WO2014086478A1

WO2014086478A1 - Inhibitors of malt1 protease

Info

Publication number: WO2014086478A1
Application number: PCT/EP2013/003644
Authority: WO
Inventors: Daniel KRAPPMANN; Daniel NAGEL; Florian Schlauderer; Katja LAMMENS; Karl-Peter Hopfner; Robert A. Chrusciel; Dale L. KLING; Matthew W. Bedore
Original assignee: Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Priority date: 2012-12-03
Filing date: 2013-12-03
Publication date: 2014-06-12

Abstract

The present invention relates to compounds which are inhibitors of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALTl) and to their use in therapy, in particular in the treatment or prevention of a disease or disorder which is treatable by an inhibitor of a paracaspase. The present invention also relates to pharmaceutical compositions containing such compounds.

Description

INHIBITORS OF MALTl PROTEASE

TECHNICAL FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Upon antigenic stimulation, MALTl is a key mediator of upstream NF-κΒ signaling to control lymphocyte activation, survival and differentiation (Hailfinger et al., Immunol. Rev. 2009, 232, 334- 347; Thome, Nat. Rev. Immunol. 2008, 8, 495-500). Together with CARMA1 (also known as CARD11) and BCL10, MALTl assembles the so-called CBM complex that bridges proximal antigen receptor signaling events to the ΙκΒ kinase (IKK) complex, the gatekeeper of the canonical NF-KB pathway (Scheidereit, Oncogene 2006, 25, 6685-6705). Upon T cell antigen receptor (TCR)/CD28 co- stimulation, MALTl acts as a protein scaffold that recruits other critical signaling molecules like TRAF6, CASP8 and A20 to the CBM complex (Thome, Nat. Rev. Immunol. 2008, 8, 495-500). Further, covalent ubiquitin modifications in MALTl catalyzed by the E3 ligase TRAF6 facilitate the association of two downstream protein kinase complexes, TAB2-TAK1 and ΝΕΜΟ-ΙΚΚα/β, which ultimately leads to IKK activation (Oeckinghaus et al., EMBO J. 2007, 26, 4634-4645).

In addition to its scaffolding function, MALTl contains a paracaspase domain that displays high homology to CASP from mammals and metacaspases from plants and fungi (Uren et al., Mol. Cell 2000, 6, 961-967). Like metacaspases, MALTl cleaves substrates after arginine residues, indicating that the enzymatic cleavage activity is quite distinct from CASP, that in general requires an aspartate at the PI position (Vercammen et al., J. Biol. Chem. 2004, 279, 45329-45336). MALTl proteolytic activity is induced upon TCR/CD28 co-stimulation, which promotes cleavage of the substrates BCL10, A20, CYLD and RelB (Coornaert et al., Nat. Immunol. 2008, 9, 263-271 ; Hailfinger et al., PNAS USA 2011, 108, 14596-14601; Rebeaud et al., Nat. Immunol. 2008, 9, 272-281 ; Staal et al., EMBO J. 2011 , 30, 1742-1752). Inhibition of MALTl protease activity by the antagonistic tetra-peptide Z-VRPR- FMK, that was originally designed as an inhibitor of metacaspases in plants, impairs optimal NF-KB activation and IL-2 production in T cells (Duwel et al., J. Immunol. 2009, 182, 7718-7728; Rebeaud et al., Nat. Immunol. 2008, 9, 272-281). Similarly, mutation of the catalytic cysteine 464 renders MALTl proteolytically inactive and also impairs IL-2 production after complementation of MALTl -deficient T cells (Duwel et al., J. Immunol. 2009, 182, 7718-7728). Dysregulation of the activity of the MALTl protease plays a crucial role in the development of a number of diseases, in particular diseases or disorders which are treatable by an inhibitor of a paracaspase and paracaspase-dependent immune diseases. A tumor-promoting role of MALTl has been found in a subset of diffuse-large B cell lymphoma (DLBCL) and mucosa-associated lymphatic tissue (MALT) lymphoma (Ngo et al., Nature 2006, 441, 106-1 10). By gene expression profiling, DLBCL can be classified into distinct entities and the most abundant subtypes are the activated B cell-like (ABC-) DLBCL and the germinal center B cell-like (GCB-) DLBCL (Alizadeh et al., Nature 2000, 403, 503-511 ; Rosenwald and Staudt, Leukemia & Lymphoma 2003, 44 Suppl 3, S41 -47; Rosenwald et al., New Engl. J. Med. 2002, 346, 1937-1947; Savage et al., Blood 2003, 102, 3871-3879; Wright et al., PNAS USA 2003, 100, 9991-9996). Based on the gene expression signature the ABC-DLBCL subtype originates from B-lymphocytes stimulated through their B cell antigen receptor (BCR). With a 5-year survival rate of 35%, ABC-DLBCL patients have the worst prognosis, reflecting the aggressive clinical behavior of ABC-DLBCL cells (Lenz et al., New Engl. J. Med. 2008, 359, 2313-2323). The hallmark of ABC-, but not GCB-DLBCL cells is the constitutive activation of the NF-κΒ signaling pathway (Alizadeh et al., Nature 2000, 403, 503-511 ; Davis et al., J. Exp. Med. 2001, 194, 1861-1874). Congruent with this, a recent genetic study of the DLBCL coding genome revealed the preferential association of gene alterations in the NF-κΒ and BCL6-BLIMP1 axis in ABC-DLBCL and in BCL2 and MYC in GCB-DLBCL, suggesting that anti-apoptotic NF-κΒ signaling is indeed critical for ABC- DLBCL survival (Pasqualucci et al., Nat. Genet. 201 1, 43, 830-837). While some ABC-DLBCL patients carry oncogenic CARMA1 mutations (Lenz et al., Science 2008, 319, 1676-1679), the majority of ABC-DLBCL is characterized by chronic active BCR signaling and in -20% of the cases activating mutations in the BCR proximal regulator CD79A and B are found (Davis et al., Nature 2010, 463, 88- 92). Consistent with a requirement for BCR signaling, an RNA interference screen identified CARMAl , BCL10 or MALTl as critical regulators of NF-κΒ activation, survival and growth of ABC- DLBCL (Ngo et al., Nature 2006, 441, 106-110). Furthermore, inhibition of MALTl proteolytic activity by Z-VRPR-FMK inhibits NF-κΒ dependent gene expression and exerts toxic effects specifically in ABC-DLBCL cells (Ferch et al., J. Exp. Med. 2009, 206, 2313-2320; Hailfinger et al., PNAS USA 2009, 106, 19946-19951). MALTl paracaspase activity also contributes to the pathogenesis of MALT lymphoma that are characterized by the translocation t(l I; 18)(q21 ;q21), which creates a fusion between the C-terminus of MALTl, including the paracaspase domain and the N-terminus of IAP2 (API2-MALT1) (Isaacson and Du, Nat. Rev. Cancer 2004, 4, 644-653). The paracaspase domain of API2 -MALTl fusion protein catalyzes the cleavage of NIK and thereby enhances non-canonical NF- KB activation, which confers apoptosis resistance (Rosebeck et al., Science 2011, 331, 468-472). Thus, specific small molecule inhibitors against the MALTl paracaspase could be beneficial for the treatment of lymphoma associated with deregulated MALTl activity, such as the aggressive subtype of ABC-DLBCL or MALT lymphoma expressing the oncoprotein fusion API2 -MALTl . The peptide Z- VRPR-FMK inhibits MALTl ; however, due to its poor pharmacological properties, Z-VRPR-FMK needs to be administered in very high concentrations to exert effects on cells and antagonistic peptides in general are not adequate for clinical applications.

In view of the above, it would be desirable to provide novel compounds which are inhibitors of a paracaspase, in particular inhibitors of MALTl . A further object of the present invention is the provision of compounds which are useful in the treatment or prevention of diseases or disorders that are treatable by an inhibitor of a paracaspase, such as those that are associated with deregulated MALTl .

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a compound selected from the group consisting of a phenothiazine derivative having the general formula (I)

and hydrates, solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, and tautomers thereof, wherein

R¹ to R⁸ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azido, -N0₂, -OR", -N(R¹²)(R¹³), -ON(R¹²)(R¹³), -N⁺(-0 )(R¹²)(R¹³), -S(0)o-2R", -S(O)₀-₂ORⁿ, -OS(O)₀-₂Rⁿ, -OS(O)₀-2OR^u, -S(O)₀-₂N(R¹²)(R¹³), -OS(0)o-₂N(R¹²)(R¹³), -NiR^SCOy^¹¹, -NRⁿS(0)o-₂ORⁿ, -NRⁿS(O)₀-₂N(R¹²)(R¹³), -C(=X)R", -C(=X)XR", -XC(=X)R¹¹, and -XC(=X)XR' \ wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted;

or R¹ and R² may join together with the atoms to which they are attached to form a ring which is optionally substituted; R² and R³ may join together with the atoms to which they are attached to form a ring which is optionally substituted; R³ and R⁴ may join together with the atoms to which they are attached to form a ring which is optionally substituted; R⁵ and R⁶ may join together with the atoms to which they are attached to form a ring which is optionally substituted; R⁶ and R⁷ may join together with the atoms to which they are attached to form a ring which is optionally substituted; and/or R⁷ and R⁸ may join together with the atoms to which they are attached to form a ring which is optionally substituted;

R⁹ is -D-E-G-E'-R⁴⁰, wherein

D is -Li-Qq-L'r-, wherein L and L' are independently selected from the group consisting of alkylene, alkenylene, and alkynylene; Q is selected from the group consisting of -NR¹¹-, -0-, -S(0)o-2-, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; and each of 1, q, and Γ is 0 or 1, wherein when q is 0, Γ is 0 and Q can only be -NR¹¹-, -O- or -S(0)o-2- if Γ is 1 ; wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted;

E is selected from the group consisting of a covalent bond, -0-, -S(0)o-2-, -C(=X)-, -NR²⁰-, -C(R²²)=N-, -N=C(R²²)-, -C(=X)-NR²⁰-, and -NR²⁰-C(=X)-;

G is selected from the group consisting of -(NR³⁰)_a-C(=X)-(NR³¹)_b- and -(NR³⁰)_a-S(O)i-2-(NR³¹)b-, wherein a is 0 or 1 , b is 0 or 1 , and a+b is 1 or 2;

E' is selected from the group consisting of a covalent bond, -0-, -S(0)o-2-, -C(=X)-, -NR²¹-, -C(R²³)=N-, -N=C(R²³)-, -C(=X)-NR²¹-, and -NR²¹-C(=X)-;

R⁴⁰ is selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted;

X is independently selected from O, S, and NR¹⁴;

R¹¹ is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R¹² and R¹³ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R¹² and R¹³ may join together with the nitrogen atom to which they are attached to form the group -N=CR^,5R¹⁶, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R¹⁴ is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -OR", wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R¹⁵ and R¹⁶ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH_yR⁵⁰2-y, or R¹⁵ and R¹⁶ may join together with the atom to which they are attached to form a ring which is optionally substituted, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted; R²⁰ and R²¹ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R²² and R²³ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH_yR⁵⁰2- , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R³⁰ and R³¹ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

or

one of R²⁰ and R²² and one of R²¹ and R²³ may join together with the atoms to which they are attached to form a ring which is optionally substituted; or R³⁰ and R³¹ may join together with the atoms to which they are attached to form a ring which is optionally substituted; or R³⁰ and one of R²¹ and R²³ may join together with the atoms to which they are attached to form a ring which is optionally substituted; or R³¹ and one of R²⁰ and R²² may join together with the atoms to which they are attached to form a ring which is optionally substituted;

y is an integer from 0 to 2 (i.e., 0, 1 , or 2); and

R⁵⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted.

In a preferred embodiment, E is selected from the group consisting of -C(R²²)=N-, a covalent bond, -NR²⁰-, -C(=X)-, -N=C(R²²)-, -C(=X)-NR²⁰-, and -NR²⁰-C(=X)-. More preferably, E is selected from the group consisting of -C(R² )=N-, a covalent bond, -NR²⁰-, and -C(=X)-NR²⁰-.

In a preferred embodiment, E' is selected from the group consisting of -NR²¹-, a covalent bond, -0-, -S-, -C(R²³)=N-, -N=C(R²³)-, -C(=X)-NR²¹-, and -NR²¹-C(=X)-. More preferably, E' is selected from the group consisting of -NR²¹-, a covalent bond, -0-, -S-, and -N=C(R²³)-.

In a preferred embodiment, a+b is 1.

In a preferred embodiment, the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N- N(R³⁰)-C(=X)-N(R²¹)-, -C(=X)-N(R³¹)-, -N(R³⁰)-C(=X)-, -N(R³⁰)-S(O)₂-, -S(0)₂-N(R³¹)-, -C(=X)- N(R²⁰)-N(R³⁰)-C(=X)-N(R²¹)-, -N(R³⁰)-C(=X)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R ⁰)-C(=O)-S-, -N(R³⁰)- C(=S)-0-, -N(R³⁰)-C(=S)-S-, -N(R²⁰)-N(R³⁰)-C(=X)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=X)-, and -C(R²²)=N- N(R³⁰)-C(=X)-.

In another preferred embodiment, a+b is 2.

In a preferred embodiment, the moiety -E-G-E'- is selected from the group consisting of -N(R²⁰)- N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)-, -N(R²⁰)-N(R ⁰)-C(=X)-N(R³¹)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)-C(=X)- N(R³¹)-N(R²¹)-, and -C(R²²)=N-N(R ⁰)-C(=X)-N(R³¹)-N=C(R²³)-. In a preferred embodiment, L and L' are independently selected from the group consisting of Ci-e alkylene, C2-6 alkenylene, and C2-6 alkynylene; and Q is selected from the group consisting of -NR^{1 1}-, 3- to 10-membered arylene, 3- to 10-membered heteroarylene, 3- to 10-membered cycloalkylene, and 3- to 10-membered heterocycloalkylene, wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted.

In a preferred embodiment, Q is selected from the group consisting of phenylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, pyranylene, cyclopentadienylene, thiazolylene, isothiazolylene, oxazolylene, isoxazolylene, pyrazolylene, imidazolylene, pyrrolylene, furanylene, thienylene, thiadiazolylene, triazolylene, and hydrogenated forms of the forgoing groups, wherein each of the forgoing groups and hydrogenated forms thereof is optionally substituted.

In a preferred embodiment, D is selected from the group consisting of Ci-e alkylene, -(C1.3 alkylene)- NR^u-(Ci-3 alkylene)-, -(C1-3 alkylene)-(5- to 6-membered arylene)-(Ci-3 alkylene)o-i-, -(C1-3 alkylene)- (5- to 6-membered heteroarylene)-(Ci-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered cycloalkylene)- (Ci-3 alkylene)o-i-, and -(C1-3 alkylene)-(5- to 6-membered heterocycloalkylene)-(Ci-3 alkylene)o-i-, wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted.

In a preferred embodiment, R⁴⁰ is selected from the group consisting of -H, CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted. In a particularly preferred embodiment, R⁴⁰ is selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, morpholino, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, isoxazolyl, oxazolyl, benzothiazolyl, pyrazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, thiadiazolyl, triazolyl, phenoxazinyl, thiazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolothiazolyl, pyrrolooxazolyl, pyrrolopyrrolyl, phenothiazinyl, isoquinolinyl, imidazolyl, benzoimidazolyl, pyrrolyl, furanyl, thienyl, pyranyl, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, isothiazolyl, pyrazinyl, pyrrolizinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, quinolinyl, phthalazinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, 2,6-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, 1 ,7-phenanthrolinyl, 1,8-phenanthrolinyl, 1 ,10-phenanthrolinyl, 3,8-phenanthrolinyl, 4,7- phenanthrolinyl, phenazinyl, chromanyl, isochromanyl, and hydrogenated forms of the forgoing aryl/heteroaryl groups, wherein each of the forgoing alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups and hydrogenated forms thereof is optionally substituted.

In a preferred embodiment, the ring formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, or (vi) R⁷ and R⁸ is a 3- to 7-membered ring, which is optionally substituted. In a particularly preferred embodiment, the ring formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, or (vi) R⁷ and R⁸ has 5 or 6 members and is an aromatic, cycloaliphatic, heteroaromatic, or heterocyclic ring, wherein the heteroaromatic / heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of O, S, and NR⁶⁰, wherein R⁶⁰ is selected from the group consisting of R¹¹, -OR¹¹, -NH_yR⁵⁰2-_y, and -S(0)o-2R^H, wherein R¹¹ and y are as defined above. In a preferred embodiment, R² and/or R⁷ are selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C₂-₆ alkynyl, halogen, -CN, azido, -NO2, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶¹, -S(0)₂N(R⁶²)(R⁶³), -N(R⁶¹)S(0)₂R⁶¹ , -C(=X)R⁶¹, -C(=X)XR⁶¹, -XC(=X)R⁶¹, and -XC(=X)XR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, C1-4 alkyl, C₂-4 alkenyl, and C₂-4 alkynyl, and wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO₂, -OH, -0(Ci-₄ alkyl), -SH, -S(C_M alkyl), -NH(Ci-₄ alkyl), -N(C_M alkyl)₂, COOH, and COO(Ci-₄ alkyl).

In a preferred embodiment, the phenothiazine derivative is selected from the group consisting of:

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-phenylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-4-ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-3 -ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-[4-(dimethylamino)phenyl] semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(4-methoxyphenyl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-{4-[2-(dimethylamino) ethoxy]phenyl} semicarbazone; (lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(3,4-dimethylisoxazol-5-yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N'-(2-hydroxyethyl)-N-(3-methylisoxazol-5-yl)semi- carbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-isoxazol-3 -ylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(5-methylisoxazol-3-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3 -methyl- 1 H-pyrazol-5 -yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyri^ 2-yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(4-pyridin-3-yl-l,3-thiazol-2-yl)semicarbazone;

N-(3-methylisoxazol-5-yl)-3-(10H-phenothiazin-10-ylmethyl)-4,5-dihydro-lH-pyrazole-l-carboxamide;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-l,3-benzoxazol-2-ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3-benzodioxol-5 -ylsemicarbazone;

N",N"'-bis[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]carbonohydrazide;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3-benzothiazol-2-ylsemicarbazone;

1 -[3-(l OH-phenothiazin- 10-yl)propyl]-3-phenylurea;

phenyl [3 -( 1 OH-phenothiazin- 10-yl)propyl] carbamate;

N- [3 -( 1 OH-phenothiazin- 10-yl)propyl]benzenesulfonamide;

1 -[3-(l OH-phenothiazin- 10-yl)propyl)-3-phenylthiourea;

1 -methyl- 1 -[3 -( 1 OH-phenothiazin- 10-yl)propyl] -3 -phenylthiourea;

2- [( 1 OH-phenothiazin- 10-yl)carbonyl] -N-phenylhydrazinecarbothioamide;

(2E/Z)-N'-[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]-3-(phenylsulfonyl)acrylohydrazide;

( 1 E/Z)-3-( 1 OH-phenothiazin- 10-yl)propanal N-phenylsemicarbazone;

2-[2-(10H-phenothiazin-10-yl)ethyl]-N-phenylhydrazinecarboxamide;

5-methyl-N'-[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]isoxazole-3-carbohydrazide;

3 -amino-N'- [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene] - 1 H- 1 ,2,4-triazole- 1 -carbohydrazide;

5-[(10H-phenothiazin-10-yl)methyl]-4-propyl-2,4-dihydro-3H-l,2,4-triazole-3-thione;

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene]amino} imidazolidin-2-one;

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene]amino} -3-phenylimidazolidin-2-one;

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene]amino} imidazolidine-2,4-dione;

N-methyl-2-(10H-phenothiazin-10-ylacetyl)hydrazinecarbothioamide;

2-[(10H-phenothiazin-10-yl)acetyl]-N-propylhydrazinecarbothioamide;

N-allyl-2-( 1 OH-phenothiazin- 10-ylacetyl)hydrazinecarbothioamide;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- [3 -(dimethylamino)propyl] semicarbazone;

10-[(l-methylpiperidin-3-yl)methyl]-2-propyl-10H-phenothiazine; 2-allyl-10-[(l-methylpiperidin-3-yl)methyl]-10H-phenothiazine;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(4,5,6,7-tetrahydro-[l,3]thiazolo[5,4-c]pyridin-2- yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde Ν- {4-[2-(dimethylamino)ethoxy]phenyl} semicarbazone; (lE/Z)-[2-(methylthio)-10H-phenothiazin-10-yl]acetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone; (2E/Z)-2-[2-(10H-phenothiazin-10-yl)ethylidene]-N-(3-methylisoxazol-5-yl)hydrazinecarbox- imidamide;

N-(3 -methylisoxazol-5-yl)-3 - [( 1 OH-phenothiazin- 10-yl)methyl] - 1 H-pyrazole- 1 -carboxamide;

N-(3-methylisoxazol-5-yl)-6-[(10H-phenothiazin-10-yl)methyl]piperidine-2-carboxamide;

2,3-dihydrocyclopenta[b]phenothiazin-10(lH)ylacetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone;

N-(3 -methylisoxazol-5 -yl)-6-[( 1 OH-phenothiazin- 10-yl)methyl]pyridine-2-carboxamide;

(lE/Z)-(2-propyl-10H-phenothiazin-10-yl)acetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone;

1 OH-phenothiazin- 10-ylacetaldehyde N-(2-fluoropyridin-4-yl)semicarbazone;

2-ethyl- 10- [( 1 -methylpiperidin-3 -yl)methyl] - 1 OH-phenothiazine;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde thiosemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-methylthiosemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-propylthiosemicarbazone;

(2E/Z)-2-[2-( 1 OH-phenothiazin- 10-yl)ethylidene]hydrazinecarboximidamide;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-methylsemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-( 1 ,3-dimethyl- 1 H-pyrazol-5-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3-methylisothiazol-5-yl)semicarbazone;

(1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde N-phenylthiosemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde semicarbazone;

( 1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde NN-dimethylsemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyrimidin-2-ylsemicarbazone;

4-methyl-N-[( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene]piperazine- 1 -carbohydrazide;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-( 1 -methylpyrrolidin-3-yl)semicarbazone;

( 1 E/Z)-[2-(methylthio)- 1 OH-phenothiazin- 10-yl]acetaldehyde N-phenylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3-methoxyphenyl) semicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- [4-(4-methylpiperazin- 1 -yl)phenyl] semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(2-methylpyridin-4-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-quinolin-7-ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde NN'-dimethylthiosemicarbazone;

2-(10H-phenothiazin-10-ylacetyl)-N-[3-(trifluoromethyl)phenyl]hydrazinecarbothioamide;

3-(10H-phenothiazin-10-ylmethyl)-N-phenyl-4,5-dihydro-lH-pyrazole-l-carboxamide; phenyl (2E/Z)-2-[2-(10H-phenothiazin-10-yl)ethylidene]hydrazinecarboxylate;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]pyridin- 2-yl) semicarbazone; and

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[3-(2-moφholin-4-ylethoxy)phenyl]semicarbazone.

In a particularly preferred embodiment, the phenothiazine derivative is selected from the group consisting of:

1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-4-ylsemicarbazone;

10H-phenothiazin-10-ylacetaldehyde N-(5-methylisoxazol-3-yl)semicarbazone;

10H-phenothiazin-10-ylacetaldehyde N-(3,4-dimethylisoxazol-5-yl)semicarbazone;

1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l ,3]thiazolo[5,4-c]pyridin-2- yl)semicarbazone;

10H-phenothiazin-10-ylacetaldehyde N-{3-[2-(dimethylamino)ethoxy]phenyl}semicarbazone;

(1E/Z)-1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]pyridin- 2-yl) semicarbazone; and

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[3-(2-mo holin-4-ylethoxy)phenyl]semicarbazone.

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable excipient.

In a third aspect, the invention provides a compound of the first aspect or a pharmaceutical composition of the second aspect for inhibiting a paracaspase. In a preferred embodiment, the paracaspase is MALT1. In a fourth aspect, the invention provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use in therapy.

