction conditions of Curtius rearrangement with formula (I-4) or formula (B-1) to produce compound of formula (ID') or formula (ID''), respectively.

[0210] General Scheme-V [ka] The general scheme of synthesis of the compound represented by formula (B-2) is shown in the above scheme. The compound of formula (B-2) can be obtained by reacting the compound of formula (I-5) and the compound of formula (B-1) in the presence of a coupling agent to obtain the compound of formula (B-2).

[0211] Intermediate 1: 8-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-amine [ka] Step a: Synthesis of (E)-3-fluoro-2-hydrazinylidene-5-nitro-1,2-dihydropyridine To a stirred solution of 2-chloro-3-fluoro-5-nitropyridine (10.0 g, 56.648 mmol) in pyridine (50.0 mL) was added hydrazine hydrate (80%) (4.249 g, 84.980 mmol) at room temperature under nitrogen atmosphere, and the reaction mixture was then stirred at 45° C. for 1 h. The mixture was concentrated, co-distilled with methanol, and concentrated. The resulting residue was washed with n-pentane and dried under reduced pressure to give 16.5 g of (E)-3-fluoro-2-hydrazinylidene-5-nitro-1,2-dihydropyridine. 1H NMR(400MHz,DMSO-d6)δ 8.73(d,J=1.2Hz,1H),7.72(dd,J=12Hz,J=11.6Hz,1H),6.27(bs,2H).;M / z=173.10[M+H] + .

[0212] Step b: Synthesis of 8-fluoro-6-nitro-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of (E)-3-fluoro-2-hydrazinylidene-5-nitro-1,2-dihydropyridine (8.0 g, 46.478 mmol) in POCl3 (10 ml) was added formic acid (3.209 g, 69.718 mmol) and the reaction mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 5 g of 8-fluoro-3-methyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridine. 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),8.89(s,1H),8.5(d,J=8Hz,1H).;M / z=183.0[M+H] + .

[0213] Step c: Synthesis of 8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-amine To a stirred solution of 8-fluoro-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (4.7 g, 25.809 mmol) in a mixture of solvents ethanol and THF (50.0 mL, 1:1 ratio) was added ammonium chloride (6.968 g, 129.040 mmol) and iron (7.207 g, 129.040 mmol) in water (25.0 mL). The reaction mixture was stirred at 70° C. for 12 hours. The reaction mixture was diluted with ethyl acetate and filtered through a Celite® bed. The organic layer was separated from the aqueous layer and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.0 g of 8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-amine. 1H NMR(400MHz,DMSO-d6)δ 8.25(s,1H),7.93(d,J=1.2Hz,1H),7.22(m,1H),5.41(bs,2H).;LCMS:153.1[M+H] + .

[0214] Intermediate 2: 8-Fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine [ka] Step a: Synthesis of 8-fluoro-2-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of (E)-3-fluoro-2-hydrazinylidene-5-nitro-1,2-dihydropyridine (10.0 g, 58.098 mmol) in POCl3 (80 ml) was added acetic acid (5.233 g, 87.147 mmol) and the reaction mixture was stirred at 90° C. for 12 hours. The mixture was then concentrated. The resulting residue was diluted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, brine solution, dried over sodium sulfate and concentrated to give a mixture of 8-fluoro-2-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine and 8-fluoro-3-methyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridine. The resulting residue was diluted with saturated NaHCO3 solution and stirred at 50° C. for 2 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated to give 4.5 g (39.49%) of 8-fluoro-2-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine. 1 H NMR(400MHz,DMSO-d6)δ 10.01(d,J=1.6Hz,1H),8.41-8.37(m,1H),2.54(s,3H).;M / z=197.0[M+H].

[0215] Step b: Synthesis of 8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine To a stirred solution of 8-fluoro-3-methyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (4.5 g, 22.943 mmol) in ethanol (40 mL) was added THF (40.0 mL), an aqueous solution of ammonium chloride (9.204 g, 172.070 mmol) (40.0 mL) and iron (9.610 g, 172.070 mmol). The reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered through a Celite® bed. The organic layer was separated from the aqueous layer and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3 g of 8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine. 1 H NMR(400MHz,DMSO-d6)δ 7.79(s,1H),7.00(d,J=12Hz,1H),5.27(bs,2H),2.33(s,3H).;LCMS:167.10[M+H] +

[0216] Intermediate 3: Phenyl (8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamate [ka] Step a: Synthesis of 8-chloro-6-nitro-[1,2,4]triazolo[1,5-a]pyridine To a stirred solution of 2,3-dichloro-5-nitropyridine (3.0 g, 15.545 mmol) in pyridine (8 mL) was added hydrazine hydrate (80%) (2.334 g, 46.620 mmol) at room temperature, then the reaction mixture was stirred at 45° C. for 45 minutes. The mixture was concentrated, co-distilled with methanol and concentrated. The resulting residue was washed with n-pentane and dried under reduced pressure. To this residue was added ethyl orthoformate (8.249 g, 77.730 mmol) and paratoluenesulfonic acid monohydrate (2.957 g, 15.540). The reaction mixture was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.0 g of 8-chloro-6-nitro-[1,2,4]triazolo[1,5-a]pyridine. 1 H NMR(400MHz,DMSO-d6)δ 10.24(d,J=1.6Hz,1H),8.88(s,1H),8.64(d,J=2.0Hz,1H).;M / z=199.10[M+H] +

[0217] Step b: Synthesis of 8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-amine To a stirred solution of 8-chloro-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 7.554 mmol) in a mixture of solvents ethanol and THF (30.0 mL, 1:1 ratio) was added ammonium chloride (2.020 g, 37.760 mmol) and iron (2.115 g, 129.040 mmol) in water (15.0 mL). The reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was filtered through a Celite® bed and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.7 g of 8-chloro-[1,2,4]triazolo[4,3-a]pyridin-6-amine. LCMS: 169.0 [M+H] +

[0218] Step c: Synthesis of phenyl (8-chloro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)carbamate To a stirred solution of 8-chloro-[1,2,4]triazolo[4,3-a]pyridin-6-amine (0.5 g, 2.96 mmol) in 10 mL of acetonitrile was added phenyl chloroformate (0.55 g, 3.55 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated NaHCO3 solution, water, brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 30-40% EtOAc in hexanes) to give 0.5 g (58.39%) of phenyl (8-chloro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)carbamate. 1 H NMR(400MHz,DMSO-d6)δ 10.71 s,1H),9.08(d,1H),8.54(s,1H),7.86(d,J=1.2Hz,1H),7.48-7.44(t,2H),7.31-7.26(m,3H).;LCMS:289.0[M+H] + .

