MALT1 inhibitors

Abstract

Disclosed are compounds, compositions, and methods for treating diseases, syndromes, conditions, or disorders affected by the regulation of MALT1.

Description

[Technical Field]

[0001] The present invention relates to novel compounds that are MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) inhibitors. The compounds may be useful in the treatment of diseases, syndromes, conditions, or disorders, including, but not limited to, cancer and immune disorders, particularly MALT1-associated diseases, syndromes, conditions, or disorders. The present invention also relates to pharmaceutical compositions comprising one or more of such compounds, processes for preparing such compounds and compositions, and the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmune diseases, syndromes, disorders, or conditions associated with MALT1 inhibitors. [Background technology]

[0002] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a classical NF-κB K MALT1 is a key mediator of the B signaling pathway. It is the only human paracaspase and transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex, which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL / lymphoma 10), and MALT1. MALT1 mediates NF-κB by two mechanisms. K First, MALT1 acts as a scaffolding protein, mediating NF-κB signaling, such as TRAF6, TAB-TAK1, or NEMO-IKKα / β. K Second, MALT1 recruits NF-κB signaling proteins, such as RelB, A20, or CYLD, as cysteine ​​proteases. K The ultimate endpoint of MALT1 activity is the cleavage of negative regulators of NF-κB signaling, thereby deactivating them. K Nuclear translocation of B transcription factor complexes and NF K Activation of B signal transduction.

[0003] NF K Constitutive activation of B signaling is a hallmark of ABC-DLBCL (diffuse large B-cell lymphoma of the activated B-cell-like subtype), a more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin's lymphoma (NHL), accounting for approximately 25% of lymphoma cases, and ABC-DLBCL constitutes approximately 40% of DLBCL cases. K Activation of the B pathway is driven by mutations in signaling components such as CD79A / B, CARD11, MYD88, or A20 in ABC-DLBCL patients.

[0004] The use of BTK inhibitors, such as ibrutinib, has been shown to improve NF-κB in ABC-DLBCL. K This provides clinical proof of concept that inhibition of NF-κB signaling is effective. K MALT1 inhibitors, downstream of BTK in the B signaling pathway, could target ABC-DLBCL patients who are unresponsive to ibrutinib, primarily those with CARD11 mutations, and also treat patients with acquired resistance to ibrutinib.

[0005] Small molecule tool compound inhibitors of the MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceuticals.

[0006] Chromosomal translocations generating the API2-MALT1 fusion oncoprotein are the most common mutations identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a fusion protein that is involved in NF-κB lymphoma. K API2-MALT1 is a potent activator of the B pathway. It mimics the ligand-bound TNF receptor and inhibits canonical NF-κB. K Furthermore, API2-MALT1 promotes TRAF2-dependent ubiquitination of RIP1, which acts as a scaffold to activate NF-κB signaling.K cleavage and generation of stable, constitutively active fragments of NF-κB-inducing kinase (NIK), thereby inhibiting non-canonical NF-κB. K It has been shown to activate pathway B.

[0007] In addition to lymphoma, MALT1 has been shown to play an important role in innate and adaptive immunity. MALT1 protease inhibitors can attenuate disease onset and progression in murine experimental allergic encephalomyelitis (EMA), a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutants exhibit a loss of marginal zone B cells and B1 B cells, and systemic immunodeficiency is characterized by reduced T cell and B cell activation and proliferation. However, these mice also develop spontaneous multiorgan autoimmune inflammation at 9–10 weeks of age. The reasons why MALT1 protease-dead knock-in mice exhibit a breakdown in tolerance, while conventional MALT1 KO mice do not, are not yet fully understood. One hypothesis suggests that the imbalanced immune homeostasis in MALT1 protease-dead knock-in mice may be caused by an incomplete deficiency in T cells and B cells, but a severe deficiency in immune regulatory cells. Similarly, MALT deficiency in humans is associated with combined immunodeficiency disorders. Considering the difference between genetic mutations and pharmacological inhibition, the phenotype of MALT1 protease-dead knock-in mice may not resemble that of patients treated with MALT1 protease inhibitors. Reduction of immunosuppressive T cells by MALT1 protease inhibition may benefit cancer patients by potentially increasing antitumor immunity.

[0008] Therefore, the MALT1 inhibitors of the present invention may provide therapeutic benefit to patients suffering from cancer and / or immune disorders. Summary of the Invention [Means for solving the problem]

[0009] The present invention relates to a compound of formula (I)

[0010] [ka] [In the formula, R 1 teeth,

[0011] [ka] represents q is 1 or 2; R x is hydrogen; C 1~4 alkyl; halo or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R y But hydrogen; C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R z is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, ring

[0012] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0, 1, or 2; R 3a is hydrogen or C 1~4 represents alkyl, R 3b But hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; Adamantyl; C 6~10 carbon bicyclic;Het 1 ; Oxo, halo, cyano, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-R 7 , -C(=O)-NR 4a R 4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , Het 3a , Het 3b , as well as -OH, halo, -S(=O)(=NH)-C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -S(=O)2-NR 4a R 4b , and -S(=O)2-C 1~4 C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; Oxo, halo, cyano, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-R 7 , -C(=O)-NR 4a R4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , as well as -OH, halo, -S(=O)(=NH)-C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -S(=O)2-NR 4a R 4b , and -S(=O)2-C 1~4 C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl 6~10 Carbobicyclic; or Cyano, Halo, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-R 7 , -C(=O)-NR 4a R 4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , -CF3, Cy 1 , Het 3a , Het3b , -O-Het 3b , -C(=O)-Het 3a , -C(=O)-Het 3b , and

[0013] [ka] C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 1~4 represents alkyl, or R 3a and R 3b together with the nitrogen atom to which they are attached to form Het 2 Forming Cy 1 But C 3~6 Cycloalkyl; or halo, -OH, -OR 7 , -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-C 1~4 Alkyl, -NH-(C=O)-C 3~6 Cycloalkyl, -C(=O)-NR 4a R 4b , and -NH-S(=O)2-R 7 C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 3~6 represents cycloalkyl, Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het 1 is a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in the heterocyclyl may be oxo, halo, cyano, —OH, OR7 -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-R 7 , -C(=O)-NR 4a R 4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , as well as OH, halo, S(=O)(=NH)-C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -S(=O)2-NR 4a R 4b , and -S(=O)2-C 1~4 C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-NR 4a R 4b , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -C(=O)-C 3~6C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cycloalkyl, —OH, and halo 1~4 may be substituted with alkyl, Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het 2 is a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, wherein one or more of the carbon atoms in the heterocyclyl may be oxo, halo, cyano, —OH, —OR 7 , Het 6 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-R 7 , -C(=O)-NR 4a R 4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , as well as -OH, halo, -S(=O)(=NH)-C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -S(=O)2-NR 4a R 4b , Het 4 and -S(=O)2-C 1~4C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , Het 4 , or -C(=O)-C 3~6 optionally substituted with cycloalkyl; Het 3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het 3a represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in the heterocyclyl may be oxo, halo, -OH, -OR 7 , -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-C 1~4 Alkyl, -NH-(C=O)-C 3~6 Cycloalkyl, -C(=O)-NR 4a R 4b , and -NH-S(=O)2-R 7and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-NR 4a R 4b , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -C(=O)-C 3~6 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cycloalkyl, —OH, and halo 1~4 may be substituted with alkyl, Het 3b represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het 3b represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in the heterocyclyl may be oxo, halo, —OH, C 1~4 Alkyl, -OR 7 , -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-C 1~4 Alkyl, -NH-(C=O)-C 3~6 Cycloalkyl, -C(=O)-NR 4a R 4b , and -NH-S(=O)2-R 7and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-NR 4a R 4b , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -C(=O)-C 3~6 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cycloalkyl, —OH, and halo 1~4 may be substituted with alkyl, Het 4 represents a monocyclic, C-bonded 4- to 7-membered, fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); Het 5 represents a monocyclic, C-bonded 4- to 7-membered, fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); Het 6 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); R 4a and R 4bare each independently hydrogen, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 Alkyl-OC 1~4 represents alkyl, R 4c and R 4d are each independently 1~4 Alkyl or -OC 1~4 represents alkyl, R 6 is C 1~4 alkyl; or C substituted with one -OH 1~4 represents alkyl, R 7 each of which is optionally substituted with 1, 2 or 3 halo substituents; 1~4 Alkyl or C 3~6 represents cycloalkyl, p1 and p2 are each independently 1, 2, or 3. and tautomeric or stereoisomeric forms thereof and pharmaceutically acceptable salts thereof.

[0014] The present invention also relates to a compound of formula (A)

[0015] [ka] [In the formula, R 1 teeth,

[0016] [ka] represents q is 1 or 2; R x is hydrogen; C 1~4 alkyl; halo or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R y is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R z is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, ring

[0017] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0, 1, or 2; R 6 is C 1~4 alkyl; or C substituted with one -OH 1~4 represents alkyl] Active intermediates of and their tautomeric or stereoisomeric forms and pharmaceutically acceptable salts thereof.

[0018] In the context of the present invention, all references to "compounds of formula (I)" and "intermediates of formula (A)" may also refer to solvates or pharmaceutically acceptable salt forms thereof, even if not explicitly mentioned, which are included within the scope of the present invention. It will be clear that this also applies to subgroups of formula (I) and formula (A).

[0019] The compounds of formula (I) and intermediates of formula (A) may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention is intended to encompass both the solvated and unsolvated forms.

[0020] As used herein, bonds are shown only as solid lines, and not as solid wedge or hashed wedge bonds, hashed or bolded bonds, or as having a particular configuration around one or more atoms (e.g., by stereodescriptors such as R, S, "R or S," "S or R," trans, cis, etc.), so that each possible stereoisomer (stereoisomeric form) or mixture of two or more stereoisomers is envisioned. When the stereochemistry of any particular chiral atom is not specified in the structures shown herein, all possible stereoisomers are contemplated and included as compounds of the invention, either as pure stereoisomers or as mixtures of two or more stereoisomers.

[0021] Above and below, the term "compound of formula (I)" also refers to its tautomeric and stereoisomeric forms (stereoisomers; e.g., enantiomers and diastereomers), even if not explicitly mentioned. However, as mentioned in the previous paragraph, when the stereochemistry is specified by a bond shown as a solid wedge bond or a hashed wedge bond, a hashed bond or a bolded bond, or is otherwise shown to have a particular configuration (e.g., R, S, "R or S," "S or R," trans, cis), the stereoisomer is so specified and defined. It will be apparent that this also applies to subgroups of formula (I). It will be apparent that this also applies to the corresponding intermediates of formula (A).

[0022] In the context of the present invention, a bond shown as a solid line but with a stereodescriptor is to be understood to mean that such stereocenter is designated and defined according to the stereodescriptor.

[0023] It is to be understood that in the context of the present invention, bonds shown as solid lines but designated "R or S" or "S or R" are used to indicate that such stereocenters are chirally pure but have an unknown configuration (stereoisomeric pure and enantiomerically pure but undetermined absolute stereochemistry at the stereocenter designated "R or S" or "S or R").

[0024] Substituents on a divalent cyclic saturated group (e.g., a cyclopropyl moiety) or partially saturated group can have either the cis or trans configuration. Terms such as "trans A" or "trans B" mean that one particular trans form was obtained, but the absolute stereochemistry has not been determined.

[0025] Those skilled in the art will recognize the hashed and bolded bonds on the 1,3-disubstituted cyclobutyl moiety as shown below:

[0026] [ka] In the formula, X 1 and X 2 represents a substituent, Indicates that the substituents on the cyclobutyl moiety have a trans configuration.

[0027] Those skilled in the art will recognize the bolded bonds on the 1,3-disubstituted cyclobutyl moiety, as shown below:

[0028] [ka] In the formula, X 1 and X 2 represents a substituent, Indicates that the substituents on the cyclobutyl moiety have a cis configuration.

[0029] Those skilled in the art will recognize the hashed and bolded bonds on the 1,4-disubstituted cyclohexyl moiety as shown below:

[0030] [ka] In the formula, X 1 and X 2 represents a substituent, Indicates that the substituents on the cyclohexyl moiety have a trans configuration.

[0031] Those skilled in the art will recognize the bolded bonds on the 1,4-disubstituted cyclohexyl moiety, as shown below:

[0032] [ka] In the formula, X 1 and X 2 represents a substituent, Indicates that the substituents on the cyclohexyl moiety have a cis configuration.

[0033] Atropisomers (or atropoisomers) are stereoisomers with specific spatial configurations resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0034] If the compound contains a double bond, the substituent may be in the E or Z configuration.

[0035] Thus, the present invention and the term "compounds of formula (I)" are also meant to include, where chemically possible, enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof. It will be apparent that this also applies to intermediates of formula (A).

[0036] The meanings of all terms, i.e., enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, are known to those skilled in the art. Configurations are designated according to standard precedence rules according to the Cahn-Ingold-Prelog system.

[0037] As used herein, the term "compound of the invention" or "compound according to the invention" is meant to include compounds of formula (I) including tautomers and stereoisomers, pharmaceutically acceptable salt forms, and solvates thereof.

[0038] The present invention also provides pharmaceutical compositions comprising, consisting of, and / or consisting essentially of a compound of formula (I) together with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable diluent. It will be apparent that this also applies to intermediates of formula (A).

[0039] Additionally, there is provided a process for preparing a pharmaceutical composition comprising, consisting of, and / or consisting essentially of a compound of formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable diluent. It will be apparent that this also applies to intermediates of formula (A).

[0040] The present invention further provides methods for treating or ameliorating a disease, syndrome, condition, or disorder in a subject, including a mammal and / or a human, that is affected by inhibition of MALT1, including, but not limited to, cancer and / or immune disorders, using compounds of formula (I).It will be apparent that this also applies to intermediates of formula (A).

[0041] The present invention is also directed to the use of any of the compounds described herein in the preparation of a medicament, wherein the medicament is prepared for the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT1, such as cancer and / or immune disease.

[0042] The present invention also relates to the preparation of compounds of formula (I) that act as inhibitors of MALT1. The present invention also relates to the preparation of intermediates of formula (A) that act as inhibitors of MALT1.

[0043] Exemplifying the invention is a method of treating a disease, syndrome, condition, or disorder mediated by MALT1 using a compound of formula (I). The disease, syndrome, condition, or disorder mediated by MALT1 includes lymphomas, leukemias, carcinomas, and sarcomas, such as non-Hodgkin's lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's lymphoma, and sarcomas, comprising, consisting of, and / or consisting essentially of, administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the invention. Chronic globulinemia, lymphocytic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell lung cancer , gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, oral cancer, mouth cancer, and GIST (gastrointestinal stromal tumor).

[0044] In another embodiment, the MALT1-mediated disease, syndrome, condition, or disorder is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

[0045] One embodiment of the present invention is directed to the treatment of autoimmune and inflammatory diseases, such as arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic dermatitis, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, bullous disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease, and the like. The present invention relates to compounds of formula (I) for use in the treatment of immune disorders affected by inhibition of MALT1, including, but not limited to, pulmonary diseases including COPD, cystic fibrosis, pneumonia, pulmonary edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium disease, and polymyositis.

[0046] In another embodiment, the present invention is directed to a compound of formula (I) for (use in) the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT1 selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0047] In alternative embodiments, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia.

[0048] In yet another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is lymphoma.

[0049] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL).

[0050] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is the germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

[0051] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is the non-germinal center B-cell-like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

[0052] In a further embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is chronic lymphocytic leukemia (CLL). In another embodiment, the disorder or condition is small lymphocytic lymphoma (SLL).

[0053] In another embodiment of the invention, the lymphoma is a MALT lymphoma.

[0054] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is Waldenstrom's Macroglobulinemia (WM).

[0055] In yet another embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

[0056] In an alternative embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-Hodgkin's lymphoma (NHL). In a further embodiment, the non-Hodgkin's lymphoma (NHL) is B-cell NHL. In another embodiment, the non-Hodgkin's lymphoma (NHL) is relapsed / refractory B-cell NHL.

[0057] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is selected from the group consisting of relapsed / refractory non-germinal center B-cell-like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL), relapsed / refractory Waldenstrom's macroglobulinemia (WM), relapsed / refractory mantle cell lymphoma (MCL), relapsed / refractory follicular lymphoma (FL), and relapsed / refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

[0058] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed / refractory non-germinal center B-cell-like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

[0059] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is relapsed / refractory Waldenstrom's macroglobulinemia (WM).

[0060] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is relapsed / refractory mantle cell lymphoma (MCL).

[0061] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is relapsed / refractory follicular lymphoma (FL).

[0062] In another embodiment of the invention, the disease, syndrome, condition or disorder affected by inhibition of MALT1 is relapsed / refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

[0063] The compounds of formula (I) are useful in treating autoimmune and inflammatory disorders such as sepsis-related acute lung injury (ALI), acute respiratory distress syndrome (ARDS), arthritis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic dermatitis, dermatomyositis, psoriasis, basilar arthritis, basilar arthritis, rheumatic fever, gout, ... inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease It can be used to treat immune disorders including, but not limited to, Chet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, bullous disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including pulmonary edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium disease, and polymyositis.

[0064] In another embodiment of the invention, the compounds of the invention may be used in combination with one or more other pharmaceutical agents, more particularly in combination with other anti-cancer agents, such as chemotherapeutic agents, anti-proliferative agents or immunomodulatory agents, or adjunct agents in cancer treatment, such as immunosuppressants or anti-inflammatory agents.

[0065] Possible combinations of the compounds of the present invention may include BTK (Bruton's tyrosine kinase) inhibitors such as ibrutinib, SYK inhibitors, PKC inhibitors, PI3K pathway inhibitors, BCL family inhibitors, JAK inhibitors, PIM kinase inhibitors, rituximab or other B cell antigen binding antibodies, and immune cell redirection agents (e.g., blinatumomab or CAR T cells), and immunomodulatory agents such as daratumab, anti-PD1 antibodies, and anti-PD-L1 antibodies.

[0066] It will be understood that variations to the above-described embodiments of the invention can be made while still falling within the scope of the invention. Each feature disclosed herein, unless otherwise stated, may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless otherwise stated, each feature disclosed is only one example of a generic series of equivalent or similar features.

[0067] All possible combinations of the above embodiments are considered to fall within the scope of the present invention.

[0068] In another embodiment, the present invention relates to a compound of formula (I) for (use in) the treatment of said diseases, syndromes, conditions or disorders that are affected by the inhibition of MALT1.

[0069] In another embodiment, the present invention relates to a composition comprising a compound of formula (I) for (use in) the treatment of said diseases, syndromes, conditions or disorders that are affected by the inhibition of MALT1.

[0070] In another embodiment, the present invention relates to a method of treating a disease, syndrome, condition, or disorder mediated by MALT1.

[0071] Another embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and its uses as described in any of the other embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0072] With respect to substituents, the term "independently" refers to the situation where several substituents are selected independently of each other and can be the same or different from each other.

[0073] "About" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of how the value is measured or determined, i.e., the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the Examples or elsewhere herein, "about" means within 1 standard deviation, or up to 5%, whichever is greater, per the practice in the art.

[0074] The transitional phrases "comprising," "consisting essentially of," and "consisting of" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics" of the claimed invention. Embodiments described with the phrase "comprising" (or its equivalents) also provide as embodiments embodiments described independently with "consisting of" and "consisting essentially of."

[0075] As used herein, the prefix "C x~y " (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1~4 An alkyl group contains 1 to 4 carbon atoms, and so on.

[0076] As used herein, "C" as a group or part of a group 1~4The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, and the like.

[0077] As used herein, "C" as a group or part of a group 3~6 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] A fused bicyclic ring or group is two rings that share two atoms and a bond between those atoms.

[0079] A spiro-bicyclic ring or spiro-bicyclic group is two rings joined by a single atom.

[0080] A bridged ring or bridged bicyclic group is two rings that have three or more atoms in common.

[0081] As used herein, "C" refers to a group or part of a group. 6~10 The term "carbobicyclic" defines a saturated bicyclic hydrocarbon radical having 6 to 10 carbon atoms. 6~10 Carbobicyclic rings can be fused, spiro, or bridged, such as spiro[3.3]heptanyl and bicyclo[1.1.1]pentanyl.

[0082] The term "monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N" defines a C-linked fully saturated monocyclic group having a total of 4 to 7 ring members (including heteroatoms) containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, such as C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C-linked tetrahydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4-oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, and C-linked piperidinyl.

[0083] Bicyclic C-linked 6-11 membered fully saturated heterocyclyl groups can be fused, spiro or bridged.

[0084] The term "bicyclic C-bonded 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N" defines a C-bonded fully saturated bicyclic group having a total of 6 to 11 ring members (including heteroatoms) containing 1, 2 or 3 heteroatoms each independently selected from O, S and N, such as, for example:

[0085] [ka]

[0086] The term "monocyclic N-linked 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S, and N" defines an N-linked fully saturated monocyclic radical having a total of 4 to 7 ring members (including heteroatoms) including one N atom and optionally one or two heteroatoms each independently selected from O, S, and N, e.g., N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N-linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, and N-linked piperidinyl.