In a fifth aspect, the present invention provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use in a method of treating or preventing a disease or disorder which is treatable by an inhibitor of a paracaspase. Preferably, the paracaspase is MALT1. In a preferred embodiment, the disease or disorder is cancer. In a particularly preferred embodiment, the cancer is a lymphoma, preferably diffuse large B-cell lymphoma (DLBCL). In a further embodiment, the disease or disorder is a paracaspase-dependent immune disease, preferably an allergic inflammation. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Establishment of the in vitro MALTl cleavage assay for High Throughput Screening (HTS). (A) Scheme of the MALTl protease assay. Release of the fluorophore AMC by proteolytic action of GSTMALTl against the fluorogenic peptide Ac-LRSR-AMC containing the BCL10 derived MALTl cleavage site results in an increase of fluorescence. (B) Kinetics of the MALTl cleavage reaction. Purified recombinant GSTMALTl expressed from bacteria was incubated for 1 h at 30°C with 50 μΜ of Ac-LRSR-AMC and the proteolytic activity was determined by measuring the increase of AMC fluorescence. Whereas the catalytic inactive MALTl C453A failed to cleave the substrate, inhibition with 1 nM of the inhibitory peptide Z-VRPR-FMK led to a ~ 50% decrease of MALTl activity. (C) MALTl is inhibited by Z-VRPR-FMK. Increasing amounts of the peptide led to a total loss of MALTl activity. For evaluation of the data the relative fluorescence of the untreated control was set to 100% and the values of inhibitor treated wells were calculated accordingly. (D) The pan- caspase inhibitor Ac-DEVD-CHO was not significantly active on MALTl even at 200 μΜ. (E) Enzymatic characterization of the MALTl paracaspase using different protease inhibitors. MALTl activity was diminished by common concentrations of the cysteine protease inhibitors Antipain (1 μΜ) and Chymostatin (100 μΜ), but not by high concentration of E-64 (100 μΜ) or low concentration of Leupeptin (1 μΜ). The aspartyl-protease inhibitor Pepstatin A (100 μΜ), the serine protease inhibitor Aprotinin (5 μg/ml) and the serine/cysteine protease inhibitor TLCK (1 μΜ) had no effects on MALTl activity. The inhibitory profile was compared to the Arabidopsis metacaspases AtMC4 and AtMC9 (see Figure 9). Graphs are showing the mean of at least three independent experiments and error bars indicate standard deviation (SD).

Figure 2: Phenothiazine derivatives identified by HTS inhibit MALTl activity. (A) Chemical structures of phenothiazines and a structurally related compound identified as potential MALTl inhibitors. Compound A (mepazine; 10-[(l-methyl-3-piperidinyl)methyl]-10H-phenothiazine acetate), B (2-chlorophenothiazine) and C ([2-(3-isobutoxy-10H-phenothiazin-10-yl)ethyl]dimethylamine) are phenothiazines and compound D has a similar structure . (B) While treatment with increasing amounts of phenothiazine from 5 to 50 μΜ led to a dose-dependent decline of GSTMALTl activity, enzymatic CASP8 action was not significantly reduced. Graphs (in B) are showing one representative of two and error bars indicate SD.

Figure 3: Selective MALTl inhibition of mepazine, thioridazine and promazine. (A) Molecular structures of the three inhibitory compounds. All three bear a short hydrophobic side chain at the nitrogen with a similar atomic composition and spacing. (B) Dose response curves and IC50 values for mepazine, thioridazine and promazine. (C) Mepazine acts as a non-competitive MALTl inhibitor. Michaelis-Menten kinetics was determined by increasing concentration of LRSR-AMC substrate in the absence or presence of 1 μΜ mepazine. Mepazine reduces the VMAX but not the KM of MALTl . (D) Mepazine acts as a reversible MALTl inhibitor. GSTMALTl coupled to glutathione sepharose beads was treated with mepazine (10, 20 or 50 μΜ) for 30 min. MALTl activity was assayed after washing the beads for 0, 3 or 6 times before cleavage reaction was started. (E) Phenothiazines are selective MALTl inhibitors and fail to significantly inhibit CASP3 and CASP8 activity up to concentrations of 50 μΜ. Data represent the average of at least three independent experiments and error bars indicate SD. Figure 4: Mepazine and thioridazine mediated inhibition of MALTl leading to impaired T cell activation in primary mouse CD4⁺ T cells, human PBMCs and Jurkat T cells. (A) Jurkat T cells were left untreated or incubated for 3 h with 10 μΜ of mepazine or thioridazine and then left unstimulated or stimulated for 15, 30, 60, 90 and 120 minutes with anti-CD3/CD28. Addition of mepazine and thioridazine led to a strong decrease in the activation of cellular MALTl activity. (B) Treatment of Jurkat T cells with mepazine and thioridazine prevented stimulus and MALTl dependent cleavage of RelB in a dose-dependent manner. Jurkat T cells were treated with either solvent or 2, 5, 10 or 20 μΜ of mepazine or thioridazine for 4 h and 1 h MG132 to stabilize RelB cleavage fragment (RelBA). Cells were stimulated with P/I for 30 min. RelB and RelBA were analyzed by Western Blot. Blots show a representative of at least three independent experiments. (C) To analyze the inhibitory impact of the phenothiazine compounds on T cell activation the JL-2 secretion of Jurkat T cells was measured by ELISA after P/I or anti-CD3/CD28 stimulation for 20h in the presence or absence of 5 and 10 μΜ mepazine or thioridazine. Both compounds led to diminished extracellular JL-2 levels after T cell activation. (D) Impact of phenothiazine compounds on the activation of primary murine CD4⁺ T- cells. Quantitative PCR was used to determine IL-2 mRNA levels after 3 h pre-treatment with mepazine or thioridazine and induction with anti-CD3/CD28 for 4h. IL-2 mRNA levels were significantly reduced in compound treated cells compared to solvent treated control cells. In consequence, treatment of the cells with both compounds and subsequent T cell activation with anti- CD3/CD28 antibodies for 20h resulted in lower levels of secreted IL-2. Graphs (in B-D) show the mean of at least three independent experiments. Error bars indicate SD. (E) Primary human PBMCs from two donors were subjected to 5 and 10 μΜ of mepazine and thioridazine for 3 h before induction with anti- CD3/CD28 for 20h. In all donors the extracellular IL-2 levels are dose-dependently reduced in the presence of mepazine and thioridazine, respectively.

Figure 5: Phenothiazine treatment impairs MALTl activity and a subsequent substrate cleavage in ABC-DLBCL cells. (A) Cellular MALTl activity in DLBCL was analyzed after 4h incubation with mepazine and thioridazine. MALTl was isolated via antibody-based precipitation and its proteolytic activity was determined in a plate reader detecting the fluorescence emission of released AMC fluorophores. Both compounds inhibited MALTl protease activity from ABC-DLBCL cells in a dose- dependent manner with variations depending on the cell line or phenothiazine. Graphs are showing the mean of at least three independent experiments and error bars indicate SD. (B) Treatment of DLBCL cells with mepazine and thioridazine could prevent the constitutive MALTl dependent cleavage of BCL10 in a dose-dependent manner. Cells were treated with different doses of compounds for 20 h and the presence of BCL10 and the cleavage product BCL10A5 was analyzed via Western Blot. Data are representative of at least three independent experiments.

Figure 6: Mepazine treatment impairs NF-κΒ target gene binding and expression in ABC- DLBCL cells. (A) ABC-DLBCL cells were treated with 10 and 20 μΜ of mepazine for 20h and subsequently analyzed for NF-κΒ DNA binding by EMSA. In all four cell-lines NF-κΒ target gene binding was impaired. Treatment with mepazine consequently decreased the protein levels of the anti- apoptotic NF-κΒ targets BCL-XL and c-FLIP-L. Data are representative of three independent experiments. (B) To determine the effect on NF-κΒ target gene expression, ABC- and GCB-DLBCL control cells were treated with mepazine for 20h and the levels of the constitutively secreted cytokines IL-6 and IL-10 were analyzed via ELISA. Treatment of the cells resulted in a -50% decreased IL-6 and IL-10 secretion in ABC cell lines. To account for the drastic variations in cellular IL-6 and IL-10 secretion in the individual cell lines, IL amounts are illustrated with two different scales. Graphs are showing the mean of at least three independent experiments and error bars indicate SD.

Figure 7: Phenothiazines are selectively toxic to ABC-DLBCL cells. (A) to (D) To test the effect of the phenothiazines on the viability of ABC-DLBCL cells, four different ABC-DLBCL cell lines and three GCB-DLBCL cell lines (BJAB, Su-DHL-6 and Su-DHL-4) as control cells were treated with indicated concentrations of mepazine or thioridazine (single treatment). Viability of the cells was subsequently analyzed after two days with a MTT cytotoxicity test (A and C) or after four days by cell- counting (B and D). Both compounds were able to promote a decrease in cell-viability in ABC-DLBCL cell lines, without significantly affecting GCB-DLBCL cells. (E) Analysis of apoptosis in ABC- DLBCL cell lines after mepazine treatment. Five ABC-DLBCL and two GCB-DLBCL cell lines were treated for five days with 15 μΜ mepazine. Apoptotic cells were identified by FACS analysis as AnnexinV-PE positive and 7-AAD negative cells. While apoptosis was not increased in GCB-DLBCL control cell lines, an increment of the apoptotic cell population ranging from 10% to 25% was detected in all ABC-DLBCL cell lines. Data (in B and D) are the mean from three independent experiments. Graphs (in A, C and E) are showing the mean of at least three independent experiments and error bars indicate SD.

Figure 8: Mepazine and thioridazine interfere with growth and induce apoptosis in the ABC- DLBCL cell line OCI-LylO in vivo. (A) Transplantation of OCI-LylO or Su-DHL-6 cells resuspended in matrigel (BD) into the flanks of NOD.Cg-Prkdcscid I12rgtmlWjl/SzJ (NSG) mice was carried out on day 0. Tumor size was determined by caliper measurement. Intraperitoneal administration of solvent, mepazine (300 μg/d) or thioridazine (400 μξ/ά) into 3 respective mice of each group was started 24 h after transplantation and given continuously every 24 h for the entire treatment period. Both phenothiazines selectively impair growth of the ABC-DLBCL cell line OCI-LylO. Statistical analysis was performed using a two-way anova test resulting in highly significant p values being < 0.0001 from day 16 to 22. (B) Phenothiazine compounds enhance apoptosis in OCI-LylO, but not Su-DHL-6 cells in vivo. Apoptosis was determined on tumor sections by TU EL staining after 22 days of treatment. Pictures show staining of representative tumor sections. (C) Mepazine and thioridazine inhibit RelB cleavage in OCI-LylO tumors. Expression of RelB and the MALT 1 -dependent cleavage product RelBA were detected in extracts of OCI-LylO tumor specimens by Western Blotting after 22 days. The blot shows results from mice treated with solvent, mepazine or thioridazine, displaying three independent samples for each.

Figure 9: Inhibitory profile of MALT1 implies a high similarity to Arabidopsis metacaspases. The activity of MALTl in presence of one of several protease inhibitors was determined and the results are shown in Figure 9. Similar to AtMC4 and AtMC9 neither 100 μΜ of the aspartyl protease inhibitor Pepstatin A nor the serine protease inhibitor Aprotinin (5 μg/ml) were able to inhibit MALTl proteolytic activity. Chymostatin (100 μΜ) and Antipain (1 μΜ) strongly inhibited MALTl and the metacaspases, wherein Leupeptin (1 μΜ) had a stronger effect on AtMC4/9. The cysteine protease inhibitor E-64 did not inhibit MALTl, whereas it had mild effects on both metacaspases. While TLCK (1 μΜ) had a slight impact on metacaspases, MALTl activity was not affected. High doses (100 μΜ) of DEVD tetra-peptide caspase inhibitors did not inhibit MALTl or AtMC4/9.

Figure 10: Parameters for MALTl HTS. In the primary screen -18.000 small molecules of the ChemBioNet diversity library were tested with a final concentration of 10 μΜ against 170 nM of GSTMALTl in a 384 well format. The resulting 300 hits with the best inhibitory potential were further validated in secondary assays using different doses from 5 to 50 μΜ. 15 secondary hits were identified corresponding to -0.08 % of the original library. Figure 11: Proteolytic CASP8 assay. (A) Establishment of the proteolytic CASP8 assay. Different amounts of active recombinant CASP8 (0.25, 0.5 and 1 μg) were tested with 50 μΜ of the caspase substrate Ac-DEVD-AMC. Enzymatic activity was determined in accordance to the GSTMALTl assay. To analyze the inhibitory impact of phenothiazines on CASP8 250 pg was used. Data is representative of two independent experiments. (B) CASP8 activity against Ac-DEVD-AMC in the presence Ac-DEVD-CHO resulted in an almost total decline of enzymatic activity at a concentration of 50 pM. Graphs show the mean of three independent experiments. Error bars indicate SD.

Figure 12: Promazine inhibits MALT1 activity and selectively induces apoptosis in ABC-DLBCL cells, whereas promethazine does not significantly inhibit viability of ABC-DLBCL or GCB- DLBCL cells. (A) Promazine inhibits cellular MALT1 activity. Constitutive MALTl activity in ABC- DLBCL is reduced after 4 h promazine treatment of the cells. (B) and (C) Promazine impairs ABC- DLBCL cell viability. Consistent with the results obtained in the cellular MALTl cleavage assay, promazine had the mildest effects on ABC-DLBCL cell viability. (D) and (E) The MALTl non-active promethazine is not affecting ABC-DLBCL viability. ABC- and GCB-DLBCL cell lines were treated for 4 days with 10 and 20 μΜ of promethazine, which did not significantly impair viability of both DLBCL subgroups. Data is the mean of three independent experiments. Error bars (in A, B and E) indicate SD. Figure 13: Test results of phenothiazine derivatives (PDs) of the invention. Several compounds of the present invention have been tested using reactions and conditions similar to those used for testing mepazine, thioridazine and promazine. The results (IC50 values and % inhibition determined by the in vitro MALTl cleavage assay, IC50 values determined by the cellular MALTl cleavage assay, and EC50 values determined by the IL-6 production assay) for 5 exemplary compounds of the invention are shown.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Although the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. For example, if in a preferred embodiment R² of the compound of the invention is n-propyl and in another preferred embodiment -E-G-E'- of the compound of the invention is -C(R²²)=N-N(R³⁰)- C(=X)-N(R²¹)-, then in a preferred embodiment, R² of the compound of the invention is n-propyl and -E-G-E'- is -C(R²²)=N-N(R³⁰)-C(=X)-N(R²¹)-.

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", H.G.W. Leuenberger, B. Nagel, and H. Kolbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques which are explained in the literature in the field (cf, e.g., Molecular Cloning: A Laboratory Manual, 2^nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The terms "a" and "an" and "the" and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

The term "alkyl" refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1 ,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, and the like.

The term "alkylene" refers to a diradical of a saturated straight or branched hydrocarbon. Preferably, the alkylene comprises from 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (i.e., 1,1 -ethylene, 1 ,2-ethylene), propylene (i.e., 1,1 -propylene, 1,2- propylene (-CH(CH₃)CH2-), and 1,3-propylene), the butylene isomers (e.g., 1,1-butylene, 1 ,2-butylene, 2,2-butylene, 1 ,3-butylene, 2,3-butylene (cis or trans or a mixture thereof), 1 ,4-butylene, 1,1-iso- butylene, 1 ,2-iso-butylene, and 1,3-iso-butylene), the pentylene isomers (e.g., 1,1-pentylene, 1,2- pentylene, 1,3-pentylene, 1 ,4-pentylene, 1 ,5-pentylene, 1,1-iso-pentylene, 1,1 -sec-pentyl, 1,1 -neo- pentyl), the hexylenisomers (e.g., 1,1-hexylene, 1 ,2-hexylene, 1,3-hexylene, 1 ,4-hexylene, 1,5- hexylene, 1 ,6-hexylene, and 1,1-isohexylene), and the like.

The term "alkenyl" refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenyl group by 2 and, if the number of carbon atoms in the alkenyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 4, i.e., 1, 2, 3, or 4, carbon-carbon double bonds. Preferably, the alkenyl group comprises from 2 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises from 2 to 10 carbon atoms and 1, 2, 3, 4, or 5 carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1 , 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1 -propenyl, 2-propenyl (i.e., allyl), 1- butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,

1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3- nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4- decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, and the like. If an alkenyl group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom.

The term "alkenylene" refers to a diradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenylene group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenylene group by 2 and, if the number of carbon atoms in the alkenylene group is uneven, rounding the result of the division down to the next integer. For example, for an alkenylene group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenylene group has 1 to 4, i.e., 1, 2, 3, or 4, carbon-carbon double bonds. Preferably, the alkenylene group comprises from 2 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenylene group comprises from 2 to 10 carbon atoms and 1, 2, 3, 4, or 5 carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon- carbon double bonds, such as 2 to 6 carbon atoms and 1 , 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenylene groups include ethen-1 ,2-diyl, vinylidene, 1- propen-l ,2-diyl, l-propen-l ,3-diyl, l-propen-2,3-diyl, allylidene, l-buten-l,2-diyl, l-buten-l ,3-diyl, 1 - buten-l ,4-diyl, l-buten-2,3-diyl, 1 -buten-2,4-diyl, l-buten-3,4-diyl, 2-buten-l ,2-diyl, 2-buten-l,3-diyl,

2- buten-l,4-diyl, 2-buten-2,3-diyl, 2-buten-2,4-diyl, 2-buten-3,4-diyl, and the like. If an alkenylene group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom.

The term "alkynyl" refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximal number of carbon-carbon triple bonds in the alkynyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkynyl group by 2 and, if the number of carbon atoms in the alkynyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 4, i.e., 1, 2, 3, or 4, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynyl group comprises from 2 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkynyl group comprises from 2 to 10 carbon atoms and 1, 2, 3, 4, or 5 (preferably 1,

2, or 3) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, such as 2 to 6 carbon atoms and 1 , 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6- octynyl, 7-octynyl, 1-nonylyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6-nonynyl, 7-nonynyl, 8- nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl, 9- decynyl, and the like. If an alkynyl group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom.

The term "alkynylene" refers to a diradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximal number of carbon-carbon triple bonds in the alkynylene group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkynylene group by 2 and, if the number of carbon atoms in the alkynylene group is uneven, rounding the result of the division down to the next integer. For example, for an alkynylene group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynylene group has 1 to 4, i.e., 1, 2, 3, or 4, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynylene group comprises from 2 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkynylene group comprises from 2 to 10 carbon atoms and 1 , 2,

3, 4, or 5 (preferably 1, 2, or 3) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, such as 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynylene groups include ethyn-l,2-diyl, l-propyn-l,3-diyl, l-propyn-3,3-diyl, 1-butyn- 1,3-diyl, l-butyn-l ,4-diyl, l-butyn-3,4-diyl, 2-butyn-l,4-diyl and the like. If an alkynylene group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. The term "aryl" or "aromatic ring" refers to a monoradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 carbon atoms which can be arranged in one ring (e.g., phenyl) or two or more condensed rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenylium, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl. Preferably, "aryl" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl.

The term "arylene" refers to a diradical of an aromatic cyclic hydrocarbon as specified above. Preferably, the arylene group contains 3 to 14 carbon atoms which can be arranged in one ring (e.g., phenylene), or two or more condensed rings (e.g., naphthylene). Exemplary arylene groups are derived from cyclopropenylium, cyclopentadienyl, benzene, indene, naphthalene, azulene, fluorene, anthracene, or phenanthracene by removing two hydrogen atoms. Preferably, "arylene" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenylene and naphthylene. The term "heteroaryl" or "heteroaromatic ring" means an aryl group as defined above in which one or more carbon atoms in the aryl group are replaced by heteroatoms of O, S, or N. Preferably, heteroaryl refers to a five or six-membered aromatic monocyclic ring wherein 1 , 2, or 3 carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Alternatively, it means an aromatic bicyclic or tricyclic ring system wherein 1, 2, 3, 4, or 5 carbon atoms are replaced with the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group the maximum number of O atoms is 1 , the maximum number of S atoms is 1 , and the maximum total number of O and S atoms is 2. Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,5- and 1 ,2,3-), pyrrolyl, imidazolyl, pyrazolyl, triazolyl (1 ,2,3- and 1,2,4-), tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl, pyrimidinyl, pyrazinyl, triazinyl (1 ,2,3-, 1,2,4-, and 1,3,5-), benzofuranyl (1- and 2-), indolyl, isoindolyl, benzothienyl (1- and 2-), lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl (1,2,3- and 1,2,4- benzotriazinyl), pyridazinyl, phenoxazinyl, thiazolopyridinyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl (1 ,5-, 1 ,6-, 1,7-, 1,8-, and 2,6-), cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (1 ,7-, 1 ,8-, 1 ,10-, 3,8-, and 4,7-), phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. Exemplary 5- or 6-memered heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrolyl, imidazolyl, pyrazolyl, triazolyl (1 ,2,3- and 1 ,2,4-), thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1 ,2,5-), pyridyl, pyrimidinyl, pyrazinyl, triazinyl (1 ,2,3-, 1 ,2,4-, and 1,3,5-), and pyridazinyl. The term "heteroarylene" means a heteroaryl group as defined above in which one hydrogen atom has been removed resulting in a diradical. Exemplary heteroarylene groups include furanylene, thienylene, oxazolylene, isoxazolylene, oxadiazolylene (1,2,5- and 1,2,3-), pyrrolylene, imidazolylene, pyrazolylene, triazolylene (1,2,3- and 1,2,4-), thiazolylene, isothiazolylene, thiadiazolylene (1,2,3- and 1,2,5-), pyridinylene, pyrimidinylene, pyrazinylene, triazinylene (1,2,3-, 1,2,4-, and 1,3,5-), benzofuranylene (1- and 2-), indolylene, isoindolylene, benzothienylene (1- and 2), lH-indazolylene, benzimidazolylene, benzoxazolylene, indoxazinylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, quinolinylene, isoquinolinylene, benzodiazinylene, quinoxalinylene, quinazolinylene, benzotriazinylene (1,2,3- and 1 ,2,4-benzotriazinyl), pyridazinylene, phenoxazinylene, thiazolopyridinylene, pyrrolothiazolylene, phenothiazinylene, isobenzofuranylene, chromenylene, xanthenylene, phenoxathiinylene, pyrrolizinylene, indolizinylene, indazolylene, purinylene, quinolizinylene, phthalazinylene, naphthyridinylene (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), cinnolinylene, pteridinylene, carbazolylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), phenazinylene, oxazolopyridinylene, isoxazolopyridinylene, pyrrolooxazolylene, and pyrrolopyrrolyl. Exemplary 5- or 6-memered heteroarylene groups include furanylene, thienylene, oxazolylene, isoxazolylene, oxadiazolylene (1,2,5- and 1,2,3-), pyrrolylene, imidazolylene, pyrazolylene, triazolylene (1,2,3- and 1,2,4-), thiazolylene, isothiazolylene, thiadiazolylene (1,2,3- and 1,2,5-), pyridylene, pyrimidinylene, pyrazinylene, triazinylene (1,2,3-, 1,2,4-, and 1,3,5-), and pyridazinylene.

The term "cycloalkyl" or "cycloaliphatic" represents cyclic non-aromatic versions of "alkyl" and "alkenyl" with preferably 3 to 14 carbon atoms, such as 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 3 to 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cylcodecyl, cylcodecenyl, and adamantyl. The term "cycloalkyl" is also meant to include bicyclic and tricyclic versions thereof. If bicyclic rings are formed it is preferred that the respective rings are connected to each other at two adjacent carbon atoms, however, alternatively the two rings are connected via the same carbon atom, i.e., they form a spiro ring system or they form "bridged" ring systems. Preferred examples of cycloalkyl include C3-Cs-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, and bicyclo[4.2.0]octyl. The term "cycloalkylene" means a cycloalkyl group as defined above in which one hydrogen atom has been removed resulting in a diradical. Exemplary heteroarylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, spiro[3,3]heptylene, spiro[3,4]octylene, spiro[4,3]octylene, bicyclo[4.1.0]heptylene, bicyclo[3.2.0]heptylene, bicyclo[2.2.1]heptylene, bicyclo[2.2.2]octylene, bicyclo[5.1.0]octylene, bicyclo[4.2.0]octylene, adamantylene, and the like.