[0219] Intermediate 4: Phenyl (8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamate [ka] To a stirred solution of 8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (0.15 g, 0.903 mmol) in 4 mL of acetonitrile was added phenyl chloroformate (0.212 g, 1.355 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated NaHCO3 solution, water, brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 30-40% EtOAc in hexanes) to give 0.16 g (61.90%) of phenyl (8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamate. 1 H NMR(400MHz,DMSO-d6)δ 10.65(s,1H),8.88(s,1H),7.56(d,J=11.6Hz,1H),7.47-7.43(t,2H),7.31-7.25(m,3H),2.47(s,3H).;LCMS:287.1[M+H] + .

[0220] Intermediate 5: 8-Chloroimidazo[1,2-a]pyridin-6-amine [ka] Step a: Synthesis of 8-chloro-6-nitroimidazo[1,2-a]pyridine To a stirred solution of 3-chloro-5-nitropyridin-2-amine (1.5 g, 8.643 mmol) in EtOH (30 mL) was added concentrated HCl (10.0 ml) and 2-bromo-1,1-diethoxyethane (8.516 g, 43.215 mmol) and the reaction mixture was stirred at 80° C. for 12 h. The mixture was cooled to 0° C. and the precipitated solid was filtered, washed with cold EtOH and dried under reduced pressure to give 0.86 g (56%) of 8-chloro-6-nitroimidazo[1,2-a]pyridine. M / z=198.10 [M+H] +

[0221] Step b: Synthesis of 8-chloroimidazo[1,2-a]pyridin-6-amine To a stirred solution of 8-chloro-6-nitroimidazo[1,2-a]pyridine (0.8 g, 4.049 mmol) in a mixture of solvents ethanol and THF (30.0 mL, 1:1 ratio) was added ammonium chloride (2.168 g, 40.409 mmol) and iron (2.261 g, 40.409 mmol) in water (15.0 mL). The reaction mixture was stirred at 90° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and filtered through a Celite® bed. The organic layer was separated from the aqueous layer and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.2 g (29.47%) of 8-chloroimidazo[1,2-a]pyridin-6-amine. LCMS: 168.10 [M+H] +

[0222] Intermediate 6: 8-Fluoroimidazo[1,2-a]pyridin-6-amine [ka] Intermediate 6 was prepared in the same manner as Intermediate 5, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. Yield: 0.5g. M / z=152.10[M+H] +

[0223] Intermediate-7: 8-Fluoro-3-methylimidazo[1,2-a]pyridin-6-amine [ka] Step a: Synthesis of 8-fluoro-3-methyl-6-nitroimidazo[1,2-a]pyridine A microwave vial (MW) was charged with 3-fluoro-5-nitropyridin-2-amine (0.5 g, 3.161 mmol), 2-bromopropanal (2.252 g, 16.442 mmol) and EtOH (10 mL) and subjected to microwave at 100 °C for 2 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 30-40% EtOAc in hexanes) to give 0.13 g (21.07%) of 8-fluoro-3-methyl-6-nitroimidazo[1,2-a]pyridine. LCMS: 196.1 [M+H] + .

[0224] Step b: Synthesis of 8-fluoro-3-methylimidazo[1,2-a]pyridin-6-amine To a stirred solution of 8-fluoro-3-methyl-6-nitroimidazo[1,2-a]pyridine (0.1 g, 0.512 mmol) in a mixture of solvents ethanol and THF (18.0 mL, 1:1 ratio) was added ammonium chloride (0.164 g, 3.070 mmol) and iron (0.172 g, 3.070 mmol) in water (8.0 mL). The reaction mixture was stirred at 70° C. for 5 hours. The reaction mixture was filtered through a Celite® bed and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.065 g of 8-fluoro-3-methylimidazo[1,2-a]pyridin-6-amine. LCMS: 166.1 [M+H] + .

[0225] Intermediate 8: 8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-amine [ka] Step a: Synthesis of 8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine A sealed tube was charged with 3-fluoro-5-nitropyridin-2-amine (1.0 g, 6.365 mmol), 1-chloropropan-2-one (0.648 g, 7.001 mmol) and NMP (10 mL) and subjected to microwave at 150 °C for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 30-50% EtOAc in hexanes) to give 0.35 g (28.18%) of 8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine. LCMS: 196.1 [M+H] + .

[0226] Step b: Synthesis of 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine To a stirred solution of 8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine (0.35 g, 1.792 mmol) in a mixture of solvents ethanol and THF (20.0 mL, 1:1 ratio) was added ammonium chloride (0.575 g, 10.750 mmol) and iron (0.601 g, 10.750 mmol) in water (10.0 mL). The reaction mixture was stirred at 70° C. for 5 hours. The reaction mixture was filtered through a Celite® bed and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.25 g of 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine. LCMS: 166.1 [M+H] + .

[0227] Intermediate 9: 8-Fluoro-2,3-dimethylimidazo[1,2-a]pyridin-6-amine [ka] Step a: Synthesis of 3-bromo-8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine To a stirred solution of 8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine (intermediate 8) (0.5 g, 2.561 mmol) in AcOH (15 mL) was added bromine (0.225 g, 2.810 mmol) at 0 °C, and then the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate, washed with water, saturated NaHCO3 solution, brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, 30-50% EtOAc in hexanes) to give 0.12 g (17.09%) of 3-bromo-8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine. LCMS: 276.0 [M+H] + .