[0087] Bicyclic N-linked 6-11 membered fully saturated heterocyclyl groups can be fused, spiro or bridged.

[0088] The term "bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S, and N" defines an N-linked fully saturated bicyclic group having a total of 6 to 11 ring members (including heteroatoms) containing an N atom and optionally one or two heteroatoms each independently selected from O, S, and N, such as, for example:

[0089] [ka]

[0090] Unless otherwise specified or apparent from the context, cyclic moieties, such as fully saturated heterocyclyl groups, can be attached to the remainder of the molecule of formula (I) via any available ring carbon atom (C-bonded) or nitrogen atom (N-bonded).

[0091] A C-bond means attached to the rest of the molecule through any available carbon atom.

[0092] N-linked means attached to the rest of the molecule through any available nitrogen atom.

[0093] The terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine atoms.

[0094] Those skilled in the art will recognize that when n is 0, R 2 will realize that there is no

[0095] It will be apparent to those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0096] -S(=O)(=NH)-C 1~4 It will be apparent to one skilled in the art that a group such as alkyl represents:

[0097] [ka]

[0098] In general, it will be apparent to one skilled in the art that a group such as -S(=O)(=NH)-R (where R is an optional substituent) represents:

[0099] [ka]

[0100] -N=S(=O)-(C 1~4 It will be apparent to one skilled in the art that a group such as alkyl)2 represents:

[0101] [ka]

[0102] -NH-(C=O)-C 1~4 It will be apparent to one skilled in the art that a group such as alkyl represents:

[0103] [ka]

[0104] -NH-(C=O)-C 3~6 It will be apparent to one skilled in the art that a group such as cycloalkyl represents:

[0105] [ka]

[0106] -NH-(SO2)-C 1~4 It will be apparent to one skilled in the art that a group such as alkyl represents:

[0107] [ka]

[0108] In general, it will be apparent to one skilled in the art that a group such as -NH-(SO2)-R (where R is an optional substituent) represents:

[0109] [ka]

[0110] Whenever a substituent is represented by a chemical structure, "---" represents the bond of the bond to the remainder of the molecule of Formula (I) or Formula (A).

[0111] When any variable occurs more than one time in any constituent, each definition is independent.

[0112] When any variable occurs more than one time in any formula (eg, formula (I)), each definition is independent.

[0113] Generally, when the term "substituted" is used in the present invention, unless otherwise specified or clear from the context, it will be understood by those skilled in the art to mean that one or more hydrogens, specifically 1 to 4 hydrogens, more specifically 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical shown in the expression "substituted" are replaced with a selection from the specified group, provided that the normal valences are not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to withstand isolation to a useful degree of purity from the reaction mixture (post-reaction isolation, for example, purification by silica gel chromatography).

[0114] Those skilled in the art will understand that the term "optionally substituted" means that the atom or radical designated in the expression using "optionally substituted" may be substituted or unsubstituted (which means substituted or unsubstituted, respectively).

[0115] Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

[0116] The stereodescriptor label "R" or "(R)" at a stereocenter indicates that the stereocenter is in the pure R configuration as defined in the art. Similarly, the stereodescriptor label "S" or "(S)" means that the stereocenter is in the pure S configuration.

[0117] A compound containing one stereocenter drawn without a stereobond designation is a mixture of two stereoisomers unless otherwise indicated (e.g., via a stereodescriptor). A compound containing two stereocenters, both drawn without a stereobond designation, is a mixture of four diastereomers unless otherwise indicated (e.g., via a stereodescriptor).

[0118] Unlabeled stereocenters shown without a stereochemical bond designation are a mixture of R and S configurations. For unlabeled stereocenters depicted with a stereochemical bond designation, the absolute stereochemistry is as depicted.

[0119] Above and below, the term "compounds of formula (I)" is intended to include its stereoisomers and tautomeric forms. However, as noted in the previous paragraph, where the stereochemistry is specified by a bond shown as a solid wedge bond or a hashed wedge bond, or is otherwise shown to have a particular configuration (e.g., R, S), that stereoisomer is so specified and defined. It will be apparent that this also applies to subgroups of formula (I).

[0120] Unless otherwise specified, it is intended that the definition of any substituent or variant thereof at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are sufficiently chemically stable to be isolated and that can be synthesized by the methods described herein in combination with techniques known in the art.

[0121] The term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0122] The term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, including a compound of the present invention, that elicits in a tissue system, animal, or human the biological or medicinal response that a researcher, veterinarian, physician, or other clinical professional seeks to obtain, including reduction or inhibition of an enzyme or protein, or amelioration of symptoms, mitigation of a disease, delay or slowing of disease progression, or prevention of a disease.

[0123] In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a condition, disorder, or disease (i) mediated by MALT1, or (ii) associated with MALT1 activity, or (iii) characterized by MALT1 activity (normal or abnormal); or (2) reduce or inhibit the activity of MALT1; or (3) reduce or inhibit the expression of MALT1; or (4) alter the protein levels of MALT1.

[0124] The term "composition" refers to a product containing therapeutically effective amounts of specified ingredients, as well as any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0125] The term "MALT1-mediated" refers to any disease, syndrome, condition, or disorder that may occur in the absence of MALT1, but may occur in the presence of MALT1. Suitable examples of MALT1-mediated diseases, syndromes, conditions, or disorders include lymphomas, leukemias, carcinomas, and sarcomas, such as non-Hodgkin's lymphoma (including B-cell NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, lymphocytic T-cell leukemia, chronic myeloid leukemia (CML), and leukemia-associated lymphoma (LEU). ), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell lung cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, oral cancer, mouth cancer, and GIST (gastrointestinal stromal tumor).

[0126] As used herein, the term "MALT1 inhibitor" refers to an agent that inhibits or reduces at least one pathology, symptom, disorder, and / or disease of MALT1.

[0127] As used herein, unless otherwise noted, the terms "affect" or "affected" (when referring to a disease, syndrome, condition, or disorder affected by inhibition of MALT1) include reducing the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition, or disorder and / or preventing the onset of one or more symptoms or manifestations of said disease, syndrome, condition, or disorder.

[0128] As used herein, the terms "treat," "treating," or "treatment" of any disease, condition, syndrome, or disorder refer, in one embodiment, to ameliorating the disease, condition, syndrome, or disorder (i.e., slowing, preventing, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be discernible by the patient. In a further embodiment, "treat," "treating," or "treatment" refers to modulating the disease, condition, syndrome, or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome, or disorder.

[0129] The compounds of the present invention may be useful in methods for treating or ameliorating diseases, syndromes, conditions, or disorders affected by inhibition of MALT1, which methods comprise, consist of, and / or consist essentially of administering to a subject, including animals, mammals, and humans, in need of such treatment, amelioration, and / or prevention, a therapeutically effective amount of a compound of formula (I).

[0130] One embodiment of the present invention relates to a method for treating a MALT1-dependent or MALT1-mediated disease or condition in a subject in need of treatment, including animals, mammals, and humans in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0131] In another embodiment, the MALT1-dependent or MALT1-mediated disease or condition is selected from cancers of hematopoietic origin or solid tumors such as chronic myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.

[0132] In particular, the compounds of formula (I) may be useful in treating or ameliorating diseases, syndromes, conditions, or disorders such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

[0133] More specifically, the compounds of formula (I) may be useful for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and mucosa-associated lymphoid tissue (MALT) lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined herein.

[0134] Additionally, the compounds of formula (I) may be useful for treating or ameliorating an immune disease, syndrome, disorder, or condition selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

[0135] Wherever possible, any embodiment of a compound of formula (I) listed above or below also applies to an intermediate of formula (A).

[0136] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0137] [ka] represents R x is hydrogen; C 1~4 alkyl; halo or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R y is C 1~4 Alkyl; C 3~6cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R z is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, ring

[0138] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0, 1, or 2; R 3a represents hydrogen, R 3b But hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl;-C 1~4 Alkyl-Cy 1 ; Halo, -OH, -OC 1~4 Alkyl, -OCF3, -OCHF2, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-C 1~4 Alkyl, -NH-(C=O)-C 3~6 Cycloalkyl, -C(=O)-NR 4a R 4b , and -NH-(SO2)-C 1~4 C substituted with one substituent selected from the group consisting of alkyl 3~6 cycloalkyl; Halo, -OH, -OC 1~4 Alkyl, -OCF3, -OCHF2, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-C 1~4 Alkyl, -NH-(C=O)-C 3~6 Cycloalkyl, -C(=O)-NR 4a R 4b , and -NH-(SO2)-C 1~4 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 alkyl; C on N atom 1~4 Alkyl, -C(=O)-NR 4a R 4b , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, or -C(=O)-C 3~6 3- or 4-piperidinyl optionally substituted with cycloalkyl;

[0139] [ka] represents or R 3a and R 3b together with the nitrogen atom to which they are attached

[0140] [ka] Forming Cy 1 is C 3~6 Cycloalkyl; or halo, -OH, -OC 1~4 Alkyl, -OCF3, -OCHF2, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b, -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, -N=S(=O)-(C 1~4 alkyl)2, -NH-(C=O)-C 1~4 Alkyl, -NH-(C=O)-C 3~6 Cycloalkyl, -C(=O)-NR 4a R 4b , and -NH-(SO2)-C 1~4 C substituted with one substituent selected from the group consisting of alkyl 3~6 represents cycloalkyl, R 4a and R 4b are each independently hydrogen or C 1~4 represents alkyl, R 5 are hydrogen, OH, -OC 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-C 3~6 Cycloalkyl, -S(=O)2-NR 4a R 4b or -C(=O)-NR 4a R 4b represents R 6 represents methyl,

[0033] n1, n2, n3, n4, n5, n6, n7 and n8 are each independently 1 or 2, and relate to compounds of formula (I) as defined herein, and to tautomeric and stereoisomeric forms thereof.

[0141] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, wherein R 1 teeth,

[0142] [ka] represents q is 1 or 2; R x represents a halo, R y is hydrogen or C1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, ring

[0143] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0, 1, or 2; R 3a is hydrogen or C 1~4 represents alkyl, R 3b But hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; Adamantyl; C 6~10 carbon bicyclic;Het 1 ; Oxo, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -NH-(C=O)-R 7 , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -NH-S(=O)2-R 7 , Het 3a , Het 3b , as well as -OH, halo, -S(=O)(=NH)-C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -S(=O)2-NR 4a R 4b , and -S(=O)2-C 1~4C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; -OR 7 , -S(=O)2-R 7 , and -S(=O)2-NR 4a R 4b C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 6~10 Carbobicyclic; or Cyano, Halo, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -C(=O)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , -Cy 1 , Het 3a , Het 3b , -O-Het 3b , -C(=O)-Het 3a ,and

[0144] [ka] C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~4 represents alkyl, or R 3a and R 3btogether with the nitrogen atom to which they are attached to form Het 2 Forming Cy 1 But C 3~6 Cycloalkyl; or -S(=O)2-C 1~4 Alkyl, and -S(=O)2-NR 4a R 4b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 3~6 represents cycloalkyl, Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het 1 is a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; One or more of the carbon atoms in the heterocyclyl may be oxo, -OH, -OR 7 -S(=O)2-R 7 , -C(=O)-NR 4a R 4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , and —OH, and —C(═O)—NR 4a R 4b C optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-C 1~4Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -C(=O)-C 3~6 Cycloalkyl or C substituted with 1, 2 or 3 -OH 1~4 may be substituted with alkyl, Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het 2 represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in the heterocyclyl is Het 6 , -S(=O)2-NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -C(=O)-NR 4a R 4b and 1, 2 or 3 -S(=O)2-C 1~4 C optionally substituted with alkyl 1~4 alkyl, wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more N atoms in the heterocyclyl is Het 4 may be substituted with Het 3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more carbon atoms in the heterocyclyl are optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of oxo and —OH; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , or -C(=O)-C 3~6 optionally substituted with cycloalkyl; Het 3b represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het 3b represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more carbon atoms in the heterocyclyl may be oxo, halo, —OH, C 1~4 Alkyl and -OR 7 and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 or -S(=O)2-C 1~4 may be substituted with alkyl, Het 4 represents a monocyclic, C-bonded 4- to 7-membered, fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); Het 5represents a monocyclic, C-bonded 4- to 7-membered, fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); Het 6 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); R 4a and R 4b are each independently hydrogen, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 Alkyl-OC 1~4 represents alkyl, R 4c and R 4d are each independently 1~4 Alkyl or -OC 1~4 represents alkyl, R 6 is C 1~4 alkyl; or C substituted with one -OH 1~4 represents alkyl, R 7 each of which is optionally substituted with 1, 2 or 3 halo substituents; 1~4 Alkyl or C 3~6 represents cycloalkyl, Compounds of formula (I) as defined herein, wherein p1 and p2 are 2, and tautomeric and stereoisomeric forms thereof. and pharmaceutically acceptable salts thereof.

[0145] The present invention relates in particular to compounds of formula (I) as defined herein, their tautomeric and stereoisomeric forms, R 1 teeth,

[0146] [ka] represents q is 1 or 2; R x represents a halo, R y is hydrogen or C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, ring

[0147] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0, 1, or 2; R 3a is hydrogen or C 1~4 represents alkyl, R 3b But hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; Adamantyl; C 6~10 carbon bicyclic;Het 1 ; Oxo, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -NH-(C=O)-R 7 , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -NH-S(=O)2-R 7 , Het3a , Het 3b , as well as -OH, halo, -S(=O)(=NH)-C 1~4 Alkyl, -C(=O)-NR 4a R 4b , -S(=O)2-NR 4a R 4b , and -S(=O)2-C 1~4 C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl 1~4 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl 3~6 cycloalkyl; -OR 7 , -S(=O)2-R 7 , and -S(=O)2-NR 4a R 4b C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of 6~10 Carbobicyclic; or Cyano, Halo, -OH, -OR 7 , -S(=O)2-R 7 , -S(=O)2-NR 4a R 4b , -NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -C(=O)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl-OR 7 , -NH-S(=O)2-R 7 , -Cy 1 , Het 3a , Het 3b , -O-Het 3b , -C(=O)-Het 3a ,and

[0148] [ka] C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of 1~4 represents alkyl, or R 3a and R 3b together with the nitrogen atom to which they are attached to form Het 2 Forming Cy 1 But C 3~6 Cycloalkyl; or -S(=O)2-C 1~4 Alkyl, and -S(=O)2-NR 4a R 4b C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of 3~6 represents cycloalkyl, Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het 1 is a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; However, the monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl and the bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl are the following heterocyclyls: C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C-linked tetrahydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4-oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, C-linked piperidinyl,

[0149] [ka] represents wherein one or more of the carbon atoms in the heterocyclyl may be oxo, —OH, —OR 7 -S(=O)2-R7 , -C(=O)-NR 4a R 4b , -S(=O)(=NH)-NR 4a R 4b , -P(=O)-R 4c R 4d , -OC 1~4 Alkyl-C(=O)-NR 4a R 4b , and —OH, and —C(═O)—NR 4a R 4b C optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of 1~4 and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , -C(=O)-C 3~6 Cycloalkyl or C substituted with 1, 2 or 3 -OH 1~4 may be substituted with alkyl, Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het 2 is a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, However, the monocyclic N-bonded 4- to 7-membered fully saturated heterocyclyl and the bicyclic N-bonded 6- to 11-membered fully saturated heterocyclyl are the following heterocyclyls: N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N-linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, N-linked piperidinyl,

[0150] [ka] is selected from wherein one or more of the carbon atoms in the heterocyclyl is -S(=O)2-NR 4a R 4b , -S(=O)(=NH)-R 7 , -N=S(=O)-(C 1~4 alkyl)2, -C(=O)-NR 4a R 4b and 1, 2 or 3 -S(=O)2-C 1~4 C optionally substituted with alkyl 1~4 and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more N atoms in the heterocyclyl is Het 4 may be substituted with Het 3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; However, the monocyclic N-bonded 4- to 7-membered fully saturated heterocyclyl is the following heterocyclyl: selected from N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N-linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, and N-linked piperidinyl; wherein one or more carbon atoms in the heterocyclyl are optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of oxo and —OH; wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 , -C(=O)-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl, -S(=O)2-NR 4a R 4b , or -C(=O)-C 3~6 optionally substituted with cycloalkyl; Het 3b represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het 3b represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; However, the monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl and the bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl are the following heterocyclyls: C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C-linked tetrahydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4-oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, C-linked piperidinyl, and

[0151] [ka] is selected from wherein one or more carbon atoms in the heterocyclyl may be oxo, halo, —OH, C 1~4 Alkyl and -OR 7 and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl may be substituted to form S(=O), S(=O)2 or S(=O)(=NH); wherein one or more of the N atoms in the heterocyclyl is C 1~4 Alkyl, Het 5 or -S(=O)2-C 1~4 may be substituted with alkyl, Het 4 represents a C-linked oxetanyl; Het 5 represents a C-linked oxetanyl. R 4a and R 4b are each independently hydrogen, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 Alkyl-OC 1~4 represents alkyl, R 4c and R 4d are each independently 1~4 Alkyl or -OC 1~4 represents alkyl, R 6 is C 1~4 alkyl; or C substituted with one -OH 1~4 represents alkyl, R 7 each of which is optionally substituted with 1, 2 or 3 halo substituents; 1~4 Alkyl or C 3~6 represents cycloalkyl, Compounds of formula (I) as defined herein, wherein p1 and p2 are 2, and tautomeric and stereoisomeric forms thereof. and pharmaceutically acceptable salts thereof.

[0152] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0153] [ka] represents q is 1, R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, ring

[0154] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0 or 1, R 3a But hydrogen, R 3b is C 1~4 Alkyl; C 3~6 cycloalkyl; or -S(=O)2-R 7 and -S(=O)(=NH)-R 7 C substituted with one substituent selected from the group consisting of 3~6 represents cycloalkyl, R 6 is C 1~4 alkyl; or C substituted with one -OH 1~4 represents alkyl, R 7 is C 1~4 Compounds of formula (I) as defined herein, which represent alkyl, their tautomeric and stereoisomeric forms and pharmaceutically acceptable salts thereof.

[0155] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0156] [ka] represents q is 1, R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, ring

[0157] [ka] represents phenyl, n is 0, R 3a represents hydrogen, R 3b One -S(=O)2-R 7 C is replaced by 3~6 represents cycloalkyl, R 6 is C 1~4 represents alkyl, R 7 is C 1~4 Compounds of formula (I) as defined herein, which represent alkyl, and tautomeric and stereoisomeric forms thereof and pharmaceutically acceptable salts thereof.

[0158] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0159] [ka] represents q is 1, R x represents chloro, R y represents methyl, R z represents CF3, ring

[0160] [ka] represents phenyl, n is 0, R 3a represents hydrogen, R 3b One -S(=O)2-R 7 C is replaced by 3~6 represents cycloalkyl, R 6 represents methyl, R 7 represents methyl, The present invention relates to compounds of formula (I) as defined herein, and to the tautomeric and stereoisomeric forms thereof, and to the pharmaceutically acceptable salts thereof.

[0161] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0162] [ka] represents R x is hydrogen, C 1~4 represents alkyl or halo, R y is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R zis C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 forming a cycloalkyl, R 6 represents CH3, ring

[0163] [ka] represents phenyl or pyridyl, R 2 represents a halo, n is 0, 1, or 2; R 3a represents hydrogen, R 3b But hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; -OH, -S(=O)2-C 1~4 Alkyl, -NR 4a R 4b , -S(=O)(=NH)-C 1~4 Alkyl, and -N=S(=O)-(C 1~4 C substituted with one substituent selected from the group consisting of alkyl)2 3~6 cycloalkyl; -C 1~4 Alkyl-S(=O)2-C 1~4 alkyl; C substituted with 1, 2 or 3 halo substituents 1~4 Alkyl; C on N atom 1~4 3- or 4-piperidinyl optionally substituted with alkyl;

[0164] [ka] represents or R 3a and R 3btogether with the nitrogen atom to which they are attached,

[0165] [ka] Forming R 4a and R 4b are each independently hydrogen or C 1~4 represents alkyl, R 5 represents hydrogen or -OH, Compounds of formula (I) as defined herein, wherein n1, n2, n3, n4, n5, n6, n7 and n8 are each independently 1 or 2, and tautomeric and stereoisomeric forms thereof. and pharmaceutically acceptable salts thereof.

[0166] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0167] [ka] represents R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 6 represents CH3, ring

[0168] [ka] represents phenyl, R 2 represents a halo, n is 0, 1, or 2; R 3a represents hydrogen, R 3b is C 1~4 alkyl; or one -S(=O)2-C 1~4 Alkyl-substituted C 3~6 Compounds of formula (I) as defined herein, which represent cycloalkyl, and tautomeric and stereoisomeric forms thereof and pharmaceutically acceptable salts thereof.