The term "heterocyclyl" or "heterocyclic ring" means a cycloalkyl group as defined above in which from 1, 2, 3, or 4 carbon atoms in the cycloalkyl group are replaced by heteroatoms of O, S, or N. Preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. The term "heterocyclyl" is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro or perhydro forms) of the above-mentioned heteroaryl groups. Exemplary heterocyclyl groups include morpholino, isochromanyl, chromanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydrooxazolyl, di- and tetrahydroisoxazolyl, di- and tetrahydrooxadiazolyl (1,2,5- and 1,2,3-), dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3- and 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydrothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and

1.2.5- ), di- and tetrahydropyridyl, di- and tetrahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4-, and 1,3,5-), di- and tetrahydrobenzofuranyl (1- and 2-), di- and tetrahydroindolyl, di- and tetrahydroisoindolyl, di- and tetrahydrobenzothienyl (1- and 2), di- and tetrahydro- lH-indazolyl, di- and tetrahydrobenzimidazolyl, di- and tetrahydrobenzoxazolyl, di- and tetrahydroindoxazinyl, di- and tetrahydrobenzisoxazolyl, di- and tetrahydrobenzothiazolyl, di- and tetrahydrobenzisothiazolyl, di- and tetrahydrobenzotriazolyl, di- and tetrahydroquinolinyl, di- and tetrahydroisoquinolinyl, di- and tetrahydrobenzodiazinyl, di- and tetrahydroquinoxalinyl, di- and tetrahydroquinazolinyl, di- and tetrahydrobenzotriazinyl (1,2,3- and 1,2,4-), di- and tetrahydropyridazinyl, di- and tetrahydrophenoxazinyl, di- and tetrahydrothiazolopyridinyl (such as

4.5.6- 7-tetrahydro[l,3]thiazolo[5,4-c]pyridinyl or 4,5,6-7-tetrahydro[l,3]thiazolo[4,5-c]pyridinyl, e.g., 4,5,6-7-tetrahydro[l,3]thiazolo[5,4-c]pyridin-2-yl or 4,5,6-7-tetrahydro[l,3]thiazolo[4,5-c]pyridin-2- yl), di- and tetrahydropyrrolothiazolyl (such as 5,6-dihydro-4H-pyrrolo[3,4-d][l,3]thiazolyl), di- and tetrahydrophenothiazinyl, di- and tetrahydroisobenzofuranyl, di- and tetrahydrochromenyl, di- and tetrahydroxanthenyl, di- and tetrahydrophenoxathiinyl, di- and tetrahydropyrrolizinyl, di- and tetrahydroindolizinyl, di- and tetrahydroindazolyl, di- and tetrahydropurinyl, di- and tetrahydroquinolizinyl, di- and tetrahydrophthalazinyl, di- and tetrahydronaphthyridinyl (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), di- and tetrahydrocinnolinyl, di- and tetrahydropteridinyl, di- and tetrahydrocarbazolyl, di- and tetrahydrophenanthridinyl, di- and tetrahydroacridinyl, di- and tetrahydroperimidinyl, di- and tetrahydrophenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), di- and tetrahydrophenazinyl, di- and tetrahydrooxazolopyridinyl, di- and tetrahydroisoxazolopyridinyl, di- and tetrahydropyrrolooxazolyl, and di- and tetrahydropyrrolopyrrolyl. Exemplary 5- or 6-memered heterocyclyl groups include morpholino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydrooxazolyl, di- and tetrahydroisoxazolyl, di- and tetrahydrooxadiazolyl (1,2,5- and 1,2,3-), dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3- and 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydroisothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), di- and tetrahydropyridyl, di- and tetrahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4-, and 1,3,5-), and di- and tetrahydropyridazinyl.

The term "heterocycloalkylene" means a heterocyclyl group as defined above in which one hydrogen atom has been removed resulting in a diradical. Exemplary heterocycloalkylene groups include pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, indolinylene, isoindolinylene, etc.

The term "halogen" or "halo" means fluoro, chloro, bromo, or iodo. The term "azido" means N3^".

The term "optionally substituted" indicates that one or more hydrogen atom(s) is/are replaced with a group (i.e., a 1^st level substituent) different from hydrogen such as alkyl (preferably, Ci-6 alkyl), alkenyl (preferably, C2-6 alkenyl), alkynyl (preferably, C2-6 alkynyl), aryl (preferably, 3- to 14-membered aryl), heteroaryl (preferably, 3- to 14-membered heteroaryl), cycloalkyl (preferably, 3- to 14-membered cycloalkyl), heterocyclyl (preferably, 3- to 14-membered heterocyclyl), halogen, -CN, azido, -NO2, -OR⁷¹, -N(R⁷²)(R⁷³), -ON(R⁷²)(R⁷³), -N⁺(-0 )(R⁷²)(R⁷³), -S(0)o-₂R⁷¹, -S(O)₀-₂OR⁷¹, -OS(O)₀-₂R⁷¹, -OS(0)o-₂OR⁷¹, -S(0)o-₂N(R⁷²)(R⁷³), -OS(O)₀-₂N(R⁷²)(R⁷³), -N(R⁷¹)S(O)₀-₂R⁷¹, -NR^7, S(O)₀-₂OR⁷¹, -NR⁷¹S(0)o-₂N(R⁷²)(R⁷³), -C^X^R⁷¹, -0(=Χ')Χ¾⁷¹, -X¹C(=X¹)R⁷¹, and -X¹C(=X¹)X'R⁷¹, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of the 1^st level substituent may themselves be substituted by one, two or three substituents (i.e., a 2^nd level substituent) selected from the group consisting of Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, -CF₃, -CN, azido, -N0₂, -OR⁸¹, -N(R⁸²)(R⁸³), -ON(R⁸²)(R⁸³), -N⁺(-0 )(R⁸²)(R⁸³), -S(O)₀-₂R⁸¹, -S(0)o-₂OR⁸¹, -OS(0)o-₂R⁸¹, -OS(O)₀-₂OR⁸¹, -S(O)₀-₂N(R⁸²)(R⁸³), -OS(O)₀-₂N(R⁸²)(R⁸³), -N(R⁸¹)S(0)o-₂R⁸¹, -NR⁸¹S(O)₀-₂OR⁸¹, -NR⁸¹S(O)₀-₂N(R⁸²)(R⁸³), -C(=X²)R⁸¹, -C(=X²)X²R⁸¹, -X²C(=X²)R⁸¹, and -X²C(=X²)X R⁸¹, wherein each of the Ci-₆ alkyl, C₂.₆ alkenyl, C₂-e alkynyl, 3- to 14- membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups of the 2^nd level substituent is optionally substituted with one, two or three substituents (i.e., a 3^rd level substituent) independently selected from the group consisting of C1-3 alkyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(G.₃ alkyl), -S(Ci-₃ alkyl), -N¾, -NH(Ci_₃ alkyl), -N(C..₃ alkyl)₂, -NHS(0)₂(Ci-₃ alkyl), -S(0)₂NH₂._z(Ci-₃ alkyl)_z, -C(=0)OH, -C(=0)0(G.₃ alkyl),

alkyl)_z, and -N(C,.₃

alkyl)_z, wherein z is 0, 1, or 2 and G.₃ alkyl is methyl, ethyl, propyl or isopropyl;

wherein

R⁷¹, R⁷², and R⁷³ are independently selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of Ci-₃ alkyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(Ci.₃ alkyl), -S(Ci-₃ alkyl), -NH₂, -NH(C,-₃ alkyl), -N(C,.₃ alkyl)₂, -NHS(0)₂(G-₃ alkyl), -S(0)₂NH₂._z(C,-₃ alkyl)_z, -C(=0)OH, -C(=0)0(C,.₃ alkyl), -C(=0)NH₂-_z(C,-₃ alkyl)_z, -NHC(=0)(C,.₃ alkyl), -NHC(=NH)NH_z.₂(C,-₃ alkyl)_z, and -N(Ci-₃

alkyl)_z, wherein z is 0, 1, or 2 and Ci-₃ alkyl is methyl, ethyl, propyl or isopropyl,

or R⁷² and R⁷³ may join together with the nitrogen atom to which they are attached to form a 5- or 6- membered ring, which is optionally substituted with one, two or three substituents selected from the group consisting of Ci-₃ alkyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(Ci-₃ alkyl), -S(Ci_₃ alkyl), -NH₂, -NH(C,-₃ alkyl), -N(C,-₃ alkyl)₂, -NHS(0)₂(Ci-₃ alkyl), -S(0)₂NH₂-_z(C,.₃ alkyl)_z, -C(=0)OH,

alkyl)_z, and -N(Ci-₃

alkyl)_z, wherein z is 0, 1 , or 2 and Ci-₃ alkyl is methyl, ethyl, propyl or isopropyl;

R⁸¹, R⁸², and R⁸³ are independently selected from the group consisting of -H, C1-4 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of Ci-₃ alkyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(Ci-₃ alkyl), -S(G-₃ alkyl), -NH₂, -NH(C,-3 alkyl), -N(Ci_₃ alkyl)., -NHS(0)₂(C,.₃ alkyl), -S(0)₂NH₂._z(C₁.₃ alkyl)_z, -C(=0)OH, -C(=0)0(C,.₃ alkyl), -C(=0)NH₂._z(C,.₃ alkyl)_z, -NHC(=0)(C,.₃ alkyl), -NHC(=NH)NH_Z.₂(C,.₃ alkyl)_z, and -N(Ci-₃

alkyl)_z, wherein z is 0, 1, or 2 and G-₃ alkyl is methyl, ethyl, propyl or isopropyl,

or R⁸² and R⁸³ may join together with the nitrogen atom to which they are attached to form a 5- or 6- membered ring, which is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -0(Ci-3 alkyl), -S(Ci_₃ alkyl), -NH2, - H(Ci-3 alkyl), -N(C,.₃ alkyl)₂, -NHS(0)₂(C₁.₃ alkyl), -S(0)₂NH₂-z(C,.3 alkyl)_z, -C(=0)OH, -C(=0)0(C,-3 alkyl),

alkyl)_z, and -N(Ci-3

alkyl)_z, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl;

X¹ and X² are independently selected from O, S, and NR⁸⁴, wherein R⁸⁴ is -H or C1-3 alkyl.

Typical 1^st level substituents are preferably selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered (such as 5- or 6-membered) aryl, 3- to 14-membered (such as 5- or 6-membered) heteroaryl, 3- to 14-membered (such as 3- to 7-membered) cycloalkyl, 3- to 14- membered (such as 3- to 7-membered) heterocyclyl, halogen, -CN, azido, -N0₂, -OR⁷¹, -N(R⁷²)(R⁷³), -S(0)o-₂R⁷¹, -S(0)o-₂OR⁷¹, -OS(0)o-₂R⁷\ -OS(O)₀-₂OR⁷¹, -S(O)₀-₂N(R⁷²)(R⁷³), -OS(O)₀-₂N(R⁷²)(R⁷³), -N(R⁷¹)S(0)o-₂R⁷¹, -NR⁷¹S(0)o-₂OR⁷¹, -C(=X')R⁷¹, -C(=X¹)X^IR⁷¹, -X¹C(=X¹)R⁷¹, and -X¹C(=X¹)X'R⁷¹, such as Ci-4 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, halogen, -CF3, -CN, azido, -N0₂, -OH, -0(Ci-3 alkyl), -S(C,.₃ alkyl), -NH₂, -NH(G.₃ alkyl), -N(C,.₃ alkyl)₂, -NHS(0)₂(C₁-₃ alkyl), -S(0)₂NH₂-_z(G-₃ alkyl)_z, -C(=0)OH,

alkyl), -NHC(=NH)NH_z.₂(C,-3 alkyl)_z, and -N(Ci-₃

alkyl)_z, wherein z is 0, 1, or 2 and Ci-3 alkyl is methyl, ethyl, propyl or isopropyl; X¹ is independently selected from O, S, NH and N(C¾); and R⁷¹, R⁷², and R⁷³ are as defined above or, preferably, are independently selected from the group consisting of -H, C1-4 alkyl, C₂-4 alkenyl, C₂.₄ alkynyl, 5- or 6-membered cycloalkyl, 5- or 6- membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, -CF3, -CN, azido, -N0₂, -OH, -0(C,.₃ alkyl), -S(G-₃ alkyl), -NH₂, -NH(G-₃ alkyl), -N(C,.₃ alkyl)₂, -NHS(0)₂(C,-₃ alkyl), -S(0)₂NH₂._z(Ci-3 alkyl)_z, -C(=0)OH, -C(=0)0(C,.₃ alkyl), -C(=0)NH₂._z(C,.₃ alkyl)_z, -NHC(=0)(Ci-3 alkyl),

alkyl)_z, and -N(Ci-₃ alkyl)_z, wherein z is 0, 1, or 2 and G-₃ alkyl is methyl, ethyl, propyl or isopropyl; or R⁷² and R⁷³ may join together with the nitrogen atom to which they are attached to form a 5- or 6-membered ring, which is optionally substituted with one, two or three substituents selected from the group consisting of G-₃ alkyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(C,.₃ alkyl), -S(Ci-₃ alkyl), -NH₂, -NH(C,-₃ alkyl), -N(C,-3 alkyl)₂, -NHS(0)₂(C,.₃ alkyl), -S(0)₂NH₂._z(Ci_3 alkyl)_z, -C(=0)OH, -C(=0)0(G-₃ alkyl),

alkyl)_z, and -N(C,-₃

alkyl)_z, wherein z is 0, 1, or 2 and Ci-₃ alkyl is methyl, ethyl, propyl or isopropyl. Typical 2^nd level substituents are preferably selected from the group consisting of Ci-₄ alkyl, C2-4 alkenyl, C₂.₄ alkynyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OH, -0(Ci_3 alkyl), -S(Ci-3 alkyl), -NH₂, -NH(G.₃ alkyl), -N(C,-₃ alkyl)₂, -NHS(0)₂(G.₃ alkyl), -S(0)₂NH₂._z(Ci-3 alkyl)_z, -C(=0)OH, -C(=0)0(C, -3 alkyl),

alkyl),

alkyl)_z, and -N(Ci_-3 alkyl)_z, wherein z is 0, 1, or 2 and Ci-3 alkyl is methyl, ethyl, propyl or isopropyl.

Typical 3^rd level substituents are preferably selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, partially and completely hydrogenated forms of the forgoing groups, morpholino, C1-3 alkyl, halogen, -CF₃, -OH, -OCH₃, -SCH₃, -NH₂._z(CH₃)_z, -C(=0)OH, and -C(=0)OCH₃, wherein z is 0, l, or 2.

The term "aromatic" as used in the context of hydrocarbons means that the whole molecule has to be aromatic. For example, if a monocyclic aryl is hydrogenated (either partially or completely) the resulting hydrogenated cyclic structure is classified as cycloalkyl for the purposes of the present invention. Likewise, if a bi- or polycyclic aryl (such as naphthyl) is hydrogenated the resulting hydrogenated bi- or polycyclic structure (such as 1 ,2-dihydronaphthyl) is classified as cycloalkyl for the purposes of the present invention (even if one ring, such as in 1,2-dihydronaphthyl, is still aromatic). A similar distinction is made within the present application between heteroaryl and heterocyclyl. For example, indolinyl, i.e., a dihydro variant of indolyl, is classified as heterocyclyl for the purposes of the present invention, since only one ring of the bicyclic structure is aromatic and one of the ring atoms is a heteroatom. The phrase "partially hydrogenated form" of an unsaturated compound or group as used herein means that part of the unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group without removing all unsaturated moieties. The phrase "completely hydrogenated form" of an unsaturated compound or group is used herein interchangeably with the term "perhydro" and means that all unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group. For example, partially hydrogenated forms of a 5-membered heteroaryl group (containing 2 double bonds in the ring, such as furan) include dihydro forms of said 5- membered heteroaryl group (such as 2,3-dihydrofuran or 2,5-dihydrofuran), whereas the tetrahydro form of said 5-membered heteroaryl group (e.g., tetrahydrofuran, i.e., THF) is a completely hydrogenated (or perhydro) form of said 5-membered heteroaryl group. Likewise, for a 6-membered heteroaryl group having 3 double bonds in the ring (such as pyridyl), partially hydrogenated forms include di- and tetrahydro forms (such as di- and tetrahydropyridyl), whereas the hexahydro form (such as piperidinyl in case of the heteroaryl pyridyl) is the completely hydrogenated (or perhydro) derivative of said 6-membered heteroaryl group. Consequently, a hexahydro form of an aryl or heteroaryl can only be considered a partially hydrogenated form according to the present invention if the aryl or heteroaryl contains at least 4 unsaturated moieties consisting of double and triple bonds between ring atoms.

The term "optional" or "optionally" as used herein means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances where said event, circumstance, or condition occurs and instances in which it does not occur.

"Isomers" are compounds having the same molecular formula but differ in structure ("structural isomers") or in the geometrical positioning of the functional groups and/or atoms ("stereoisomers"). "Enantiomers" are a pair of stereoisomers which are non-superimposable mirror-images of each other. A "racemic mixture" or "racemate" contains a pair of enantiomers in equal amounts and is denoted by the prefix (±). "Diastereomers" are stereoisomers which are non-superimposable mirror-images of each other. "Tautomers" are structural isomers of the same chemical substance that spontaneously interconvert with each other, even when pure. The term "solvate" as used herein refers to an addition complex of a dissolved material in a solvent (such as an organic solvent (e.g., an aliphatic alcohol (such as methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, and the like), water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A "hydrate" is a solvate wherein the solvent is water.

In isotopically labeled compounds one or more atoms are replaced by a corresponding atom having the same number of protons but differing in the number of neutrons. For example, a hydrogen atom may be replaced by a deuterium atom. Exemplary isotopes which can be used in the compounds of the present invention include deuterium, ⁿC, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³²S, ³⁶C1, and ¹²⁵I. The term "half-life" relates to the period of time which is needed to eliminate half of the activity, amount, or number of molecules. In the context of the present invention, the half-life of a compound of formula (I) is indicative for the stability of said compound.

The terms "patient", "individual", or "animal" relate to mammals. For example, mammals in the context of the present invention are humans, non-human primates, domesticated animals such as dogs, cats, sheep, cattle, goats, pigs, horses etc., laboratory animals such as mice, rats, rabbits, guinea pigs, etc. as well as animals in captivity such as animals of zoos. The term "animal" as used herein also includes humans.

The expression "disease or disorder which is treatable by an inhibitor of a paracaspase" as used herein relates to a disease/disorder which is associated with deregulated, in particular constitutive, proteolytic activity of a paracaspase compared to the state in a healthy individual. In one embodiment, the deregulated, in particular constitutive, proteolytic activity of a paracaspase is caused by an activating (e.g., oncogenic) mutation of CARMA1. In one embodiment, the deregulated, in particular constitutive, proteolytic activity of a paracaspase is caused by a constitutive antigen receptor signaling, preferably, by a constitutive B cell antigen receptor signaling. In one embodiment, the deregulated, in particular constitutive, proteolytic activity of a paracaspase is caused by an activating mutation in a regulator (e.g., activator) of the paracaspase and/or in a regulator (e.g., activator) of the antigen receptor signaling, e.g., in a regulator (e.g., activator) of the B cell antigen receptor signaling, such as CD79A and/or CD79B. In a preferred embodiment, the paracaspase is MALTl.

The expression "constitutive activity" of a molecule (such as an enzyme or receptor) as used herein means that the molecule exerts its biological activity (such as proteolytic activity) in the absence of a ligand bound to the molecule.

The expression "deregulated activity" of an enzyme or receptor as used herein means that the biological activity of the enzyme or receptor is increased (or even constitutive) since (i) one or more inhibitory regulator molecules of the enzyme or receptor which normally limit the activity of the enzyme or receptor with respect to (1) the effectiveness of the enzyme or receptor (wherein the effectiveness may be expressed as moles of substrate converted per time unit or release of second messanger(s) per time unit) and/or (2) the time period during which the enzyme or receptor is active are altered (e.g., mutated or inhibited), thereby decreasing (or even abolishing) the activity of the inhibitory regulator molecules, and/or (ii) one or more activating regulator molecules of the enzyme or receptor which increase the activity of the enzyme or receptor with respect to (1) the effectiveness of the enzyme or receptor (wherein the effectiveness may be expressed as moles of substrate converted per time unit or release of second messenger(s) per time unit) and/or (2) the time period during which the enzyme or receptor is active are altered (e.g., mutated or enhanced) thereby increasing the activity of the activating regulator molecules.

The expression "activating mutation" in a molecule (such as a protein or peptide) as used herein means that (i), if the unmutated molecule is an inhibitor, the mutation reduces or abolishes the inhibitory activity of the molecule, or (ii), if the unmutated molecule is an activator, the mutation enhances the activity of the molecule.

Within the context of the present invention, the indication that a moiety (such as G) is a specific group having a non-palindromic structure (such as the group "-C(0)-NH-") means that G can only be the group as specified (i.e., "-C(0)-NH-") and does not encompass the reverse structure (i.e., G cannot be "-NH-C(O)-").