[0228] Step b: Synthesis of 8-fluoro-2,3-dimethyl-6-nitroimidazo[1,2-a]pyridine To a stirred solution of 3-bromo-8-fluoro-2-methyl-6-nitroimidazo[1,2-a]pyridine (0.110 g, 0.401 mmol) in toluene (5 mL) was added HO (1 mL), KPO (0.169, 0.790 mmol), Pd(OAc) (0.007, 0.030 mmol), SPhos (0.033, 0.080 mmol) and trimethylboroxine (0.077, 0.610 mmol), then the reaction mixture was degassed with nitrogen for 5 min and stirred at 80° C. for 8 h. The reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.15 g of 8-fluoro-2,3-dimethyl-6-nitroimidazo[1,2-a]pyridine. LCMS: 210.0 [M+H] +

[0229] Step c: Synthesis of 8-fluoro-2,3-dimethylimidazo[1,2-a]pyridin-6-amine To a stirred solution of 8-fluoro-2,3-dimethyl-6-nitroimidazo[1,2-a]pyridine (0.15 g, 0.717 mmol) in a mixture of solvents ethanol and THF (12.0 mL, 1:1 ratio) was added ammonium chloride (0.230 g, 4.300 mmol) and iron (0.240 g, 4.300 mmol) in water (6.0 mL). The reaction mixture was stirred at 70° C. for 5 hours. The reaction mixture was filtered through a Celite® bed and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.16 g of 8-fluoro-2,3-dimethylimidazo[1,2-a]pyridin-6-amine. LCMS: 180.10 [M+H] +

[0230] Example 1: (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)urea [ka] Step a: Synthesis of (S)-tert-butyl 4-methoxy-3-oxopentanoate To a stirred solution of (S)-2-methoxypropanoic acid (5.0 g, 48.026 mmol) in THF (100 mL) at 0° C., CDI (8.566 g, 52.820 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 h. In a separate flask, a stirred solution of 3-(tert-butoxy)-3-oxopropanoic acid (11.538 g, 72.039 mmol) in 60 mL of THF was added at 0° C., 2 M isopropylmagnesium chloride in THF (14.345 g, 139.270 mmol) was added dropwise and the reaction mixture was stirred at 20° C. under nitrogen atmosphere for 3 h. This solution was then added dropwise to the acylimidazole solution at 0° C. and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 10% aqueous citric acid (12.5 ml), extracted with AcOEt, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated to give 6.83 g of (S)-tert-butyl 4-methoxy-3-oxopentanoate. 1 H NMR(400MHz,DMSO-d6)δ 3.86-3.84(q,1H),3.508-3.491(m,2H),3.27(s,3H),1.40(s,9H),1.19(d,J=6.4Hz,3H).

[0231] Step b: Synthesis of (S)-tert-butyl 2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate A mixture of (S)-tert-butyl 4-methoxy-3-oxopentanoate (6.830 g, 33.77 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.024 ml, 33.77 mmol) was stirred at 120° C. for 1.5 h. Then, a solution of 5-chloro-1H-pyrazol-3-amine (3.969 g, 33.77 mmol) in EtOH (41 ml) was added and the reaction mixture was stirred at 85° C. for 1 h. The mixture was concentrated and the crude product was purified by flash column chromatography (SiO2, 20% EtOAc in hexanes) to give 6.3 g (59.84%) of (S)-tert-butyl 2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate. 1H NMR(400MHz,DMSO-d6)δ 8.64(s,1H),7.02(s,1H),5.26-5.25(q,1H),3.21(s,3H),1.61(d,J=6.4Hz,3H),1.54(s,9H).;LCMS:312.1[M+H] +

[0232] Step c: Synthesis of (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid To a stirred solution of (S)-tert-butyl 2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (6.30 g, 20.207 mmol) in DCM (30 ml) at room temperature was added TFA (30 ml). The reaction mixture was stirred at room temperature for 12 h and concentrated. The residue was triturated with diethyl ether and the suspension was evaporated to dryness to give 4.5 g of (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (crude). 1 H NMR(300MHz,DMSO-d6)δ 8.73(s,1H),7.03(s,1H),5.44-5.37(q,1H),3.20(s,3H),1.64(d,J=6.6Hz,3H).;LCMS:256.10[M+H] +

[0233] Step d: Synthesis of (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)urea To a stirred solution of (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.310 g, 0.840 mmol) in dioxane (3 ml) was added DPPA (0.277 g, 1.008 mmol) and TEA (0.425 g, 4.200 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then 8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (0.418 g, 2.520 mmol) in dioxane (3 ml) was added. The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, evaporated, the residue was dissolved in ethyl acetate, and the organic layer was washed with saturated aqueous NaHCO3, water, brine solution, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (SiO2, 10% ethyl acetate in hexanes) to give 0.05 g (9.84%) of (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.07(d,J=1.8Hz,1H),8.88(s,1H),8.47(s,1H),7.54(d,J=11.8Hz,1H),6.87(s, 1H),5.36(q,J=6.6Hz,1H),3.29(s,3H),1.54(d,J=6.6Hz,3H).;LCMS:405.0[M+H] +

[0234] The compounds shown in the following table were prepared by procedures similar to those described in Example I, with appropriate variations in reactants, amounts of reagents, solvents and reaction conditions.

[0235] The physiochemical properties of the compounds are summarized in the table below.

[0236] [Table 10]

[0237] [Table 11]

[0238] [Table 12]

[0239] [Table 13]

[0240] [Table 14]

[0241] [Table 15]

[0242] [Table 16]

[0243] Example 31: 1-(2-chloro-7-(1-methoxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea [ka] Example 31 was prepared in a similar manner to that described in Example 1.

[0244] The crude compound was purified by preparative thin layer chromatography (SiO2; 70% EtOAc in hexanes) to give 0.035 g (44.50%) of 1-(2-chloro-7-(1-methoxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1H NMR(400MHz,DMSO-d6)δ 9.97(s,1H),9.01(d,J=19.6Hz,2H),8.38(s,1H),7.55(d,J=10.2Hz,1H),6.97(s,1H),5.10(s,1H),3 .38(s,3H),2.51(s,3H),1.27(m,1H),1.11(d,J=6.7Hz,3H),0.84(d,J=6.7Hz,3H).;LCMS:447.1[M+H] + .

[0245] The racemic compound (0.3 g) was separated by SFC [column: CHIRALPAK IH (250 mm x 21.2 mm) 5 micron)], conditions: solvent, A: n-hexane, B: 0.1% DEA in ethanol, isocratic: 50(A):50(B), flow rate: 20 mL / min to give peak-1 (isomer-1; Example-31a) 0.09 g of 1-(2-chloro-7-(1-methoxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.97(s,1H),9.02(d,J=20.0Hz,2H),8.38(s,1H),7.55(d,J=11.7Hz,1H),6.97(s,1H),5.11(d,J=7.0Hz,1H), 3.39(s,3H),2.51(s,3H),1.25-1.30(m,1H),1.11(d,J=6.7Hz,3H),0.84(d,J=6.7Hz,3H).;LCMS:447.0[M+H] + , and peak 2 (isomer 2; Example 31b) 0.09 g of 1-(2-chloro-7-(1-methoxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),9.04-8.99(m,2H),7.55(dd,J=11.7,1.6Hz,2H),6.97(s,1H),5.80(s,1H),5.11(d,J=7.0Hz,1H ),3.38(s,3H),2.52(s,3H),1.22-1.32(1H),1.11(d,J=6.7Hz,3H),0.84(d,J=6.7Hz,3H);LCMS:446.95[M+H] + .