[0169] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0170] [ka] represents R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 6 represents CH3. ring

[0171] [ka] represents phenyl, n is 0, R 3a represents hydrogen, R 3b One -S(=O)2-C 1~4 Alkyl-substituted C 3~6 Compounds of formula (I) as defined herein, which represent cycloalkyl, and tautomeric and stereoisomeric forms thereof and pharmaceutically acceptable salts thereof.

[0172] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0173] [ka] represents R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 6 represents CH3, ring

[0174] [ka] represents phenyl, n is 1, R 3a represents hydrogen, R 3b One -S(=O)2-C 1~4 Alkyl-substituted C 3~6 Compounds of formula (I) as defined herein, which represent cycloalkyl, and tautomeric and stereoisomeric forms thereof and pharmaceutically acceptable salts thereof.

[0175] The present invention relates in particular to compounds of formula (I) as defined herein, and tautomeric and stereoisomeric forms thereof, R 1 teeth,

[0176] [ka] represents R x represents a halo, R y is C 1~4represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 6 represents CH3, ring

[0177] [ka] represents phenyl, n is 1, R 3a represents hydrogen, R 3b is C 1~4 Compounds of formula (I) as defined herein, which represent alkyl, and tautomeric and stereoisomeric forms thereof and pharmaceutically acceptable salts thereof.

[0178] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x is hydrogen; C 1~4 alkyl; halo or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R y But hydrogen; C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R z is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 Represents alkyl.

[0179] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x is C1~4 alkyl; halo or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R y But hydrogen; C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R z is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 Represents alkyl.

[0180] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x is C 1~4 C substituted with alkyl, halo, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R y But hydrogen; C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R z is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, or R y and R z together with the carbon atoms to which they are attached, form C 3~6 Forms a cycloalkyl.

[0181] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x is hydrogen; C 1~4alkyl; halo or C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R y and R z together with the carbon atoms to which they are attached, form C 3~6 Forms a cycloalkyl.

[0182] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x is C 1~4 C substituted with alkyl, halo, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R y and R z together with the carbon atoms to which they are attached, form C 3~6 Forms a cycloalkyl.

[0183] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x represents chloro, R y represents methyl, R z represents trifluoromethyl.

[0184] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R x represents chloro.

[0185] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R z represents trifluoromethyl.

[0186] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R y is C 1~4 Alkyl; C 3~6 cycloalkyl; or C substituted with 1, 2 or 3 halo substituents 1~4 It is alkyl.

[0187] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 2 represents fluoro.

[0188] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 1 teeth,

[0189] [ka] represents q is 1, R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 3a But hydrogen, R 3b is C 1~4 Alkyl; C 3~6 cycloalkyl; or -S(=O)2-R 7 and -S(=O)(=NH)-R 7 C substituted with one substituent selected from the group consisting of 3~6 represents cycloalkyl, R 7 is C 1~4 Represents alkyl.

[0190] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 1 teeth,

[0191] [ka] represents q is 1, R x represents a halo, R y is C 1~4 represents alkyl, R z is C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 3a But hydrogen, R 3b is C 1~4 Alkyl; C 3~6 cycloalkyl; or -S(=O)2-R 7 and -S(=O)(=NH)-R 7 C substituted with one substituent selected from the group consisting of 3~6 represents cycloalkyl.

[0192] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 1 teeth,

[0193] [ka] represents q is 1, R x represents a halo, R y is C 1~4 represents alkyl, R zis C substituted with 1, 2 or 3 halo substituents 1~4 represents alkyl, R 3a represents hydrogen, R 3b is S(=O)2-R 7 and -S(=O)(=NH)-R 7 C substituted with one substituent selected from the group consisting of 3~6 represents cycloalkyl, R 7 is C 1~4 Represents alkyl.

[0194] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 1 teeth,

[0195] [ka] represents q is 1, R x represents chloro, R y represents methyl, R z represents trifluoromethyl, R 3a represents hydrogen, R 3b is S(=O)2-R 7 and -S(=O)(=NH)-R 7 C substituted with one substituent selected from the group consisting of 3~6 represents cycloalkyl, R 7 represents methyl.

[0196] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 1 teeth,

[0197] [ka] Represents.

[0198] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 1 teeth,

[0199] [ka] Represents.

[0200] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein n is 0.

[0201] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein n is 1.

[0202] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the ring is

[0203] [ka] Represents phenyl.

[0204] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the ring is

[0205] [ka] represents phenyl, and R 6 represents methyl.

[0206] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 3b is C 1~4 Alkyl; or one S(=O)2-C 1~4 Alkyl-substituted C 3~6 represents cycloalkyl.

[0207] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 3b is C 1~4 Represents alkyl.

[0208] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 3b One -S(=O)2-C 1~4 Alkyl-substituted C 3~6 Cycloalkyl; in particular, one -S(=O)2-C 1~4 It represents cyclobutyl substituted with alkyl; more particularly, cyclobutyl substituted with one -S(=O)2-CH3.

[0209] In one embodiment, the present invention provides a compound having the substituent -S(=O)2-C 1~4

[0033] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or any subgroup thereof, as referred to in any of the other embodiments, wherein alkyl is limited to -S(=O)2-CH3.

[0210] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein R 6 represents CH3.

[0211] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the cyclopropyl moiety of formula (I) is trans.

[0212] [ka]

[0213] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the cyclopropyl moiety of formula (I) is cis.

[0214] [ka]

[0215] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the cyclopropyl moiety of formula (I) is trans,

[0216] [ka] In the formula, R 6 represents methyl.

[0217] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the cyclopropyl moiety of formula (I) is cis,

[0218] [ka] In the formula, R 6 represents methyl.

[0219] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the substituents on the cyclopropyl moiety of formula (I) is as shown below in formula (Ia):

[0220] [ka]

[0221] In one embodiment, the invention relates to the compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the substituents on the cyclopropyl moiety of formula (I) is as shown below in formula (Ib):

[0222] [ka]

[0223] In one embodiment, the invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the substituents of formula (I) and the cyclopropyl moiety is as shown below in formula (I-a1):

[0224] [ka]

[0225] In one embodiment, the invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof as mentioned in any of the other embodiments, or any subgroup thereof, wherein the stereochemistry of the substituents of formula (I) and the cyclopropyl moiety is as shown below in formula (I-b1):

[0226] [ka]

[0227] Wherever possible, any embodiment of the compounds of formula (I) listed above also applies to the intermediates of formula (A).

[0228] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in the general reaction scheme:

[0229] In one embodiment, the compound of formula (I) is an exemplified compound: its tautomeric and stereoisomeric forms, and any of the free bases and pharmaceutically acceptable salts thereof.

[0230] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 17.

[0231] In one embodiment, the compound of formula (I) is selected from compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 17; its tautomeric and stereoisomeric forms, and pharmaceutically acceptable salts thereof.

[0232] In one embodiment, the compound of formula (I) is selected from compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 17; and pharmaceutically acceptable salts thereof.

[0233] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318.

[0234] In one embodiment, the compound of formula (I) is selected from compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318; its tautomeric and stereoisomeric forms, and pharmaceutically acceptable salts thereof.

[0235] In one embodiment, the compound of formula (I) is selected from compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318; and pharmaceutically acceptable salts thereof.

[0236] In one embodiment, the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 0, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 6, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147 , 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 2 10, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 1, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272,273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319 and 320.

[0237] In one embodiment, the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 0, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 6, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147 , 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 2 10, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 1, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272,273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319 and 320; its tautomeric and stereoisomeric forms, and pharmaceutically acceptable salts thereof.

[0238] In one embodiment, the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 0, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 6, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147 , 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 2 10, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 1, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272,273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319 and 320; and pharmaceutically acceptable salts thereof.

[0239] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of any of the exemplified compounds.

[0240] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is any of the exemplified compounds, It also relates to a pharmaceutical composition comprising a compound selected from the group consisting of any of its tautomeric and stereoisomeric forms and pharmaceutically acceptable salts thereof.

[0241] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 17.

[0242] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16 and 17; It is selected from the group consisting of its tautomeric and stereoisomeric forms and pharmaceutically acceptable salts thereof.

[0243] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318.

[0244] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318; It is selected from the group consisting of its tautomeric and stereoisomeric forms and pharmaceutically acceptable salts thereof.

[0245] In one embodiment, the compound of formula (I) is Compound 1 or a pharmaceutically acceptable salt thereof.

[0246] In one embodiment, the compound of formula (I) is Compound 2 or a pharmaceutically acceptable salt thereof.

[0247] In one embodiment, the compound of formula (I) is compound 3 or a pharmaceutically acceptable salt thereof.

[0248] In one embodiment, the compound of formula (I) is compound 7 or a pharmaceutically acceptable salt thereof.

[0249] In one embodiment, the compound of formula (I) is compound 8 or a pharmaceutically acceptable salt thereof.

[0250] In one embodiment, the compound of formula (I) is compound 9 or a pharmaceutically acceptable salt thereof.

[0251] In one embodiment, the compound of formula (I) is compound 10 or a pharmaceutically acceptable salt thereof.

[0252] In one embodiment, the compound of formula (I) is compound 11 or a pharmaceutically acceptable salt thereof.

[0253] In one embodiment, the compound of formula (I) is compound 12 or a pharmaceutically acceptable salt thereof.

[0254] In one embodiment, the compound of formula (I) is compound 14 or a pharmaceutically acceptable salt thereof.

[0255] In one embodiment, the compound of formula (I) is compound 15 or a pharmaceutically acceptable salt thereof.

[0256] In one embodiment, the compound of formula (I) is compound 16 or a pharmaceutically acceptable salt thereof.

[0257] In one embodiment, the compound of formula (I) is compound 17 or a pharmaceutically acceptable salt thereof.

[0258] In one embodiment, the compound of formula (I) is compound 22 or a pharmaceutically acceptable salt thereof.

[0259] In one embodiment, the compound of formula (I) is compound 28 or a pharmaceutically acceptable salt thereof.

[0260] In one embodiment, the compound of formula (I) is compound 34 or a pharmaceutically acceptable salt thereof.

[0261] In one embodiment, the compound of formula (I) is compound 36 or a pharmaceutically acceptable salt thereof.

[0262] In one embodiment, the compound of formula (I) is compound 37 or a pharmaceutically acceptable salt thereof.

[0263] In one embodiment, the compound of formula (I) is compound 39 or a pharmaceutically acceptable salt thereof.

[0264] In one embodiment, the compound of formula (I) is compound 40 or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment, the compound of formula (I) is compound 41 or a pharmaceutically acceptable salt thereof.

[0266] In one embodiment, the compound of formula (I) is compound 129 or a pharmaceutically acceptable salt thereof.

[0267] In one embodiment, the compound of formula (I) is compound 131 or a pharmaceutically acceptable salt thereof.

[0268] In one embodiment, the compound of formula (I) is compound 132 or a pharmaceutically acceptable salt thereof.

[0269] In one embodiment, the compound of Formula (I) is compound 148 or a pharmaceutically acceptable salt thereof.

[0270] In one embodiment, the compound of formula (I) is compound 178 or a pharmaceutically acceptable salt thereof.

[0271] In one embodiment, the compound of formula (I) is compound 191 or a pharmaceutically acceptable salt thereof.

[0272] In one embodiment, the compound of Formula (I) is compound 193 or a pharmaceutically acceptable salt thereof.

[0273] In one embodiment, the compound of formula (I) is compound 201 or a pharmaceutically acceptable salt thereof.

[0274] In one embodiment, the compound of Formula (I) is compound 204 or a pharmaceutically acceptable salt thereof.

[0275] In one embodiment, the compound of Formula (I) is compound 267 or a pharmaceutically acceptable salt thereof.

[0276] In one embodiment, the compound of formula (I) is compound 294 or a pharmaceutically acceptable salt thereof.

[0277] In one embodiment, the compound of Formula (I) is compound 318 or a pharmaceutically acceptable salt thereof.

[0278] In one embodiment, the compound of formula (I) is

[0279] [ka] or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof. In particular, the stereochemistry of the cyclopropyl moiety is trans.

[0280] In one embodiment, the compound of formula (I) is

[0281] [ka] or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof. In particular, the stereochemistry of the cyclopropyl moiety is trans.

[0282] In one embodiment, the compound of formula (I) is

[0283] [ka] or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof. In particular, the stereochemistry of the cyclopropyl moiety is trans.

[0284] In one embodiment, the compound of formula (I) is

[0285] [ka] or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof. In particular, the stereochemistry of the cyclopropyl moiety is trans.

[0286] In one embodiment, the compound of formula (I) is

[0287] [ka] or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof. In particular, the stereochemistry of the cyclopropyl moiety is trans.

[0288] In one embodiment, the compound of formula (I) is

[0289] [ka] or a pharmaceutically acceptable salt thereof.

[0290] In one embodiment, the compound of formula (I) is

[0291] [ka] or a pharmaceutically acceptable salt thereof.

[0292] In one embodiment, the compound of formula (I) is

[0293] [ka] or a pharmaceutically acceptable salt thereof.

[0294] In one embodiment, the compound of formula (I) is

[0295] [ka] or a pharmaceutically acceptable salt thereof.

[0296] In one embodiment, the compound of formula (I) is

[0297] [ka] or a pharmaceutically acceptable salt thereof.

[0298] In one embodiment, the compound of formula (I) is

[0299] [ka] or a pharmaceutically acceptable salt thereof.

[0300] In one embodiment, the compound of formula (I) is

[0301] [ka] or a pharmaceutically acceptable salt thereof.

[0302] In one embodiment, the compound of formula (I) is

[0303] [ka] or a pharmaceutically acceptable salt thereof.

[0304] In one embodiment, the compound of formula (I) is

[0305] [ka] or a pharmaceutically acceptable salt thereof.

[0306] In one embodiment, the compound of formula (I) is

[0307] [ka] or a pharmaceutically acceptable salt thereof.

[0308] In one embodiment, the compound of formula (I) is

[0309] [ka] or a pharmaceutically acceptable salt thereof.

[0310] In one embodiment, the compound of formula (I) is

[0311] [ka] or a pharmaceutically acceptable salt thereof.

[0312] In one embodiment, the compound of formula (I) is

[0313] [ka] or a pharmaceutically acceptable salt thereof.

[0314] In one embodiment, the compound of formula (I) is

[0315] [ka] or a pharmaceutically acceptable salt thereof.

[0316] In one embodiment, the compound of formula (I) is

[0317] [ka] is.

[0318] In one embodiment, the compound of formula (I) is

[0319] [ka] is.

[0320] In one embodiment, the compound of formula (I) is

[0321] [ka] is.

[0322] In one embodiment, the compound of formula (I) is

[0323] [ka] is.

[0324] In one embodiment, the compound of formula (I) is

[0325] [ka] is.

[0326] In one embodiment, the compound of formula (I) is

[0327] [ka] is.

[0328] In one embodiment, the compound of formula (I) is

[0329] [ka] is.

[0330] In one embodiment, the compound of formula (I) is

[0331] [ka] is.

[0332] In one embodiment, the compound of formula (I) is

[0333] [ka] is.

[0334] In one embodiment, the compound of formula (I) is

[0335] [ka] is.

[0336] In one embodiment, the compound of formula (I) is (1R,3S)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0337] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0338] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(-S-methylsulfonimidoyl)cyclobutyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0339] In one embodiment, the compound of formula (I) is (1S,3R)-2,2-difluoro-1-methyl-3-(4-((R)-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0340] In one embodiment, the compound of Formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-(2-sulfamoylethyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0341] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-((dimethylphosphoryl)methyl)-2,2-difluoro-1-methylcyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0342] In one embodiment, the compound of formula (I) is (1S,3R)—N-((trans)-3-acetamidocyclobutyl)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methylcyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0343] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-(((trans)-3-((S)-S-methylsulfonimidoyl)cyclobutyl)methyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0344] In one embodiment, the compound of Formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-(3-(cyclopropanesulfonamido)propyl)-2,2-difluoro-1-methylcyclopropane-1-carboxamide, or a pharmaceutically acceptable salt thereof.

[0345] In one embodiment, the compound of Formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-(3-(methylamino)cyclobutyl)cyclopropane-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0346] In one embodiment, the compound of formula (I) is (1R,3S)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide.

[0347] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide.

[0348] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(-S-methylsulfonimidoyl)cyclobutyl)cyclopropane-1-carboxamide.

[0349] In one embodiment, the compound of formula (I) is (1S,3R)-2,2-difluoro-1-methyl-3-(4-((R)-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide.

[0350] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-(2-sulfamoylethyl)cyclopropane-1-carboxamide.

[0351] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-((dimethylphosphoryl)methyl)-2,2-difluoro-1-methylcyclopropane-1-carboxamide.

[0352] In one embodiment, the compound of formula (I) is (1S,3R)—N-((trans)-3-acetamidocyclobutyl)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methylcyclopropane-1-carboxamide.

[0353] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-(((trans)-3-((S)-S-methylsulfonimidoyl)cyclobutyl)methyl)cyclopropane-1-carboxamide.

[0354] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-(3-(cyclopropanesulfonamido)propyl)-2,2-difluoro-1-methylcyclopropane-1-carboxamide.

[0355] In one embodiment, the compound of formula (I) is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-(3-(methylamino)cyclobutyl)cyclopropane-1-carboxamide.

[0356] In one embodiment, the activated intermediate of formula (A) is

[0357] [ka] or a pharmaceutically acceptable salt thereof.

[0358] In one embodiment, the activated intermediate of formula (A) is

[0359] [ka] or a pharmaceutically acceptable salt thereof.

[0360] All possible combinations of the above-described embodiments are considered to fall within the scope of the present invention.

[0361] The compounds of formula (I) can be prepared according to a process comprising the following reaction steps:

[0362] [ka]

[0363] The reaction conditions in each of the above reaction steps may be as described in the general synthesis method (general scheme).

[0364] When used in medicine, salts of the compounds of formula (I) refer to non-toxic "pharmaceutically acceptable salts." However, other salts may be useful in the preparation of the compounds of formula (I) or their pharmaceutically acceptable salt forms. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include, for example, acid addition salts that may be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Furthermore, when the compounds of formula (I) contain an acidic moiety, suitable pharmaceutically acceptable salts thereof may include, for example, salts formed with suitable organic ligands, such as alkali metal salts (sodium salt or potassium salt), alkaline earth metal salts, e.g., calcium salt or magnesium salt, and quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, and the like. The salts include, but are not limited to, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0365] Representative acids and bases that can be used in the preparation of pharmaceutically acceptable salts include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-dicarboxylic acid, and the like. Sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthyl 2-sulfonic acid Acids including toluene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid, as well as ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, cocamidopropyl benzyl alcohol, methylparaben ... Bases include phosphorus, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0366] Embodiments of the present invention include prodrugs of compounds of formula (I). Generally, such "prodrugs" are functional derivatives of compounds that can be readily converted in vivo into the required compound. Thus, in the methods of therapeutic or prophylactic embodiments of the present invention, the term "administering" encompasses treatment or prevention of the various diseases, conditions, syndromes, and disorders described with a specifically disclosed compound or with a compound that is not specifically disclosed but that is converted to the specified compound in vivo after administration to a patient. Routine procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0367] The pharmaceutically acceptable salts referred to above or hereinafter are meant to include the therapeutically active non-toxic acid and base addition salts which the compounds of formula (I) and their solvates are able to form.

[0368] Those skilled in the art will recognize that the compounds described herein may exist as tautomers, and other tautomeric configurations of the structures shown herein are also possible.Tautomers are constitutional isomers that are easily interconverted.It is understood that all tautomeric forms are encompassed by the structures shown, even if not specifically shown, as one possible tautomeric configuration of a group of compounds.

[0369] Where compounds according to embodiments of the present invention have at least one chiral center, they may accordingly exist as enantiomers. Where compounds have two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs, which as such are intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of the present invention. Those skilled in the art will understand that the term compound, as used herein, can also include solvates of Formula (I).

[0370] Where the processes for preparing compounds according to certain embodiments of the present invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques, such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantioselective synthesis or resolution. The compounds can be resolved into their component enantiomers by standard techniques, such as salt formation with optically active acids, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base to form diastereomeric pairs. The compounds can also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

[0371] Within the scope of the present invention, when any one or more elements are referred to, particularly with respect to compounds of formula (I), it is intended to include within its scope all isotopes and isotopic mixtures of that element, whether naturally occurring or synthetically produced, and either at natural abundance or in isotopically enriched form. For example, a reference to hydrogen includes within its scope 1 H,2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C, and 16 O and 18 O. These isotopes may be radioactive or non-radioactive. The radiolabeled compounds of formula (I) 3 H, 11 C. 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 The isotopes may include one or more isotopes selected from the group of Br. Preferably, the isotopes are 2 H, 3 H, 11 C, and 18 F. Deuterated compounds are specifically intended to be included within the scope of the present invention.

[0372] In any of the processes for preparing the compounds of the various embodiments of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by conventional protecting groups, which can be removed at a subsequent convenient stage using methods known in the art.