Compounds

R¹ to R⁸ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azido, -N0₂, -OR", -N(R¹²)(R¹³), -ON(R¹²)(R¹³), -N⁺(-0 )(R¹²)(R¹³), -S(0)o-₂Rⁿ, -S(0)o-₂ORⁿ, -OS(O)₀-2Rⁿ, -OS(O)₀-2ORⁿ, -S(O)₀-₂N(R¹²)(R¹³), -OS(0)o-₂N(R¹²)(R¹³), -N(R^H)S(OV2Rⁿ, -NR^uS(0)o-20R^H, -NR"S(0)o-2N(R¹²)(R¹³), -C(=X)Rⁿ, -C(=X)XR", -XC(=X)R", and -XC(=X)XRⁿ, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted; or R¹ and R² may join together with the atoms to which they are attached to form a ring which is optionally substituted; R² and R³ may join together with the atoms to which they are attached to form a ring which is optionally substituted; R³ and R⁴ may join together with the atoms to which they are attached to form a ring which is optionally substituted; R⁵ and R⁶ may join together with the atoms to which they are attached to form a ring which is optionally substituted; R⁶ and R⁷ may join together with the atoms to which they are attached to form a ring which is optionally substituted; and/or R⁷ and R⁸ may join together with the atoms to which they are attached to form a ring which is optionally substituted;

R⁹ is -D-E-G-E'-R⁴⁰, wherein

D is -Li-Q_q-L'i_'-, wherein L and L' are independently selected from the group consisting of alkylene, alkenylene, and alkynylene; Q is selected from the group consisting of -NR¹¹-, -0-, -S(0)o-2-, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; and each of 1, q, and Γ is 0 or 1 , wherein when q is 0, is 0 and Q can only be -NR¹¹-, -O- or -S(0)o-2- if is 1 ; wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted;

G is selected from the group consisting of -(NR³⁰)_a-C(=X)-(NR³¹)_b- and -(NR³⁰)_a-S(O)i-₂-(NR³¹)b-, wherein a is 0 or 1 , b is 0 or 1 , and a+b is 1 or 2;

E' is selected from the group consisting of a covalent bond, -0-, -S(O)₀-2-, -C(=X)-, -NR²¹-, -C(R²³)=N-, -N=C(R²³)-, -C(=X)-NR²¹-, and -NR²¹-C(=X)-;

X is independently selected from O, S, and NR¹⁴;

R¹² and R¹³ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R¹² and R¹³ may join together with the nitrogen atom to which they are attached to form the group -N=CR¹⁵R¹⁶, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R¹⁴ is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -OR¹¹, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted; R¹⁵ and R¹⁶ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH_yR⁵⁰ ₂-_y, or R¹⁵ and R¹⁶ may join together with the atom to which they are attached to form a ring which is optionally substituted, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted; R²⁰ and R²¹ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R²² and R²³ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH_yR⁵⁰2-_y, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

or

y is an integer from 0 to 2 (i.e., 0, 1, or 2); and

In one embodiment, each of R¹ to R⁸, if it does not join together with another of R¹ to R⁸ to form a ring, is independently selected from the group consisting of -H, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -CN, azido, -NO2, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶¹, -S(0)₂N(R⁶ )(R⁶³), -N(R⁶¹)S(0)₂R⁶¹, -C(=X)R⁶¹, -C(=X)XR⁶¹, -XC(=X)R⁶¹, and -XC(=X)XR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, C alkyl, C₂-4 alkenyl, and C₂-4 alkynyl, and X is independently selected from the group consisting of O, S, NH, and NCH3, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(CM alkyl)₂, COOH, and COO(G-₄ alkyl). In one embodiment, each of R¹ to R⁸, if it does not join together with another of R¹ to R⁸ to form a ring, is independently selected from the group consisting of -H, C alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, -CN, azido, -NO2, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶\ -S(0)₂R⁶¹, -S(0)₂N(R⁶²)(R⁶³), -N(R⁶¹)S(0)₂R⁶¹, -C(0)R⁶¹, -C(0)OR⁶¹, -OC(0)R⁶¹, and -OC(0)OR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, Ci-4 alkyl, C2-4 alkenyl, and C₂-4 alkynyl, and wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(C,.₄ alkyl), -SH, -S(C_M alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(Ci-4 alkyl)₂, -COOH, and -COO(Ci-4 alkyl). In one embodiment, each of R¹ to R⁸, if it does not join together with another of R¹ to R⁸ to form a ring, is independently selected from the group consisting of -H, CM alkyl, C₂-₄ alkenyl, halogen, -CN, azido, -NO2, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -C(0)R⁶¹, and -C(0)OR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, Ci alkyl, C2 alkyl, and C3 alkyl, wherein each of the alkyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, -OH, -OCH3, -OCH2CH3, -OCH(CH₃)₂, -OCH2CH2CH3, -SH, -SCH3, -SCH2CH3, -SCH(CH₃)₂, -SCH₂CH₂CH₃, -NH₂, -NH(Ci-3 alkyl), -N(C,-₃ alkyl)₂, -COOH, and -COO(C,-₃ alkyl). In one embodiment, each of R¹ to R⁸, if it does not join together with another of R¹ to R⁸ to form a ring, is independently selected from the group consisting of -H, methyl, ethyl, propyl, -CH=CH₂, -CH₂CH=CH2, halogen, -CF₃, -CN, azido, -N0₂, -O-methyl, -O-ethyl, -O-propyl, -OCF3, -S-methyl, -S-ethyl, -S-propyl, -NH₂, -NHCH3, -N(CH₃)₂, -NH(CH₂CH₃), -N(CH₃)(CH₂CH₃), -N(CH₂CH₃)₂, -C(0)H, -C(0)CH₃, -COOH, -COOCH3, and -COOCH2CH3, wherein each of the methyl, ethyl, and propyl groups is optionally substituted with one substituent independently selected from the group consisting of halogen, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CH2OCH3, -SH, -SCH3, -SCH2CH3, -COOH, and -COOCH3.

In one embodiment, one or two of R¹ to R⁸ (preferably, R² and/or R⁷, more preferably R²), if they do not join together with another of R¹ to R⁸ to form a ring, is/are independently selected from the group consisting of -H, Ci_-6 alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, halogen, -CN, azido, -N0₂, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶¹, -S(0)₂N(R⁶²)(R⁶³), -N(R⁶¹)S(0)₂R⁶¹, -C(=X)R⁶¹, -C(=X)XR⁶¹, -XC(=X)R⁶¹, and -XC(=X)XR⁶¹, wherein R⁶', R⁶² and R⁶³ are independently selected from the group consisting of -H, CM alkyl, C2-4 alkenyl, and C2-4 alkynyl, and X is independently selected from the group consisting of O, S, NH, and NCH3, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(C M alkyl), -SH, -S(C_M alkyl), -NH(C_M alkyl), -N(C_M alkyl)₂, COOH, and COO(Ci-4 alkyl). In one embodiment, one or two of R¹ to R⁸ (preferably, R² and/or R⁷, more preferably R²), if they do not join together with another of R¹ to R⁸ to form a ring, is/are independently selected from the group consisting of -H, C M alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, -CN, azido, -N0₂, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶¹, -S(0)₂N(R⁶²)(R⁶³), -N(R^6,)S(0)₂R⁶¹, -C(0)R⁶¹, -C(0)OR⁶¹, -OC(0)R⁶¹, and -OC(0)OR⁶¹ , wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, Ci-4 alkyl, C₂-4 alkenyl, and C2-4 alkynyl, and wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(G-₄ alkyl), -SH, -S(CM alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(Ci-4 alkyl)₂, -COOH, and -COO(Ci-4 alkyl). In one embodiment, one or two of R¹ to R⁸ (preferably, R² and/or R⁷, more preferably R²), if they do not join together with another of R¹ to R⁸ to form a ring, is/are independently selected from the group consisting of -H, C alkyl, C₂-₄ alkenyl, halogen, -CN, azido, -NO2, -OR⁶¹ , -N(R⁶²)(R⁶³), -SR⁶¹, -C(0)R⁶¹, and -C(0)OR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, G alkyl, C2 alkyl, and C3 alkyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, -OH, -OCH3, -OCH₂CH₃, -OCH(CH₃)₂, -OCH2CH2CH3, -SH, -SCH₃, -SCH2CH3, -SCH(CH₃)₂, -SCH₂CH₂CH₃, -NH₂, -NH(C ,.₃ alkyl), -N(G.₃ alkyl)₂, -COOH, and -COO(G-₃ alkyl). In one embodiment, one or two of R¹ to R⁸ (preferably, R² and/or R⁷, more preferably R²), if they do not join together with another of R¹ to R⁸ to form a ring, is/are independently selected from the group consisting of -H, methyl, ethyl, propyl, -CH=CH₂, -CH₂CH=CH₂, halogen, -CF₃, -CN, azido, -NO2, -O-methyl, -O-ethyl, -O-propyl, -OCF₃, -S- methyl, -S-ethyl, -S-propyl, -NH₂, -NHCH₃, -N(CH₃)₂, -NH(CH₂CH₃), -N(CH₃)(CH₂CH₃), -N(CH₂CH₃)₂, -C(0)H, -C(0)CH₃, -COOH, -COOCH₃, and -COOCH₂CH₃, wherein each of the methyl, ethyl, and propyl groups is optionally substituted with one substituent independently selected from the group consisting of halogen, -CN, -OH, -OCH3, -OCH₂CH₃, -OCH₂CH₂OH, -OCH₂CH₂OCH₃, -SH, -SCH₃, -SCH₂CH₃, -COOH, and -COOCH₃. In one embodiment, one or two of R¹ to R⁸ (preferably, R² and/or R⁷, more preferably R²), if they do not join together with another of R¹ to R⁸ to form a ring, is/are independently selected from the group consisting of -H, methyl, ethyl, propyl, -CH=CH₂, -CH₂CH=CH₂, F, CI, Br, -CF₃, -OCH₃, -OCH₂CH₃, -OCF₃, -SCH₃, -SCH₂CH₃, -NH₂, -NHCH₃, -N(CH₃)₂, -NH(CH₂CH₃), -N(CH₃)(CH₂CH₃), -N(CH₂CH₃)₂, -COOH, and -COOCH₃. In each of the above embodiments, the remaining substituents of R¹ to R⁸ (e.g., R¹, R³, R⁴, R⁵, R⁶, and R⁸ in case R² and R⁷ have the particular meanings set forth above) may be independently selected from the group consisting of -H, methyl, F, CI, Br, -CF₃, -OCH₃, -OCF3, -SCH3, -NH₂, -NHCH₃, -N(CH₃)₂, -COOH, and -COOCH₃, such as -H, methyl, F, CI, Br, -CF₃, and -OCH3.

In any of the above embodiments, the ring formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, and/or (vi) R⁷ and R⁸ preferably is a 3- to 7-membered ring (e.g., a ring having 5 or 6 members) which is optionally substituted. The ring may be an aromatic, cycloaliphatic, heteroaromatic, or heterocyclic ring, wherein the heteroaromatic / heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of O, S, and NR⁶⁰, wherein R⁶⁰ is selected from the group consisting of R¹¹, -OR¹¹, -NH_yR⁵⁰ ₂-_y, and -S(0)i-₂R^u, wherein R¹¹, R⁵⁰, and y are as defined above. In one embodiment, the ring formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, and/or (vi) R⁷ and R⁸ is a 5- or 6-membered aromatic, cycloaliphatic, heteroaromatic, or heterocyclic ring, wherein the heteroaromatic / heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of O, S, and N, wherein at least one heteroatom is N. In one embodiment, the ring formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, and/or (vi) R⁷ and R⁸ is selected from the group consisting of cyclopentadiene, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1 ,2,4-triazine, and di- or tetrahydro forms of each of the foregoing. In one embodiment, the ring formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, or (vi) R⁷ and R⁸ is cyclopentene, such as 2,3-dihydrocyclopentadiene. In one embodiment, the total number of rings formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, and (vi) R⁷ and R⁸ is 0, 1 or 2, preferably 0 or 1. Thus, in the embodiment, wherein the total number of rings formed by (i) R¹ and R², (ii) R² and R³, (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, and (vi) R⁷ and R⁸ is 1 , only two adjacent substituents (i.e., either (i) R¹ and R², or (ii) R² and R³, or (iii) R³ and R⁴, or (iv) R⁵ and R⁶, or (v) R⁶ and R⁷, or (vi) R⁷ and R⁸, preferably, (ii) R² and R³) join together with the atoms to which they are attached to form a ring, wherein the ring is as defined in any of the above embodiments and the remaining of R¹ to R⁸ are selected from the particular groups of moieties specified above for the situation that they do not join together to form a ring. For example, the remaining R¹ to R⁸ which do not join together to form a ring may be selected from -H, Ci-6 alkyl, C2-6 alkenyl, C₂-6 alkynyl, halogen, -CN, azido, -N0₂, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶¹, -S(0)₂N(R⁶²)(R⁶³), -N(R⁶¹)S(0)₂R⁶¹, -C(=X)R⁶¹, -C(=X)XR⁶¹, -XC(=X)R⁶¹, and -XC(=X)XR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, C alkyl, C_2-4 alkenyl, and C₂-₄ alkynyl, and X is independently selected from the group consisting of O, S, NH, and NCH3, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(Ci-₄ alkyl), -SH, -S(d-₄ alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(CM alkyl)₂, -COOH, and -COO(Ci-₄ alkyl). In one embodiment, R² and R³ join together with the atoms to which they are attached to form a ring as defined in any of the above embodiments and the remaining R¹ and R⁴ to R⁸ are selected from the particular groups of moieties specified above for the situation that they do not join together to form a ring, e.g., R¹ and R⁴ to R⁸ are selected from the group consisting of -H, Ci-6 alkyl, C₂-6 alkenyl, C₂-6 alkynyl, halogen, -CN, azido, -NO2, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶¹ , -S(0)₂N(R⁶ )(R⁶³), -N(R⁶¹)S(0)₂R⁶¹, -C(=X)R⁶¹, -C(=X)XR⁶¹, -XC(=X)R⁶¹, and -XC(=X)XR⁶¹, wherein R⁶¹ , R⁶² and R⁶³ are independently selected from the group consisting of -H, CM alkyl, C₂.₄ alkenyl, and C₂.₄ alkynyl, and X is independently selected from the group consisting of O, S, NH, and NCH3, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO₂, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(Ci_₄ alkyl), -N(C_M alkyl)₂, -COOH, and -COO(C,-₄ alkyl). In an alternative embodiment, R¹ to R⁸ do not join together to form a ring.

In one embodiment, the phenothiazine derivative has the general formula (Π)

wherein R¹ and R⁸ are independently selected from H and methyl; R² and R⁷ are independently selected from the group consisting of -H, methyl, ethyl, propyl, -CH=CH₂, -CH₂CH=CH2, F, CI, Br, -CF3, -OCH3, -OCH2CH3, -OCF3, -SCH3, -SCH2CH3, -NH₂, -NHCH3, -N(CH₃)₂, -NH(CH₂CH₃), -N(CH₃)(CH₂CH₃), -N(CH₂CH₃)2, -COOH, and -COOCH3; R³, R⁴, R⁵, and R⁶ are independently selected from the group consisting of -H, methyl, F, CI, Br, -CF₃, -OCH3, -OCF3, -SCH₃, -NH₂, -NHCH3, -N(CH₃)₂, -COOH, and -COOCH3, such as -H, methyl, F, CI, Br, -CF₃, and -OCH₃; and R⁹ is as defined above or below. In one embodiment of the phenothiazine derivative having the general formula (Π), R¹ and R⁸ are both H; R² and R⁷ are independently selected from the group consisting of -H, methyl, ethyl, propyl, -CH=CH₂, -CH₂CH=CH₂, F, CI, Br, -CF₃, -OCH3, -OCH2CH3, -OCF3, -SCH₃, -SCH2CH3, -NH₂, -NHCH3, -N(CH₃)₂, -NH(CH₂CH₃), -N(CH₃)(CH₂CH₃), -N(CH₂CH₃)₂, -COOH, and -COOCH3; R³, R⁴, R⁵, and R⁶ are independently selected from the group consisting of -H, methyl, F, CI, Br, -CF3, -OCH3, -OCF3, -SCH3, -NH₂, -NHCH3, -N(CH₃)₂, -COOH, and -COOCH3, such as -H, methyl, F, CI, Br, -CF₃, and -OCH₃ (more preferably R³ to R⁶ are H); and R⁹ is as defined above or below. In one embodiment, the phenothiazine derivative has the general formula (III)

wherein R¹ and R⁸ are independently selected from H and methyl; R² and R³ join together with the atoms to which they are attached to form a 5- or 6-memebred ring which is optionally substituted as specified above; R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of -H, methyl, F, CI, Br, -CF₃, -OCH₃, -OCF₃, -SC¾, -NH₂, -NHCH₃, -N(CH₃)₂, -COOH, and -COOCH₃, such as -H, methyl, F, CI, Br, -CF₃, and -OCH₃; and R⁹ is as defined above or below. In one embodiment of the phenothiazine derivative having the general formula (HI), R¹ and R⁸ are both H; R² and R³ join together with the atoms to which they are attached to form a 5- or 6-membered ring selected from the group consisting of cyclopentadiene, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1 ,2,4-triazine, and di- or tetrahydro forms of each of the foregoing (preferably R² and R³ join together with the atoms to which they are attached to form a cyclopentene ring), wherein the ring is optionally substituted with one, two or three 3^rd level substituents as defined above (preferably, one, two or three substituents selected from the group consisting of C,-₃ alkyl, halogen, -CF₃, -OH, -OCH₃, -SCH₃, -NH₂-_Z(CH₃)_Z, -C(=0)OH, and -C(=0)OCH₃, wherein z is 0, 1, or 2); R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of -H, methyl, F, CI, Br, -CF₃, -OCH₃, -OCF₃, -SCH₃, -NH₂, -NHCH₃, -N(CH₃)₂, -COOH, and -COOCH₃, such as -H, methyl, F, CI, Br, -CF₃, and -OCH₃ (more preferably R⁴ to R⁷ are H); and R⁹ is as defined above or below. In any of the above embodiments (including those of formulas (I) to (HI)), L and L' may be independently selected from the group consisting of Ci-6 alkylene, C₂-6 alkenylene, and C₂-6 alkynylene, wherein each of the alkylene, alkenylene, and alkynylene groups is optionally substituted. In one embodiment, L and L' are independently selected from the group consisting of C alkylene, C₂-₄ alkenylene, and C₂.₄ alkynylene, wherein each of the alkylene, alkenylene, and alkynylene groups is optionally substituted with one, two, or three (preferably one or two, more preferably one) substituents independently selected from the group consisting halogen, -CN, -OH, -OCH₃, -OCH₂CH₃, =0, -OCH₂CH₂OH, -OCH₂CH₂OCH₃, -SH, -SCH₃, -SCH₂CH₃, -COOH, and -COOCH₃. In one embodiment, L and L' are independently selected from the group consisting of methylene, ethylene, and propylene, each of which is optionally substituted with one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH₃, =0, -SH, -SCH₃, -COOH, and -COOCH₃, preferably one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH₃.

In any of the above embodiments (including those of formulas (I) to (ΠΙ)), Q may be selected from the group consisting of -NR¹¹-, -0-, -S-, 3- to 10-membered arylene, 3- to 10-membered heteroarylene, 3- to 10-membered cycloalkylene, and 3- to 10-membered heterocycloalkylene, wherein each of the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted. In one embodiment, Q is selected from the group consisting of -NR¹¹-, 5- to 6-membered arylene, 5- to

6- membered heteroarylene, 3- to 7-membered (such as 4- or 6-membered) cycloalkylene, and 3- to

7- membered (such as 4- or 6-membered) heterocycloalkylene, wherein each of the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(Ci-4 alkyl), -SH, -S(C_M alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(G-₄ alkyl)₂, -COOH, and -COO(Ci-4 alkyl). Preferably, the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups are selected from the group consisting of phenylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, pyranylene, cyclopentadienylene, thiazolylene, isothiazolylene, oxazolylene, isoxazolylene, oxadiazolyne, pyrazolylene, imidazolylene, pyrrolylene, furanylene, thienylene, thiadiazolylene, triazolylene, tetrazolylene, and hydrogenated forms (such as di-, tetra- or perhydr forms) of the forgoing groups. In one embodiment, Q is selected from the group consisting of -NH-, cyclopentylene, phenylene, cyclohexylene, cyclohexadienylene, cyclohexenylene, pyridinylene, dihydropyridinylene, tetrahydropyridinylene, piperidinylene, pyrazolylene, dihydropyrazolylene, pyrazolidinylene, oxazolylene, oxadiazolylene, pyrrolylene, dihydropyrrolylene, pyrrolidinylene, imidazolylene, dihydroimidazolylene, imidazolidinylene, pyrazinylene, dihydropyrazinylene, tetrahydropyrazinylene, piperazinylene, pyridazinylene, dihydropyridazinylene, tetrahydropyridazinylene, hexahydropyridazinylene, pyrimidinylene, dihydropyrimidinylene, tetrahydropyrimidinylene, hexahydropyrimidinylene, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-3 alkyl), -SH, -S(Ci-₃ alkyl), -NH₂, -NH(G-₃ alkyl), -N(Ci_-3 alkyl)₂, -COOH, and -COO(Ci-3 alkyl). In one embodiment, Q is selected from the group consisting of -NH-, phenylene (such as 1,3-phenylene), oxazolylene (such as oxazol-2,4-diyl), oxadiazolylene (such as 1 ,2,4- oxadiazol-3,5-diyl), pyrazolylene (such as lH-pyrazol-l ,3-diyl), dihydropyrazolylene (such as 4,5- dihydro-lH-pyrazol-l,3-diyl), piperidinylene (such as piperidin-2,6-diyl), and pyridinylene (such as pyridin-2,6-diyl), each of which may be optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CH3, -OH, and =0. In any of the above embodiments (including those of formulas (I) to (ΙΠ)), D may be selected from the group consisting of Cue alkylene, -(C1-3 alkylene)-NRⁿ-(Ci-3 alkylene)-, -(C1-3 alkylene)-0-(G-₃ alkylene)-, -(C1-3 alkylene)-S-(G-₃ alkylene)-, -(C1-3 alkylene)-(5- to 6-membered arylene)-(G.₃ alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered heteroarylene)-(G-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered cycloalkylene)-(G-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered heterocycloalkylene)-(Ci-3 alkylene)o-i-, wherein each of the alkylene, alkenylene, and alkynylene groups is optionally substituted (e.g., with one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH3, =0, -SH, -SC¾, -COOH, and -COOCH3, preferably one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH3) and each of the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(Ci_₄ alkyl), -SH, -S(Ci-₄ alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(CM alkyl)2, -COOH, and -COO(Ci-4 alkyl)). In one embodiment, D is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, -CH2NR^{l l}CH2- (wherein R" is H or C1-3 alkyl), -CH2OCH2-, -CH2CH₂NR^HCH2- (wherein R¹¹ is H or C1-3 alkyl), -CH₂CH₂OCH₂-, -CH2NRⁿCH₂CH2-, (wherein R¹¹ is H or Ci_-3 alkyl), -CH2CH₂NRⁿCH₂CH2- (wherein Rⁿ is H or C1-3 alkyl), -CH2CH2OCH2CH2-, -(Ci-2 alkylene)-(5- to 6-membered arylene)-, -(C1-2 alkylene)-(5- to 6-membered heteroarylene)-, -(Ci-₂ alkylene)-(5- to 6-membered cycloalkylene)-, and -(C1-2 alkylene)-(5- to 6-membered heterocycloalkylene)-, wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted as specified above. Preferably, the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups are selected from the group consisting of phenylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, pyranylene, cyclopentadienylene, thiazolylene, isothiazolylene, oxazolylene, isoxazolylene, oxadiazolylene, pyrazolylene, imidazolylene, pyrrolylene, furanylene, thienylene, thiadiazolylene, triazolylene, tetrazolylene, and hydrogenated forms (such as di-, tetra- or perhydro forms) of the forgoing groups, such as cyclopentylene, phenylene, cyclohexylene, cyclohexadienylene, cyclohexenylene, pyridinylene, dihydropyridinylene, tetrahydropyridinylene, piperidinylene, pyrazolylene, dihydropyrazolylene, pyrazolidinylene, oxazolylene, oxadiazolylene, pyrrolylene, dihydropyrrolylene, pyrrolidinylene, imidazolylene, dihydroimidazolylene, imidazolidinylene, pyrazinylene, dihydropyrazinylene, tetrahydropyrazinylene, piperazinylene, pyridazinylene, dihydropyridazinylene, tetrahydropyridazinylene, hexahydropyridazinylene, pyrimidinylene, dihydropyrimidinylene, tetrahydropyrimidinylene, hexahydropyrimidinylene. In one embodiment, D is selected from the group consisting of methylene, ethylene, propylene, -CH2NR"CH2- (wherein R¹¹ is H or Ci-3 alkyl), -CH₂OCH₂-, -CH2CH₂NR^UCH₂- (wherein R¹¹ is H or C1.3 alkyl), -CH₂CH₂OCH₂-, -CH₂NR^UCH2CH₂-, (wherein R^u is C,.₃ alkyl), -CH2CH2NR¹ 'CH₂CH₂- (wherein R" is H or C1.3 alkyl), -CH2CH2OCH2CH2-, and -(C1-3 alkylene)-Q-, wherein Q is selected from the group consisting of cyclopentylene, phenylene, cyclohexylene, cyclohexadienylene, cyclohexenylene, pyridinylene, dihydropyridinylene, tetrahydropyridinylene, piperidinylene, pyrazolylene, dihydropyrazolylene, pyrazolidinylene, pyrrolylene, dihydropyrrolylene, pyrrolidinylene, imidazolylene, dihydroimidazolylene, oxazolylene, oxadiazolylene, imidazolidinylene, pyrazinylene, dihydropyrazinylene, tetrahydropyrazinylene, piperazinylene, pyridazinylene, dihydropyridazinylene, tetrahydropyridazinylene, hexahydropyridazinylene, pyrimidinylene, dihydropyrimidinylene, tetrahydropyrimidinylene, and hexahydropyrimidinylene, such as 4,5-dihydro-lH-pyrazol-l,3-diyl, 1H- pyrazol-l,3-diyl, piperidin-2,6-diyl, and pyridin-2,6-diyl. In one embodiment, D is selected from the group consisting of methylene, ethylene, propylene, -(CH2)-Q-, -(CH2)2-Q-, and -(CH2)3-Q-, wherein Q is selected from the group consisting of phenylene (such as 1,3-phenylene), oxazolylene (such as oxazol-2,4-diyl), oxadiazolylene (such as l,2,4-oxadiazol-3,5-diyl), pyrazolylene (such as lH-pyrazol- 1,3-diyl), dihydropyrazolylene (such as 4,5-dihydro-lH-pyrazol-l,3-diyl), piperidinylene (such as piperidin-2,6-diyl), and pyridinylene (such as pyridin-2,6-diyl), each of which may be optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -C¾, -ΟΗ, and =0.