[0246] Example 32: 1-(2-chloro-7-(cyclopropyl(methoxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea [ka] Example 32 was prepared in a similar manner to that described in Example 1. The crude compound was purified by flash column chromatography (SiO2; 70% EtOAc in hexanes) to give 0.180 g (32.58%) of 1-(2-chloro-7-(cyclopropyl(methoxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),9.04-9.00(m,2H),8.48(s,1H),7.56(dd,J=11.7,1.6Hz,1H),6.98(s,1H),4.81(d,J=9.0Hz, 1H),3.39(s,3H),2.51(s,3H),1.55-1.52(m,1H),0.71-0.64(m,2H),0.52-0.42(m,2H).;LCMS:445.1[M+H] + .

[0247] The racemate (0.15 g) was separated by SFC [column: Cellulose-1 (250 mm x 20.2 mm) 5 micron)] under conditions: solvent, A: n-hexane, B: EtOH, flow rate: 18 mL / min to give peak 1 (isomer 1; Example 32a) 0.02 g of 1-(2-chloro-7-(cyclopropyl(methoxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.96(s,1H),9.02(d,J=19.6Hz,2H),8.49(s,1H),7.57(d,J=11.7Hz,1H),6.98(s,1H),4.81(d,J=8.6Hz,1H ),3.38(d,J=6.7Hz,3H),2.52(s,3H),1.47-1.60(m,1H),0.69(m,2H),0.38-0.55(m,2H).;LCMS:445.1[M+H] + , Peak 2 (Isomer 2; Example 32b) 0.02 g of 1-(2-chloro-7-(cyclopropyl(methoxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.96(s,1H),9.02(d,J=19.6Hz,2H),8.49(s,1H),7.57(d,J=11.7Hz,1H),6.98(s,1H),4.81(d,J=8.6Hz,1H ),3.38(d,J=6.7Hz,3H),2.52(s,3H),1.47-1.60(m,1H),0.69(m,2H),0.38-0.55(m,2H).;LCMS:445.1[M+H] + .

[0248] Example 33: 1-(2-chloro-7-(1-methoxypropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea [ka] Example 33 was prepared in a similar manner to that described in Example 1.

[0249] The crude compound was purified by flash column chromatography (SiO2; 50% ethyl acetate in hexanes) to give 0.15 g (31.16%) of 1-(2-chloro-7-(1-methoxypropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.91(s,1H),9.01(d,J=19.2Hz,2H),8.45(s,1H),7.56(d,J=11.7Hz,1H),6.96(s,1H),5.31-5. 28(m,1H),3.39(s,3H),2.51(s,3H),2.06-1.91(m,2H),0.99(t,J=7.4Hz,3H);LCMS:433.1[M+H] + .

[0250] The racemate (0.12 g) was separated by SFC [column: CHIRALPAK-IG (250 mm x 21.2 mm) 5 micron, conditions: solvents, A: n-hexane, B: EtOH, time / % B: 0 / 50, 20 / 50; flow rate: 18 mL / min to give peak 1 (isomer 1; Example 33a) 0.03 g of 1-(2-chloro-7-(1-methoxypropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.83(s,1H),8.93(d,J=19.6Hz,2H),8.37(s,1H),7.48(d,J=11.7Hz,1H),6.89(s,1H),5.23-5.20( m,1H),3.30(s,3H),2.43(s,3H),1.95(d,J=7.0Hz,2H),0.91(t,J=7.2Hz,3H).;LCMS:433.20[M+H] +, Peak 2 (Isomer 2, Example 33b) 0.03 g of 1-(2-chloro-7-(1-methoxypropyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz,DMSO-d6)δ 9.81-9.94(1H),8.93(d,J=21.9Hz,2H),8.32-8.47(1H),7.42-7.54(1H),6.89(s,1H),5.18-5.28 (1H),3.30(s,3H),2.46-2.43(s,3H),1.76-2.03(m,2H),0.91(t,J=7.4Hz,3H).;LCMS:433.1[M+H] + .

[0251] Example 34: 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea [ka] Step a: Synthesis of 3,5-dibromo-2-methylisonicotinaldehyde A stirred solution of 3,5-dibromo-2-methylpyridine (3.8 g, 15.14 mmol) in dry THF was cooled to -70°C and then LDA (2M in THF) (1.94 g, 18.17 mmol) was added under nitrogen atmosphere. The reaction was stirred at -70°C for 1 h followed by the addition of DMF (2.5 ml). The reaction mixture was stirred at -70°C for 1 h. The reaction mixture was then quenched with saturated NH4Cl solution at -30°C to -20°C, water was added, the mixture was allowed to warm to room temperature and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by flash column chromatography (SiO2; 5-10% ethyl acetate in hexanes) to give 1.95 g (46.16%) of 3,5-dibromo-2-methylisonicotinaldehyde. 1H NMR(300MHz,DMSO-d6)δ 10.08(s,1H),8.75(s,1H),2.62(s,3H).;LCMS:279.8[M+H] + .

[0252] Step b: Synthesis of 1-(3,5-dibromo-2-methylpyridin-4-yl)ethan-1-ol A stirred solution of 3,5-dibromo-2-methylisonicotinaldehyde (1.9 g, 6.81 mmol) in dry THF (30 ml) was cooled to 0° C., then MeMgBr (3M in DEE) (1.21 g, 10.21 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with saturated NH4Cl solution, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1.75 g (87.09%) of 1-(3,5-dibromo-2-methylpyridin-4-yl)ethan-1-ol. 1 H NMR(300MHz,DMSO-d6)δ 8.51(s,1H),5.58(d,J=3.9Hz,1H),5.39-5.35(q,1H),2.58(s,3H),1.42(d,J=6.6Hz,3H).;LCMS:295.8[M+H] + .