[0373] Although the compounds of the present invention (including their pharmaceutically acceptable salts and solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, excipient, and / or diluent selected in view of the intended route of administration and standard pharmaceutical or veterinary practice. Accordingly, certain embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0374] By way of example, in pharmaceutical compositions according to embodiments of the present invention, the compound of formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.

[0375] Solid oral dosage forms, such as tablets or capsules, containing the compounds of the present invention can be administered in at least one dosage form at a time, as needed. The compounds can also be administered in sustained release formulations.

[0376] A therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof includes a dosage range of about 0.1 mg to about 3000 mg, or any specific amount or range therein, although it will be apparent to one of skill in the art that the therapeutically effective amount of a compound of formula (I) will vary depending on the disease, syndrome, condition, and disorder being treated.

[0377] The compounds of the present invention were found to inhibit MALT1 activity.

[0378] In some embodiments, inhibition of MALT1 by provided compounds may be useful in the treatment or prevention, particularly the treatment, of the non-limiting list of cancers described herein.

[0379] The present invention relates to compounds of formula (I) for use as pharmaceuticals.

[0380] The present invention relates to intermediates of formula (A) for use as pharmaceuticals.

[0381] The present invention relates to compounds of formula (I) for use in inhibiting MALT1 activity.

[0382] The present invention relates to intermediates of formula (A) for use in inhibiting MALT1 activity.

[0383] The present invention relates to compounds of formula (I) for use in the treatment of the diseases mentioned herein.

[0384] The present invention relates to intermediates of formula (A) for use in the treatment of the diseases mentioned herein.

[0385] The present invention relates to compounds of formula (I) for the treatment or prevention, especially for the treatment, of such diseases.

[0386] The present invention relates to intermediates of formula (A) for the treatment or prevention, especially the treatment, of said diseases.

[0387] The present invention relates to compounds of formula (I) in the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions.

[0388] The present invention relates to intermediates of formula (A) in the treatment or prevention, in particular the treatment, of MALT1 mediated diseases or conditions.

[0389] The present invention relates to compounds of formula (I) for the manufacture of a medicament.

[0390] The present invention relates to intermediates of formula (A) for the preparation of pharmaceuticals.

[0391] The present invention relates to a compound of formula (I) for the manufacture of a medicament for the inhibition of MALT1.

[0392] The present invention relates to intermediates of formula (A) for the preparation of medicaments for the inhibition of MALT1.

[0393] The present invention relates to a compound of formula (I) for the manufacture of a medicament for the treatment or prevention, in particular the treatment, of any one of the disease conditions mentioned herein.

[0394] The present invention relates to intermediates of formula (A) for the manufacture of a medicament for the treatment or prevention, in particular the treatment, of any one of the disease states mentioned herein.

[0395] The present invention relates to a compound of formula (I) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein.

[0396] The present invention relates to intermediates of formula (A) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein.

[0397] The present invention relates to compounds of formula (I) which can be administered to mammals, preferably humans, to treat or prevent any one of the diseases described herein.

[0398] The present invention relates to intermediates of formula (A) which can be administered to mammals, preferably humans, to treat or prevent any one of the diseases mentioned herein.

[0399] In view of the utility of the compounds of formula (I), there is provided a method for treating a warm-blooded animal, including a human, suffering from, or preventing a warm-blooded animal, including a human, from suffering from, any one of the diseases mentioned herein.

[0400] In view of the utility of the intermediates of formula (A), there is provided a method for treating a warm-blooded animal, including a human, suffering from, or for preventing a warm-blooded animal, including a human, from suffering from, any one of the diseases mentioned herein.

[0401] General synthesis methods In this section, and in all other sections, unless the context indicates otherwise, reference to formula (I) also includes all other subgroups and embodiments thereof defined herein.

[0402] The general preparation of some representative examples of compounds of formula (I) is described below, and in certain examples they are usually prepared from starting materials that are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art of organic chemistry. The following schemes are merely illustrative of examples of the present invention and are not intended to limit the present invention in any way.

[0403] Alternatively, intermediates or compounds of the present invention can also be prepared by analogous reaction protocols described in the following general schemes and specific examples in combination with standard synthetic processes commonly used by those skilled in the art.

[0404] Those skilled in the art will understand that in the reactions depicted in the schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (e.g., hydroxy, amino, or carboxy groups) if these are desired in the final product to prevent their undesired participation in the reaction. Generally, conventional protecting groups can be used in accordance with standard practice. The protecting groups can be removed at a subsequent convenient stage using methods known in the art.

[0405] Those skilled in the art will appreciate that in the reactions depicted in the schemes, for example, when NaH, LDA, or MeMgBr are used in the reaction, it may be advisable or necessary to carry out the reaction under an inert atmosphere, such as, for example, under an atmosphere of N gas.

[0406] It will be apparent to those skilled in the art that it may be necessary to cool the reaction mixture before working on the reaction (e.g., referring to the series of operations required to isolate and purify the product of a chemical reaction, such as quenching, column chromatography, extraction, etc.).

[0407] Those skilled in the art will appreciate that heating the reaction mixture under stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to reduce the overall reaction time.

[0408] Those skilled in the art will appreciate that the alternative chemical reaction sequences shown in the schemes below may also lead to the desired compounds of formula (I).

[0409] Those skilled in the art will appreciate that the intermediates and final compounds shown in the following schemes can be further functionalized according to methods well known to those skilled in the art. The intermediates and compounds described herein can be isolated in free form or as a salt or solvate thereof. The intermediates and compounds described herein can be synthesized in the form of a mixture of tautomeric and stereoisomeric forms, which can be separated from one another according to art-known resolution procedures.

[0410] For abbreviations used in the following schemes, see the table of abbreviations in the "Examples" section.

[0411] In preparing compounds of the present invention, protection of remote functional groups (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups (NH-PG) include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyl (Bn), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Suitable hydroxy-protecting groups include, but are not limited to, triisopropylsilyl and acetyl. The need for such protection is readily determined by one skilled in the art.

[0412] In general, compounds of formula I can be prepared as illustrated below in general Scheme 1, where the variables are described above.

[0413] General Scheme 1

[0414] [ka]

[0415] In general scheme 1, compounds of formula (I) can be prepared via a coupling reaction between intermediates of formula (II) and formula (III), where X represents a suitable leaving group, such as a halogen, in particular Cl, Br, or I. This reaction can be carried out by, for example, CsCO 3、 The reaction can be carried out in the presence of a suitable base such as K3PO4 or K2CO3. The reaction can be carried out in a reaction-inert solvent such as tBuOH, toluene, or dioxane. The reaction is typically carried out in the presence of a catalytic system comprising a suitable catalyst such as tBuXPhos Pd G3, BrettPhos Pd G3, or SPhos Pd G4 and a ligand such as BrettPhos. Preferably, the reaction is carried out under an inert atmosphere, such as a nitrogen or argon atmosphere, and under conventional heating or microwave irradiation at a suitable temperature range, such as room temperature to 60°C. R 6 C substituted with =OH 1~4 It will be appreciated by those skilled in the art that in the case of alkyl, an additional deprotection step may be performed and the hydroxy group may be protected with a suitable protecting group.

[0416] In general, intermediates of formula (II) can be synthesized as shown in general Scheme 2 below.

[0417] General Scheme 2

[0418] [ka]

[0419] In General Scheme 2, the following reaction conditions typically apply:

[0420] Step 1. A commercially available intermediate of formula (IV) or an intermediate of formula (IV) prepared according to general scheme 3 (for q=1) is reacted with, for example, DMF-DMA at a suitable temperature, such as, for example, 35° C., to give an intermediate of formula (V).

[0421] Step 2. The intermediate of formula (V) is reacted with commercially available 1H-pyrazol-5-amine of formula (VI) in the presence of an acid, such as AcOH, in a suitable solvent, such as toluene, and at a suitable temperature range, such as room temperature to 95° C., to give the intermediate of formula (VII).

[0422] Step 3. For example, PG 1 The intermediate of formula (VII) where =Boc is reacted with a suitable acid such as HCl or TFA in a suitable solvent such as dichloromethane or dioxane at a suitable temperature range such as 0°C to room temperature to give the intermediate of formula (II).

[0423] Alternatively, intermediates of formula (IVa) where q=1 can be synthesized as shown in general scheme 3 below, where the variables are described above.

[0424] General Scheme 3

[0425] [ka]

[0426] In general scheme 3, the following reaction conditions typically apply:

[0427] Step 1. The intermediate of formula (VIII) is reacted with an acylating agent such as an acyl chloride of formula (IX) in the presence of a base such as triethylamine in a suitable solvent such as chloroform and at a suitable temperature such as 0°C to give an intermediate of formula (X).

[0428] Step 2. The intermediate of formula (X) is reacted with a suitable base, such as NaH, in a suitable solvent, such as THF, and at a suitable temperature range, such as 75° C., to give the intermediate of formula (XI).

[0429] Step 3. The intermediate of formula (XI) is reacted with an alkylating reagent such as 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate or other alkylating agents known to those skilled in the art in the presence of a suitable base such as NaH in a suitable solvent such as DMF and at a suitable temperature such as 0° C. to room temperature to give the intermediate of formula (XII).

[0430] Step 4. The intermediate of formula (XII) is reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as THF, and at a suitable temperature range, such as 25°C to 80°C, to give the intermediate of formula (XIII).

[0431] Process 5.PG 2 is a suitable protecting group, for example benzyl, is deprotected under suitable conditions known to those skilled in the art, such as metal catalyzed hydrogenation in a suitable solvent, for example EtOH, at a suitable temperature, for example 25° C., to give an intermediate of formula (XIVa). The intermediate of formula (XIVa) can be reacted with a suitable reagent, for example PG, in a suitable solvent, for example THF, in the presence of a suitable base, for example triethylamine (TEA), at a suitable temperature, for example 25° C. 1 = Boc is protected with an alternative protecting group by reaction with di-tert-butyl dicarbonate, 1 is a suitable protecting group, for example Boc, to give an intermediate of formula (XIVb).

[0432] Step 6. The intermediate of formula (XIVb) is oxidized in the presence of a suitable oxidizing agent, such as pyridinium chlorochromate, in a suitable solvent, such as DCM, and at a suitable temperature, such as 40° C., to provide the intermediate of formula (IVa).

[0433] In general, intermediates of formula (III) where X is a leaving group, e.g., a halogen as described above in Scheme 1, particularly Cl, Br, I, can be prepared as illustrated below in General Scheme 4, where the variables are as described above.

[0434] General Scheme 4

[0435] [ka]

[0436] Step 1. An intermediate of formula (XV) is reacted with a phosphonate of formula (XVI) according to Horner-Wadsworth-Emmon reaction conditions. Those skilled in the art will understand that the selection of the R' substituent in intermediate (XVI) allows for the formation of Z- or E-form intermediate (XVII). For example, when R' represents -CHCF, the Z isomer is typically obtained. For example, when R' represents ethyl, the E isomer is typically obtained.

[0437] The reaction is carried out in the presence of a suitable base, such as NaH, in a suitable solvent, such as THF, at a suitable temperature range, such as 0° C. to 25° C., to provide an intermediate of formula (XVII). 6 C is substituted with one -OH 1~4 The intermediate of formula (XVII) which is alkyl can be prepared by one skilled in the art following literature procedures (e.g., Pereire, AA et al., Eur. J. Org. Chem. 2017, 12, 1578-1582). 6 C is substituted with one -OH 1~4 It will be appreciated that for compounds of formula (XVII) that are alkyl, the alcohol moiety may be protected with a suitable protecting group, for example triisopropylsilyl, which is maintained throughout the synthetic scheme.

[0438] Step 2. Reaction of the intermediate of formula (XVII) with a suitable reducing agent, such as DIBAL-H, in a suitable solvent, such as THF, and at a suitable temperature range, such as 0° C. to 25° C., provides an intermediate of formula (XVIIIa). The intermediate of formula (XVIIIa) is protected with a suitable protecting group, such as triisopropylsilyl ether or acetyl, by reaction with a suitable reagent, such as triisopropylsilyl chloride or acetic anhydride, in the presence of a base, such as imidazole, pyridine or triethylamine (TEA), in a suitable solvent, such as DCM, at a suitable temperature, such as 25° C., to provide an intermediate of formula (XVIIIb) (wherein PG = triisopropylsilyl or acetyl).

[0439] Step 3. The intermediate of formula (XVIIIb) is reacted with a suitable difluorocyclopropanation reagent, such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in a suitable solvent, such as bis(2-methoxyethyl)ether, at a suitable temperature, such as 120° C., in the presence of an additive, such as potassium iodide and trimethylchlorosilane, to obtain an intermediate of formula (XIXa). Alternatively, the intermediate of formula (XVIIIb) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, in a suitable solvent, such as toluene, optionally in the presence of a catalyst, such as tetrabutylammonium bromide, at a suitable temperature, such as 110° C., to obtain an intermediate of formula (XIXa). Intermediate of formula (XIXa), wherein PG is a suitable protecting group, such as triisopropylsilyl or acetyl, is reacted with a suitable deprotection reagent / procedure, such as tetrabutylammonium fluoride (in a suitable solvent, such as THF) or potassium carbonate (in a suitable solvent, such as methanol), at a suitable temperature range, such as 0°C to 25°C, to provide intermediate of formula (XIXb).

[0440] Step 4. The intermediate of formula (XIXb) is reacted with a suitable oxidizing agent, such as (diacetoxyiodo)benzene, in the presence of a suitable catalyst, such as TEMPO, and a suitable base, such as NaHCO, in a suitable solvent, such as a mixture of water and ACN, at a suitable temperature, such as 25°C, to obtain an intermediate of formula (XX).

[0441] Step 5. The intermediate of formula (XX) is reacted with the appropriate amine R in the presence of a suitable coupling reagent, such as HATU and a suitable base, such as triethylamine, typically in a solvent, such as ACN, at a suitable temperature, such as room temperature. 3a R 3b NH (where the variables are described above) to provide an intermediate of formula (III).

[0442] Step 6. Alternatively, the intermediate of formula (XVI) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, optionally in the presence of a catalyst such as tetrabutylammonium bromide, in a suitable solvent, such as toluene, at a suitable temperature, such as 110° C., to give the intermediate of formula (XXI).

[0443] Step 7. The intermediate of formula (XXI) is reacted under hydrolysis conditions to give an intermediate of formula (XX). This reaction can be carried out in a suitable solvent system, such as water / THF optionally containing EtOH or MeOH, in the presence of a suitable base, such as LiOH, at a suitable temperature range, such as room temperature.

[0444] Alternatively, compounds of formula (I) can be prepared by reacting an activated intermediate of formula (A) with R 3a R 3b It can be prepared by a coupling reaction between NH and an amine (commercially available or can be prepared by one skilled in the art).

[0445] General Scheme 5

[0446] [ka]

[0447] In general scheme 5, an activated intermediate of formula (A) is reacted with an appropriate amine R 3a R 3bNH, where the variables are as defined above. This reaction is carried out in the presence of a suitable reagent, such as HATU, a suitable base, such as TEA, typically in a solvent, such as ACN, at a suitable temperature, such as room temperature, to provide an intermediate of formula (I). 6 C substituted with =OH 1~4 It will be appreciated by those skilled in the art that if the alkyl and hydroxy are protected with a suitable protecting group, an additional deprotection step may be performed.

[0448] In general, activated intermediates of formula (A) can be prepared as illustrated in general Scheme 6 below, where the variables are described above.

[0449] General Scheme 6

[0450] [ka]

[0451] Step 1. An intermediate of formula (XXI), where X is a leaving group such as a halogen, particularly Cl, Br, I as described above in Scheme 1, is reacted with an intermediate of formula (II) under coupling reaction conditions to give an intermediate of formula (XXII). This reaction can be carried out in the presence of a suitable base, such as CsCO 3、 The reaction can be carried out in the presence of KPO or KCO. The reaction can be carried out in a reaction-inert solvent such as, for example, tBuOH, toluene, DMA, or dioxane. The reaction is typically carried out in the presence of a catalyst system comprising a suitable catalyst, such as tBuXPhos Pd G3, BrettPhos Pd G3, or SPhos Pd G4, and a ligand, such as BrettPhos. Preferably, the reaction is carried out under an inert atmosphere, such as a nitrogen or argon atmosphere, and under conventional heating or microwave irradiation, at a suitable temperature range, for example, room temperature to 60°C.

[0452] Step 2. The intermediate of formula (XXII) is reacted and hydrolyzed to give the activated intermediate of formula (A). This reaction can be carried out in the presence of a suitable base such as LiOH, in a suitable solvent system such as water / THF, and at a suitable temperature range such as room temperature.

[0453] In preparing compounds of the present invention, protection of remote functionality (e.g., primary amines or alcohols) of intermediates may be necessary. The need for such protection will vary with the nature of the remote functionality and the conditions of the preparation method. Suitable amino protecting groups include, but are not limited to, t-butoxycarbonyl (Boc) and acetyl. Suitable alcohol protecting groups include t-butyldimethylsilyl. The need for such protection is readily determined by one skilled in the art.

[0454] It will be understood that, where appropriate functional groups are present, the compounds of the various formulas, or any intermediates used in their preparation, may be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.

[0455] The compounds of formula (I) may be synthesized in the form of racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. An alternative way to separate the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0456] In preparing compounds of the present invention, protection of remote functional groups (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art.

[0457] Specific Examples The following examples further illustrate the present invention.

[0458] Example Several methods for preparing the intermediates and compounds of the present invention are illustrated in the following examples. Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively, could be synthesized by one skilled in the art by using well-known methods.

[0459] [Table 1-1]

[0460] [Table 1-2]

[0461] As will be appreciated by one of skill in the art, compounds synthesized using the protocols provided may contain residual solvents or small amounts of impurities.

[0462] Those skilled in the art will understand that, even if not explicitly mentioned in the experimental protocols below, column chromatographic purification was typically followed by collection of desired fractions and evaporation of the solvent.

[0463] When stereochemistry is not indicated, this means a mixture of stereoisomers unless otherwise indicated or clear from the context.

[0464] As will be understood by those skilled in the art, compounds synthesized using the protocols as specified may exist as solvates, e.g., hydrates, and / or contain residual solvents or trace impurities. Compounds or intermediates isolated as salt forms may be of integer stoichiometry, i.e., mono- or di-salt, or of intermediate stoichiometry. When an intermediate or compound in the experimental section below is designated as an "HCl salt" without specifying the number of equivalents of HCl, this means that the number of equivalents of HCl was not determined.

[0465] Preparation of intermediates For intermediates that were used in the next reaction step as crude or as partially purified intermediates, in some cases no molar amount is stated for such intermediate in the next reaction step, or alternatively an estimated molar amount or theoretical molar amount is indicated in the reaction protocols set out below for such intermediate in the next reaction step.

[0466] Intermediate 1

[0467] [ka]

[0468] A 10 L three-neck flask was charged with ethyl 2-(benzylamino)acetate (550 g, 2.85 mol, 1.00 equiv), CHCl3 (5.5 L), and TEA (576 g, 5.70 mmol, 2.00 equiv). Propanoyl chloride (290 g, 3.13 mol, 1.10 equiv) in CHCl3 (300 mL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into H2O (6 L). The resulting solution was extracted with DCM (2 × 2 L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: EtOAc / PE 1:2) to give Intermediate 1 (561 g, 79% yield) as a pale yellow oil.

[0469] Intermediate 2

[0470] [ka]

[0471] A solution of intermediate 1 (561 g, 2.25 mol, 1.00 equiv) in THF (2 L) was added dropwise to a mixture of NaH (108 g, 2.70 mol, 1.20 equiv, 60%) and THF (10 L) at 75 °C. After 12 h at 75 °C, the reaction was cooled to 20 °C, water (100 mL) was added, and the mixture was concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: MeOH / DCM 1:30) to give intermediate 2 (231 g, 50% yield) as an off-white solid.

[0472] Intermediate 3

[0473] [ka]

[0474] NaH (45.5 g, 1.14 mol, 1.00 equiv, 60%) was added portionwise to intermediate 2 (231 g, 1.14 mol, 1.00 equiv) in DMF (4.6 L) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. 5-(Trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (457 g, 1.14 mol, 1.00 equiv) was added to the mixture at −55 °C. The mixture was gradually warmed to 25 °C and stirred for 1 h. The mixture was poured into an ice / water mixture (10 L) and extracted with EtOAc (2 × 5 L). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: EtOAc / PE 1:4) to give intermediate 3 (275 g, 89% yield) as a pale yellow oil.

[0475] Intermediate 4

[0476] [ka]

[0477] LAH (154 g, 4.10 mol, 4.00 equiv.) was added to a mixture of intermediate 3 (275 g, 1.01 mol, 1.00 equiv.) in THF (5.5 L) at 0 °C. The mixture was warmed to 80 °C and stirred at this temperature for 15 h. The mixture was cooled to 0 °C, and 154 g of water, 154 g of aqueous NaOH (10%), and 154 g of HO were added. The mixture was stirred at 25 °C for 30 min, and the precipitate was filtered off. The filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: MeOH / DCM 1:50) to give intermediate 4 (204 g, 78% yield) as a colorless oil.