In any of the above embodiments (including those of formulas (I) to (III)), E may be selected from the group consisting of -C(R²²)=N-, a covalent bond, -NR²⁰-, -C(=X)-, -N=C(R²²)-, -C(=X)-NR²⁰-, and -NR²⁰-C(=X)-. In one embodiment, E is selected from the group consisting of -C(R²²)=N-, a covalent bond, -NR²⁰-, and -C(=X)-NR²⁰-. In one embodiment, E is selected from the group consisting of -C(R²²)=N-, a covalent bond, and -NR²⁰-. Preferably, R²⁰ and R²² are independently selected from the group consisting of -Η, Ci-₆ alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -ΟΗ, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(CM alkyl)₂, COOH, and COO(Ci-₄ alkyl), preferably, with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R²⁰ and R²² are independently selected from the group consisting of -H and methyl. In one embodiment, E is selected from the group consisting of -CH=N-, -C(CH3)=N-, a covalent bond, -NH-, and -NCH₃-. In one embodiment, E can only be -O- or -S- if a is 0 and E can only be -S(0)i-₂-, -C(=X)-, -C(R²²)=N-, -N=C(R²²)-, or -NR²⁰-C(=X)- if a is 1.

In any of the above embodiments (including those of formulas (I) to (III)), E' may be selected from the group consisting of -NR²¹-, a covalent bond, -0-, -S-, -C(R²³)=N-, -N=C(R²³)-, -C(=X)-NR²¹-, and -NR²¹-C(=X)-. In one embodiment, E' is selected from the group consisting of -NR²¹-, a covalent bond, -0-, -S-, and -N=C(R²³)-. In one embodiment, E' is selected from the group consisting of -NR²¹-, a covalent bond, and -0-. Preferably, R²¹ and R²³ are independently selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(G-₄ alkyl), -SH, -S(Ci-₄ alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(Ci-₄ alkyl)₂, COOH, and COO(G-₄ alkyl), preferably, with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R²¹ and R²³ are independently selected from the group consisting of -H and methyl. In one embodiment, E' is selected from the group consisting of -NH-, -NCH3-, a covalent bond, -0-, -S-, and -N=CH-. In one embodiment, F can only be -O- or -S- if b is 0 and E' can only be -S(0)i-₂-, -C(=X)-, -C(R²²)=N-, -N=C(R²²)-, or -NR²⁰-C(=X)- if b is 1.

In any of the above embodiments (including those of formulas (I) to (ΠΙ)), one of R²⁰ and R²² and one of R²¹ and R²³ (i.e., R²⁰ and R²¹, or R²⁰ and R²³, or R²² and R²¹, or R²² and R²³) may join together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl (preferably dihydrotriazolyl, tetrahydrotriazolyl, imidazolidinyl) which is optionally substituted (e.g., with =0 or =S). Alternatively, R³⁰ and R³¹ may join together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl (preferably dihydrotriazolyl, tetrahydrotriazolyl, imidazolidinyl) which is optionally substituted (e.g., with =0 or =S). Alternatively, R³⁰ and one of R²¹ and R²³ (i.e., R³⁰ and R²¹ or R³⁰ and R²³) may join together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl (preferably dihydrotriazolyl, tetrahydrotriazolyl, imidazolidinyl) which is optionally substituted (e.g., with =0 or =S). Alternatively, R³¹ and one of R²⁰ and R²² (i.e., R³¹ and R²⁰ or R³¹ and R²²) may join together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl (preferably dihydrotriazolyl, tetrahydrotriazolyl, imidazolidinyl) which is optionally substituted (e.g., with =0 or =S). In any of the above embodiments (including those of formulas (I) to (ΙΠ)), a+b may be 1. In this embodiment, G is selected from the group consisting of -(NR³⁰)-C(=X)- (i.e., -(NR³⁰)-C(O)-, -(NR³⁰)- C(S)-, -(NR³⁰)-C(=NR¹⁴)-), -C(=X)-(NR³¹)- (i.e., -C(0)-(NR³¹)-, -C(S)-(NR³¹)-, -C(=NR¹⁴)-(NR³¹)-), -(NR³⁰)-S(O)-, -(NR ⁰)-S(O)₂-, -S(0)-(NR³¹)- and -S(0)₂-(NR³¹)-. Preferably, G is selected from the group consisting of -(NR³⁰)-C(O)-, -(NR³⁰)-C(S)-, -(NR³⁰)-C(=NR¹⁴)-, -C(0)-(NR³¹)-, -C(S)-(NR³¹)-, -(NR ⁰)-S(O)2-, and -S(0)2-(NR³¹)-. In one embodiment, G is selected from the group consisting of -(NR³⁰)-C(O)-, -(NR³⁰)-C(S)-, -(NR³⁰)-C(=NR¹⁴)-, -C(0)-(NR³¹)-, -C(S)-(NR³¹)-, and -(NR³⁰)-S(O)₂-. Preferably, R³⁰ is selected from the group consisting of -H, Ci-₆ alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-4 alkyl), -SH, -S(CM alkyl), -NH₂, -NH(C_M alkyl), -N(C,.₄ alkyl)₂, COOH, and COO(Ci-₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH₃. In one embodiment, R³⁰ is selected from the group consisting of -H and C1-3 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³⁰ is selected from the group consisting of -H, -C¾, and -CH₂CH20H. Preferably, R¹⁴ is selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and -OR¹¹, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-₄ alkyl), -NH₂, -NH(CM alkyl), -N(CM alkyl)₂, COOH, and COO(Ci-₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH3) and R¹¹ is -H or Ci-₆ alkyl (such as C1.3 alkyl, e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R¹⁴ is -H. Preferably, R³¹ is selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci_4 alkyl), -SH, -S(C,-4 alkyl), -NH₂, -NH(C_M alkyl), -N(Ci-₄ alkyl)₂, COOH, and COO(G-₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH3. In one embodiment, R³¹ is selected from the group consisting of -H and C1-3 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³¹ is -H or methyl.

In any of the above embodiments (including those of formulas (I) to (ΙΠ)), in particular those where a+b is 1, the moiety -E-G-E'- is preferably selected from the group consisting of -C(R²²)=N-N(R³⁰)- C(=X)-N(R²¹)-, -C(=X)-N(R³¹)-, -N(R³⁰)-C(=X)-, -N(R³⁰)-S(O)₂-, -S(0)₂-N(R³¹)-, -C(=X)-N(R²⁰)- N(R³⁰)-C(=X)-N(R²¹)-, -N(R³⁰)-C(=X)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R³⁰)-C(=O)-S-, -N(R³⁰)-C(=S)- 0-, -N(R³⁰)-C(=S)-S-, -N(R²⁰)-N(R³⁰)-C(=X)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=X)-, and -C(R²²)=N-N(R³⁰)- C(=X)-. In one embodiment, the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N- N(R ⁰)-C(=O)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R²¹)-, -C(R²²)=N-N(R ⁰)-C(=NR¹⁴)-N(R²¹)-, -C(=0)-N(R³¹)-, -C(=S)-N(R³¹)-, -N(R³⁰)-S(O)₂-, -N(R³⁰)-C(=O)-N(R²¹)-, -N(R³⁰)-C(=S)-N(R²¹)-, -N(R³⁰)-C(=NR¹⁴)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R²⁰)-N(R ⁰)-C(=O)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=S)- N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=O)-, and -C(R²²)=N-N(R³⁰)-C(=S)-. In these embodiments of -E-G-E'-, R²⁰, R²¹, and R²² are preferably independently selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, and C₂-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(C alkyl), -SH, -S(CM alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(CM alkyl)₂, COOH, and COO(Ci-₄ alkyl), preferably, with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R²⁰, R²¹, and R²² are independently selected from the group consisting of -H and methyl. Preferably, R³⁰ is selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(C,.₄ alkyl)₂, COOH, and COO(Ci-₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH₃. In one embodiment, R³⁰ is selected from the group consisting of -H and C1-3 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³⁰ is selected from the group consisting of -H, -CH₃, and -CH2CH2OH. Preferably, R¹⁴ is selected from the group consisting of -H, Ci-6 alkyl, C₂-6 alkenyl, C₂-6 alkynyl, and -OR", wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci_4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(G-₄ alkyl), -N(Ci-₄ alkyl)₂, COOH, and COO(Ci-₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH₃) and R¹¹ is -H or Ci-₆ alkyl (such as G_-3 alkyl, e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R¹⁴ is -H. Preferably, R³¹ is selected from the group consisting of -H, Ci-6 alkyl, C₂-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(C,.₄ alkyl), -N(CM alkyl)₂, COOH, and COO(G-₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH₃. In one embodiment, R³¹ is selected from the group consisting of -H and C1-3 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SC¾, -COOH, and -COOCH3. In one embodiment, R³¹ is -H or methyl. In one embodiment, the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R ⁰)-C(=O)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=NR¹⁴)- N(R²¹)-, -C(=0)-N(R³¹)-, -C(=S)-N(R³¹)-, -N(R³⁰)-S(O)₂-, -N(R³⁰)-C(=O)-N(R²¹)-, -N(R³⁰)-C(=S)- N(R²¹)-, -N(R³⁰)-C(=NR¹⁴)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R²⁰)-N(R³⁰)-C(=O)-N(R²¹)-, -N(R²⁰)-N(R³⁰)- C(=S)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=O)-, and -C(R²²)=N-N(R³⁰)-C(=S)-, wherein R¹⁴, R²⁰, R²¹, R²², R³⁰, and R³¹ are independently selected from the group consisting of -H and methyl. In one embodiment, the moiety -E-G-E'- is -C(R² )=N-N(R³⁰)-C(=O)-N(R²¹)- or -C(R²²)=N-N(R³⁰)-C(=S)- N(R²¹)-, wherein R²¹, R²², and R³⁰ are independently selected from the group consisting of -H and methyl. embodiment, the phenothiazine derivative has the general formula (IV)

wherein R¹ to R⁸ are as defined above (in particular with respect to formulas (I) to (ΓΠ)); R⁹ is -D-E-G- E'-R⁴⁰, wherein D is selected from the group consisting of Ci-e alkylene, -(C1-3 alkylene)-NR^u-(Ci-3 alkylene)-, -(C1-3 alkylene)-0-(Ci-3 alkylene)-, -(C1-3 alkylene)-S-(Ci-3 alkylene)-, -(C1-3 alkylene)-(5- to 6-membered arylene)-(Ci-3 alkylene)o i-, -(C1.3 alkylene)-(5- to 6-membered heteroarylene)-(Ci-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered cycloalkylene)-(Ci-3 alkylene)o-i-, or -(C1-3 alkylene)- (5- to 6-membered heterocycloalkylene)-(Ci-3 alkylene)o-i-, wherein each of the alkylene, alkenylene, and alkynylene groups is optionally substituted (e.g., with one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH3, =0, -SH, -SCH₃, -COOH, and -COOCH3, preferably one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH3, SH, -SCH₃, -COOH, and -COOCH₃) and each of the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(Ci_₄ alkyl), -SH, -S(C_M alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(Ci-4 alkyl)₂, -COOH, and -COO(Ci-₄ alkyl)); the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=X)-N(R²¹)-, -C(=X)-N(R³¹)-, -N(R³⁰)-C(=X)-, -N(R³⁰)-S(O)₂-, -S(0)₂-N(R³¹)-, -C(=X)-N(R²⁰)-N(R³⁰)-C(=X)-N(R²¹)-, -N(R³⁰)-C(=X)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R³⁰)-C(=O)-S-, -N(R³⁰)-C(=S)-O-, -N(R³⁰)-C(=S)-S-, -N(R²⁰)-N(R³⁰)-C(=X)-N(R²¹)-, -N(R²⁰)- N(R³⁰)-C(=X)-, and -C(R²²)=N-N(R³⁰)-C(=X)-; and R⁴⁰ is as defined above or below. In one embodiment of the phenothiazine derivative having the general formula (rV), R¹ to R⁸ are as defined above (in particular with respect to formula (II) or (ΙΠ)); D is selected from the group consisting of methylene, ethylene, propylene, -(CH₂)-Q-, -(CH₂)2-Q-, and -(CH₂)3-Q-, wherein Q is selected from the group consisting of phenylene (such as 1,3-phenylene), oxazolylene (such as oxazol-2,4-diyl), oxadiazolylene (such as l,2,4-oxadiazol-3,5-diyl), pyrazolylene (such as lH-pyrazol-l,3-diyl), dihydropyrazolylene (such as 4,5-dihydro-lH-pyrazol-l,3-diyl), piperidinylene (such as piperidin-2,6- diyl), and pyridinylene (such as pyridin-2,6-diyl), each of which may be optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CH3, -OH, and =0; the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R ⁰)-C(=O)-N(R²¹)-, -C(R² )=N-N(R³⁰)-C(=S)- N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=NR¹⁴)-N(R²¹)-, -C(=0)-N(R³¹)-, -C(=S)-N(R³¹)-, -N(R³⁰)-S(O)₂-, -N(R³⁰)-C(=O)-N(R²¹)-, -N(R ⁰)-C(=S)-N(R²¹)-, -N(R³⁰)-C(=NR¹⁴)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R²⁰)- N(R³⁰)-C(=O)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=S)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=O)-, and -C(R²²)=N- N(R³⁰)-C(=S)-, wherein R¹⁴, R²⁰, R²¹, R²², R³⁰, and R³¹ are independently selected from the group consisting of -H and methyl; and R⁴⁰ is as defined above or below.

In another embodiment, a+b may be 2. In this embodiment, G is selected from the group consisting of -(NR³⁰)-C(=X)-(NR³¹)- (i.e., -(NR³⁰)-C(=O)-(NR³¹)-, -(NR ⁰)-C(=S)-(NR³¹)-, -(NR³⁰)-C(=NR¹⁴)- (NR³¹)-), -(NR³⁰)-S(O)-(NR³¹)-, and -(NR³⁰)-S(O)₂-(NR³¹)-. Preferably, G is selected from the group consisting of -(NR³⁰)-C(=O)-(NR³¹)-, -(NR³⁰)-C(=S)-(NR³¹)-, -(NR³⁰)-C(=NR¹⁴)-( R³¹)-, and -(NR³⁰)- S(0)₂-(NR³¹)-. Preferably, R³⁰ and R³¹ are independently selected from the group consisting of -H, Ci-6 alkyl, C₂-6 alkenyl, and C₂-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(CM alkyl), -SH, -S(CM alkyl), -NH₂, -NH(Ci_₄ alkyl), -N(C M alkyl)₂, COOH, and COO(Ci-4 alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³⁰ and R³¹ are independently selected from the group consisting of -H and C1-3 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³⁰ and R³¹ are independently selected from the group consisting of -H and -C¾. Preferably, R¹⁴ is selected from the group consisting of -H, Ci-6 alkyl, C₂-6 alkenyl, C₂-e alkynyl, and -OR¹¹, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(Ci-₄ alkyl), -N(CM alkyl)₂, COOH, and COO(G.₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH₃) and R^{1 1} is -H or Ci_-6 alkyl (such as C1.3 alkyl, e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH3. In one embodiment, R¹⁴ is -H. In any of the above embodiments where a+b is 2 (including those of formulas (I) to (ΠΙ)), the moiety -E-G-E'- is preferably selected from the group consisting of -N(R²⁰)-N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)- (i.e., -N(R²⁰)-N(R³⁰)-C(=O)-N(R³¹)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=S)-N(R³¹)-N(R²¹)-, -N(R²⁰)-N(R³⁰)- C(=NR¹⁴)-N(R³¹)-N(R²¹)-), -N(R²⁰)-N(R³⁰)-C(=X)-N(R³¹)-N=C(R²³)- (i.e., -N(R ⁰)-N(R³⁰)-C(=O)- N(R³¹)-N=C(R²³)-, -N(R²⁰)-N(R³⁰)-C(=S)-N(R³¹)-N=C(R²³)-, -N(R²⁰)-N(R³⁰)-C(=NR¹⁴)-N(R³¹)- N=C(R²³)-), -C(R²²)=N-N(R ⁰)-C(=X)-N(R ¹)-N(R²¹)- (i.e., -C(R²²)=N-N(R³⁰)-C(=O)-N(R³¹)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R^3,)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=NR¹⁴)-N(R³¹)-N(R²¹)-), and -C(R²²)=N-N(R³⁰)-C(=X)-N(R^3,)-N=C(R²³)- (i.e., -C(R²²)=N-N(R³⁰)-C(=O)-N(R³¹)-N=C(R²³)-, -C(R² )=N-N(R³⁰)-C(=S)-N(R³¹)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)-C(=NR¹⁴)-N(R³¹)-N=C(R²³)-). Preferably, the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=O)- N(R^3,)-N=C(R²³)-, -C(R² )=N-N(R³⁰)-C(=S)-N(R^3I)-N=C(R²³)-, and -C(R²²)=N-N(R ⁰)-C(=NR¹⁴)- N(R³¹)-N=C(R²³)-. Preferably, R³⁰ and R³¹ are independently selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(G-₄ alkyl), -SH, -S(Ci-₄ alkyl), -NH₂, -NH(Ci.₄ alkyl), -N(Ci-4 alkyl)2, COOH, and COO(Ci-4 alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³⁰ and R³¹ are independently selected from the group consisting of -H and C1-3 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH3. In one embodiment, R³⁰ and R³¹ are independently selected from the group consisting of -H and -CH3. Preferably, R¹⁴ is selected from the group consisting of -H, Ci-6 alkyl, G-6 alkenyl, C2-6 alkynyl, and -OR¹¹, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(Ci-4 alkyl), -SH, -S(Ci-4 alkyl), -NH₂, -NH(G_₄ alkyl), -N(G-₄ alkyl)₂, COOH, and COO(G_₄ alkyl), preferably with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH3) and R¹¹ is -H or G_-6 alkyl (such as C₁-3 alkyl, e.g., methyl, ethyl, or propyl) optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH₃, -SH, -SCH3, -COOH, and -COOCH3. In one embodiment, R¹⁴ is -H. Preferably, R²¹ and R²³ are independently selected from the group consisting of -H, G-6 alkyl, G-6 alkenyl, and G-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted, e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -NO2, -OH, -0(G-4 alkyl), -SH, -S(G_₄ alkyl), -NH₂, -NH(G-₄ alkyl), -N(G-₄ alkyl)₂, COOH, and COO(G-₄ alkyl), preferably, with one substituent selected from the group consisting of -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH3, -COOH, and -COOCH3. In one embodiment, R²¹ and R²³ are independently selected from the group consisting of -H and methyl. In one embodiment, the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=O)-N(R^3,)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R³¹)- N=C(R²³)-, and -C(R²²)=N-N(R³⁰)-C(=NR^I4)-N(R³¹)-N=C(R²³)-, wherein R¹⁴, R²⁰, R²¹, R²³, R³⁰, and R³¹ are independently selected from the group consisting of -H and methyl. In one embodiment, the phenothiazine derivative has the general formula (V)

wherein R¹ to R⁸ are as defined above (in particular with respect to formulas (Γ) to (EH)); R⁹ is -D-E-G- E'-R⁴⁰, wherein D is selected from the group consisting of G-6 alkylene, -(G-3 alkylene)-NR^u-(G-3 alkylene)-, -(C1-3 alkylene)-0-(G-3 alkylene)-, -(G-3 alkylene)-S-(G-3 alkylene)-, -(G-3 alkylene)-(5- to 6-membered arylene)-(G-3 alkylene)o-i-, -(G-3 alkylene)-(5- to 6-membered heteroarylene)-(G-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered cycloalkylene)-(G-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered heterocycloalkylene)-(G_3 alkylene)o-i-, wherein each of the alkylene, alkenylene, and alkynylene groups is optionally substituted (e.g., with one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH₃, =0, -SH, -SCH₃, -COOH, and -COOCH3, preferably one substituent selected from the group consisting -F, -CI, -Br, -CN, -OH, -OCH3, -SH, -SCH₃, -COOH, and -COOCH₃) and each of the arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted (e.g., with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(G-₄ alkyl), -SH, -S(G-₄ alkyl), -NH₂, -NH(G-₄ alkyl), -N(G-4 alkyl)₂, -COOH, and -COO(G_₄ alkyl)); the moiety -E-G-E'- is selected from the group consisting of -N(R²⁰)-N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)- (i.e., -N(R²⁰)-N(R³⁰)-C(=O)-N(R³¹)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=S)-N(R³¹)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=NR¹⁴)-N(R³¹)-N(R²¹)-), -N(R²⁰)-N(R³⁰)- C(=X)-N(R³¹)-N=C(R²³)- (i.e., -N(R²⁰)-N(R ⁰)-C(=O)-N(R^3I)-N=C(R²³)-, -N(R ⁰)-N(R³⁰)-C(=S)-N(R³¹)- N=C(R²³)-, -N(R²⁰)-N(R³⁰)-C(=NR^,4)-N(R³¹)-N=C(R²³)-), -C(R²²)=N-N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)- (i.e., -C(R² )=N-N(R³⁰)-C(=O)-N(R³¹)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R³¹)-N(R²¹)-, -C(R²²)=N- N(R³⁰)-C(=NR¹⁴)-N(R³¹)-N(R²¹)-), and -C(R²²)=N-N(R³⁰)-C(=X)-N(R³¹)-N=C(R²³)- (i.e., -C(R²²)=N- N(R³⁰)-C(=O)-N(R³ >)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R³¹ )-N=C(R²³)-, -C(R²²)=N-N(R³⁰)- C(=NR¹⁴)-N(R ¹)-N=C(R²³)-); and R⁴⁰ is as defined above or below. In one embodiment of the phenothiazine derivative having the general formula (V), R¹ to R⁸ are as defined above (in particular with respect to formula (II) or (III)); D is selected from the group consisting of methylene, ethylene, propylene, -(CH₂)-Q-, -(CH₂)₂-Q-, and -(CH₂)3-Q-, wherein Q is selected from the group consisting of phenylene (such as 1 ,3-phenylene), oxazolylene (such as oxazol-2,4-diyl), oxadiazolylene (such as l,2,4-oxadiazol-3,5-diyl), pyrazolylene (such as lH-pyrazol-l,3-diyl), dihydropyrazolylene (such as 4,5-dihydro-lH-pyrazol-l,3-diyl), piperidinylene (such as piperidin-2,6-diyl), and pyridinylene (such as pyridin-2,6-diyl), each of which may be optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CH3, -OH, and =0; the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=O)-N(R³¹)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R³¹)-N=C(R²³)-, and -C(R²²)=N-N(R³⁰)-C(=NR¹⁴)-N(R³¹)-N=C(R²³)-, wherein R¹⁴, R²⁰, R²¹, R²³, R³⁰, and R³¹ are independently selected from the group consisting of -H and methyl; and R⁴⁰ is as defined above or below.