[0253] Step c: Synthesis of 3,5-dibromo-4-(1-methoxyethyl)-2-methylpyridine A stirred solution of 1-(3,5-dibromo-2-methylpyridin-4-yl)ethan-1-ol (1.7 g, 5.76 mmol) in dry THF was cooled to 0 °C. Sodium hydride 60% (0.415 g, 17.28 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 30 min, followed by the addition of methyl iodide (1.22 g, 8.64 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction mixture was quenched with saturated NH4Cl solution, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by flash column chromatography (SiO2; 5-10% ethyl acetate in hexanes) to give 1.75 g (98.27%) of 3,5-dibromo-4-(1-methoxyethyl)-2-methylpyridine. 1 H NMR (400 MHz, methanol-d4) δ 8.49 (s, 1H), 5.18-5.16 (q, 1H), 3.16 (s, 3H), 2.64 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H). LCMS: 310.0 [M + H] + .

[0254] Step d: Synthesis of N-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-1,1-diphenylmethanimine To a stirred solution of 3,5-dibromo-4-(1-methoxyethyl)-2-methylpyridine (1.8 g, 5.82 mmol) in toluene (30 mL) was added diphenylmethanimine (1.16 g, 6.4 mmol), sodium-tert-butoxide (0.56 g, 5.825 mmol), rac-BINAP (0.54 g, 0.87 mmol) and Pd2(dba)3 (0.267 g, 0.290 mmol), then the reaction mixture was degassed with nitrogen for 5 min. The reaction mixture was heated at 120° C. for 18 h. The reaction mixture was cooled and filtered through a Celite® bed. The filtrate was concentrated under reduced pressure to give 2.38 g of N-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-1,1-diphenylmethanimine. LCMS: 411.0 [M+H] + .

[0255] Step e: Synthesis of 5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-amine To a stirred solution of N-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-1,1-diphenylmethanimine (3.8 g, 9.28 mmol) in dry DCM, concentrated HCl (4 ml) was added and the reaction mixture was stirred at 40° C. for 24 h. The reaction mixture was cooled to room temperature, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by flash column chromatography (SiO2; 20-30% EtOAc in hexanes). The pure fractions were concentrated under reduced pressure to give 0.9 g (39.55%) of 5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-amine. 1 H NMR(400MHz,DMSO-d6)δ 7.79(s,1H),5.38(bs,2H),4.90-4.89(q,1H),3.14(s,3H),2.38(s,3H),1.33(d,J=6.8Hz,3H).;LCMS:245.0[M+H]

[0256] Step f: Synthesis of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea To a stirred solution of 5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-amine (0.05 g, 0.204 mmol) in 10 mL of dry THF was added DMAP (0.075 g, 0.610 mmol) and phenyl (8-chloro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)carbamate (0.118 g, 0.408 mmol). The reaction mixture was stirred at 70° C. for 1 h and at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated KHSO4 solution, water, brine solution, dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by flash column chromatography (SiO, 5% MeOH in DCM) followed by preparative high performance liquid chromatography [column: LUNA, 250 mm × 21.1 mm × 5 micron; conditions: A: water, B: ACN, flow rate: 20 mL / min] to give 0.012 g (13.38%) of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR (400 MHz, methanol-d4) δ 9.29 (t, J = 1.4 Hz, 1H), 9.06 (d, J = 1.2 Hz, 1H), 8.40 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 5.19 (s, 1H), 3.39 (s, 3H), 2.64 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H); LCMS: 440.9 [M + H] + .

[0257] The racemate (0.009 g) was separated by SFC. [Column: CELLULOSE-4 (250 mm x 21.2), 5 μm. Conditions: Solvent, A: n-Hexane, B: Ethanol. Isocratic: Time / %B 0 / 40, 20 / 40, Flow rate: 20 mL / min to give peak 1 (isomer 1; Example 34a) 0.0025 g (25.0%) of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1H NMR(400MHz, methanol-d4)δ 9.29(d,J=2.0Hz,1H),9.07(s,1H),8.40(s,1H),7.76(d,J=2.0Hz,1H),5.21(q,J =6.8Hz,1H),3.40(s,3H),2.65(s,3H),1.52(d,J=6.7Hz,3H);LCMS:441.10[M+H] + , and peak 2 (isomer 2; Example 34b) 0.0025 g (25.0%) of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR (400 MHz, methanol-d4) δ 9.28 (d, J = 2.0 Hz, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 5.20 (t, J = 6.7 Hz, 1H), 3.39 (s, 3H), 2.64 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H). LCMS: 440.9 [M + H] + .

[0258] Example 35: 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea [ka] Example 35 was prepared by a procedure similar to that described in Example 34.

[0259] The crude compound was purified by flash column chromatography on silica gel (SiO2; 50-60% EtOAc in hexanes) to give 0.04 g (21.61%) of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1H NMR(400MHz,DMSO-d6)δ 10.05(s,1H),9.07-8.97(m,2H),8.71(d,J=9.9Hz,1H),7.73(d,J=1.8Hz,1H),5.06(q,J=6. 8Hz,1H),3.33(s,3H),2.58(s,3H),2.47(s,3H),1.44(d,J=6.8Hz,3H).;LCMS:454.85[M+H] + .

[0260] The racemate (0.03 g) was separated by SFC. [Column: Chiral pack (250 mm x 20 mm), 5 μm. Conditions: Solvent, % A: Ethanol, % B: n-Hexane. Isocratic: Time / B: 0.1 / 40 and 10 / 40; Flow rate: 18 mL / min gave peak 1 (isomer 1; Example 35a) 0.01 g (33.39%) of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. (400MHz, methanol-d4) δ 9.17(d,J=2.0Hz,1H), 9.06(s,1H), 7.69(d,J=2.0Hz,1H), 5.19(t,J=6.8Hz,1H), 3.39(s,3H), 2.64(s,3H), 2.54(s,3H), 1.51(d,J=7.0Hz,3H).;LCMS: 455.10[M+H] + , and peak 2 (isomer 2; Example 35b) 0.01 g (33.39%) of 1-(5-bromo-4-(1-methoxyethyl)-6-methylpyridin-3-yl)-3-(8-chloro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)urea. 1 H NMR(400MHz, methanol-d4)δ 9.17(d,J=1.6Hz,1H),9.06(s,1H),7.70(d,J=2.0Hz,1H),5.20(q,J=6.8Hz,1H), 3.39(s,3H),2.64(s,3H),2.54(s,3H),1.51(d,J=6.7Hz,3H).;LCMS:455.10[M+H] + .