[0478] Intermediate 5

[0479] [ka]

[0480] HCl (787 mL, 1 M) and Pd / C (8.37 g, 78.7 mmol, 0.10 equiv) were added to a solution of intermediate 4 (204 g, 787 mmol, 1.00 equiv) in EtOH (2 L). The mixture was degassed and flushed with hydrogen. The mixture was stirred under a hydrogen atmosphere (balloon) at 25° C. for 18 h. HCl (787 mL, 1 M) was then added and the mixture was stirred at 25° C. for 30 min. The solids were filtered off and the filtrate was concentrated in vacuo to give intermediate 5 (106 g, 66% yield; as the HCl salt, equivalent weight not determined) as a yellow solid that was used without further purification.

[0481] Intermediate 6

[0482] [ka]

[0483] Di-tert-butyl dicarbonate (169 g, 773 mmol, 1.50 equiv.) was added to a mixture of intermediate 5 (106 g, 515 mmol, 1.00 equiv.), THF (2 L), and TEA (2089 g, 2.06 mol, 4.00 equiv.). The flask was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: EtOAc / PE 1:4) to give intermediate 6 (134 g, 96% yield) as a white solid.

[0484] Intermediate 7

[0485] [ka]

[0486] A mixture of intermediate 6 (134 g, 0.496 mol, 1.00 equiv), DCM (2.6 L), PCC (534 g, 2.48 mol, 5.00 equiv) and silica gel (268 g, 4.46 mol, 9.00 equiv) was stirred for 12 h at 40° C. The mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography on silica gel (eluent: EtOAc / PE 1:10) to give intermediate 7 (79 g, 60% yield) as a white solid.

[0487] Intermediate 8

[0488] [ka]

[0489] Intermediate 7 (79 g, 296 mmol, 1.00 equiv) and DMF-DMA (790 mL) were stirred for 1 h at 35° C. The mixture was concentrated to give Intermediate 8 (100 g, crude) as a pale yellow oil, which was used without further purification.

[0490] Intermediate 9

[0491] [ka]

[0492] A mixture of intermediate 8 (100 g, 310 mmol, 1.00 equiv.), 5-chloro-2H-pyrazol-3-amine [CAS: 916211-79-5] (36.5 g, 310 mmol, 1.00 equiv.), toluene (1 L), and AcOH (100 mL) was stirred at 95 °C for 15 h. The reaction was cooled to 25 °C and concentrated in vacuo. NaHCO (1000 mL) was added to the mixture, and the resulting solution was extracted with EtOAc (2 × 1 L). The organic layers were combined, dried over anhydrous MgSO, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: EtOAc / PE 15:85) to give intermediate 9 (39.7 g, 34% yield) as a yellow oil.

[0493] Intermediate 10

[0494] [ka]

[0495] A mixture of intermediate 9 (39.7 g, 105 mmol, 1.00 equiv.), DCM (400 mL), and TFA (80 mL) was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo, and NaHCO (500 mL) was added. The resulting mixture was extracted with DCM (3 × 300 mL). The organic layers were combined, dried over anhydrous MgSO, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluent: EtOAc:PE (1:1)) to afford 2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine (intermediate 10, [CAS: 2661482-67-1], 15.2 g, 51% yield) as a yellow solid.

[0496] Intermediates 11 and 12

[0497] [ka]

[0498] Intermediate 10 (5.0 g) was separated into enantiomers via chiral SFC using Chiralcel Diacel IH 20 x 250 mm as stationary phase, mobile phase: CO, EtOH + 0.4 iPrNH to give the following two fractions: Fraction 1: Intermediate 11 (2.35 g, 47% yield) Fraction 2: Intermediate 12 (2.35 g, 47% yield)

[0499] Intermediate 13

[0500] [ka]

[0501] To a cooled (0 °C) suspension of NaH (60% in mineral oil, 2.59 g, 64.85 mmol) in THF (100 mL) was added triethylphosphonopropionate (13.9 mL, 64.85 mmol) dropwise. The reaction was stirred for 30 min, and then a solution of 4-bromobenzaldehyde [1122-91-4] (10.0 g, 54.0 mmol) in THF (20 mL) was added dropwise, maintaining the internal temperature between 0 °C and 5 °C. The mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (60 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc up to 90 / 10). The fractions containing the compound were combined and concentrated in vacuo to give Intermediate 13 (12.3 g, 84% yield) as a colorless oil.

[0502] Intermediate 14

[0503] [ka]

[0504] To a cooled (0 °C) solution of Intermediate 13 (12.3 g, 45.7 mmol) in dry THF (230 mL) under nitrogen, DIBAL-H (1 M in THF, 115 mL, 115 mmol) was added dropwise. The mixture was then allowed to warm slowly to room temperature and stirred for 1 h. The reaction was cooled to 0 °C, diluted with EtOAc (100 mL), and quenched with a saturated aqueous solution of Rochelle's salt (250 mL). After stirring for 1 h, the reaction was allowed to warm to room temperature, the organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 14 (9.8 g, 94% yield) as a white solid.

[0505] Intermediate 15

[0506] [ka]

[0507] To a solution of intermediate 14 (8.70 g, 38.3 mmol) and imidazole (3.13 g, 46.0 mmol) in DCM (100 mL) precooled to 0 °C, triisopropylsilyl chloride (9.0 mL, 42.1 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with water (100 mL) and DCM (100 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (eluent: heptane / DCM up to 90 / 10) to give intermediate 15 (14 g, 95% yield) as a colorless oil.

[0508] Intermediate 16

[0509] [ka]

[0510] To a 20 mL pressure tube containing Intermediate 15 (1.15 g, 3.0 mmol) and tetrabutylammonium bromide (48.3 mg, 0.15 mmol), toluene (6 mL) and (bromodifluoromethyl)trimethylsilane (1.4 mL, 9 mmol) were added. The reaction was stirred at 110 °C for 6 h. Six identical reactions were run in parallel and combined before workup and purification. The reactions were cooled to room temperature, diluted with water (10–15 mL) and EtOAc (20–25 mL), respectively, and combined. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (50 mL), cooled to 0 °C, and TBAF (1 M in THF, 27 mL, 27 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1 h. The volatiles were removed under reduced pressure, and the residue was diluted with water (50 mL) and EtOAc (100 mL). The aqueous layer was separated, and the organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc 70 / 30) to give intermediate 16 (4.6 g, 92% yield) as a yellowish oil.

[0511] Intermediate 17

[0512] [ka]

[0513] To a solution of intermediate 16 (3.81 g, 13.75 mmol) in water / MeCN (87 mL / 87 mL) was added TEMPO (1.07 g, 6.87 mmol), (diacetoxyiodo)benzene (13.29 g, 41.25 mmol), and NaHCO (2.89 g, 34.37 mmol). The mixture was stirred at room temperature for 6 hours, then diluted with water, and aqueous HCl (1 M) was added until the pH reached approximately 2. EtOAc was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO, filtered, and evaporated. The product was stirred in diisopropyl ether and filtered. The filtrate was evaporated and stirred in heptane to give a precipitate, which was filtered and dried over anhydrous MgSO to give intermediate 17 (3.46 g, 86% yield) as a white solid.

[0514] Intermediate 18

[0515] [ka]

[0516] To a mixture of Intermediate 17 (315 mg, 1.08 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (823 mg, 2.16 mmol), and N,N-diethylethanamine (0.60 mL, 4.33 mmol) in ACN (9 mL) was added methylamine (2 M in THF, 1.35 mL, 2.70 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with EtOAc (30 mL) and water (15 mL). The aqueous layer was separated and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc up to 50 / 50) to give intermediate 18 (320 mg, 97% yield) as a colorless oil.

[0517] Intermediates 19 and 20

[0518] [ka]

[0519] Intermediate 18 (1 g, 3.29 mmol) was purified by preparative chiral SFC (stationary phase: Chiralpak AS-H 30 × 250 mm, mobile phase: CO:iPrOH 85:15). The compound-containing fractions were combined and evaporated in vacuo to give intermediate 19 (447 mg, 44% yield) and intermediate 20 (480 mg, 48% yield).

[0520] Intermediate 21

[0521] [ka]

[0522] To a mixture of Intermediate 17 (200.0 mg, 0.687 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (522.5 mg, 1.37 mmol), and N,N-diethylethanamine (0.38 mL, 2.75 mmol) in MeCN (5.2 mL) was added 3-(methylsulfonyl)cyclobutan-1-amine hydrochloride [2639792-63-3] (205.0 mg, 1.37 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EtOAc and water. The aqueous layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluent: MeOH / DCM 0-7%) to give intermediate 21 (264 mg, 91% yield) as a white solid.

[0523] Intermediate 22

[0524] [ka]

[0525] Intermediate 22 was prepared by the same reaction protocol as intermediate 21, starting from trans-3-methylsulfonylcyclobutylamine hydrochloride [1408075-97-7] (1.25 g, 6.73 mmol) instead of 3-(methylsulfonyl)cyclobutan-1-amine hydrochloride [2639792-63-3] to give intermediate 22 (1.16 g, 73% yield) as a pale yellow solid.

[0526] Intermediate 23

[0527] [ka]

[0528] Intermediate 23 was prepared by the same reaction protocol as intermediate 13, starting from 4-bromo-2,3-difluorobenzaldehyde [644985-24-0] (5 g, 22.6 mmol) instead of 4-bromobenzaldehyde [1122-91-4] to give intermediate 23 (3.5 g, 51% yield).

[0529] Intermediate 24

[0530] [ka]

[0531] Intermediate 24 was prepared by the same reaction protocol as intermediate 14, starting from intermediate 23 (3.2 g, 10.5 mmol) instead of intermediate 13 to give intermediate 24 (2.3 g, 83% yield).

[0532] Intermediate 25

[0533] [ka]

[0534] Intermediate 25 was prepared by the same reaction protocol as for intermediate 15, starting from intermediate 24 (2.3 g, 8.7 mmol) instead of intermediate 14 to give intermediate 25 (3.3 g, 90% yield).

[0535] Intermediate 26

[0536] [ka]

[0537] Intermediate 26 was prepared by the same reaction protocol as intermediate 16, starting from intermediate 25 (3 g, 6.4 mmol) instead of intermediate 15 to give intermediate 26 (1.65 g, 67% yield).

[0538] Intermediate 27

[0539] [ka]

[0540] Intermediate 27 was prepared by the same reaction protocol as for intermediate 17, starting from intermediate 26 (1.65 g, 5.27 mmol) instead of intermediate 16 to give intermediate 27 (1.1 g, 30% yield).

[0541] Intermediate 28

[0542] [ka]

[0543] Intermediate 28 was prepared by the same reaction protocol as for intermediate 21, starting from intermediate 27 (1.1 g, 3.36 mmol) instead of intermediate 17 to give intermediate 28 (1.16 g, 74% yield) as a pale yellow solid.

[0544] Intermediate 29

[0545] [ka]

[0546] Intermediate 29 was prepared by the same reaction protocol as intermediate 13, starting from 4-bromo-2-fluorobenzaldehyde [57848-46-1] (5 g, 1.2 mmol) instead of 4-bromobenzaldehyde [1122-91-4] to give intermediate 29 (7 g, 84% yield).

[0547] Intermediate 30

[0548] [ka]

[0549] Intermediate 30 was prepared by the same reaction protocol as intermediate 14, starting from intermediate 29 (5 g, 17.4 mmol) instead of intermediate 13 to give intermediate 30 (6 g, 93% yield).

[0550] Intermediate 31

[0551] [ka]

[0552] Intermediate 31 was prepared by the same reaction protocol as intermediate 15, starting from intermediate 30 (5 g, 20.4 mmol) instead of intermediate 14 to give intermediate 31 (6 g, 72% yield).

[0553] Intermediate 32

[0554] [ka]

[0555] Intermediate 32 was prepared by the same reaction protocol as intermediate 16, starting from intermediate 31 (3.5 g, 8.7 mmol) instead of intermediate 15 to give intermediate 32 (1.8 g, 55% yield).

[0556] Intermediate 33

[0557] [ka]

[0558] Intermediate 33 was prepared by the same reaction protocol as for intermediate 17, starting from intermediate 32 (1.8 g, 6.1 mmol) instead of intermediate 16 to give intermediate 33 (1.6 g, 51% yield).

[0559] Intermediate 34

[0560] [ka]

[0561] Intermediate 34 was prepared by the same reaction protocol as for intermediate 21, starting from intermediate 33 (1.6 g, 5.18 mmol) instead of intermediate 17 to give intermediate 34 (1.09 g, 47% yield) as a white solid.

[0562] Intermediate 35

[0563] [ka]

[0564] Intermediate 35 was prepared by the same reaction protocol as intermediate 13, starting from 4-bromo-3-fluorobenzaldehyde [133059-43-5] (10 g, 1.2 mmol) instead of 4-bromobenzaldehyde [1122-91-4] to give intermediate 35 (11 g, 74% yield).

[0565] Intermediate 36

[0566] [ka]

[0567] Intermediate 36 was prepared by the same reaction protocol as intermediate 14, starting from intermediate 35 (11 g, 38.3 mmol) instead of intermediate 13 to give intermediate 36 (9 g, 93% yield).

[0568] Intermediate 37

[0569] [ka]

[0570] Intermediate 37 was prepared by the same reaction protocol as intermediate 15, starting from intermediate 36 (9 g, 36.7 mmol) instead of intermediate 14 to give intermediate 37 (11 g, 75% yield).

[0571] Intermediate 38

[0572] [ka]

[0573] Intermediate 38 was prepared by the same reaction protocol as intermediate 16, starting from intermediate 37 (3.5 g, 7.7 mmol) instead of intermediate 15 to give intermediate 38 (2.1 g, 92% yield).

[0574] Intermediate 39

[0575] [ka]

[0576] Intermediate 39 was prepared by the same reaction protocol as for intermediate 17, starting from intermediate 38 (2.1 g, 7.1 mmol) instead of intermediate 16 to give intermediate 39 (2.0 g, 91% yield).

[0577] Intermediate 40

[0578] [ka]

[0579] Intermediate 40 was prepared by the same reaction protocol as for intermediate 21, starting from intermediate 39 (2.0 g, 6.47 mmol) instead of intermediate 17 to give intermediate 40 (1.13 g, 40% yield) as a white solid.

[0580] Intermediates 41 and 42

[0581] [ka]

[0582] Intermediate 17 (63 g, 216.42 mmol) was purified by preparative chiral SFC (stationary phase: Chiralpak IG 5 × 30 cm, 10 μm, mobile phase: CO / MeOH: 85 / 15). The compound-containing fractions were combined and evaporated in vacuo to give Intermediate 41 (25.8 g, 41% yield) and Intermediate 42 (25.8 g, 41% yield) as white solids.

[0583] Starting from intermediate 41 and the indicated reagents, the following intermediates were synthesized by a similar reaction protocol as described for intermediate 21.

[0584] [Table 2]

[0585] Intermediate 47

[0586] [ka]

[0587] To a mixture of Intermediate 13 (118 g, 438.43 mmol), toluene (826 mL), and tetrabutylammonium bromide [1643-19-2] (4.24 g, 13.15 mmol), (bromodifluoromethyl)trimethylsilane [115262-01-6] (1424.76 g, 7014.99 mmol) was added dropwise (using a syringe pump) at 110 °C over 24 hours. The resulting mixture was stirred at 110 °C for an additional 5 hours. The reaction mixture was poured into ice water (1.5 L). The resulting mixture was extracted with PE (3 × 1 L). The combined organic layers were washed with brine (3 × 0.5 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (30:1) to give intermediate 47 (92 g, 66% yield) as a pale yellow oil.

[0588] Intermediates 48 and 49

[0589] [ka]

[0590] Intermediate 47 (100 g, 313.34 mmol) was purified by preparative chiral HPLC (stationary phase: Chiralpak IG 5 × 25 cm, 10 μm, mobile phase: hexane / EtOH: 99 / 1). The compound-containing fractions were combined and evaporated in vacuo to give intermediate 48 (23.8 g, 23% yield) as a brown oil and intermediate 49 (48.7 g, 47% yield) as a brown oil.

[0591] Intermediate 50

[0592] [ka]

[0593] Intermediate 11 (3.0 g, 10.84 mmol), Intermediate 48 (3.46 g, 10.84 mmol), CsCO (5.3 g, 16.27 mmol), and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate [1447963-75-8] (948.0 mg, 1.19 mmol) were placed in a reaction vessel. Dry DMA (120 mL) was then added, and the reaction mixture was degassed by bubbling nitrogen through it for 10 minutes. The mixture was stirred at 60 °C for 2 hours. The crude product was then cooled to room temperature and diluted with brine, water, and EtOAc. The phases were separated, the aqueous layer was extracted twice with EtOAc, the combined organic layers were dried over MgSO, the solids were filtered, and the solvent was removed in vacuo. The crude product was then purified by flash column chromatography (mobile phase: DCM, 100% yield) to give intermediate 50 (3.32 g, 59% yield) as a yellow solid.

[0594] Intermediate 51 (active intermediate)

[0595] [ka]

[0596] LiOH in water (30.44 mL, 2 M, 60.89 mmol) was added to a solution of intermediate 50 (10.45 g, 20.3 mmol) in THF (150 mL) at room temperature. The reaction was stirred at room temperature for 12 h. The solvent was evaporated, and the residue was acidified to pH 2 and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give intermediate 51 (9.96 g, 100% yield) as a yellow solid. 1H NMR (chloroform-d, 400 MHz) δ ppm: 8.60 (s, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.12-7.18 (m, 2H), 6.72 (s, 1H), 4.34 (d, J = 11.0 Hz, 1H), 4.02-4.10 (m, 1H), 3.72 (dd, J = 15.1, 2.8 Hz, 1H), 2.01 (s, 3H), 1.25 (t, J = 2.2 Hz, 3H). MW, Rt: 2.28, [M+H] + :487.1, Method 6 is confirmed.

[0597] Intermediate 52

[0598] [ka]

[0599] mCPBA[937-14-4] (58.36 mg, 0.26 mmol) was added to a stirred solution of intermediate 45 (96.8 mg, 0.25 mmol) in dry DCM (2 mL) at 0 °C. The reaction was stirred for 3.5 h while allowing to reach room temperature and then diluted with saturated NaHCO and DCM. The phases were separated, the aqueous layer was extracted with DCM, and the combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give intermediate 52 (99.2 mg, 84% yield) as a white solid without further purification.

[0600] Intermediate 53

[0601] [ka]

[0602] A mixture of Intermediate 52 (99 mg, 0.24 mmol), tert-butyl carbamate (42.84 mg, 0.37 mmol), magnesium oxide [1309-48-4] (39.29 mg, 0.97 mmol), and rhodium(II) acetate dimer [15956-28-2] (5.66 mg, 0.013 mmol) was degassed, and dry DCM (2.5 mL) was added, followed by (diacetoxyiodo)benzene [3240-34-4] (117.73 mg, 0.37 mmol). The reaction mixture was stirred at 40 °C for 5 h, then allowed to reach room temperature and filtered through a pad of dicalite, rinsing with DCM. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (mobile phase: 100:0 to 20:80 heptane:EtOAc) to afford intermediate 53 (120.3 mg, 80% yield) as a colorless film.

[0603] Intermediate 54

[0604] [ka]

[0605] Intermediate 54 was prepared by the same reaction protocol as for intermediate 50 starting from intermediate 11 (24.3 mg, 0.088 mmol) and intermediate 53 (60.0 mg, 0.097 mmol) to give intermediate 54 (59.4 g, 72% yield) as a yellow film.

[0606] Intermediate 55

[0607] [ka]

[0608] Triisopropylsilyl chloride [13154-24-0] (1.7 mL, 0.9 g / mL, 7.94 mmol) was added to a stirred solution of methyl (2E)-3-(4-bromophenyl)-2-(hydroxymethyl)-2-propenoate [1505472-36-5] (1.79 g, 6.6 mmol), DMAP [1122-58-3] (87 mg, 0.71 mmol), and imidazole [288-32-4] (582.6 mg, 8.56 mmol) in dry DCM (35 mL) at room temperature. The reaction was stirred for 24 hours, then additional triisopropylsilyl chloride (0.4 mL, 1.87 mmol) and imidazole (111.5 mg, 1.64 mmol) were added, and the resulting mixture was stirred for an additional 24 hours. The crude product was diluted with water and DCM, the phases were separated, and the aqueous layer was extracted once with DCM. The combined organic layers were dried over MgSO, the solids were filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (mobile phase: 100:0 to 90:10 hexanes:EtOAc) to give Intermediate 55 (2.0 g, 71% yield) as a colorless oil.

[0609] Intermediate 56

[0610] [ka]

[0611] A mixture of intermediate 55 (1.0 g, 2.34 mmol), tetrabutylammonium bromide [1643-19-2] (37.7 mg, 0.17 mmol), dry toluene (2 mL), and TMSCFBr [115262-01-6] (7.3 mL, 46.8 mmol) was stirred at 110 °C for 72 h and then concentrated under reduced pressure. The crude product was purified by flash column chromatography (mobile phase: hexane 100:0 to 90:10 hexane:EtOAc) to give intermediate 56 (930 mg; purity 33%, yield 27%).