In any of the above embodiments (including those of formulas (I) to (V)), R⁴⁰ may be selected from the group consisting of -H, CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted. In one embodiment, R⁴⁰ is selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C₂-6 alkynyl, 3- to 14-membered heteroaryl containing at least one nitrogen atom, and 3- to 14-membered heterocyclyl containing at least one nitrogen atom, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted. In one embodiment, R⁴⁰ is selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, morpholino, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, isoxazolyl, oxazolyl, benzothiazolyl, pyrazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, thiadiazolyl, triazolyl, phenoxazinyl, thiazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolothiazolyl, pyrrolooxazolyl, pyrrolopyrrolyl, phenothiazinyl, isoquinolinyl, imidazolyl, pyrrolyl, furanyl, thienyl, pyranyl, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, isothiazolyl, pyrazinyl, pyrrolizinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, quinolinyl, phthalazinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8-naphthyridinyl, 2,6-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, 1,7-phenanthrolinyl, 1,8 -phenanthrolinyl, 1,10-phenanthrolinyl, 3,8-phenanthrolinyl, 4,7- phenanthrolinyl, phenazinyl, chromanyl, isochromanyl, and partially or completely hydrogenated (such as di-, tetra- or, where appropriate, hexahydro) forms of the forgoing aryl/heteroaryl groups, wherein each of the forgoing alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups and hydrogenated forms thereof is optionally substituted. In one embodiment, R⁴⁰ is selected from the group consisting of -H, Ci-4 alkyl, C₂-4 alkenyl, morpholino, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, isoxazolyl, oxazolyl, benzothiazolyl, pyrazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, thiadiazolyl, triazolyl, phenoxazinyl, thiazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolothiazolyl, pyrrolooxazolyl, pyrrolopyrrolyl, phenothiazinyl, isoquinolinyl, imidazolyl, benzoimidazolyl, pyrrolyl, furanyl, thienyl, pyranyl, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, isothiazolyl, pyrazinyl, pyrrolizinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, quinolinyl, phthalazinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8- naphthyridinyl, 2,6-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, phenazinyl, and partially or completely hydrogenated (such as di-, tetra- or, where appropriate, hexahydro) forms of the forgoing aryl/heteroaryl groups, wherein each of the forgoing alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups and hydrogenated forms thereof is optionally substituted. In one embodiment, R⁴⁰ is selected from the group consisting of -H, C1-3 alkyl, C2-3 alkenyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, isoxazolyl, oxazolyl, benzothiazolyl, pyrazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, thiadiazolyl, triazolyl, phenoxazinyl, thiazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolothiazolyl, pyrrolooxazolyl, pyrrolopyrrolyl, phenothiazinyl, and partially or completely hydrogenated forms of the forgoing aryl/heteroaryl groups, wherein each of the forgoing alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups and (partially or completely) hydrogenated (such as di-, tetra- or, where appropriate, hexahydro) forms thereof is optionally substituted. For example, a partially hydrogenated form of thiazolopyridinyl includes di- and tetrahydrothiazolopyridinyl, such as 4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridinyl or 4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]pyridinyl (preferably 4,5,6,7-tetrahydro[l,3]thiazolo[5,4- c]pyridin-2-yl or 4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]pyridin-2-yl), and a partially hydrogenated form of pyrrolothiazolyl includes di- and tetrahydropyrrolothiazolyl, such as 5,6-dihydro-4H-pyrrolo[3,4- d][l,3]thiazolyl.

In any of the above embodiments (including those of formulas (I) to (V)), the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of R⁴⁰ are optionally substituted with one, two or three substituents independently selected from the 1^st level substituents specified above, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of the 1^st level substituents may themselves be substituted by one, two or three substituents independently selected from the 2^nd level substituents specified above, and the Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14- membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups of the 2^nd level substituents may optionally be substituted with one, two or three substituents independently selected from the 3^rd level substituents specified above. In one embodiment, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of R⁴⁰ are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 14-membered (such as 5- or 6-membered) aryl, 3- to 14- membered (such as 5- or 6-membered) heteroaryl, 3- to 14-membered (such as 3- to 7-membered) cycloalkyl, 3- to 14-membered (such as 3- to 7-membered) heterocyclyl, halogen, -CN, azido, -NO2, -OR⁷¹, -N(R⁷²)(R⁷³), -S(0)o-₂R⁷¹, -S(0)o-₂OR⁷¹, -OS(O)₀-₂R⁷¹, -OS(O)₀-₂OR⁷¹, -S(O)₀-₂N(R⁷²)(R⁷³), -OS(0)o-₂N(R⁷²)(R⁷³), -N(R⁷¹)S(0)o-₂R⁷¹, -NR⁷¹S(O)₀-₂OR⁷¹, -C(=X')R⁷¹, -C(=X¹)X¹R⁷¹, -X'C(=X¹)R⁷¹, and -X¹C(=X')X^IR⁷¹, wherein X¹ is independently selected from O, S, NH and N(CH₃); and R⁷¹, R⁷², and R⁷³ are as defined above or, preferably, are independently selected from the group consisting of -H, - Ci-4 alkyl, C2-4 alkenyl, C₂-4 alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6- membered heteroaryl, and 5- or 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents selected from the group consisting of C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -0(Ci-3 alkyl), -S(d-₃ alkyl), -NH₂, -NH(Ci-₃ alkyl), -N(Ci-₃ alkyl)₂, morpholino, -NHS(0)₂(Ci-₃ alkyl), -S(0)₂NH₂._z(Ci-3 alkyl)z, -C(=0)OH,

alkyl),

alkyl)_z, and -N(G-₃ alkyl)_z, wherein z is 0, 1, or 2 and C₁-3 alkyl is methyl, ethyl, propyl or isopropyl; or R⁷² and R⁷³ may join together with the nitrogen atom to which they are attached to form a 5- or 6-membered ring (preferably morpholino), which is optionally substituted with one, two or three substituents selected from the group consisting of Ci-₃ alkyl, halogen, -CF₃, -CN, azido, -NO2, -OH, -0(C,.₃ alkyl), -S(Ci-₃ alkyl), -NH₂, -NH(C,.₃ alkyl), -N(Ci-3 alkyl)₂, -NHS(0)₂(C,-3 alkyl), -S(0)2NH2-_Z(C,.₃ alkyl)_z, -C(=0)OH, -C(=0)0(C,-₃ alkyl),

)_z, -NHC(=0)(G.₃ alkyl), alkyl)_z, and -N(Ci_₃

alkyl)_z, wherein z is 0, 1, or 2 and G-₃ alkyl is methyl, ethyl, propyl or isopropyl. In one embodiment, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of R⁴⁰ are optionally substituted with one, two or three substituents independently selected from the group consisting of C₁-4 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, 5- or 6-membered aryl (preferably phenyl), 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(Ci-₃ alkyl), -S(Ci-₃ alkyl), -NH₂, -NH(Ci-₃ alkyl), -N(G-₃ alkyl)₂, -NHS(0)₂(C, .3 alkyl), -S(0)₂NH₂._z(Ci_₃ alkyl)_z, -C(=0)OH,

alkyl)_z,

alkyl)_z, wherein z is 0, 1, or 2 and G-₃ alkyl is methyl, ethyl, propyl or isopropyl, each of which may be optionally substituted (such as with morpholino). In one embodiment, the alkyl, alkenyl, and alkynyl groups of R⁴⁰ are optionally substituted with one substituent independently selected from the group consisting of 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, -S(0)o-₂(5- or 6-membered aryl), halogen, -CF₃, -CN, azido, -NO2, -OH, -0(Ci-3 alkyl), -S(C,.₃ alkyl), -NH₂, -NH(G-₃ alkyl), -N(G-₃ alkyl)₂, -NHS(0)₂(C, -3 alkyl), -S(0)₂NH₂. z(Ci-3 alkyl)_z,

alkyl)_z, -NHC(=0)(C,_3 alkyl),

alkyl)_z, and -N(G-₃ alkyl)_z, wherein z is 0, 1, or 2 and Ci-3 alkyl is methyl, ethyl, propyl or isopropyl. In one embodiment, R⁴⁰ is selected from the group consisting of -H, C₁-3 alkyl and C₂-3 alkenyl, wherein the alkyl and alkenyl groups are optionally substituted with one substituent independently selected from the group consisting of 5- to 14- membered heteroaryl or heterocyclyl which contains, as ring atoms, one, two, three or four heteroatoms selected from N, O, and S, wherein the number of ring atoms being N is 1, 2, or 3, the number of ring atoms being O is 0 or 1, and the number of ring atoms being S is 0 or 1, -S(0)o-2(5- or 6-membered aryl or heteroaryl), halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(C,.₃ alkyl), -S(G_₃ alkyl), -NH₂, -NH(C,.₃ alkyl), -N(Ci-3 alkyl)₂, -NHS(0)₂(G.₃ alkyl), -S(0)₂NH₂._z(C,.₃ alkyl)_z, -C(=0)OH, -C(=0)0(G-₃ alkyl),

)_z, -NHC(=0)(Ci_₃ alkyl), alkyl)_z, and -N(G-₃

alkyl)_z, wherein z is 0, 1, or 2 and Ci-₃ alkyl is methyl, ethyl, propyl or isopropyl. In one embodiment, R⁴⁰ is selected from the group consisting of -H, Ci-3 alkyl and C₂-₃ alkenyl, wherein the alkyl and alkenyl groups are optionally substituted with one substituent independently selected from the group consisting of 5- to 14-membered heteroaryl or heterocyclyl which contains, as ring atoms, one, two, three or four heteroatoms selected from N, O, and S, wherein the number of ring atoms being N is 1, 2, or 3, the number of ring atoms being O is 0 or 1 , and the number of ring atoms being S is 0 or 1, -S(0)₂(6-membered aryl or heteroaryl), halogen, and -N(Ci-₃ alkyl)₂. Alternatively or additionally, R⁴⁰ may be selected from the group consisting of 5- to 10- membered aryl, heteroaryl, or heterocyclyl (such as phenyl, isoxazolyl, pyridyl, thiazolopyridinyl, benzothiazolyl, benzoxazolyl, pyrazolyl, thiazolyl, benzodioxyl, isothiazolyl, pyrimidinyl, or thiazolyl) each of which may be optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-₃ alkyl, halogen, -CF₃, -CN, azido, -N0₂, -OH, -0(Ci-₃ alkyl), -S(Ci-₃ alkyl), -NH₂, -NH(C,.₃ alkyl), -N(Ci_-3 alkyl)₂, -NHS(0)₂(G-₃ alkyl), -S(0)₂NH₂._z(C₁.₃ alkyl)_z, -C(=0)OH,

alkyl),

alkyl)_z, and -N(Ci-₃ alkyl)C(=NH)NH₂._z(Ci.₃ alkyl)_z, wherein z is 0, 1, or 2 and each Ci-₃ alkyl (including methyl, ethyl, propyl or isopropyl) may be optionally substituted with one substituent selected from the group consisting of halogen, -OH, -OCH₃, -NH₂, -NHCH₃, and -N(CH₃)₂.

In any of the above embodiments, it is preferred that 1 is 1 , q is 0 or 1 and Γ is 0 (thus, D is -L- or -L- Q-). In an alternative embodiment, 1 is 1, q is 1 and Γ is 1 (thus, D is -L-Q-L'-). Therefore, in one embodiment, R⁹ may be selected from the group consisting of -L-E-G-E'-R⁴⁰, -L-Q-E-G-E'-R⁴⁰, and -L- Q-L'-E-G-E'-R⁴⁰, wherein L, Q, L', E, G, E', -E-G-E'-, and R⁴⁰ are as defined in any of the above paragraphs. For example, in one embodiment, D is -L- or -L-Q-, wherein L is selected from the group consisting of methylene, ethylene, and propylene, -L-Q- is selected from the group consisting of -(CH₂)-Q-, -(CH₂)₂-Q-, and -(CH₂)₃-Q-, and Q is selected from the group consisting of phenylene (such as 1 ,3-phenylene), oxazolylene (such as oxazol-2,4-diyl), oxadiazolylene (such as l ,2,4-oxadiazol-3,5- diyl), pyrazolylene (such as lH-pyrazol-l,3-diyl), dihydropyrazolylene (such as 4,5-dihydro-lH- pyrazol-l ,3-diyl), piperidinylene (such as piperidin-2,6-diyl), and pyridinylene (such as pyridin-2,6- diyl), each of which may be optionally substituted with one substituent selected from the group consisting of -F, -CI, -Br, -CH₃, -OH, and =0; the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=O)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=S)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=NR¹⁴)- N(R²¹)-, -C(=0)-N(R³¹)-, -C(=S)-N(R³¹)-, -N(R³⁰)-S(O)₂-, -N(R³⁰)-C(=O)-N(R²¹)-, -N(R³⁰)-C(=S)- N(R²¹)-, -N(R³⁰)-C(=NR¹⁴)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R²⁰)-N(R ⁰)-C(=O)-N(R²¹)-, -N(R²⁰)-N(R³⁰)- C(=S)-N(R²¹)-, -C(R²²)=N-N(R³⁰)-C(=O)-, and -C(R²²)=N-N(R³⁰)-C(=S)-, wherein R¹⁴, R²⁰, R²¹, R²², R³⁰, and R³¹ are independently selected from the group consisting of -H and methyl; and R⁴⁰ is as set forth in any of the above paragraphs.

In one embodiment, the compounds of the first aspect do not encompass 1- [3 -(1 OH-phenothiazin- 10- yl)propyl]guanidine, 3-(10H-phenothiazin-10-ylmethyl)piperidine-l-carboximidamide and 2-(10H- phenothiazin- 10-ylacetyl)-N-phenylhydrazinecarbothioamide.

Particularly preferred compounds of the invention are selected from the following group of phenothiazine derivates and their hydrates, solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, and tautomers:

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-phenylsemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-4-ylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-pyridin-3-ylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[4-(dimethylamino)phenyl]semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-{4-[2-(dimethylamino) ethoxy]phenyl}semicarbazone; (1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3,4-dimethylisoxazol-5-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N'-(2-hydroxyethyl)-N-(3 -methylisoxazol-5 - yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-isoxazol-3-ylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l ,3]thiazolo[5,4-c]pyridin-

2-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3-benzoxazol-2-ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3 -benzodioxol-5 -ylsemicarbazone;

N",N" -bis[( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene]carbonohydrazide;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3-benzothiazol-2-ylsemicarbazone;

1 -[3 -( 1 OH-phenothiazin- 10-yl)propyl] -3 -phenylurea; phenyl [3 -( 1 OH-phenothiazin- 10-yl)propyl] carbamate;

N- [3 -( 1 OH-phenothiazin- 10-yl)propyl]benzenesulfonamide;

l-[3-(10H-phenothiazin-10-yl)propyl)-3-phenylthiourea;

1- methyl-l-[3-(10H-phenothiazin-10-yl)propyl]-3-phenylthiourea;

2-[(10H-phenothiazin-10-yl)carbonyl]-N-phenylhydrazinecarbothioamide;

( 1 E/Z)-3-( 1 OH-phenothiazin- 10-yl)propanal N-phenylsemicarbazone;

2- [2-(10H-phenothiazin-10-yl)ethyl]-N-phenylhydrazinecarboxamide;

3-amino-N'-[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]-lH-l,2,4-triazole-l-carbohydrazide^

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene] amino } imidazolidin-2-one;

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene] amino } -3 -phenylimidazolidin-2-one;

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene] amino } imidazolidine-2,4-dione;

N-methyl-2-( 1 OH-phenothiazin- 10-ylacetyl)hydrazinecarbothioamide;

2-[( 1 OH-phenothiazin- 10-yl)acetyl] -N-propylhydrazinecarbothioamide;

N-allyl-2-( 1 OH-phenothiazin- 10-ylacetyl)hydrazinecarbothioamide;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[3-(dimethylamino)propyl]semicarbazone;

10-[(l-methylpiperidin-3-yl)methyl]-2-propyl-10H-phenothiazine;

2-allyl- 10- [( 1 -methylpiperidin-3 -yl)methyl] - 1 OH-phenothiazine;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-{4-[2-(dimethylamino)ethoxy]phenyl}semicarbazone; (lE/Z)-[2-(methylthio)-10H-phenothiazin-10-yl]acetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone; (2E/Z)-2-[2-(10H-phenothiazin-10-yl)ethylidene]-N-(3-methylisoxazol-5- yl)hydrazinecarboximidamide;

N-(3 -methylisoxazol-5 -yl)-3 -[( 1 OH-phenothiazin- 10-yl)methyl] - 1 H-pyrazole- 1 -carboxamide;

2,3-dihydrocyclopenta[b]phenothiazin-10(lH)ylacetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone; N-(3-methylisoxazol-5-yl)-6-[(10H-phenothiazin-10-yl)methyl]pyridine-2-carboxamide;

1 OH-phenothiazin- 10-ylacetaldehyde N-(2-fluoropyridin-4-yl)semicarbazone;

2-ethyl- 10-[( 1 -methylpiperidin-3 -yl)methyl]- 1 OH-phenothiazine;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde thiosemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-methylthiosemicarbazone; ( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-propylthiosemicarbazone;

(2E/Z)-2-[2-( 1 OH-phenothiazin- 10-yl)ethylidene]hydrazinecarboximidamide;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-methylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-( 1 ,3 -dimethyl- 1 H-pyrazol-5 -yl)semicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3-methylisothiazol-5-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-phenylthiosemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde NN-dimethylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyrimidin-2-ylsemicarbazone;

4-methyl-N-[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]piperazine-l-carbohydrazide;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-( 1 -methylpyrrolidin-3 -yl)semicarbazone;

(lE/Z)-[2-(methylthio)-10H-phenothiazin-10-yl]acetaldehyde N-phenylsemicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3-methoxyphenyl) semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- [4-(4-methylpiperazin- 1 -yl)phenyl] semicarbazone; (1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(2-methylpyridin-4-yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-quinolin-7-ylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N,N'-dimethylthiosemicarbazone;

2- (10H-phenothiazin-10-ylacetyl)-N-[3-(trifluoromethyl)phenyl]hydrazinecarbothioamide;

3- ( 1 OH-phenothiazin- 10-ylmethyl)-N-phenyl-4,5-dihydro- lH-pyrazole- 1 -carboxamide ;

phenyl (2E/Z)-2-[2-( 1 OH-phenothiazin- 10-yl)ethylidene]hydrazinecarboxylate;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]pyridin- 2-yl) semicarbazone; and

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-[3-(2-mo holin-4-ylethoxy)phenyl] semicarbazone. Within this group the following phenothiazine derivates are preferred:

1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-4-ylsemicarbazone;

1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methylisoxazol-3-yl)semicarbazone;

1 OH-phenothiazin- 10-ylacetaldehyde N-(3,4-dimethylisoxazol-5-yl)semicarbazone;

1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridin-2- yl)semicarbazone;

10H-phenothiazin-10-ylacetaldehyde N-{3-[2-(dimethylamino)ethoxy]phenyl} semicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]pyridin-

2-yl) semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[3-(2-mo holin-4-ylethoxy)phenyl]semicarbazone, and their hydrates, solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, and tautomers.

It is intended that the compounds of the present invention (in particular, the compounds of any one of formulas (I) to (V)) encompass not only the compounds as depicted but also their solvates (e.g., hydrates), salts (in particular, pharmaceutically acceptable salts), complexes, racemic mixtures, non- racemic mixtures, diastereomers, enantiomers, tautomers, crystalline forms, non-crystalline forms, amorphous forms, unlabeled forms and isotopically labeled forms.

The compounds of the invention which contain a basic functionality may form salts with a variety of inorganic or organic acids. Exemplary inorganic and organic acids/bases as well as exemplary acid/base addition salts of the compounds of the present invention are given in the definition of "pharmaceutically acceptable salt" in the section "Pharmaceutical composition", below. The compounds of the invention which contain an acidic functionality may form salts with a variety of inorganic or organic bases. The compounds of the invention which contain both basic and acidic functionalities may be converted into either base or acid addition salt. The neutral forms of the compounds of the invention may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

The compounds of the invention may be in a prodrug form. Prodrugs of the compounds of the invention are those compounds that upon administration to an individual undergo chemical conversion under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when, for example, placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Exemplary prodrugs are esters or amides which are hydrolyzable in vivo.

As it is evident from the examples, the inventors have found that the compounds of the invention inhibit the activity of MALT1, in particular the proteolytic activity of MALT1. In one embodiment, the compounds of the invention are selective inhibitors of MALT1 , i.e., they inhibit the activity of the paracaspase MALT1, but do not inhibit the activity of a caspase (such as CASP3 and/or CASP8) and/or a metacaspase (such as AtMC4 and/or AtMC9). In one embodiment, the compounds of the invention exhibit pharmacological properties (bioavailability, toxicity, side effects, dosing, patient compliance, compatibility, stability, half-life, etc.), which are in at least one aspect superior to the pharmacological properties exhibited by the tetra-peptide Z-VRPR-FMK. Pharmaceutical compositions

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be administered to an individual by any route, such as enterally or parenterally.

The compositions according to the present invention are generally applied in "pharmaceutically acceptable amounts" and in "pharmaceutically acceptable preparations". Such compositions may contain salts, buffers, preserving agents, carriers and optionally other therapeutic agents. "Pharmaceutically acceptable salts" comprise, for example, acid addition salts which may, for example, be formed by mixing a solution of compounds 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, where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2- naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19 (1977)). The term "excipient" when used herein is intended to indicate all substances in a pharmaceutical formulation which are not active ingredients such as, e.g., carriers, binders, lubricants, thickeners, surface active agents, preservatives, emulsifiers, buffers, flavoring agents, colorants, or antioxidants. The compositions according to the present invention may comprise a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for enteral (such as oral) or parenteral administration (such as intravenous, intramuscular, subcutaneous, spinal or epidermal administration (e.g., by injection or infusion)). Depending on the route of administration, the active compound, i.e., the compound of the invention, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

A composition of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for the preparation of such formulations are generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

To administer a compound of the invention by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the compound may be administered to an individual in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al. (1984) J. Neuroimmunol. 7: 27).

Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.

Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the individuals to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

For the therapeutic compositions, formulations of the present invention include those suitable for enteral administration (such as oral or rectal) or parenteral administration (such as nasal, topical (including vaginal, buccal and sublingual). The formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the individual being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect.

Generally, out of one hundred per cent, this amount will range from about 0.01 per cent to about ninety-nine percent of active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent.

Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration of compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The phrases "enteral administration" and "administered enterally" as used herein means that the drug administered is taken up by the stomach and/or the intestine. Examples of enteral administration include oral and rectal administration. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral administration, usually by injection or topical application, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraosseous, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intracerebral, intracerebroventricular, subarachnoid, intraspinal, epidural and intrasternal administration (such as by injection and/or infusion) as well as topical administration (e.g., epicutaneous, inhalational, or through mucous membranes (such as buccal, sublingual or vaginal)). Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, pH buffering agents, and dispersing agents. Prevention of the presence of microorganisms may be ensured both by sterilization procedures, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art (cf., e.g., Remington, The Science and Practice of Pharmacy, Edited by Allen, Loyd V., Jr., 22^nd edition, Pharmaceutical Sciences, September 2012; Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7^th edition, Lippincott Williams & Wilkins Publishers, 1999.).

Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start with doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. It is preferred that administration be oral, intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the site of the target. If desired, the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

In one embodiment, the compounds or compositions of the invention may be administered by infusion, preferably slow continuous infusion over a long period, such as more than 24 hours, in order to reduce toxic side effects. The administration may also be performed by continuous infusion over a period of from 2 to 24 hours, such as of from 2 to 12 hours. Such regimen may be repeated one or more times as necessary, for example, after 6 months or 12 months. η yet another embodiment, the compounds or compositions of the invention are administered by maintenance therapy, such as, e.g., once a week for a period of 6 months or more.

For oral administration, the pharmaceutical composition of the invention can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulphate). Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparation can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxycarbonates, soric acids). The preparations can also contain buffer salts, flavouring, coloring and sweetening agents as deemed appropriate. Preparations for oral administration can be suitably formulated to give controlled release of the pharmaceutical composition of the invention.

The pharmaceutical composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.

For administration by inhalation, the pharmaceutical composition of the invention is conveniently delivered in the form of an aerosol spray presentation from a pressurised pack or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, nitrogen, or other suitable gas). In the case of a pressurised aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatine, for use in an inhaler or insufflator can be formulated containing a powder mix of the pharmaceutical composition of the invention and a suitable powder base such as lactose or starch.