[0261] The following compounds were prepared by procedures similar to those described in Example 34, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. The physicochemical properties of the compounds are summarized in the table below.

[0262] [Table 17]

[0263] Example 38: 1-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(7-cyclopropyl-2-methylthiazolo[5,4-b]pyridin-6-yl)urea [ka] To a stirred solution of 7-cyclopropyl-2-methylthiazolo[5,4-b]pyridin-6-amine (0.15 g, 0.731 mmol, (synthesized using reference WO2018020474) in 2 mL of dry THF, DMAP (0.134 g, 1.101 mmol) and phenyl (8-chloro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)carbamate (0.423 g, 1.468 mmol) were added. The reaction mixture was stirred at 70° C. for 2 h and then at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by flash column chromatography (SiO2; 40-50% EtOAc in hexanes). The pure fractions were concentrated under reduced pressure to give 0.035 g (11.97%) of 1-(8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(7-cyclopropyl-2-methylthiazolo[5,4-b]pyridin-6-yl)urea. 1 H NMR (400 MHz, methanol-d4) δ 9.22-9.27 (1H), 8.64 (s, 1H), 8.41 (s, 1H), 7.78-7.82 (1H), 2.82 (s, 3H), 1.55-1.61 (m, J = 2.4 Hz, 1H), 1.17-1.34 (m, J = 6.8 Hz, 4H). LCMS: 400.20 [M + H]+ .

[0264] Example 39: 1-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)urea [ka] To a stirred solution of 7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-amine (prepared according to the procedure described in WO2018020474, 0.05 g, 0.244 mmol) in 8 mL of dry THF solution, DMAP (0.041 g, 0.33 mmol) and phenyl(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamate (0.096 g, 0.336 mmol) were added. The reaction mixture was stirred at 70° C. for 1 h and then at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, then dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by flash column chromatography (SiO; 40-50% EtOAc in hexanes) to give 0.02 g (21.49%) of 1-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(7-(1-methoxyethyl)-2-methylthiazolo[5,4-b]pyridin-6-yl)urea. 1 H NMR (300 MHz, methanol-d4) δ 9.18 (s, 1H), 9.09 (s, 1H), 7.50-7.45 (t, 1H), 5.60-5.57 (q, 1H), 3.40 (s, 3H), 2.84 (s, 3H), 2.54 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H). LCMS: 416.1 [M + H] + .

[0265] The compounds shown in the following table were prepared by procedures similar to those described in Example I, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. The physicochemical properties of the compounds are summarized in the following table.

[0266] [Table 18]

[0267] [Table 19]

[0268] [Table 20]

[0269] Example P1: Biochemical Assays The potency of compounds to inhibit MALT-1 (isoform 1) enzyme was tested in a fluorescence assay using recombinant MALT-1 (isoform 1, aa-840) produced in-house. The assay buffer was 50 mM HEPES (pH 7.5), 100 mM NaCl, 10 mM DTT, 1 mM EDTA, 0.9 M sodium citrate, 0.01% CHAPS. 1.5 nM of MALT-1 enzyme was incubated with various concentrations of test compound (1 μM) in the presence of buffer (1% DMSO) for 30 min at 30 °C. The protease reaction was initiated by adding 50 μM of AC-LRSR-MAC (Peptide International, USA) substrate and incubated for 240 min. After 240 min of incubation, the fluorescence emission of the samples was measured at 460 nm with excitation at 355 nm. The percentage of inhibition was calculated using the following formula: (control OD-(sample OD / control OD)) × 100. IC 50 Values ​​were determined by fitting the dose-response data to a sigmoidal curve fitting equation using Graph pad prism software V8.

[0270] Selected compounds of the present invention are IC 50 The results are summarized in the following table into groups +++, ++, and +, where "+++" group indicates IC<0.05 μM.50 The "++" group includes compounds with IC values ​​between 0.051 μM and 0.25 μM (inclusive). 50 The "+" group includes compounds with IC values ​​greater than 0.25 μM. 50 The compounds include those having a value. "ND" refers to not determined.

[0271] [Table 21]

[0272] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application (including all definitions herein) will control.

[0273] Equivalent While specific embodiments of the present invention have been described, the above specification is illustrative and not limiting. Many variations of the present invention will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the present invention should be determined by reference to the claims, their full scope of equivalents, and the specification, together with such variations.

Claims

1. Compounds of formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, X represents N or C; R ｘ and R ｙ may occur once or twice together with the atoms to which they are attached. ６ forming a fused 5-membered heteroaryl substituted with R ｔ and R ｚ each independently represents hydrogen or alkyl; R １ is hydrogen, halogen, cyano, hydroxy, amino, alkoxy, alkyl or haloalkyl; R ２ is hydrogen, halogen, alkyl or haloalkyl; R ３ is an aryl, cycloalkyl, heterocyclyl or group of the formula -CHR ａ R ｂ wherein said aryl, cycloalkyl, and heterocyclyl are optionally substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxy, haloalkyl, and alkyl; R ａ and R ｂ independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, haloalkyl, or cycloalkyl; R ４ is, at each occurrence, independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, or cycloalkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, may occur once or twice as R ５ forming a fused 5-membered heteroaryl substituted with R ５ is independently at each occurrence hydrogen, alkyl, halogen, haloalkyl, cyano, alkoxy, haloalkoxy, amino, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R ６ is independently for each occurrence hydrogen, halogen, hydroxy, cyano, alkoxy, alkyl, or cycloalkyl, wherein said alkyl is optionally substituted with 1 to 3 substituents independently selected from hydroxy, oxo, halogen, alkylamino, alkoxy, and heterocycloalkyl; n is 1, 2 or 3).

2. 2. The compound of claim 1, wherein X represents N.

3. R ｘ and R ｙ may occur once or twice together with the atoms to which they are attached. ６ 3. The compound according to claim 1 , wherein the compound forms a fused 5-membered heteroaryl substituted with

4. The fused 5-membered heteroaryl is 【Chemistry 2】 is selected from: 【Chemistry 3】 The compound according to claim 3 , wherein represents a condensation point.

5. R １ A compound according to any one of claims 1 to 4, wherein represents hydrogen, halogen, cyano, alkoxy or haloalkyl.