[0612] Intermediate 57

[0613] [ka]

[0614] LiOH (2.0 M in HO; 1.8 mL, 3.6 mmol) was added to a solution of intermediate 56 (570.4 mg; mixture) in THF (3.4 mL). The reaction was stirred at room temperature overnight and then diluted with HCl 1.0 M until the pH was acidic. EtOAc was added, the phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO, the solids were filtered, and concentrated under reduced pressure to give intermediate 57 as a brown oil, which was used in the next step without further purification (assuming quantitative yield).

[0615] Intermediate 58

[0616] [ka]

[0617] Ammonium chloride [12125-02-9] (169.7 mg, 3.17 mmol) was added to a stirred solution of intermediate 57 (crude), HATU [148893-10-1] (903.9 mg, 2.38 mmol), and TEA (0.66 mL, 0.73 g / mL, 4.78 mmol) in ACN (11 mL). The reaction was stirred at room temperature for 2 days and then diluted with EtOAc and water. The phases were separated, the aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (mobile phase: 100:0 to 70:30 hexanes:EtOAc) to give intermediate 58 (112.6 mg, 20% yield) as a yellow film.

[0618] Intermediate 59

[0619] [ka]

[0620] To a solution of intermediate 55 (140 g, 328 mmol) in THF (750 mL) was added DIBALH[1191-15-7] (1 M, 983 mL) dropwise at −70° C. (dry ice / EtOH) for 30 min. The mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched by the addition of saturated potassium sodium tartrate (100 mL) at −70° C., then diluted with water (1000 mL) and extracted with EtOAc (3×700 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (mobile phase: 100:1 to 8:1 petroleum ether:EtOAc) to give intermediate 59 (89.3 g, 68% yield) as a colorless oil.

[0621] Intermediate 60

[0622] [ka]

[0623] To a solution of intermediate 59 (89.0 g, 223 mmol) in DCM (450 mL) was added TEA (45.1 g, 446 mmol, 62.0 mL) and acetic anhydride [108-24-7] (34.1 g, 334 mmol, 31.3 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to give the crude product. The residue was purified by column chromatography (mobile phase: petroleum ether: EtOAc, 100:1 to 8:1) to give intermediate 60 (78 g, 177 mmol, 79% yield) as a colorless oil.

[0624] Intermediate 61

[0625] [ka]

[0626] To a solution of intermediate 60 (17.0 g, 38.5 mmol) in diglyme (20 mL) was added bis(trimethylsilyl)acetamide [10416-59-8] (783 mg, 3.85 mmol, 951 μL, 0.1 equiv.) dropwise at 170 °C, and sodium 2-bromo-2,2-difluoroacetate [84349-27-9] (75.8 g, 385 mmol, 10 equiv.) in diglyme (240 mL) was added dropwise at 170 °C for 5–8 h. The resulting mixture was stirred at 170 °C for 2 h. The reaction mixture was quenched by the addition of HO (500 mL) and then extracted with EtOAc (3 × 200 mL). The mixture was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: 100:1 to 10:1 petroleum ether: EtOAc) to give intermediate 61 (30.0 g, 55% yield, 70% purity) as a yellow oil.

[0627] Intermediate 62

[0628] [ka]

[0629] A mixture of intermediate 61 (30.0 g, 61.0 mmol), K2CO3 (16.8 g, 122 mmol) in MeOH (150 mL) was degassed and purged with nitrogen, and then the mixture was stirred under a N2 atmosphere at 25 °C for 1 h. The reaction mixture was quenched by adding water (10 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: 100:1 to 10:1 petroleum ether: EtOAc) to give intermediate 62 (30.0 g, crude) as a colorless oil.

[0630] Intermediates 63 and 64

[0631] [ka]

[0632] Intermediate 62 was purified by preparative chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm * 50 mm, 10 μm); mobile phase: [CO-EtOH (0.1% NHHO)]; B: 20%, isocratic elution mode). The compound-containing fractions were combined and evaporated in vacuo to give Intermediate 63 (14.6 g, 98% purity) and Intermediate 64 (13.2 g, 98% purity) as yellow oils.

[0633] Intermediate 65

[0634] [ka]

[0635] To a solution of intermediate 63 (13.2 g, 29.4 mmol) in DCM (130 mL) was added Dess-Martin periodinane [87413-09-0] (15.0 g, 35.2 mmol, 10.9 mL) at 0 °C, and the mixture was stirred at 20 °C under a nitrogen atmosphere for 1 h. The resulting mixture was quenched with saturated NaHCO (50 mL) and saturated NaSO (50 mL), the phases were separated, and the organic layer was concentrated. The crude product was used in the next step without further purification. To a solution of crude (12.9 g, 28.8 mmol) 2-methyl-2-butene [513-35-9] (4.04 g, 57.7 mmol, 6.11 mL) in THF (50 mL) and acetone (50 mL) was added a solution of sodium chlorite [7758-19-2] (3.91 g, 43.3 mmol, 1.5 equiv) and NaH2PO4 [7558-80-7] (10.4 g, 86.5 mmol) in water (50 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h, then quenched with saturated NaHCO3 (50 mL) and saturated Na2SO3 (50 mL), the phases were separated, and the organic layer was concentrated. The residue was purified by column chromatography (mobile phase: 100:1 to 10:1 petroleum ether: EtOAc) to give intermediate 65 (10.0 g, 74% yield) as a colorless oil.

[0636] Intermediate 66

[0637] [ka]

[0638] Starting from ethyl 2-(diethoxyphosphoryl)-4-methylpentanoate [17145-91-4] (2.12 g, 7.56 mmol) and 4-bromo-benzaldehyde [1122-91-4] (1.16 mg, 6.30 mmol), intermediate 66 was prepared by the same reaction protocol as intermediate 13 to give intermediate 66 (861 mg, 44% yield).

[0639] Intermediate 67

[0640] [ka]

[0641] Intermediate 67 was prepared starting from intermediate 66 (861 mg, 2.767 mmol) by a similar reaction protocol as for intermediate 56 to give intermediate 67 (1.36 g, expected quantitative yield) as an orange residue.

[0642] Intermediate 68

[0643] [ka]

[0644] Intermediate 68 was prepared by a similar reaction protocol as for Intermediate 57, starting from Intermediate 67 (1.36 g, crude material from the previous step, assumed to be 3.765 mmol) to give Intermediate 68 (196 mg, 15% yield).

[0645] Intermediate 69

[0646] [ka]

[0647] Intermediate 69 was prepared starting from intermediate 68 (196 mg, 0.588 mmol) by the same reaction protocol as intermediate 18 to give intermediate 69 (19 mg, 9% yield) as a white solid.

[0648] Intermediate 70

[0649] [ka]

[0650] Starting from ethyl 2-(diethoxyphosphoryl)propanoate [3699-66-9] (35.22 g, 147.845 mmol) and 5-bromopicolinaldehyde [31181-90-5] (25 g, 134.404 mmol), intermediate 70 was prepared by the same reaction protocol as intermediate 13 to give intermediate 70 (21.3 g, 56% yield) as a pale yellow solid.

[0651] Intermediate 71

[0652] [ka]

[0653] Starting from intermediate 70 (21.3 g, 74.91 mmol), intermediate 71 was prepared by the same reaction protocol as intermediate 14 to give intermediate 71 (16 g, 89% yield) as a pale yellow oil.

[0654] Intermediate 72

[0655] [ka]

[0656] Intermediate 72 was prepared starting from intermediate 71 (16 g, 66.64 mmol) by the same reaction protocol as intermediate 15 to give intermediate 72 (20 g, 77% yield) as a pale yellow oil.

[0657] Intermediate 73

[0658] [ka]

[0659] Intermediate 73 was prepared starting from intermediate 72 (1.0 g, 2.58 mmol) by the same reaction protocol as intermediate 16 to give intermediate 73 (300 mg, 42% yield) as a brown paste.

[0660] Intermediate 74

[0661] [ka]

[0662] Intermediate 73 (300 mg, 1.08 mmol) was dissolved in water / MeCN (5 mL / 5 mL). TEMPO [2564-83-2] (84 mg, 0.54 mmol), (diacetoxyiodo)benzene [3240-34-4] (1.04 g, 3.24 mmol), and NaHCO (227 mg, 2.70 mmol) were added. The resulting mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure to give Intermediate 74 (160 mg, 51% yield).

[0663] The following intermediates were synthesized by a similar reaction protocol as described for intermediate 21, starting from the intermediate shown and trans-3-methylsulfonylcyclobutylamine hydrochloride [1408075-97-7].

[0664] [Table 3]

[0665] Intermediate 77

[0666] [ka]

[0667] tert-Butyl 3,3-dimethyl-4-oxopyrrolidine-1-carboxylate [1824385-39-8] (900 mg, 4.22 mmol) and N,N-dimethylformamide dimethyl acetate [4637-24-5] (617 μL, 4.64 mmol) were stirred at 90 °C for 1 h. Then, a solution of 3-chloro-1H-pyrazol-5-amine [916211-79-5] (496 mg, 4.22 mmol) in AcOH (4.2 mL) was added dropwise at 85 °C, and the resulting mixture was stirred at 85 °C for 15 h. The reaction mixture was concentrated to dryness to give a residue, which was purified by normal-phase preparative liquid chromatography (mobile phase gradient: 100:0 to 50:50 heptane:EtOAc). The product-containing fractions were combined and concentrated in vacuo to give Intermediate 77 (782 mg, 57% yield) as a pale yellow solid.

[0668] The following intermediates were synthesized by similar reaction protocols as described for intermediate 8, starting from the indicated reagents.

[0669] [Table 4]

[0670] The following intermediates were synthesized by a similar reaction protocol as described for intermediate 9, starting from the indicated intermediate.

[0671] [Table 5]

[0672] The following intermediates were synthesized by a similar reaction protocol as described for intermediate 10, starting from the indicated intermediate.

[0673] [Table 6]

[0674] The following intermediates were synthesized by similar reaction protocols as described for intermediate 50, starting from intermediate 11 and the indicated reagents.

[0675] [Table 7]

[0676] Intermediate 90

[0677] [ka]

[0678] A solution of tert-butyl (3-oxocyclobutyl)carbamate [154748-49-9] (2.0 g, 10.80 mmol), dimethylphosphine oxide [7211-39-4] (1.69 g, 21.60 mmol), and HMDS [999-97-3] (3.48 g, 21.60 mmol) was stirred overnight at 90 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (50 mL) and brine (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with saturated brine (3 × 50 mL), dried over Na SO , filtered, and concentrated to give Intermediate 90 (3 g, crude) as a white solid.

[0679] Intermediate 91

[0680] [ka]

[0681] To a mixture of intermediate 90 (300 mg, 0.894 mmol) in ACN (3 mL) was added EtN 3HF [73602-61-6] (72.09 mg, 0.45 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (30 mL) and brine (30 mL). After phase separation, the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with saturated NaHCO (3 × 30 mL), dried over NaSO, filtered, and concentrated to give intermediate 91 (90 mg, crude) as a white solid.

[0682] Intermediate 92 and Intermediate 93

[0683] [ka]

[0684] A suspension of Intermediate 91 (1.2 g, 4.56 mmol) and 4-dimethylaminopyridine [1122-58-3] (1.11 g, 9.12 mmol) in ACN (36 mL) was stirred at 0 °C under a nitrogen atmosphere. Methyl oxalyl chloride [5781-53-3] (837.59 mg, 6.84 mmol) was then added, and the mixture was allowed to warm to room temperature and stirred for an additional 2.5 h. After adding EtOAc (50 mL), the mixture was washed with saturated NaHCO (50 mL) and brine (50 mL). The organic phase was dried over NaSO and concentrated to give a yellow oil. The resulting yellow oil was dissolved in toluene (36 mL). To this solution, azobisisobutyronitrile [78-67-1] (187.11 mg, 1.140 mmol) and Bu3SnH [688-73-3] (1.99 g, 6.84 mmol) were added. The resulting solution was stirred at 90 °C overnight. After cooling to room temperature, the resulting solution was concentrated. The residue was purified by flash column chromatography (mobile phase: DCM:MeOH 100:0 to 80:20) to give the following: Fraction 1: Intermediate 92 as a yellow solid (136.3 mg, 12% yield) Fraction 2: Intermediate 93 as a yellow solid (73.3 mg, 6% yield)

[0685] Intermediate 94

[0686] [ka]

[0687] A mixture of tert-butyl cis-3-sulfamoylcyclobutylcarbamate [2567498-52-4] (6.5 g, 25.97 mmol), DCM (60 mL), and 1H-imidazole [288-32-4] (20.0 g, 293.78 mmol) was stirred at room temperature for 15 minutes. tert-Butyldimethylsilyl chloride [18162-48-6] (78.27 g, 3.99 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (150 mL) and water (150 mL). After phase separation, the aqueous phase was extracted with DCM (2 × 100 mL) and washed with brine (2 × 150 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (mobile phase: PE:EtOAc 100:0 to 50:50) gave intermediate 94 (2.5 g, 26% yield) as a yellow oil.

[0688] Intermediate 95

[0689] [ka]

[0690] Dry EtN (1.28 mL, 9.02 mmol) was added dropwise to a fresh colorless suspension of dichlorotriphenylphosphorane [2526-64-9] (3.66 g, 11.0 mmol) in CHCl (30 mL) at −5 °C and stirred for 10 min at −5 °C. To this suspension, a solution of intermediate 94 (800 mg, 2.20 mmol) in CHCl (5 mL) was added dropwise and stirred at 5 °C for 1 h. The reaction mixture was added dropwise to methylamine [74-89-5] (1.96 M in tetrahydrofuran, 160.0 mL) at 0 °C. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL). After phase separation, the aqueous phase was extracted with EtOAc (2 × 100 mL) and washed with brine (2 × 150 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (mobile phase: PE:EtOAc from 100:0 to 50:50) to give intermediate 95 (240 mg, 29% yield) as a yellow solid.

[0691] Intermediate 96

[0692] [ka]

[0693] To a stirred solution of intermediate 95 (200 mg, 0.53 mmol) in DCM (20 mL) was added AcOH (30 mL, 524.04 mmol) at room temperature. To this mixture was added a 3:1 mixture of chloroform and isopropyl alcohol (100 mL) and water (30 mL). The solution was basified with aqueous ammonia to pH 7-8, and the phases were separated. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (mobile phase: DCM:MeOH 100:0 to 80:20) to give intermediate 96 (132.7 mg, 79% yield) as an off-white solid.

[0694] The following intermediates were synthesized by a similar reaction protocol as described for intermediate 10, starting from the indicated intermediate.

[0695] [Table 8]

[0696] Intermediate 100

[0697] [ka]

[0698] Intermediate 100 was prepared by the same reaction protocol as for Intermediate 47, starting from Intermediate 35 (60.0 g, 208.96 mmol) to give Intermediate 100 (36.0 g, 48% yield) as a brown oil.

[0699] Intermediates 101 and 102

[0700] [ka]

[0701] Intermediate 100 (42.0 g, 124.58 mmol) was purified by preparative chiral SFC (column: CHIRAL Cellulose-SB, 4.6 * Purification was carried out by HPLC (100 mm, 3 μm; mobile phase A: Hex:IPA=99:1; gradient: isocratic; injection volume: 0.1 mL). Fractions containing the compounds were combined and evaporated in vacuo to give Intermediate 101 (19.2 g, 45% yield) as a pale yellow oil and Intermediate 102 (16.2 g, 38% yield) as a brown oil.

[0702] Intermediate 103

[0703] [ka]

[0704] Intermediate 103 was prepared by the same reaction protocol as for intermediate 50, starting from intermediate 102 (163.9 mg, 0.48 mmol) to give intermediate 103 (184.8 mg, 80% yield) as a yellow film.

[0705] Intermediate 104 (active intermediate)

[0706] [ka]

[0707] Intermediate 104 was prepared by a similar reaction protocol as for Intermediate 51, starting from Intermediate 103 (176.3 mg, 0.32 mmol) to give Intermediate 104 (175.9 mg, 98% purity, quantitative yield) as a yellow foam. 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.29 (d, J = 1.3 Hz, 1H), 7.24-7.31 (m, 1H), 7.16 (dd, J = 12.0, 1.0 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.70-6.75 (m, 1H), 4.27 (dd, J = 11.4, 1.2 Hz, 1H), 4.08 (brd, J = 11.5 Hz, 1H), 3.71 (dd, J = 14.5, 2.5 Hz, 1H), 1.98-2.04 (m, 3H), 1.26-1.29 (m, 3H). MW, Rt: 0.91, [M+H] + :505.2, Method :5 is confirmed.

[0708] Preparation of compounds compound 1

[0709] [ka]

[0710] A pressure tube was charged with Intermediate 22 (175 mg, 0.41 mmol), Intermediate 11 (126.11 mg, 0.46 mmol), BrettPhos Pd G3 (37.57 mg, 0.041 mmol), BrettPhos (22.24 mg, 0.041 mmol), Cs2CO3 (202.53 mg, 0.62 mmol), and 1,4-dioxane (4.05 mL). The mixture was degassed and then stirred at 60 °C for 8 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give compound 1 as a yellow solid (147 mg, 58% yield).

[0711] 1 H NMR(Chloroform-d,400MHz)δppm:8.29-8.25(m,1H),7.26-7.23(m,1H),7.18-7.06(m ,2H),6.70(s,1H),6.08(d,J=6.2Hz,1H),4.55(sxt,J=7.6Hz,1H),4.25(d,J=12. 3Hz,1H),4.06(d,J=11.7Hz,1H),3.80(tt,J=4.6,9.5Hz,1H),3.62(d,J=15.6Hz, 1H), 3.04-2.90 (m, 2H), 2.87 (s, 3H), 2.70-2.60 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

[0712] Compound 2 and Compound 3

[0713] [ka]

[0714] Compound 1 (147 mg) was separated via chiral SFC (stationary phase: Chiralcel Diacel IH 20 x 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following two fractions: Fraction 1: Compound 2 (61 mg, 24% yield starting from intermediate 22) 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.26 (d, J = 1.3 Hz, 1H), 7.26-7.22 (m, 1H), 7.15 (d, J = 11.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.08 (brd, J = 6.4 Hz, 1H), 4.55 (sxt, J = 7.6 Hz, 1H),4.26(d,J=10.5Hz,1H),4.06(d,J=11.4Hz,1H),3.79(tt,J=4.7,9.5Hz,1H),3.64-3 .59(m,1H),3.00-2.92(m,2H),2.87(s,3H),2.70-2.61(m,2H),2.00(s,3H),1.25(s,3H).

[0715] Fraction 2: Compound 3 (63 mg, 25% yield starting from intermediate 22) 1 H NMR (chloroform-d,400MHz)δppm:8.26(d,J=1.3Hz,1H),7.25-7.05(m,3H),6.70(s,1H),6.06(d,J=6.2Hz,1H),4.59-4.50(m,1H),4.24(d,J=10.5Hz,1 H),4.06(d,J=11.5Hz,1H),3.83-3.75(m,1H),3.61(d,J=16.0Hz,1H),2.9 9-2.92(m,2H),2.86(s,3H),2.69-2.60(m,2H),1.99(s,3H),1.24(s,3H).

[0716] compound 4

[0717] [ka]

[0718] Compound 4 was prepared by a similar reaction protocol to compound 1, starting from intermediate 28 (0.1 g, 0.22 mmol) instead of intermediate 22, to give compound 4 (63.4 mg, 44% yield).

[0719] 1 H NMR (chloroform-d,400MHz)δppm:8.32(s,1H),7.11-6.98(m,2H),6.72(s,1H),6.10(brd,J=6.2Hz,1H),4.54(sxt,J=7.5Hz,1H),4.32-4.22(m,1H) ,4.11(t,J=11.7Hz,1H),3.80(tt,J=9.5,4.5Hz,1H),3.57(brd,J=14.3 Hz, 1H), 3.03-2.81 (m, 5H), 2.72-2.62 (m, 2H), 2.01 (s, 3H), 1.27 (s, 3H).