The pharmaceutical composition of the invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in units dosage form (e.g., in phial, in multi-dose container), and with an added preservative. The pharmaceutical composition of the invention can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, or dispersing agents. Alternatively, the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilised powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

Therapeutic compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in US 5,399,163; US 5,383,851 ; US 5,312,335; US 5,064,413; US 4,941,880; US 4,790,824; or US 4,596,556. Examples of well-known implants and modules useful in the present invention include those described in: US 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; US 4,486,194, which discloses a therapeutic device for administering medicaments through the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; US 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and US 4,475,196, which discloses an osmotic drug delivery system. Many other such implants, delivery systems, and modules are known to those skilled in the art. In certain embodiments, the compounds of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, e.g., US 4,522,811 ; US 5,374,548; and US 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, and thus enhance targeted drug delivery (see, e.g., V.V. Ranade (1989) J. Clin. Pharmacol. 29: 685). Exemplary targeting moieties include folate or biotin (see, e.g., US 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153: 1038); antibodies (P.G. Bloeman et al. (1995) FEBS Lett. 357: 140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39: 180); and surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233: 134).

In one embodiment of the invention, the compounds of the invention are formulated in liposomes. In a more preferred embodiment, the liposomes include a targeting moiety. In a most preferred embodiment, the therapeutic compounds in the liposomes are delivered by bolus injection to a site proximal to the desired area, e.g., the site of a tumor. The composition must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. A "therapeutically effective dosage" for tumor therapy can be measured by objective tumor responses which can either be complete or partial. A complete response (CR) is defined as no clinical, radiological or other evidence of disease. A partial response (PR) results from a reduction in aggregate tumor size of greater than 50%. Median time to progression is a measure that characterizes the durability of the objective tumor response.

A "therapeutically effective dosage" for tumor therapy can also be measured by its ability to stabilize the progression of disease. The ability of a compound to inhibit cancer can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit cell growth or apoptosis by in vitro assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in an individual. One of ordinary skill in the art would be able to determine such amounts based on such factors as the individual's size, the severity of the individual's symptoms, and the particular composition or route of administration selected.

The composition must be sterile and fluid to the extent that the composition is deliverable by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

The pharmaceutical composition of the invention can also, if desired, be presented in a pack, or dispenser device which can contain one or more unit dosage forms containing the said agent. The pack can for example comprise metal or plastic foil, such as blister pack. The pack or dispenser device can be accompanied with instruction for administration.

The pharmaceutical composition of the invention can be administered as sole active agent or can be administered in combination with other agents.

Inhibition of paracaspase activity and therapeutic applications

In further aspects, the present application provides a compound of the first aspect or a pharmaceutical composition of the second aspect for inhibiting a paracaspase and for use in therapy.

It is contemplated that the compound of the first aspect may be used for inhibiting a paracaspase in vitro, such as in an isolated cell, an isolated cell culture, or a sample isolated from a subject.

As demonstrated in the examples below, the compounds of the present invention can be used to treat a disease or disorder which is treatable by an inhibitor of a paracaspase, in particular to treat a cancer that is associated with deregulated, in particular constitutive, proteolytic activity of a paracaspase compared to the state in a healthy individual.

In one embodiment, the paracaspase is MAL l . In a preferred embodiment, the disease or disorder which is treatable by an inhibitor of a paracaspase is a lymphoma, preferably diffuse large B-cell lymphoma (DLBCL). As described herein, diffuse large B-cell lymphoma (DLBCL) is a type of aggressive lymphoma. One major subtype of DLBCL which has been identified based on its genetic activity is the B-cell subtype of diffuse-large B cell lymphoma (ABC-DLBCL). As set forth above, Ferch et al., Exp. Med. 2009, 206, 2313-2320 showed that aggressive activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) cells possess constitutively assembled CARD11-BCL10-MALT1 (CBM) complexes that continuously and selectively process A20. Moreover, inhibition of MALTl paracaspase leads to ABC- DLBCL cell death and growth retardation. Thus, the examples herein below which show that the compounds of the invention specifically inhibit MALTl indicate for the first time that ABC-DLBCL can be treated by using the compound of the invention. MALT lymphoma is a cancer of the B-cell lymphocytes. It usually affects older people who are in their 60s. Most Non-Hodgkin Lymphomas (NHLs) start in the lymph nodes, but MALT lymphoma starts in a type of lymphatic tissue called mucosa-associated lymphoid tissue (MALT). The stomach is the most common area for MALT lymphoma to develop in, but it may also start in other organs such as the lung, thyroid, salivary gland or bowel. MALT lymphomas may start in areas of the body where there has been an infection or when the person has an autoimmune condition affecting that area. Because MALT lymphoma develops outside the lymph nodes, it's also known as extranodal lymphoma. Gastric MALT lymphoma is frequently associated (72-98%) with chronic inflammation as a result of the presence of Helicobacter pylori (Parsonnet J. (1994). New Engl. J. Med. 330 (18): 1267-71). The initial diagnosis is made by biopsy of suspicious lesions on esophagogastroduodenoscopy (EGD, upper endoscopy). Simultaneous tests for H. pylori are also done to detect the presence of this microbe. In other sites, chronic immune stimulation is also suspected in the pathogenesis (e.g. association between chronic autoimmune diseases such as Sjogren's syndrome and Hashimoto's thyroiditis, and MALT lymphoma of the salivary gland and the thyroid). In MALT lymphoma the frequent translocation t(l l ;18)(q21 ;q21) creates a fusion between the C-terminus of MALTl including the paracaspase domain and the N-terminus of IAP2. The paracaspase domain of IAP2 -MALTl fusion protein catalyzes the cleavage of NIK and thereby enhances non-canonical NF-κΒ activation, which confers apoptosis resistance. Two further translocations have been identified: t(l ;14)(p22;q32) which deregulates BCL10, and t(14;18)(q32;q21), which deregulates MALTl . All three translocations are believed to turn-on the same pathway, i.e. the pathway of API2-MALT. Thus, the examples herein below which show that the compounds of the present invention specifically inhibit MALTl indicate for that MALT lymphoma can be treated by using a compound of the present invention.

The inventors have identified the compounds of the present invention as a class of small molecule inhibitors that effectively and selectively inhibit proteolytic activity of recombinant and cellular MALTl protease. The compounds of the present invention are shown to interfere with inducible or constitutive MALTl activity from activated T cells or from ABC-DLBCL cells, respectively. Furthermore, the compounds of the present invention cause an impaired T cell activation as well as reduced viability selectively of the ABC subtype of DLBCL cells, processes that have been shown to critically depend on MALTl activity. Thus, the cellular data further evidence the effectiveness of the compounds of the present invention as pharmacological MALTl inhibitors.

Different assay conditions were initially tested and the effects of broad spectrum protease inhibitors to characterize cleavage activity of recombinant full length MALTl in more detail. Interestingly, the proteolytic activity of MALTl resembled Arabidopsis thaliana metacaspases AtMC4 and 9 (Vercammen et al., J. Biol. Chem. 2004, 279, 45329-45336), emphasizing that the structural homology between paracaspase and metacaspase domains is causing similar substrate binding and cleavage properties. As MALTl is the only human paracaspase with very distinct properties when compared to other human caspases, specific inhibitors as defined in accordance with the present invention are clearly promising candidates for selective inactivation of its oncogenic activity. Selectivity is critical, as impairing the execution of apoptosis by the inhibition of caspases other than MALTl would likely trigger adverse effects that could not be tolerated for lymphoma therapy. Indeed, the compounds of the present invention tested display a high preference for MALTl and are not acting on the initiator caspase CASP8 and the executioner caspase CASP3. Furthermore, as CASP8 associates with MALTl and is required for NF-κΒ signaling in T cells (Su et al., Science 2005, 307, 1465-1468), the apparent lack of CASP8 inhibition by the compounds of the present invention also underscores the requirement for proteolytic MALTl activity to trigger optimal T cell activation. The strong inhibition of cellular MALTl activity even after relatively short incubation with the compounds of the present invention clearly indicates that the substances directly affect the MALTl protease. Thus, the present invention provides (i) a compound of the invention (or a pharmaceutical composition comprising such compound optionally together with a pharmaceutically acceptable excipient) for use in a method of treating a disease or disorder which is treatable by an inhibitor of a paracaspase in an individual and (ii) a method of treating a disease or disorder which is treatable by an inhibitor of a paracaspase in an individual, comprising administering a pharmaceutically effective amount of a compound of the invention (or a pharmaceutical composition comprising such compound optionally together with a pharmaceutically acceptable excipient) to the individual. In this regard, the disease or disorder which is treatable by an inhibitor of a paracaspase is preferably cancer, more preferably a cancer that is associated with deregulated (in particular constitutive) proteolytic activity of a paracaspase compared to the state in a healthy individual. Preferably, the disease or disorder which is treatable by an inhibitor of a paracaspase is a lymphoma, preferably an extranodal lymphoma, such as a stomach, thyroid, salivary gland or bowel lymphoma. Most preferably, the disease or disorder which is treatable by an inhibitor of a paracaspase is the activated B-cell subtype of diffuse-large B cell lymphoma or MALT lymphoma. Moreover, the individual is preferably a mammal and more preferably a human. The compounds of the invention (or the pharmaceutical composition comprising such compound) may be administered to the individual by any route, preferably by any route described above in section "Pharmaceutical compositions" for the administration of the pharmaceutical composition of the invention.

In addition, the inhibitory action of the MALTl inhibitory compounds of the invention on T cell activation indicates a potential medical use as mild immunosuppressants for instance in the treatment of allergy and asthma.

Accordingly, also encompassed by the present invention is a (i) compound of the invention (or a pharmaceutical composition comprising such compound optionally together with a pharmaceutically acceptable excipient) for use in a method of treatment of paracaspase-dependent immune diseases and (ii) a method of treating a paracaspase-dependent immune disease in an individual, comprising administering a pharmaceutically effective amount of a compound of the invention (or a pharmaceutical composition comprising such compound optionally together with a pharmaceutically acceptable excipient) to the individual. In this regard, the paracaspase-dependent immune disease is preferably an allergic inflammation. In a preferred embodiment, the paracaspase is MALTl . The paracaspase-dependent immune disease may also be a T-cell driven disease where the T-cell responses are counteracted by the compounds of the invention such as in Example 21 (Rell). In this regard the paracaspase-dependent immune disease can be hypersensitivity of the immune system or a chronic inflammation such as allergy (as mentioned) or asthma. Further, the paracaspase-dependent immune disease can be an autoimmune disease, which includes but is not limited to diseases such as Sjogren's syndrome, Hashimoto's thyroiditis, multiple sclerosis, inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), lupus erythematosus, psoriasis, chronic obstructive pulmonary disease, rheumatoid arthritis or psoriatic arthritis. Moreover, the individual is preferably a mammal and more preferably a human. The compounds of the invention (or the pharmaceutical composition comprising such compound) may be administered to the individual by any route, preferably by any route described above in section "Pharmaceutical compositions" for the administration of the pharmaceutical composition of the invention.

Synthetic schemes

The compounds of the present invention were prepared as described in the Charts and Examples below, or prepared by methods analogous thereto, which are readily known and available to one of ordinary skill in the art of organic synthesis (see, for example, H. Ulrich "Phenothiazines" in "Methods of Organic Chemistry", Houben-Weyl, Georg Thieme Verlag, Stuttgart, 510-556). Chart A describes the alkylation of a substituted or unsubstituted phenothiazine (A-1) with an alkyl halide under basic conditions to afford the acetal intermediate A-2. Substituted phenothiazines are prepared by methods analogous to those reported in the literature (e.g., Dahl, T. et al., Angew. Chem. Int. Ed. 2008, 47, 726-1728.; Ma, D. et al., Angew. Chem. Int. Ed 2010, 49, 1291-1294.; Smith, N. J. Org. Chem. 1950, 15, 1125-1130. For a recent review, see: Silberg, et al., Adv. Het. Chem. 2006, 90, 205-237). Acetal A-2 is treated with an appropriate Lewis or protic acid to afford aldehyde A-3. Condensation of aldehyde A-3 with a semicarbazide (X=0) or thiosemicarbazide (X=S) of formula A-4 affords A-5. Semicarbazides and thiosemicarbazides are, in turn, readily prepared from commercially available or readily prepared amines, R³NH2 (Beukers, M. W. et al., J. Med. Chem. 2003, 46, 1492- 1503.; Metwally, A., J. Sulfur Chem., 2011 , 32, 489-519.).

A-5

X = N, O, S

Chart B describes an alternative synthesis of unsubstituted or substituted phenothiazine semicarbazones of general structure A-5. This method is advantageous in those cases where semicarbazide A-4 cannot be isolated or is of insufficient stability to be used in the method described in Chart A. Aldehyde A-3 is reacted with hydrazide B-l (Vlasak, P. et al., Coll. Czech. Chem. Comm. 1998, 63, 793-802.) to afford intermediate B-2. Reaction of B-2 with a commercially available or readily prepared amine, R³NH2, affords the semicarbazone A-5.

Chart B

A-5

Chart C describes the synthesis of semicarbazones of general structure C-4 in which R⁴ is an alkyl group. Alkylation of phenothiazine A-1 with an appropriate haloalkyl ester affords C-1. Treatment with C-1 with the adduct formed by the reaction of trimethylaluminum and NH(Me)OMe affords the amide C-2. Reaction of amide C-2 with a commercially available or readily prepared Grignard reagent, R⁴MgX, provides ketone C-3. Reaction of ketone C-3 with a semicarbazide (X=0) or thiosemicarbazide (X=S) A-4 provides the desired semicarbazone C-4.

x = o, s

C-4

Chart D describes the synthesis of pyrazolines of general structure D-3. Reaction of amide C-2 with vinyl Grignard affords vinyl ketone D-l which reacts with hydrazine to provide unsubstituted pyrazoline D-2. Reaction of D-2 with isocyanates or carbamates provides the N-acylated pyrazoline of interest.

Chart E describes the synthesis of diacylhydrazides (X=0) or their thio analogs (X=S). Commercially available or readily prepared acylhydrazide E-1 reacts under a variety of conditions with isocyanates, carbamates or acyl imidazolides to afford the compounds of interest.

x = o, s

Chart F describes the synthesis of carbamates and ureas of general structure F-3 and sulfonamides of general structure F-4. Alkylation of a substituted or unsubstituted phenothiazine (A-l) with an alkyl dihalide affords the monoalkyl intermediate F-l which reacts with ammonia, an ammonia equivalent or a suitable amine to provide the amino intermediate F-2. Reaction of the amine F-2 with a chloroformate, acyl imidazolide, isocyanate or any other appropriate reagent recognized by one skilled in the art provides the carbamate or urea of interest. By analogy, reaction of amine F-2 with a sulfonyl Chloride readily affords the sulfonamide, F-4.

x = o, s

Y - N, O

Scheme G illustrates another general method to prepare substituted phenothiazines of general structures G-2 and G-3. Alkylation of a substituted or unsubstituted phenothiazine (A-l) with an alkyl halide G-l under basic conditions affords the N-10 substituted phenothiazine, G-2. When R¹ is a chloride or bromide, G-2 can be further reacted with an organotin reagent under appropriate conditions to afford compounds of general structure G-3.

G-3

R¹ = alkyl, ally), aryl, alkenyl

EXAMPLES

Abbreviations

d: doublet

DCM: dichloromethane

DMF: N,N-dimethylformamide

DIEA: N^N-diisopropylethylamine

Flash chromatography: as described by Still, W.C., et al.,. J. Org. Chem. 1978, 43, 2923.

h: hour(s)

HO Ac: acetic acid

m: multiplet

min: minute(s)

MTBE: methyl tert-butyl ether

rt: room temperature

s: singlet

THF: tetrahydrofuran

t: triplet Those examples which are not covered by the claims are given for comparative purposes only. Experimental Procedures Cell culture and reagents

DLBCL cell lines were cultured in RPMI 1640 Medium (Invitrogen) supplemented with 20% FCS and 100 U/ml penicillin/streptomycin except the ABC line OCI-LylO which was cultured in IMDM (Invitrogen) with 20% human plasma, penicillin/streptomycin and 50 μΜ β-mercaptoethanol. Jurkat T cells were cultured according to DLBCL cell-lines with 10% FCS. The isolation of human mononuclear cells (PBMCs) from heparin-treated (1000 U/ml) whole blood was done with Lymphoprep according to manufacturer (Axis-shield). Isolation of murine CD4⁺ T-cells was performed with T-cell specific Dynabeads (Invitrogen). Primary cells were cultured in Jurkat media containing 50 μΜ β-mercaptoethanol. Stimulation of Jurkat T cells, human PBMCs and mouse CD4⁺ T-cells was either initiated by the addition of phorbol 12-myristate 13-acetate (PMA; 200 ng/ml) and ionomycin (I; 300 ng/ml) (both Calbiochem) or by hCD3/hCD28 and mIgGl/mIgG2a antibodies (BD Biosciences). Z-VRPPv-FMK (Alexis Biochemicals), mepazine acetate (Chembridge), promazine hydrochloride, thioridazine hydrochloride, promethazine hydrochloride (all Sigma Aldrich) and all PDs tested (Chembridge or Sigma) were solved in DMSO.

Recombinant and endogenous MALTl cleavage assay

GSTMALTl proteins were produced in competent BL21 RIL E. coli bacteria. Protein production was induced at an OD600 of 0.8 with 50 μΜ of isopropyl-P-D-fhiogalactopyranoside (IPTG) for 16 h at 18°C. Bacteria were harvested and lysed by sonication in lysis buffer (50 mM HEPES, pH 7.5, 10% glycerol, 0.1% Triton X-100, 1 mM dithiothreitol, 150 mM NaCl, 2 mM MgCh, incl. protease inhibitors). GSTMALTl was purified via an AKTA™ liquid chromatography system using Glutathione FastTrap columns (GE Healthcare). For the cleavage assay in 384-well microplates 200 ng of protein and 50 μΜ of the BCL-10 derived substrate Ac-LRSR-AMC was used. Following 30 min of incubation at 30°C the fluorescence of the cleaved AMC was measured for 1 h using a Synergy 2 Microplate Reader (Biotek). Protease activity was expressed in relative fluorescence units, where DMSO treated controls were set to 100% and fluorescence of compound treated wells was calculated appropriately. Cleavage of human recombinant CASP3 (Bio Vision) and CASP8 (Cayman Chemical) was assayed accordingly against Ac-DEVD-AMC as substrate and 50 and 250 pg of protein, respectively. For the endogenous MALTl protease DLBCL or Jurkat T cells (5 x 10⁶ cells) were left untreated, inhibitor (4 h and 3 h, respectively) or P/I and CD3/CD28 treated and lysed in lysis buffer at 4°C. For immunoprecipitation 4 μΐ of anti-MALTl antibody (H-300, Santa Cruz Biotechnology) was added to 400 μΐ of the cleared lysate. After incubation of 16 h at 4°C 15 μΐ of PBS-washed protein G-Sepharose Beads (Roche) were added and the samples were further incubated for 1 h. The beads were washed 3 times with PBS, resuspended in 40 μΐ of cleavage assay buffer (50 mM MES, pH 6.8, 150 mM NaCl, 10% [wt/vol] sucrose, 0,1% [wt/vol] CHAPS, 1 M ammonium citrate, 10 mM dithiothreitol) and transferred to a 384-well microwell plate. The peptide substrate Ac-LRSR-AMC was added to a final concentration of 20 μΜ and the activity was measured according to the recombinant GSTMALT1 assay. All inhibitors used were solved in DMSO and control cells were treated with appropriate amounts of the solvent.

High throughput screen (HTS) for MALTl small molecule inhibitors

The MALTl cleavage assay was used to screen -18000 small molecules of the ChemBioNet library at the Leibniz Institute for Molecular Pharmacology (FMP) in Berlin (Lisurek, M., et al., Mol. Divers. 2010, 14, 401-408). Screening volume was 11 μΐ in a 384-well non-binding assay plate (Corning) with 170 nmol GSTMALT1 against 10 μΜ final concentration of compounds. The assay was performed with 50 μΜ of Ac-LRSR-AMC substrate for 20 min at 30°C. As a negative control the recombinant MALTl mutant C453A was used, as a medium inhibition control 1 nM of the Z-VRPR-FMK peptide. The quality of the assay was confirmed by standard Z-factor determination (~ 0.7). For hit validation the 300 compounds with the best inhibitory impact from the primary screen were assayed two times with 8 different concentrations of compounds ranging from 0.7 to 90.9 μΜ.

Quantification of RNA by real-time RT-PCR

Synthesis of cDNA was performed with DNA-free RNA samples (RNeasy Mini Kit, Qiagen) by reverse transcription with random hexamers and Superscript Π (Invitrogen) according to the manufacturer's protocol. Real-time PCR was performed using LC 480 SybrGreen PCR mix (Roche) on an LC 480 Lightcycler system (Roche). Quantification of the cytokine RNA was achieved by normalizing to a β-actin housekeeping gene. The relative expression ratio was calculated according to Pfaffl, Nucl. Acids Res. 2001, 29, e45. The following primers were used: mIL-2 forward 5'-

GAGTGCC AATTCGATGATG AG-3 ' (SEQ ID NO: i); mIL-2 reverse 5'-

AGGGCTTGTTGAGATGATGC-3 ' (SEQ ID NO: 2); ηιβ-actin forward 5'-

CCTCTATGCCAAC AC AGTGC-3 ' (SEQ ID NO: 3); ηιβ-actin reverse 5'-

GTACTCCTGCTTGCTGATCC-3 ' (SEQ ID NO: 4) (Yin, M., et al, Mol. Biol. Rep. 2010, 37, 2049- 2054).

Electrophoretic mobility shift assay (EMSA). Western Blot and ELISA

Whole cell extracts, Western blotting and EMSA were performed as described previously (Duwel, M., et al., J. Immunol. 2009, 182, 7718-7728). Antibodies used were BCL-XL (Cell signaling), MALTl (H300, B12), BCL10 (HI 97), c-FLIP (Alexis Biochemicals) and β-actin (1-19). BCL10 cleavage was visualized after 20 h treatment of diffuse large B-cell lymphoma cells with different doses of phenothiazine. Human and murine IL-2 ELISAs (BenderMed Systems) were performed according to the manufacturer's protocol after pre-treatment of Jurkat T cells and the primary human and mouse cells for 3 h with PD and subsequent T-cell receptor stimulation for 20 h. IL-6 and IL-10 ELISAs (Immunotools) were performed after 20 h of inhibitor incubation on DLBCL cell-lines.

Cellular MALT1 cleavage and IL-6 production assays

Cellular effects on RelB cleavage were determined in ABC-DLBCL cell-line HBL1 (2 x 10⁵) after 3h treatment with phenothiazine, PD or DMSO (control) and 1 h MG132 (10 μΜ). Cells were subsequently lysed in lysis buffer (150 mM NaCl, 25 niM HEPES (pH 7.5), 0.2 % NP-40, 1 mM Glycerin, 10 mM NaF, 1 mM DTT, 8 mM β-glycerophosphate, 20 μΜ sodium vanadate (pH 10.0), 25x RocheComplete) and RelB cleavage was analyzed via SDS-PAGE and Western Blot (RelB antibody C1E4, Cell signaling). Analysis was done via graphical evaluation of the data (Image J), where the DMSO treated control was set to 100% and data from compound treated cells were calculated accordingly. To analyze effects on IL-6 secretion, cells of the ABC-DLBCL cell-line OCI-Ly3 (2 x 10⁶) were treated for 20 h with phenothiazines, PD or DMSO (control) and the IL-6 concentration of the cell culture media was determined via an IL-6 ELISA Kit (Immunotools). To analyze the data the DMSO- treated control was set to 100% and data from compound treated cells were calculated accordingly. EC50 values of the data were determined via nonlinear regression.