6. R ２ A compound according to any one of claims 1 to 5, wherein represents hydrogen or alkyl.

7. R ３ is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl or the formula -CHR ａ R ｂ wherein said cycloalkyl and heterocycloalkyl are optionally substituted with one or two substituents independently selected from halogen, haloalkyl, and alkyl; R ａ and R ｂ The compound of any one of claims 1 to 6, wherein independently represents hydrogen, alkyl, alkoxy, alkoxy-alkyl or 3 to 10 membered cycloalkyl.

8. R ４ is, in each occurrence, independently hydrogen, halogen, or alkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, may occur one or two times. ５ The compound according to any one of claims 1 to 7, which forms a fused 5-membered heteroaryl substituted with

9. The fused 5-membered heteroaryl is 【Chemistry 4】 is selected from: 【Chemistry 5】 The compound according to claim 8 , wherein represents a condensation point.

10. R ５ The compound of any one of claims 1 to 9, wherein, at each occurrence, is independently hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, cyano, or cycloalkyl.

11. R ６ is, in each occurrence, independently hydrogen, halogen, alkyl, alkyl-OH, alkyl-N(alkyl) ２ 11. The compound of any one of claims 1 to 10, wherein the aryl group is alkoxy-alkyl, haloalkyl, -C(=O)-(5-6 membered heterocycloalkyl) or 3-10 membered cycloalkyl.

12. X represents N or C; R １ represents hydrogen, halogen, cyano, alkoxy or haloalkyl; R ２ represents hydrogen or alkyl; R ｘ and R ｙ may occur once or twice together with the atoms to which they are attached. ６ forming a fused 5-membered heteroaryl substituted with R ３ is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl or the formula -CHR ａ R ｂ wherein said cycloalkyl and heterocycloalkyl are optionally substituted with haloalkyl; R ａ and R ｂ independently represent hydrogen, alkyl, alkoxy, alkoxy-alkyl, or 3- to 10-membered cycloalkyl; R ４ is, in each occurrence, independently hydrogen, halogen, or alkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, may occur one or two times. ５ forming a fused 5-membered heteroaryl substituted with R ５ is independently at each occurrence hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, cyano, or cycloalkyl; R ６ is, in each occurrence, independently hydrogen, halogen, alkyl, alkyl-OH, alkyl-N(alkyl) ２ , alkoxy-alkyl, haloalkyl, -C(=O)-(5-6 membered heterocycloalkyl) or 3-10 membered cycloalkyl; n is 1 or 2; A compound according to any one of claims 1 to 11.

13. X represents N or C; R １ is hydrogen, halogen, cyano, alkoxy or halo(C １ -C ６ ) alkyl; R ２ is hydrogen or (C １ -C ６ ) alkyl; R ｘ and R ｙ together with the atoms to which they are bonded, 【Chemistry 6】 forming a fused 5-membered heteroaryl selected from: 【Chemistry 7】 represents a condensation point, and each ring may have one or two occurrences of R ６ is substituted with; R ３ is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl or the formula -CHR ａ R ｂ wherein the cycloalkyl and heterocycloalkyl are halo(C １ -C ６ ) optionally substituted with alkyl; R ａ and R ｂ are independently hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ )-alkyl or 3- to 10-membered cycloalkyl; R ４ is, in each occurrence, independently hydrogen, halogen or (C １ -C ６ ) alkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, 【Chemistry 8】 forming a fused 5-membered heteroaryl selected from: 【Chemistry 9】 represents a condensation point, and each ring may have one or two occurrences of R ５ optionally substituted with; R ５ is, in each occurrence, independently hydrogen, (C １ -C ６ ) alkyl, halogen, halo(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, cyano, or 3- to 10-membered cycloalkyl; R ６ is, in each occurrence, independently selected from hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) alkyl-N(C １ -C ６ ) alkyl) ２ , (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl-, halo(C １ -C ６ ) alkyl, —C(═O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl; n is 1 or 2; A compound according to any one of claims 1 to 12.

14. Formula (IA) 【Chemistry 10】 The compound according to claim 1 , wherein the compound is represented by the formula:

15. R １ is hydrogen, halogen, cyano, (C １ -C ６ ) alkoxy or halo(C １ -C ６ ) alkyl.

16. R ２ is hydrogen or (C １ -C ６ 16. A compound according to claim 14 or 15, wherein:

17. R ６ is hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) alkyl-N[(C １ -C ６ ) alkyl] ２ , (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl-, halo(C １ -C ６ 17. The compound of any one of claims 14 to 16, wherein the aryl group is -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

18. R ４ is, in each occurrence, independently hydrogen, halogen or (C １ -C ６ ) alkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, may occur one or two times. ５ 18. The compound according to any one of claims 14 to 17, which forms a fused 5-membered heteroaryl substituted with

19. X represents N or C; R １ is hydrogen, halogen, cyano, alkoxy or halo(C １ -C ６ ) alkyl; R ２ is hydrogen or (C １ -C ６ ) alkyl; R ３ is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl or the formula -CHR ａ R ｂ wherein the cycloalkyl and heterocycloalkyl are halo(C １ -C ６ ) optionally substituted with alkyl; R ａ and R ｂ are independently hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ )-alkyl or 3- to 10-membered cycloalkyl; R ４ is, in each occurrence, independently hydrogen, halogen or (C １ -C ６ ) alkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, 【Chemistry 11】 forming a fused 5-membered heteroaryl selected from: 【Chemistry 12】 represents a condensation point, and each ring may have one or two occurrences of R ５ optionally substituted with; R ５ is, in each occurrence, independently hydrogen, (C １ -C ６ ) alkyl, halogen, halo(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, cyano, or 3- to 10-membered cycloalkyl; R ６ is hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) alkyl-N((C １ -C ６ ) alkyl) ２ , (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, —C(═O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl; n is 1 or 2; The compound according to any one of claims 14 to 18.

20. Formula (IB) 【Chemistry 13】 The compound according to claim 1 , wherein the compound is represented by the formula:

21. R ａ and R ｂ are independently hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ 21. The compound of claim 20, wherein R represents -alkyl or 3- to 10-membered cycloalkyl.

22. The formula -CHR ａ R ｂ but, 【Chemistry 14】 where: 【Chemistry 15】 22. The compound of claim 20 or 21, wherein represents a point of attachment.