[0720] Compound 5 and Compound 6

[0721] [ka]

[0722] Compound 4 (63.4 mg) was separated via chiral SFC (stationary phase: Chiralcel Diacel IH 20 x 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following two fractions: Fraction 1: Compound 5 (29.6 mg, 21% yield starting from intermediate 28) 1 H NMR (chloroform-d,400MHz)δppm:8.31(d,J=1.1Hz,1H),7.10-6.99(m,2H),6.72(s, 1H),6.08(brd,J=6.2Hz,1H),4.53(sxt,J=7.7Hz,1H),4.28(dd,J=11.4,1.5Hz, 1H),4.10(d,J=11.4Hz,1H),3.80(tt,J=9.5,4.7Hz,1H),3.57(brd,J=14.3Hz,1 H),2.99-2.92(m,2H),2.86(s,3H),2.71-2.63(m,2H),2.00(s,3H),1.27(s,3H)

[0723] Fraction 2: Compound 6 (32.8 mg, 23% yield starting from intermediate 28) 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.32 (d, J = 1.1 Hz, 1H), 7.09-6.98 (m, 2H), 6.72 (s, 1H), 6.07 (brd, J = 6.2 Hz, 1H), 4.53 (sxt, J = 7.7 Hz, 1H), 4.25 (dd, J = 11.4, 1.5 Hz, 1H), 4.1 3(d,J=11.7Hz,1H),3.80(tt,J=9.5,4.6Hz,1H),3.56(brd,J=14.5Hz,1H),2.99-2.9 2(m,2H),2.86(s,3H),2.67(ddd,J=14.4,9.6,7.3Hz,2H),2.01(s,3H),1.27(s,3H).

[0724] compound 7

[0725] [ka]

[0726] Compound 7 was prepared by a similar reaction protocol to Compound 1, starting from Intermediate 34 (175.0 g, 0.40 mmol) instead of Intermediate 22, to give Compound 7 (165.0 mg, 65% yield).

[0727] 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.62 (s, 1H), 7.32 (t, J = 8.1 Hz, 1H), 6.94-6.85 (m, 2H), 6.72 (s, 1H), 6.09 (brd, J = 6.2 Hz, 1H), 4.52 (sxt, J = 7.5 Hz, 1H), 4.32 (dd, J = 11.2, 2.6 Hz, 1H), 4 .05(dd,J=10.9,5.8Hz,1H),3.80(tt,J=9.6,4.6Hz,1H),3.49(brd,J=15.2Hz,1H),3.03- 2.89(m,2H),2.86(s,3H),2.66(ddd,J=14.5,9.6,7.2Hz,2H),2.00(s,3H),1.24(brs,3H).

[0728] Compound 8 and Compound 9

[0729] [ka]

[0730] Compound 7 (165 mg) was separated via chiral SFC (stationary phase: Chiralcel Diacel IH 20 x 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following two fractions: Fraction 1: Compound 8 (72.0 mg, 29% yield starting from intermediate 34) 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.62 (s, 1H), 7.32 (t, J = 8.3 Hz, 1H), 6.94-6.85 (m, 2H), 6.72 (s, 1H), 6.09 (brd, J = 6.1 Hz, 1H), 4.57-4.48 (m, 1H), 4.32 (d, J = 11.2 Hz, 1H), 4.0 5(d,J=11.1Hz,1H),3.80(tt,J=9.5,4.7Hz,1H),3.49(brd,J=15.0Hz,1H),2.99-2.9 1(m,2H),2.86(s,3H),2.67(ddd,J=14.5,9.6,7.1Hz,2H),2.00(s,3H),1.24(s,3H).

[0731] Fraction 2: Compound 9 (76.0 mg, 30% yield starting from intermediate 34) 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.62 (s, 1H), 7.32 (t, J = 8.2 Hz, 1H), 6.93-6.85 (m, 2H), 6.72 (s, 1H), 6.08 (brd, J = 6.3 Hz, 1H), 4.57-4.47 (m, 1H), 4.31 (d, J = 11.2 Hz, 1H), 4.0 6(d,J=11.3Hz,1H),3.80(tt,J=9.6,4.6Hz,1H),3.49(brd,J=15.3Hz,1H),2.99-2.9 1(m,2H),2.86(s,3H),2.67(ddd,J=14.4,9.6,7.2Hz,2H),2.00(s,3H),1.24(s,3H).

[0732] compound 10

[0733] [ka]

[0734] Compound 10 was prepared by a similar reaction protocol to compound 1, starting from intermediate 40 (0.17 mg, 0.40 mmol) instead of intermediate 22, to give compound 10 (151 mg, 59% yield).

[0735] 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.29-8.25 (m, 1H), 7.26-7.23 (m, 1H), 7.18-7.06 (m, 2H), 6.70 (s, 1H), 6.08 (brd, J = 6.2 Hz, 1H), 4.55 (sxt, J = 7.6 Hz, 1H), 4.25 (brd, J = 12. 3Hz,1H),4.06(brd,J=11.7Hz,1H),3.80(tt,J=9.5,4.6Hz,1H),3.62(brd,J=15.6H z,1H),3.04-2.90(m,2H),2.87(s,3H),2.70-2.60(m,2H),2.00(s,3H),1.25(s,3H).

[0736] Compound 11 and Compound 12

[0737] [ka]

[0738] Compound 10 (151 mg) was separated via chiral SFC (stationary phase: Chiralcel Diacel IH 20 x 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following two fractions: Fraction 1: Compound 11 (70.0 mg, 28% yield starting from intermediate 40) 11H NMR (chloroform-d, 400 MHz) δ ppm: 8.26 (d, J = 1.3 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.15 (d, J = 11.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.08 (brd, J = 6.4 Hz, 1H), 4.55 (sxt, J = 7.6 Hz, 1H), 4.26 (d, J = 10.5 Hz, 1H), 4.06 (d, J = 11.4 Hz, 1H), 3.79 (tt, J = 9.5, 4.7 Hz, 1H), 3.62 (brd, J = 15.8 Hz, 1H), 3.00 - 2.92 (m, 2H), 2.87 (s, 3H), 2.70 - 2.61 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

[0739] Fraction 2: Compound 12 (starting from Intermediate 40, 71.0 mg, yield 28%) 1 1H NMR (chloroform-d, 400 MHz) δ ppm: 8.26 (d, J = 1.3 Hz, 1H), 7.26 (s, 2H), 7.25 - 7.05 (m, 3H), 6.70 (s, 1H), 6.06 (brd, J = 6.2 Hz, 1H), 4.59 - 4.50 (m, 1H), 4.24 (d, J = 10.5 Hz, 1H), 4.06 (d, J = 11.5 Hz, 1H), 3.79 (tt, J = 9.5, 4.7 Hz, 1H), 3.61 (brd, J = 16.0 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.64 (ddd, J = 14.4, 9.6, 7.2 Hz, 2H), 1.99 (s, 3H), 1.24 (s, 3H).

[0740] Compound 13

[0741]

Chemical Structure

[0742] A 20 mL vessel was charged with Intermediate 10 (204.67 mg, 0.74 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (30.37 mg, 0.074 mmol), palladium(II) acetate (11.07 mg, 0.049 mmol), and potassium carbonate (170.41 mg, 1.23 mmol). The vessel was sealed and degassed. A solution of Intermediate 18 (150 mg, 0.49 mmol) in dry toluene (5.0 mL) was then poured into the vessel, which was then degassed again by bubbling N. The mixture was stirred at 60 °C for 12 h, and then the reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give compound 13 (125 mg, 51% yield).

[0743] 1 H NMR (chloroform-d,400MHz)δppm:8.57(d,J=1.1Hz,1H),7.30(m,J=8.3Hz,2H),7.12(m,J=8.4Hz,2H),6.69(s,1H),5.83(s,1H),4.31(dd,J=11. 1,2.0Hz,1H),4.03(dd,J=11.0,4.0Hz,1H),3.66-3.59(m,1H),2.93(d,J=4.8Hz,3H),1.99(s,3H),1.69-1.65(m,1H),1.21(d,J=2.0Hz,3H).

[0744] Compounds 14, 15, 16 and 17

[0745] [ka]

[0746] Compound 13 (125 mg) was separated via chiral SFC (stationary phase: Chiralcel Diacel OJ 20 x 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following four fractions: Fraction 1: Compound 14 (23.3 mg, 9% yield starting from intermediate 18) 1 H NMR (chloroform-d,400MHz)δppm:8.57(d,J=1.1Hz,1H),7.33-7.27(m,J=8.3Hz,2H),7.15-7.10(m,J=8.4Hz,2H),6.69(s,1H),5.83(brs,1H),4.31(d d,J=2.0,11.1Hz,1H),4.03(dd,J=4.0,11.0Hz,1H),3.66-3.59(m,1H),2 .93(d,J=4.8Hz,3H),1.99(s,3H),1.69-1.65(m,1H),1.25-1.16(m,3H).

[0747] Fraction 2: Compound 15 (23.0 mg, 9.3% yield starting from intermediate 18) 1 H NMR (chloroform-d, 400 MHz) δ ppm: 8.57 (s, 1H), 7.34-7.28 (m, 2H), 7.17-7.10 (m, 2H), 6.70 (s, 1H), 5.83 (brs, 1H), 4.33 (d, J = 11.0 Hz, 1H), 4.07-4.01 (m, 1H), 3.63 (dd, J = 2.5, 15.7 Hz, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.00 (s, 3H), 1.30-1.13 (m, 3H).

[0748] Fraction 3: Compound 16 (21.5 mg, 9% yield starting from intermediate 18) 1H NMR (chloroform-d,400MHz)δppm:8.58(s,1H),7.33-7.28(m,J=8.6Hz,2H),7.16-7.11(m,J=8.6Hz,2H),6.70(s,1H),5.83(brs,1H),4 .32(d,J=11.2Hz,1H),4.05(d,J=11.2Hz,1H),3.63(dd,J=2.3,15.7Hz,1H),2.94(d,J=4.8Hz,3H),2.00(s,3H),1.26-1.16(m,3H).

[0749] Fraction 4: Compound 17 (22.0 mg, 9% yield starting from intermediate 18) 1 H NMR (chloroform-d,400MHz)δppm:8.58(s,1H),7.31(d,J=8.4Hz,2H),7.13(d,J=8.6Hz,2H),6.70(s,1H),5.83(brs,1H),4.32(d ,J=11.0Hz,1H),4.05(d,J=11.2Hz,1H),3.63(dd,J=2.4,15.6Hz,1H),2.94(d,J=4.6Hz,3H),2.00(s,3H),1.27-1.16(m,3H).

[0750] The following compounds were synthesized by similar reaction protocols as described for compound 1, starting from intermediate 43 and the intermediate shown.

[0751] [Table 9]

[0752] Starting from intermediate 11 and the intermediate shown, the following compounds were synthesized by a similar reaction protocol as described for compound 1.

[0753] [Table 10-1]

[0754] [Table 10-2]

[0755] compound 33

[0756] [ka]

[0757] Intermediate 54 (59 mg, 0.063 mmol) was dissolved in MeOH (0.8 mL) and HCl (4 M in dioxane; 0.3 mL, 1.2 mmol), and the mixture was stirred at room temperature for 4 h. The mixture was dried under vacuum, and the residue was diluted with DCM. Saturated NaHCO was added, and the phases were separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried over MgSO, filtered, and evaporated. The residue was purified by flash column chromatography (mobile phase: DCM:MeOH / NHN 100:0 to 96:4) to give compound 33 (33.3 mg, 77% yield) as a yellow film.

[0758] Compound 34 and Compound 35

[0759] [ka]

[0760] Compound 33 (33 mg) was separated via chiral SFC (stationary phase: Chiralpak Diacel AD 20 × 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following four fractions: Fraction 1: Compound 34 (8.4 mg, 22% yield) as a yellow solid Fraction 2: Compound 35 (8.4 mg, 22% yield) as a yellow solid

[0761] compound 36

[0762] [ka]

[0763] TBAF (1 M in THF, 0.10 mL, 0.10 mmol) was added to a solution of intermediate 87 (52 mg, 0.066 mmol) in anhydrous THF (2 mL). The reaction was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (15 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (mobile phase: 100:0 to 0:100 heptane:EtOAc) to give compound 36 (35 mg, 80% yield) as a yellow solid.

[0764] compound 37

[0765] [ka]

[0766] A 20 mL vial was charged with compound 3 (150 mg, 0.24 mmol) and formic acid (0.018 mL, 1.22 g / mL, 0.49 mmol) in 4 mL of 1,4-dioxane, as well as CsCO (94.89 mg, 0.29 mmol) and BrettPhos Pd G (66.01 mg, 0.073 mmol). The mixture was degassed with N and stirred at 55 °C for 1 h. Saturated NaHCO sol was added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO, filtered, and evaporated. The product was purified by flash column chromatography (mobile phase: DMC:MeOH 100:0 to 97:3). The pure fractions were evaporated and re-purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 × 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give compound 37 (23.2 mg, 16% yield).

[0767] compound 38

[0768] [ka]

[0769] A solution of Intermediate 51 (49 mg, 0.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (39 mg, 52 μL, 0.30 mmol) in ACN (1 mL) was added to 2-(dimethylphosphoryl)ethan-1-amine hydrochloride [1003315-34-1] (3.0 mg, 0.20 mmol). 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide [68957-94-8] (0.13 g, 0.12 mL, 50% Wt, 0.20 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the crude material was redissolved in 2 mL of DCM / EtOAc (2 / 1) and washed with 1 mL of 1 M citric acid. The solvent was removed under reduced pressure, and the crude mixture was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30 × 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give compound 38 (34.0 mg, 58% yield).

[0770] The following compounds were synthesized from the indicated reagents by a reaction protocol similar to that described for compound 38.

[0771] [Table 11-1]

[0772] [Table 11-2]

[0773] [Table 11-3]

[0774] [Table 11-4]

[0775] Table 11-5

[0776] Table 11-6

[0777] Table 11-7

[0778] Table 11-8

[0779] Table 11-9

[0780] Table 11-10

[0781] Table 11-11

[0782] Table 11-12

[0783] Table 11-13

[0784] Table 11-14

[0785] Table 11-15

[0786] Table 11-16

[0787] Table 11-17

[0788] Table 11-18

[0789] Table 11-19

[0790] Table 11-20

[0791] Table 11-21

[0792] Table 11-22

[0793] Table 11-23

[0794] Table 11-24

[0795] Table 11-25

[0796] Table 11-26

[0797] Table 11-27

[0798] Table 11-28

[0799] Table 11-29

[0800] Table 11-30

[0801] Table 11-31

[0802] Table 11-32

[0803] Table 11-33

[0804] Table 11-34

[0805] Table 11-35

[0806] Table 11-36

[0807] Table 11-37

[0808] Table 11-38

[0809] Table 11-39

[0810] Table 11-40

[0811] Table 11-41

[0812] Table 11-42

[0813] Table 11-43

[0814] Table 11-44

[0815] Table 11-45

[0816] Table 11-46

[0817] Table 11-47

[0818] Table 11-48

[0819] Table 11-49

[0820] Table 11-50

[0821] Table 11-51

[0822] Compound 318

[0823]

change

[0824] HCl (4 M in dioxane, 0.1 mL, 0.4 mmol) was added to a solution of intermediate 89 (42 mg, 0.06 mmol) in 1,4-dioxane (0.6 mL). The reaction was stirred at room temperature for 3 hours. The mixture was poured into a saturated solution of bicarbonate, extracted twice with DCM, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography (mobile phase: 100:0 to 95:5 DCM:MeOH) to give compound 318 (28 mg, 78% yield) as a white solid.

[0825] Compounds 319 and 320

[0826] [ka]

[0827] Compound 318 (28.0 mg) was separated via chiral SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: CO, EtOH + 0.4 iPrNH). The compound-containing fractions were combined and the solvent was concentrated in vacuo to give the following two fractions: Fraction 1: Compound 319 (4.5 mg, 13% yield starting from intermediate 89) Fraction 2: Compound 320 (10.0 mg, 30% yield starting from intermediate 89)

[0828] [Table 12-1]

[0829] [Table 12-2]

[0830] [Table 12-3]

[0831] [Table 12-4]

[0832] [Table 12-5]

[0833] [Table 12-6]

[0834] [Table 13-1]

[0835] [Table 13-2]

[0836] analytical analysis High Performance Liquid Chromatography (HPLC) measurements were performed using the LC pump, diode-array (DAD) or UV detector, and column specified in each method. Additional detectors were included if necessary (see methods table below).

[0837] The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of one skilled in the art to set tuning parameters (e.g., scan range, dwell time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed with appropriate software.

[0838] Compounds were analyzed by their experimental retention times (R t ) and ions. Unless otherwise specified in the tables of data, the reported molecular ions are [M+H] +(protonated molecule) and / or [MH] - (deprotonated molecule). If the compound is not directly ionizable, the type of adduct is specified (i.e., [M+NH4] + , [M+HCOO] - For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained for the lowest isotopic mass. All results are obtained with experimental uncertainties typically associated with the methods used.

[0839] Hereinafter, "SQD" means single quadrupole detector, "MSD" means mass selected detector, "RT" means room temperature, "BEH" means crosslinked ethylsiloxane / silica hybrid, "DAD" means diode array detector, and "HSS" means high strength silica.

[0840] LCMS method code (flow rate (mL / min), column temperature (T) (°C), run time (min), "ACN" means acetonitrile.)

[0841] [Table 14]

[0842] SFC-MS method SFC measurements were performed using an analytical supercritical fluid chromatography (SFC) system configured with a binary pump and modifier to deliver carbon dioxide (CO), an autosampler, a column oven, and a diode array detector equipped with a high-pressure flow cell capable of withstanding up to 400 bar. When configured with a mass spectrometer (MS), the flow from the column was fed to the MS. Setting tuning parameters (e.g., scan range, residence time, etc.) to obtain ions that allow identification of the compound's nominal monoisotopic molecular weight (MW) is within the knowledge of one skilled in the art. Data collection was performed with appropriate software. The analytical SFC-MS method (flow rate (mL / min), column temperature (Col T) (°C), run time (min), and back pressure (BPR) (bar)) were used. "iPrNH" means isopropylamine, "iPrOH" means 2-propanol, "EtOH" means ethanol, and "min" means minutes.

[0843] [Table 15]

[0844] NMR 1 H NMR spectra were recorded on a Bruker Avance III 400 MHz spectrometer and an Avance NEO 400 MHz spectrometer. Unless otherwise stated, chloroform-d was used as the solvent. Chemical shifts are expressed in ppm relative to tetramethylsilane. "Cpd No." refers to the compound number.

[0845] [Table 16-1]

[0846] [Table 16-2]

[0847] [Table 16-3]

[0848] Pharmacological analysis Biological Examples In vitro assays include assays that measure cell morphology, protein expression, and / or cytotoxicity, enzyme inhibitory activity, and / or functional outcomes following treatment of cells with compounds of the invention. Alternatively or additionally, in vitro assays can be used to quantitate the ability of an inhibitor to bind to a protein or nucleic acid molecule within a cell.

[0849] Inhibitor binding can be measured by radiolabeling the pre-bound inhibitor, isolating the inhibitor / target molecule complex, and determining the amount of radiolabel binding. Alternatively or additionally, inhibitor binding can be determined by performing a competition experiment in which new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions for an exemplary system for assaying the compounds of Formula (I) of the present invention as MALT1 inhibitors are described in the Biological Examples below.

[0850] Such assays are exemplary only and are not intended to limit the scope of the invention. Those skilled in the art will recognize that conventional assays can be modified to develop equivalent or other assays that can be employed to comparatively evaluate or otherwise characterize the activity of the compounds and / or compositions described herein.

[0851] In vitro assay Biological Example 1 MALT1 biochemical protease assay MALT1 protease activity was assessed in an in vitro assay using the tetrapeptide as a substrate and full-length MALT1 protein (Strep-MALT1(1-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR conjugates with AMC (7-amino-4-methylcoumarin), providing a quenched fluorescent substrate for MALT1 protease (SM Biochemicals). Cleavage of AMC from the arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 μM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA), and 1.5% dimethyl sulfoxide (DMSO). Test compounds were spotted at 50 nL per well in 100% DMSO onto black 384-proxy plates (Perkin Elmer). Test compound concentrations ranged from 30 μM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme, which served as low controls (LC). High control (HC) values ​​were generated using reactions with enzyme but without compound treatment. Compounds were preincubated with MALT1 enzyme for 50 minutes at room temperature. Substrate was then added, and fluorescence was measured on a Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time zero. Reactions were then incubated at room temperature for 4 hours, and fluorescence was measured. IC 50 For calculations, time point 0 was subtracted from the 4-hour time point to correct for any potential autofluorescence of the compound. The enzymatic reaction was linear over the 4-hour incubation period. Characterization of the substrate Ac-LRSR-AMC revealed a Michaelis constant K of 200 μM. M It was decided.

[0852] Using the following formula, IC 50 values ​​were calculated (Z prime should be >0.5). LC = median low control value = Low control: reaction without enzyme HC = median high control value = High control: reaction with enzyme Effect% = 100 - [((Sample - LC) / (HC - LC) x 100] % Control = (Sample / HC) x 100 Control minimum value % = ((sample-LC) / (HC-LC)) x 100

[0853] A best fit curve was fitted by least squares to a plot of % control min versus test compound concentration. From this, the IC 50 The value (inhibitory concentration causing 50% inhibition) can be obtained. An estimate of the slope of the plot for the Hill coefficient was also obtained.