23. R １ is hydrogen, halogen, cyano, (C １ -C ６ ) alkoxy or halo(C １ -C ６ ) alkyl; R ２ is hydrogen or (C １ -C ６ ) alkyl; R ａ and R ｂ are independently hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ )-alkyl or 3- to 10-membered cycloalkyl; The formula -CHR ａ R ｂ but, 【Chemistry 16】 where: 【Chemistry 17】 represents the attachment point; R ４ is, in each occurrence, independently hydrogen, halogen or (C １ -C ６ ) alkyl; or any two adjacent R ４ Groups, together with the atoms to which they are attached, 【Chemistry 18】 forming a fused 5-membered heteroaryl selected from: 【Chemistry 19】 represents a condensation point; each ring may have one or two occurrences of R ５ optionally substituted with; R ５ is, in each occurrence, independently hydrogen, (C １ -C ６ ) alkyl, halogen, halo(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, cyano, or 3- to 10-membered cycloalkyl; R ６ is hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) alkyl-N((C １ -C ６ ) alkyl) ２ , (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl-, halo(C １ -C ６ 23. The compound of any one of claims 20 to 22, wherein the aryl group is -C(=O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl.

24. Formula (IC) 【Chemistry 20】 The compound according to claim 1 , wherein the compound is represented by the formula:

25. R ａ However, (C １ -C ６ ) alkoxy.

26. Rb is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C １ -C ６ 26. A compound according to claim 24 or 25, wherein R represents an alkyl or a 3- to 10-membered cycloalkyl.

27. The formula -CHR ａ R ｂ but, 【Chemistry 21】 where: 【Chemical 22】 A compound according to any one of claims 24 to 26, wherein represents a point of attachment.

28. R １ is hydrogen, halogen, cyano, (C １ -C ６ ) alkoxy or halo(C １ -C ６ ) alkyl; R ２ is hydrogen or (C １ -C ６ ) alkyl; R ａ However, (C １ -C ６ ) alkoxy; Rb is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl or 3- to 10-membered cycloalkyl; The formula -CHR ａ R ｂ but, 【Chemistry 23】 where: 【Chemistry 24】 represents the attachment point; R ５ is hydrogen, (C １ -C ６ ) alkyl, halogen, halo(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, cyano, or 3- to 10-membered cycloalkyl; R ６ is hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) alkyl-N((C １ -C ６ ) alkyl) ２ , (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl-, halo(C １ -C ６ ) alkyl, —C(═O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl; A compound according to any one of claims 24 to 27.

29. Formula (ID) 【Chemistry 25】 The compound according to claim 1 , wherein the compound is represented by the formula:

30. Rb is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C １ -C ６ 30. The compound of claim 29, wherein R represents an alkyl or a 3- to 10-membered cycloalkyl.

31. R １ is hydrogen, halogen, cyano, (C １ -C ６ ) alkoxy or halo(C １ -C ６ ) alkyl; R ２ is hydrogen or (C １ -C ６ ) alkyl; Rb is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl or 3- to 10-membered cycloalkyl; R ５ However, (C １ -C ６ ) alkyl, halogen, halo(C １ -C ６ ) alkyl, cyano, or 3- to 10-membered cycloalkyl; R ６ is hydrogen, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) alkyl-N((C １ -C ６ ) alkyl) ２ , (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl-, halo(C １ -C ６ ) alkyl, —C(═O)-(5- to 6-membered heterocycloalkyl) or 3- to 10-membered cycloalkyl; 31. A compound according to claim 29 or 30.

32. Formula (IE) 【Chemistry 26】 The compound according to claim 1 , wherein the compound is represented by the formula:

33. R ４ is hydrogen, halogen or (C １ -C ６ ) alkyl; or any two adjacent R ４ The radicals, together with the atoms to which they are attached, may occur once or twice: halogen, (C １ -C ６ ) alkyl, halo (C １ -C ６ ) optionally substituted with alkyl, cyano or 3- to 10-membered cycloalkyl; 【Chemistry 27】 where: 【Chemistry 28】 The compound of claim 32, wherein represents a condensation point.

34. R １ represents hydrogen or halogen; R ２ represents hydrogen; R ｂ However, (C １ -C ６ ) alkyl; R ４ is hydrogen, halogen or (C １ -C ６ ) alkyl; or any two adjacent R ４ The radicals, together with the atoms to which they are attached, may be halogen or (C １ -C ６ ) optionally substituted with alkyl; 【Chemical Formula 29】 wherein 【Chemistry 30】 represents the condensation point; R ６ is hydrogen or (C １ -C ６ ) alkyl; n is 1 or 2; 34. A compound according to any one of claims 32 or 33.

35. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 35. The compound of any one of claims 1 to 34, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, selected from:

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharma- ceutically acceptable salt, or stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier or excipient.

37. 37. A pharmaceutical composition according to claim 36 for use as a medicament.

38. 37. A pharmaceutical composition according to claim 36 for use in the treatment or prevention of a disease or disorder mediated by MALT-1.

39. 39. The pharmaceutical composition for use according to claim 38, wherein the disease or disorder is selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma (diffuse large B-cell lymphoma), mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma and chronic obstructive pulmonary disease.

40. 36. A compound according to any one of claims 1 to 35, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, for use as a medicine.

41. A method of treating a disease or disorder mediated by inhibition of MALT-1 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 35.

42. The method of claim 41, wherein the disease or disorder mediated by MALT-1 is cancer.

43. 43. The method of claim 41 or 42, wherein the disease or disorder mediated by MALT-1 is selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma (diffuse large B-cell lymphoma), mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma and chronic obstructive pulmonary disease.

44. The use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer or tautomer thereof in the manufacture of a medicament for treating or preventing a disease or disorder mediated by said inhibition of MALT-1.

45. 45. The use according to claim 44, wherein the disease or disorder mediated by said inhibition of MALT-1 is selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma (diffuse large B-cell lymphoma), mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma and chronic obstructive pulmonary disease.

46. A compound according to any one of claims 1 to 35 for use in the treatment of a disease or disorder mediated by MALT-1.

47. 47. The compound for use according to claim 46, wherein the disease or disorder mediated by said inhibition of MALT-1 is selected from bladder cancer, colon cancer, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma (diffuse large B-cell lymphoma), mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma and chronic obstructive pulmonary disease.

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