[0854] I C 50 Calculation:

[0855]

number

[0856] Used with "Lexis Dose Response Curve Fitting" version 1.0. The data obtained is shown below. Table 2 ("Cpd No." means compound number, "nd" means undetermined, and "Int" means intermediate)

[0857] [Table 17-1]

[0858] [Table 17-2]

[0859] [Table 17-3]

[0860] [Table 17-4]

[0861] [Table 17-5]

[0862] Biological Example 2 MALT1-mediated cleavage of the GloSensor reporter in Jurkat cells The MALT1 GloSensor™ detects the RelB MALT1 cleavage site sequence

[0863] [ka] This split luciferase reporter utilizes a genetically engineered form of firefly luciferase (CP UltraGlo) split into two distinct domains by the insertion of MALT1. MALT1-induced cleavage allows for a conformational change that re-establishes a functional luciferase protein that results in light emission; thus, luciferase activity surrogates for endogenous MALT1 protease activity. Jurkat MALT1 GloSensor™ was generated by electroporation, selected, and maintained in the presence of 0.5 mg / mL Geneticin. MALT1 protease is basally inactive in Jurkat cells and can be activated by treatment with PMA / ionomycin. A small-molecule MALT1 inhibitor added before PMA / ionomycin addition prevents MALT1 protease activation; therefore, cleavage of the MALT1 GloSensor splits the luciferase reporter in a dose-dependent manner.

[0864] Jurkat MALT1 GloSensor™ cells were maintained in complete RPMI 1640 medium containing 10% fetal bovine serum, 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 100 units / mL penicillin, 100 μg / mL streptomycin, and 0.5 mg / mL Geneticin. Prior to the assay, compounds were serially diluted 2.5-fold in DMSO. 100 nL of test compound was spotted per well of a 384-well plate (Perkin Elmer, catalog number 6007688). Jurkat cells were harvested by centrifugation at 1200 RPM for 5 minutes, suspended in fresh complete RPMI 1640 medium containing 2% GloSensor™ cAMP Reagent, and pre-incubated at 37°C for 45-60 minutes in a 5% CO2 incubator. A volume of 50 uL of pre-incubated Jurkat MALT1 GloSensor™ cells (1 x 10 5 Cells) were seeded into each well of a 384-well plate. A volume of 2 μL of diluted PMA / ionomycin (2.5 μg / mL / 25 μM, respectively, Sigma, catalog numbers P1585 and 407953) in DMSO was then added to each well. After 4 hours of incubation at 37°C in a 5% CO2 incubator, luminescence was measured at 37°C in an Envision (Perkin Elmer).

[0865] I C 50 Values ​​were calculated using SmartFit in GeneData Screener®:

[0866]

number

[0867] The data obtained are shown in Table 3 ("Cpd No." means compound number and "Int" means intermediate).

[0868] [Table 18-1]

[0869] [Table 18-2]

[0870] [Table 18-3]

[0871] [Table 18-4]

[0872] [Table 18-5]

[0873] [Table 18-6]

[0874] Biological Example 3 Human IL-6 / IL-10 mesoscale assay OCI Ly3 cells were grown in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 1% PenStrep (Sigma Aldrich). The cell passage number should not exceed 30. Cells should be maintained between 0.5 and 1.5 million cells / mL in culture.

[0875] For the Mesoscale assay, 100,000 OCI-Ly3 cells were seeded per well in a black 96-well plate with a clear bottom (Corning® #3904), and test compounds were added in nine dilution steps (1:2) ranging from 15 μM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (high control (HC)). Treatment with an appropriate dose of reference compound served as a positive control for MALT1 inhibition and was used to determine maximum inhibition (low control (LC)). Compounds and cells were incubated for 24 h at 37°C and 5% CO2 (assay volume is 150 μL). After 24 h of incubation, 50 μL of supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (Human) Kit, Mesoscale (MSD)) and incubated for 2 h at room temperature with vigorous shaking (600 rpm). After incubation, the plates were washed three times with phosphate-buffered saline (PBS) + 0.05% Tween-20, and 25 μL of detection antibody solution (IL-6 and IL-10 antibodies in Diluent 3 (MSD)) was added per well, followed by incubation for 2 hours with vigorous shaking (600 rpm) at room temperature. After washing three times with PBS + 0.05% Tween-20, the plates were incubated with 150 μL of 2× Read Buffer T and read on a SECTOR imager. The resulting data are shown in Table 4 ("Cpd No." means compound number, "Int" means intermediate, and "nd" means undetermined).

[0876] [Table 19-1]

[0877] [Table 19-2]

[0878] Biological Example 4 Proliferation assay OCI-Ly3 cells were grown in RPMI-1640 containing Glutamax (ThermoFisher) supplemented with 10% heat-inactivated fetal bovine serum (ThermoFisher). Cells should be maintained between 0.2 and 1.5 million cells / mL and passaged every 3–4 days during culture. OCI-Ly7 cells were grown in IMDM (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma-Aldrich), and 50 μg / mL gentamicin. Cells should be maintained between 0.15 and 3 million cells / mL and passaged every 3–4 days during culture. Cell passage number should not exceed 20.

[0879] To evaluate antiproliferative effects, 450 nL of test compound was spotted per well of a U-bottom 96-well plate (Corning®, #3975). Five hundred OCI-Ly3 or OCI-Ly7 cells were seeded in 150 μL of medium per well and incubated at 37°C and 5% CO2 for 8 days. To ensure linear cell growth, the cell plating number was selected based on the growth curve. After 8 days of incubation, 100 μL of seeded cells were resuspended by pipetting up and down and transferred to a flat-bottom black plate (Corning®, #3904). 50 μL of CellTiterGLO reagent (Promega) was added to each well, followed by 10 minutes of shaking at 300 rpm and 10 minutes of incubation at room temperature in the dark. Luminescence was then measured using an Envision (Perkin Elmer) instrument.

[0880] I C 50 Values ​​were calculated using SmartFit in GeneData Screener:

[0881]

number

[0882] The data obtained are shown in Table 5 ("Cpd No." means compound number, "nd" means undetermined, and "Int" means intermediate):

[0883] [Table 20-1]

[0884] [Table 20-2]

[0885] [Table 20-3]

[0886] [Table 20-4]

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, R １ teeth, 【Chemistry 2】 represents q is 1 or 2; R ｘ is hydrogen; C １～４ alkyl; halo or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, R ｙ is hydrogen; C １～４ Alkyl; C ３～６ cycloalkyl; or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, R ｚ But C １～４ Alkyl; C ３～６ cycloalkyl; or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, or R ｙ and R ｚ together with the carbon atoms to which they are attached, form C ３～６ forming a cycloalkyl, ring 【Transformation 3】 represents phenyl or pyridyl, R ２ represents a halo, n is 0, 1, or 2; R ３ａ is hydrogen or C １～４ represents alkyl, R ３ｂ is hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; Adamantyl; C ６～１０ Carbon bicyclic; Het １ ; Oxo, halo, cyano, -OH, -OR ７ , -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-R ７ , -C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl-O-R ７ , -NH-S (=O) ２ -R ７ , Het ３ａ , Het ３ｂ , as well as —OH, halo, —S(═O)(═NH)—C １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -S(=O) ２ -NR ４ａ R ４ｂ , and -S(=O) ２ -C １～４ C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～４ C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl ３～６ cycloalkyl; Oxo, halo, cyano, -OH, -OR ７ , -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-R ７ , -C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl-O-R ７ , -NH-S (=O) ２ -R ７ 、 and -OH, halo, -S(=O)(=NH)-C １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -S(=O) ２ -NR ４ａ R ４ｂ , and -S(=O) ２ -C １～４ C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～４ C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl ６～１０ carbobicyclic; or Cyano, halo, -OH, -OR ７ , -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-R ７ , -C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl-O-R ７ , -NH-S (=O) ２ -R ７ , -CF ３ , Cy １ , Het ３ａ , Het ３ｂ , -O-Het ３ｂ , -C(=O)-Het ３ａ , -C(=O)-Het ３ｂ , and 【Chemistry 4】 C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of １～４ Alkyl, represents or R ３ａ and R ３ｂ together with the nitrogen atom to which they are attached to form Het ２ Forming Cy １ But C ３～６ cycloalkyl; or halo, —OH, —OR ７ , -S(=O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-C １～４ Alkyl, —NH—(C═O)—C ３～６ cycloalkyl, —C(═O)—NR ４ａ R ４ｂ , and —NH—S(═O) ２ -R ７ C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of ３～６ represents cycloalkyl, Het １ represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het １ is a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in said heterocyclyl may be oxo, halo, cyano, —OH, OR ７ -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-R ７ , -C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl-O-R ７ , -NH-S (=O) ２ -R ７ 、 and OH, halo, S(=O)(=NH)-C １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -S(=O) ２ -NR ４ａ R ４ｂ , and -S(=O) ２ -C １～４ C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～４ and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, Het ５ , -C(=O)-NR ４ａ R ４ｂ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -C(=O)-C ３～６ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cycloalkyl, —OH, and halo １～４ may be substituted with alkyl, Het ２ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het ２ is a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, wherein one or more of the carbon atoms in said heterocyclyl may be oxo, halo, cyano, —OH, —OR ７ , Het ６ , -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-R ７ , -C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl-O-R ７ , -NH-S (=O) ２ -R ７ and -OH, halo, -S(=O)(=NH)-C １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -S(=O) ２ -NR ４ａ R ４ｂ , Het ４ and -S(=O) ２ -C １～４ C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～４ and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , Het ４ , or -C(=O)-C ３～６ optionally substituted with cycloalkyl; Het ３ａ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het ３ａ represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in said heterocyclyl may be oxo, halo, —OH, —OR ７ , -S(=O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-C １～４ Alkyl, —NH—(C═O)—C ３～６ cycloalkyl, —C(═O)—NR ４ａ R ４ｂ , and —NH—S(═O) ２ -R ７ and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, Het ５ , -C(=O)-NR ４ａ R ４ｂ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -C(=O)-C ３～６ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cycloalkyl, —OH, and halo １～４ may be substituted with alkyl, Het ３ｂ represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het ３ｂ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in said heterocyclyl may be oxo, halo, —OH, C １～４ Alkyl, -OR ７ , -S(=O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-C １～４ Alkyl, —NH—(C═O)—C ３～６ cycloalkyl, —C(═O)—NR ４ａ R ４ｂ , and —NH—S(═O) ２ -R ７ and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ Or S(=O)(=NH) may be formed, wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, Het ５ , -C(=O)-NR ４ａ R ４ｂ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -C(=O)-C ３～６ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of cycloalkyl, —OH, and halo １～４ may be substituted with alkyl, Het ４ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), Het ５ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), Het ６ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), R ４ａ and R ４ｂ are each independently hydrogen, C １～４ Alkyl, C ３～６ Cycloalkyl or C １～４ Alkyl-O-C １～４ represents alkyl, R ４ｃ and R ４ｄ are each independently C １～４ Alkyl or —O—C １～４ represents alkyl, R ６ is C １～４ alkyl; or C substituted with one —OH １～４ represents alkyl, R ７ each of which is optionally substituted with 1, 2 or 3 halo substituents; １～４ Alkyl or C ３～６ represents cycloalkyl, p1 and p2 are each independently 1, 2, or 3. or a tautomeric or stereoisomeric form thereof or a pharmaceutically acceptable salt thereof.

2. R ｘ represents a halo, R ｙ is hydrogen or C １～４ represents alkyl, R ｚ is a C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, or R ｙ and R ｚ together with the carbon atoms to which they are attached, form C ３～６ forming a cycloalkyl, R ３ｂ is hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; Adamantyl; C ６～１０ Carbon bicyclic; Het １ ; Oxo, —OH, —OR ７ , -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -NH-(C=O)-R ７ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , -NH-S (=O) ２ -R ７ , Het ３ａ , Het ３ｂ and -OH, halo, -S(=O)(=NH)-C １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -S(=O) ２ -NR ４ａ R ４ｂ , and -S(=O) ２ -C １～４ C optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl １～４ C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of alkyl ３～６ cycloalkyl; -OR ７ , -S(=O) ２ -R ７ , and -S(=O) ２ -NR ４ａ R ４ｂ C substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of ６～１０ carbobicyclic; or Cyano, halo, -OH, -OR ７ , -S(=O) ２ -R ７ , -S(=O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -C(=O)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl-O-R ７ , -NH-S (=O) ２ -R ７ , -Cy １ , Het ３ａ , Het ３ｂ , -O-Het ３ｂ , -C(=O)-Het ３ａ ,and 【Transformation 5】 C substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of １～４ Alkyl, represents or R ３ａ and R ３ｂ together with the nitrogen atom to which they are attached to form Het ２ Forming Cy １ is C ３～６ cycloalkyl; or —S(═O) ２ -C １～４ Alkyl, and —S(═O) ２ -NR ４ａ R ４ｂ C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of ３～６ represents cycloalkyl, Het １ represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het １ is a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in said heterocyclyl may be oxo, —OH, —OR ７ -S(=O) ２ -R ７ , -C(=O)-NR ４ａ R ４ｂ , -S(=O)(=NH)-NR ４ａ R ４ｂ , -P(=O)-R ４ｃ R ４ｄ , —O—C １～４ Alkyl-C(=O)-NR ４ａ R ４ｂ and —OH and —C(═O)—NR ４ａ R ４ｂ C optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of １～４ and optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, Het ５ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -C(=O)-C ３～６ Cycloalkyl or C substituted with 1, 2 or 3 —OH １～４ may be substituted with alkyl, Het ２ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N, or Het ２ represents a bicyclic N-linked 6-11 membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more of the carbon atoms in said heterocyclyl is Het ６ , -S(=O) ２ -NR ４ａ R ４ｂ , -S(=O)(=NH)-R ７ , -N=S(=O)-(C １～４ alkyl) ２ , -C(=O)-NR ４ａ R ４ｂ , and 1, 2 or 3 -S(=O) ２ -C １～４ C optionally substituted with alkyl １～４ and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of alkyl, wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more N atoms in said heterocyclyl are Het ４ may be substituted with Het ３ａ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more carbon atoms in the heterocyclyl are optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of oxo and —OH; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, Het ５ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , or -C(=O)-C ３～６ optionally substituted with cycloalkyl; Het ３ｂ represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N, or Het ３ｂ represents a bicyclic C-linked 6-11 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from O, S and N; wherein one or more carbon atoms in said heterocyclyl may be oxo, halo, —OH, C １～４ Alkyl and -OR ７ and optionally substituted with a total of 1, 2, or 3 substituents each independently selected from the group consisting of: wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), wherein one or more of the N atoms in said heterocyclyl is C １～４ Alkyl, Het ５ Or -S(=O) ２ -C １～４ may be substituted with alkyl, Het ４ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), Het ５ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), Het ６ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two heteroatoms each independently selected from O, S and N; wherein one or more S atoms in the heterocyclyl are substituted, such as S(=O), S(=O) ２ or may form S(=O)(=NH), p1 and p2 are 2; The compound of claim 1.

3. q is 1, R ｘ represents a halo, R ｙ is C １～４ represents alkyl, R ｚ is a C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, n is 0 or 1; R ３ａ represents hydrogen, R ３ｂ is C １～４ Alkyl; C ３～６ cycloalkyl; or -S(=O) ２ -R ７ and -S(=O)(=NH)-R ７ C substituted with one substituent selected from the group consisting of ３～６ represents cycloalkyl, R ６ is C １～４ alkyl; or C substituted with one —OH １～４ represents alkyl, R ７ is C １～４ represents alkyl, 3. The compound according to claim 1 or 2.

4. R １ teeth, 【Transformation 6】 represents R ｙ is C １～４ Alkyl; C ３～６ cycloalkyl; or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, R ｚ But C １～４ Alkyl; C ３～６ cycloalkyl; or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, or R ｙ and R ｚ together with the carbon atoms to which they are attached, form C ３～６ forming a cycloalkyl, R ３ａ represents hydrogen, R ３ｂ is hydrogen; C １～４ Alkyl; C ３～６ cycloalkyl; -C １～４ Alkyl-Cy １ ; Halo, —OH, —O—C １～４ Alkyl, -OCF ３ , -OCHF ２ , -S(=O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-C １～４ Alkyl, —NH—(C═O)—C ３～６ cycloalkyl, —C(═O)—NR ４ａ R ４ｂ , and —NH—S(═O) ２ -C １～４ C substituted with one substituent selected from the group consisting of alkyl ３～６ cycloalkyl; Halo, —OH, —O—C １～４ Alkyl, -OCF ３ , -OCHF ２ , -S(=O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-C １～４ Alkyl, —NH—(C═O)—C ３～６ cycloalkyl, —C(═O)—NR ４ａ R ４ｂ , and —NH—S(═O) ２ -C １～４ C substituted with 1, 2 or 3 substituents each independently selected from the group consisting of alkyl １～４ Alkyl; C on the N atom １～４ Alkyl, —C(═O)—NR ４ａ R ４ｂ , -C(=O)-C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, or —C(═O)—C ３～６ 3- or 4-piperidinyl optionally substituted with cycloalkyl; 【Transformation 7】 represents or R ３ａ and R ３ｂ together with the nitrogen atom to which they are attached 【Transformation 8】 Forming Cy １ But C ３～６ cycloalkyl; or halo, —OH, —O—C １～４ Alkyl, -OCF ３ , -OCHF ２ , -S(=O) ２ -C １～４ Alkyl, —S(═O) ２ -NR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, -N=S(=O)-(C １～４ alkyl) ２ , -NH-(C=O)-C １～４ Alkyl, —NH—(C═O)—C ３～６ cycloalkyl, —C(═O)—NR ４ａ R ４ｂ , and —NH—S(═O) ２ -C １～４ C substituted with one substituent selected from the group consisting of alkyl ３～６ represents cycloalkyl, R ４ａ and R ４ｂ are each independently hydrogen or C １～４ represents alkyl, R ５ is hydrogen, OH, —O—C １～４ Alkyl, —S(═O) ２ -C １～４ Alkyl, —S(═O) ２ -C ３～６ Cycloalkyl, —S(═O) ２ -NR ４ａ R ４ｂ or —C(═O)—NR ４ａ R ４ｂ represents n1, n2, n3, n4, n5, n6, n7, and n8 each independently represent 1 or 2; R ６ represents methyl, The compound of claim 1.

5. R ｘ is hydrogen, C １～４ represents alkyl or halo, R ３ａ represents hydrogen, R ３ｂ is hydrogen; C １～４ Alkyl; C ３～６ cycloalkyl; -OH, -S (=O) ２ -C １～４ Alkyl, —NR ４ａ R ４ｂ , -S(=O)(=NH)-C １～４ Alkyl, and —N═S(═O)—(C １～４ alkyl) ２ C substituted with one substituent selected from the group consisting of ３～６ cycloalkyl; -C １～４ Alkyl-S(=O) ２ -C １～４ alkyl; C substituted with 1, 2 or 3 halo substituents １～４ Alkyl; C on the N atom １～４ 3- or 4-piperidinyl optionally substituted with alkyl; 【Chemistry 9】 represents or R ３ａ and R ３ｂ together with the nitrogen atom to which they are attached 【Chemistry 10】 Forming The compound of claim 4.

6. R ｘ represents a halo, R ｙ is C １～４ represents alkyl, R ｚ is a C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, ring 【Chemistry 11】 represents phenyl, R ２ represents a halo, R ３ａ represents hydrogen, R ３ｂ is C １～４ alkyl; or one S(=O) ２ -C １～４ C substituted with alkyl ３～６ represents cycloalkyl, 6. A compound according to claim 4 or 5.

7. The compound according to any one of claims 1 to 6, wherein n is 0.

8. The compound according to any one of claims 1 to 7, wherein n is 1.

9. ring 【Chemistry 12】 represents phenyl, R ６ A compound according to any one of claims 1 to 8, wherein represents methyl.

10. Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as defined by formula (I-a1): 【Chemistry 13】 The compound according to any one of claims 1 to 9, wherein:

11. Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are represented by formula (I-b1): 【Chemistry 14】 The compound according to any one of claims 1 to 10, wherein

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

13. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use as a medicament.

14. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use in the treatment or prevention of cancer.

15. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use in the treatment or prevention of a disease, syndrome, condition or disorder, wherein the disease, syndrome, condition or disorder is affected by the inhibition of MALT1.

16. 13. A method for treating a disease, syndrome, condition or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 11 or a pharmaceutical composition of claim 12, wherein said disease, syndrome, condition or disorder is affected by inhibition of MALT1.

17. Formula (A) 【Chemistry 15】 [In the formula, R １ teeth, 【Chemistry 16】 represents q is 1 or 2; R ｘ is hydrogen; C １～４ alkyl; halo or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, R ｙ is C １～４ Alkyl; C ３～６ cycloalkyl; or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, R ｚ But C １～４ Alkyl; C ３～６ cycloalkyl; or C substituted with 1, 2 or 3 halo substituents １～４ represents alkyl, or R ｙ and R ｚ together with the carbon atoms to which they are attached, form C ３～６ forming a cycloalkyl, ring 【Chemistry 17】 represents phenyl or pyridyl, R ２ represents a halo, n is 0, 1, or 2; R ６ is C １～４ alkyl; or C substituted with one —OH １～４ represents alkyl] or its tautomeric or stereoisomeric forms or a pharmaceutically acceptable salt thereof.

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