Viability, MTT and apoptosis assays

Viability of DLBCL cell lines was analysed with a cell count assay of trypan blue stained cells after four days and by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid) cytotoxicity test after two days of dose-dependent inhibitor treatment in comparison to DMSO treated control cells. The cell-dependent reduction of MTT to formazan was measured at 450 nm with a μθ^ηί microplate spectrophotometer (Biotek). Apoptosis rates were determined with PE-Annexin V staining of 7AAD negative cells (BD Pharmingen) by FACS analysis (LSRTI, BD) after five days of compound treatment. Data was analyzed using Flow Jo software (Treestar). Example 1 - Preparation of lOH-phenothiazin-10-ylacetaldehyde N-(3-methylisoxazol-5-yl)semi- carbazone

H

Step 1 - Preparation of 10-(2,2-diethoxyethyl)-10H-phenothiazine

Sodium hydride (60% in mineral oil, 3.01 g, 75.3 mmol) was added to a stirring solution of phenothiazine (5.00 g, 25.1 mmol) in DMF (50 mL) at 0°C. After 30 minutes at this temperature 2- bromo-l,l-diethoxyethane (11.7 mL, 75.3 mmol) was added and the reaction warmed to 50°C for 36 hours. The reaction was quenched by the addition of 10 mL saturated ammonium chloride and then extracted with ethyl acetate. The organic layers were combined, washed twice with saturated sodium bicarbonate, once with water and once with brine, dried the organics over sodium sulfate, filtered and concentrated in vacuo. This residue was purified by flash chromatography using 0-20% ethyl acetate/hexanes to afford 7.69 g of the desired product as a colorless oil. ^!H NMR (400 MHz, CDCI3) δ (ppm) = 1.17-1.21 (t, 6H, J=7 Hz), 3.53-3.61 (m, 2H), 3.66-3.73 (m, 2H, 4.07-4.08 (d, 2H, J=5 Hz), 4.85-4.87 (t, 1H, J=5 Hz), 6.92-6.96 (m, 2H), 6.98-7.00 (m, 2H), 7.14-7.19 (m, 4H).

Step 2 - Preparation of 1 OH-phenothiazin-10-ylacetaldehvde

Lithium tetrafluoroborate (2.23 g, 23.8 mmol) was added to a stirring solution of 10-(2,2- diethoxyethyl)-10H-phenothiazine (1.50 g, 5.22 mmol) in acetonitrile (40 mL) and water (5 mL) at 0°C. After 20 minutes the reaction was warmed to 50°C and heated overnight. The following morning the reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed three times with saturated sodium bicarbonate, twice with water and once with brine. The organics were dried over sodium sulfate, the sodium sulfate removed by filtration and the filtrate concentrated in vacuo to afford the desired compound as a tan solid (1.20 g). LCMS: ESI+ m/z of 242 (M+H). ¾ NMR (300 MHz, CDCI3) δ (ppm) = 4.53 (d, 2H, J=1.5 Hz), 6.61-6.63 (m, 2H), 6.97-7.02 (m, 2H), 7.13-7.22 (m, 4H), 9.82-9.83 (t, 1H, J=1.5 Hz).

Step 3 - Preparation of 1 OH-phenothiazin-10-ylacetaldehyde N-(3-methylisoxazol-5-yl)semi-carbazone

To a sealed tube was added N-(3-methylisoxazol-5-yl)hydrazinecarboxaimde (95 mg, 0.61 mmol), 1 OH-phenothiazin-10-ylacetaldehyde (133 mg, 0.55 mmol) and ethanol (3 mL) and the reaction was stirred overnight at 80°C. Solids that had formed during the course of the reaction were removed by filtration and the filtrate concentrated under reduced pressure. Purification by flash chromatography using 0-20% ethyl acetate/hexanes followed by trituration with dichloromethane afforded 57 mg of the desired compound as an off white solid. LCMS: ESI+ m/z of 380 (M+H) and ESI- m/z of 378 (M-H). Ή NMR (400 MHz, DMSO) δ (ppm) = 2.18 (s, 3H), 4.69-4.71 (d, 2H, J=5 Hz), 6.00 (s, 1H), 6.96-7.00 (m, 2H), 7.10-7.12 (m, 2H), 7.18-7.23 (m, 4H), 7.29-7.32 (t, 1H, J=5 Hz), 10.28 (broad singlet, 1H), 10.90 (broad singlet, 1H).

Example 2 - Preparation of 1 OH-phenothiazin-10-ylacetaldehyde N-quinolin-7-ylsemicarbazone

To a mixture of lOH-phenothiazin-l 0-ylacetaldehyde (96 mg, 0.40 mmol) and 4-nitrophenyl hydrazinecarboxylate (68 mg, 0.35 mmol) in 1 ,2-dichloroethane (4 mL) was added acetic acid (19.7iL, 0.35 mmol) and the reaction heated at 50°C for one hour. Quinolin-7-amine (75 mg, 0.52 mmol), N,N-dimethylaniline (1 10 xL, 0.87 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) were then added and the reaction heated at 50°C for an additional three hours. The contents of the reaction were cooled to room temperature then transferred to a separatory funnel, diluted with ethyl acetate and washed three times with saturated sodium bicarbonate, once with water, once with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using 0-3% methanol in dichloromethane to afford 60 mg of the desired product as an off white solid. LCMS: ESI+ m/z of 426 (M+H) and ESI- m/z of 424 (M-H). Ή NMR (400 MHz, DMSO) δ (ppm) = 4.80-4.81 (d, 2H, J= 4 Hz), 6.95-6.99 (m, 2H), 7.04-7.06 (m, 2H), 7.16-7.23 (m, 4H), 7.39-7.41 (t, 1H, J= 4 Hz), 7.42-7.45 (m, 1H), 7.69-7.72 (m, 1H), 7.88-7.90 (m, 1H), 8.29-8.32 (m, 2H), 8.78-8.79 (m, 1H).

Example 3 - Preparation of lOH-phenothiazin-10-ylacetaldehyde N-(4,5,6,7-tetrahydro- [ 1 ,3] thiazolo [5,4-c] py ridine-2-y l)semicarbazone

Step 1 - Preparation of 9H-fluoren-9-ylmethyl 2-amino-6 -dihvdro[1.3]thia∑olo[5.4-clpyridine- 5(4H)-carboxylate

To a flask containing 9-fluorenylmethyl chloroformate (575 mg, 2.22 mmol) in dioxane (25 mL) at 0°C was added 4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridine-2-amine hydrobromide (500 mg, 2.12 mmol, prepared according to Mach, Ulrich et al., Chem. Bio. Chem. 2004, 5, 508) and potassium carbonate (878 mg, 6.35 mmol) as a solution in water (25 mL). The reaction was stirred for 30 minutes at 0°C, an hour at room temperature and then transferred to a separatory funnel. The mixture was extracted three times with ethyl acetate, the organics were combined, washed twice with water and once with brine before drying over sodium sulfate, filtering and concentrating under reduced pressure. The residue was purified by flash chromatography using 0-3% methanol in dichloromethane to afford 208 mg of the desired compound as a white solid. LCMS: ESI+ m/z of 378 (M+H). Ή NMR (300 MHz, DMSO) δ (ppm) = 2.30-2.42 (m, 2H), 3.49-3.58 (m, 2H), 4.31 (s, 2H), 4.36-4.44 (m, 2H), 6.80, (broad singlet, 2H), 7.30-7.35 (m, 2H), 7.39-7.44 (m, 2H), 7.59-7.66 (m, 2H), 7.88-7.90 (m, 2H).

Step 2 Preparation of 9H-fluoren-9-ylmethyl 2-[({(2E,Z)-2-[2-(10H-phenothiazin-10- yl)ethylidene]hvdrazino}carbonyl)amino]-6, 7-dihydro[U]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a mixture of lOH-phenothiazin-10-ylacetaldehyde (100 mg, 0.41 mmol) and 4-nitrophenyl hydriazinecarboxylate (71 mg, 0.36 mmol) in dichloroethane (4 mL) was added acetic acid (20.5 μΐ_^, 0.36 mmol) and the reaction heated for one hour at 50°C. 9H-fluoren-9-ylmethyl 2-amino-6,7- dihydro[l ,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate (204 mg, 0.54 mmol), Ν,Ν-dimethylaniline (1 14xL, 0.90 mmol) and 4-dimethylamino-pyridine (5 mg, 0.04 mmol) were then added and the reaction heated at 50°C overnight. At that time the contents of the flask were transferred to a separatory funnel, diluted with ethyl acetate and washed three times with saturated sodium bicarbonate, once with water and once with brine. The organics were then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using 0-50% ethyl acetate/hexanes to afford 62 mg of the desired compound as a white solid. LCMS: ESI+ m/z of 659 (M+H). 'H NMR (300 MHz, DMSO) δ (ppm) = 2.78-2.88 (m, 2H), 3.87-3.98 (m, 2H), 4.55-4.64 (m, 2H), 4.85-4.98 (m, 2H), 5.07-5.07 (d, 2H, J= 5 Hz), 7.24-7.34 (m, 4H), 7.44-7.54 (m, 4H), 7.59-7.73 (m, 5H), 7.88-7.96 (m, 2H), 8.00-8.08 (m, 1H), 8.08-8.15 (m, 1H). Step 3 - Preparation of 1 OH-phenothiazin-1 O-ylacetaldehyde N-(4,5, 6, 7-tetrahvdro 1,31 thiazolof5,4- clpyridine-2-yl)semicarbazone

To a flask containing 9H-fluoren-9-ylmethyl 2-[({(2E,Z)-2-[2-(10H-phenothiazin-10-yl)ethylidene]- hydrazino}carbonyl)amino]-6,7-dihydro[l,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate (50 mg, 0.08 mmol) in DMF (1 mL) was added morpholine (1 mL, 10 mmol) and the reaction stirred for 20 minutes. The contents of the flask were transferred to a separatory funnel, diluted with ethyl acetate, washed three times with water and once with brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-8% methanol containing ammonia in dichloromethane) to afford 24 mg of the desired compound as a white solid. LCMS: ESI+ m/z of 437 (M+H) and ESI- m/z of 435 (M-H). ¾ NMR (400 MHz, MeOD) δ (ppm) = 2.68-2.71 (m, 2H), 3.12-3.15 (m, 2H), 3.92 (s, 2H), 4.75-4.76 (d, 2H, J= 5 Hz), 6.94-7.02 (m, 4H), 7.13-7.22 (m, 4H), 7.36-7.39 (t, 1H, J= 5 Hz).

Example 4 - Preparation of l-(10H-phenothiazin-10-yl)acetone N-phenylsemicarbazone

Step 1 - Preparation of ethyl 1 OH-phenothiazin-10-ylacetate

To a cooled (0°C) solution of phenothiazine (5.000 g, 25.09 mmol) in DMF (50.00 mL) was added sodium hydride (3.01 g of a 60% suspension in mineral oil, 75.3 mmol). After 5 min at, the mixture was allowed to warm to room temperature and stirred an additional 30 min. Ethyl chloroacetate (8.06 mL, 75.3 mmol) was added and the mixture stirred at ambient temperature for 16h. The reaction was quenched by the addition of excess acetic acid. Volatiles were removed in vacuo and the residue purified by flash chromatography (hexane/ethyl ether 1-4% as eluent) to afford 4.97 g of the title compound as an oil. 'H NMR (300 MHz, CDC1₃) δ 1.33 (t, J= 7 Hz, 3 H), 4.33 (q, J= 7 Hz, 2 H), 4.53 (s, 2 H), 6.60-6.63 (m, 2 H), 6.93-6.96 (m, 2 H), 7.08-7.13 (m, 4 H); MS (ESI+) for Ci₆Hi₅N0₂S m/z 286.0 (M+H)⁺.

Step 2 - Preparation of lOH-phenothiazin-10-ylacetic acid

To a suspension of ethyl lOH-phenothiazin-10-ylacetate (1.000 g, 3.504 mmol) in methanol (18 mL) and tetrahydrofuran (7 mL) was added 1.0N NaOH (4.38 mL, 4.38 mmol). After 16 h at ambient temperature, the aqueous solution was extracted with ethyl ether. The aqueous layer was acidified (approx. pH 3) with IN HCl and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried (sodium sulfate), filtered and concentrated to afford 0.66 g of the title compound as a white solid that was used without further purification. 'H NMR (300 MHz, CDC¾) δ 4.62 (s, 2 H), 6.68-6.70 (m, 2 H), 6.94-6.99 (m, 2 H), 7.12-7.17 (m, 4 H); MS (ESI+) for Ci₄H_nN0₂S m/z 258.0 (M+H)⁺.

Step 3 - Preparation ofN-methoxy-N-methyl-2-(10H-phenothiazin-10-yl)acetamide

To a solution of lOH-phenothiazin-10-ylacetic acid (0.565 g, 2.19 mmol) and Ν,Ο- dimethylhydroxylamine hydrochloride (0.267 g, 2.74 mmol) in DMF (10 mL) was added Ν,Ν,Ν',Ν'- tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (0.960 g, 2.52 mmol) in DIEA (1.14 niL, 6.59 mmol). The solution was stirred at ambient temperature for 16 h and concentrated. The residue was partitioned between ethyl acetate and 0.1N HCl. The organic layer was separated and washed sequentially with brine, saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography (hexane/ethyl acetate 5- 15% as eluent) to afford 590 mg of the title compound as a white solid. ¾ NMR (300 MHz, CDC1₃) δ 3.34 (s, 3 H), 3.86 (s, 3 H), 4.73 (br s, 2 H), 6.59-6.63 (m, 2 H), 6.88-6.93 (m, 2 H), 7.05-7.12 (m, 4 H); MS (ESI+) for C16H16N2O2S m/z 301.0 (M+H)⁺.

Step 4 - Preparation of l-(10H-phenothiazin-10-yl)acetone

To a cooled (0-5°C) solution of N-methoxy-N-methyl-2-(10H-phenothiazin-10-yl)acetamide (0.300 g, 0.99 mmol) in ether (20 niL) was slowly added methylmagnesium iodide (3.0 M solution in ether, 0.366 mL, 1.10 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Two additional aliquots of methylmagnesium iodide (3.0 M solution in ether, 0.499 mL, 1.50 mmol) were added (to the re-cooled solution) after 2 and 3 hours, respectively. The reaction was quenched with saturated NH4CI and partitioned with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated to afford 0.230 g of the title compound as an off white solid that was used without further purification. ¾ NMR (400 MHz, CDCI3) δ 2.29 (s, 3 H), 4.54 (s, 2 H), 6.55-6.57 (m, 2 H), 6.94-6.99 (m, 2 H), 7.10-7.18 (m, 4 H).

Step 5 - Preparation of l-(10H-phenothiazin-10-yl)acetone N-phenylsemicarbazone

To a solution of 4-phenylsemicarbazide (30.5 mg, 0.20 mmol) in ethanol (5.00 mL) was added 1-(10H- phenothiazin-10-yl)acetone (52.0 mg, 0.20 mmol). The mixture was heated at reflux for 16h, cooled and the precipitate collected by filtration. The solids were triturated with ethanol and MTBE then dried under high vacuum to afford 64.0 mg of the title compound as a white solid. Ή NMR (400 MHz, DMSO-</₆) δ 1.90 (s, 3 H), 4.68 (br s, 2 H), 6-93-6.99 (m, 5 H), 7.15-7.27 (m, 8 H), 8.35 (s, 1 H), 9.84 (s, 1 H); MS (ESI+) for C22H20N4OS m/z 389.2 (M+H)⁺.

Example 5 - Preparation of N-(3-methylisoxazol-5-yl)-3-(10H-phenothiazin-10-ylmethyl)-4,5- dihydro-lH-pyrazole-l-carboxamide

Step 1 - Preparation of 10-(4,5-dihvdro-lH-pyrazol-3-ylmethyl)-10H-phenothiazine

To a cooled (0-5°C) solution of N-methoxy-N-methyl-2-(10H-phenothiazin-10-yl)acetamide (226 mg, 0.75 mmol) in tetrahydrofuran (6.42 mL) was added vinylmagnesium bromide (2.821 mL of a 0.80 M solution in ether, 2.26 mmol) portionwise. The mixture was quenched with saturated NH4CI and partitioned with ethyl acetate. The organic layer was separated and washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was dissolved in ethanol (3.00 mL) and hydrazine monohydrate (0.125 mL, 1.51 mmol) added. The mixture was heated at 60°C for 16 h and concentrated. The residue was purified by flash chromatography (MeOH 1-5%/DCM as eluant) to afford 64 mg of the title compound as an oil. ¾ NMR (400 MHz, CDCI3) δ 2.59-2.64 (m, 2 H), 3.28- 3.33 (m, 2 H), 4.74 (s, 2 H), 6.89-6.98 (m, 4 H), 7.14-7.18 (m, 4 H); MS (ESI+) for Ci₆Hi₅N₃S m/z 282.0 (M+H)⁺. Step 2 - Preparation of N-(3-methylisoxazol-5-yl)-3-(10H-phenothiazin-10-ylmethyl)-4,5-dihvdro-lH- pyrazole-l-carboxamide

To a solution of phenyl (3-methylisoxazol-5-yl)carbamate (24.8 g, 0.11 mmol) and 10-(4,5-dihydro-lH- pyrazol-3-ylmethyl)-10H-phenothiazine (64.0 mg, 0.11 mmol) in ethanol (4.00 mL) was added triethylamine (0.0158 mL, 0.11 mmol) and 4-dimethylaminopyridine (5.00 mg, 0.04 mmol). The mixture was heated at reflux for lh and concentrated. The residue was purified using a Combiflash Rf instrument (4 g Gold RediSep silica gel column, ethyl acetate :hexane standard gradient) to afford 17.5 mg of the title compound as a white solid. Ή NMR (400 MHz, DMSO-^) δ 2.16 (s, 3 H), 2.80-2.85 (m, 2 H), 3.70-3.75 (m, 2 H), 4.87 (s, 2 H), 5.96 (s, 1 H), 6.97-7.01 (m, 2 H), 7.05-7.06 (m, 2 H), 7.19- 7.23 (m, 4 H), 10.31 (s, 2 H); MS (ESI+) for C21H19N5O2S m/z 406.0 (M+H)⁺. Example 6 - Preparation of 2-(10H-phenothiazin-10-ylacetyl)-N-propylhydrazinecarbothioamide

Step 1 - Preparation of 2-fl OH-phenothiazin-10-yl)acetohvdrazide

To a solution of ethyl lOH-phenothiazin-10-ylacetate (1.50 g, 5.26 mmol) in ethanol (10.0 mL) was added hydrazine hydrate (2.56 mL, 26.3 mmol). The reaction mixture was heated at reflux for 18 h then cooled (0°C) for 10 min before the solid was filtered, washed with ethanol, and dried under high vacuum at 60°C for 1 h to afford 1.28 g (90%) of the title compound as a white solid. MS (ESI+) for C14H13N3OS m/z 272.1 (M+H)⁺. Step 2 - Preparation of2-(10H-phenothiazin-10-ylacetyl)-N-propylhydrazinecarbothioamide

Propyl isothiocyanate (57.0 μί, 0.553 mmol) was added to a stirred solution of 2-(10H-phenothiazin- 10-yl)acetohydrazide (100 mg, 0.37 mmol) in ethanol (2.00 mL). The mixture was heated at reflux for 4 h, cooled to rt and the resulting white solid was filtered and washed with ethanol, MBTE, and then dried under high vacuum to afford 92.0 mg of the title compound as a white solid. Only the major geometric isomer reported; ¾ NM (300 MHz, DMSO-d₆ with D₂0) δ 7.05-7.13 (m, 4H), 6.93 (t, J = 8.0 Hz, 2H), 6.67-6.78 (m, 2H), 4.52 (s, 2H), 3.41-3.50 (m, 2H), 1.49-1.60 (m, 2H), 0.88 (t, J = 8.0 Hz, 3H); MS (ESI+) for C18H20N4OS2 m/z 373.2 (M+H)⁺.

Example 7 - Preparation of l-[3-(10H-phenothiazin-10-yl)propyl]-3-phenylurea

Step 1 - Preparation of 10-(3-chloropropyl)-l OH-phenothiazine

To a flask containing phenothiazine (5.45 g, 27.3 mmol) and DMF (140 mL) at 0°C was added sodium hydride (60% in mineral oil, 2.19 g, 54.7 mmol). After stirring for 1 hour this mixture was added to a solution of l-chloro-3-iodopropane (8.65 mL, 82.0 mmol) in DMF (10 mL) over the course of 10 minutes and stirred overnight at room temperature. The reaction mixture was transferred to a separatory funnel, diluted with saturated sodium bicarbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0-2% ethyl acetate/hexanes to afford 8.3 grams of material that was of sufficient purity to be used in the next step. LCMS: ESI+ m/z of 276 and 278 (M+H for C135 and C137). ¾ NMR (400 MHz, CDC1₃) δ (ppm) = 2.24-2.30 (m, 2H), 3.68-3.71 (m, 2H), 4.10-4.13 (m, 2H), 6.92-6.99 (m, 4H), 7.18-7.22 (m, 4H). Step 2 - Preparation of 3-(l OH-phenothiazin-l 0-yl)propan-l -amine hydrochloride

To a sealed tube containing 10-(3-chloropropyl)-10H-phenothiazine (180 mg, 0.65 mmol) was added methanolic ammonia (7N, 5.00 mL, 35.0 mmol). The reaction was heated at 80°C overnight. Additional methanolic ammonia (5 ml) was added to the cooled solution and the mixture heated overnight at 80°C. The mixture was diluted with ethyl acetate and washed twice with saturated sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using 0-10% methanol (containing ammonia) in chloroform. The pure material isolated by chromatography was dissolved in 1.0M HCl in ethanol and concentrated to dryness. This material was then concentrated twice from ethyl acetate to afford 80 mg of the desired compound as an off white solid. LCMS: ESI+ m/z of 257 (M+H). Ή NMR (400 MHz, CDC1₃) δ (ppm) = 2.11-2.19 (m, 2H), 3.04-3.08 (m, 2H), 4.10-4.13 (m, 2H), 6.98-7.02 (m, 2H), 7.06-7.08 (m, 2H) 7.19- 7.27 (m, 4H).

Step 3 - Preparation of l-[3-(10H-phenothiazin-10-yl)propylJ-3-phenylurea

To a solution of 3-(10H-phenothiazin-10-yl)propan-l-amine (0.125 g, 0.49 mmol) in THF (20 mL) was added phenyl isocyanate (0.0583 mL, 0.54 mmol). The reaction mixture was stirred for 16 h at ambient temperature and concentrated. The residue was dissolved in ethyl acetate and washed with water and brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography using 0-40 % ethyl acetate/hexane as eluent to afford 140 mg of the title compound as a white solid. Ή NMR (400 MHz, DMSO-<¾ δ 11.88 (p, J= 7 Hz, 2 H), 3.17-3.21 (m, 2 H), 3.92 (t, J = 7 Hz, 2 H), 6.23 (br t, J = 6 Hz, 1 H), 6.86-6.97 (m, 3 H), 7.04-7.06 (m, 2 H), 7.16-7.22 (m, 6 H), 7.36-7.38 (m, 2 H), 8.39 (s, 1 H); MS (ESI+) for C22H21N3OS m/z 376.2 (M+H)⁺.

Example 8 - Preparation of 2-allyl-10-[(l-methylpiperidin-3-yl)methyl]-10H-phenothiazine

Step 1 - Preparation of2-chloro-10-[(l-methylpiperidin-3-yl)methyl]-10H-phenothiazine

To a cooled (0-5°C) solution of 2-chloro-10H-phenothiazine (1.200 g, 5.13 mmol) in DMF (24 mL) was added sodium hydride (1.03 g of a 60% suspension in mineral oil, 25.7 mmol) portionwise. After 2 min, the ice bath was removed and mixture stirred at ambient temperature for 20 min. To the reaction mixture was added 3-(chloromethyl)-l-methylpiperidine hydrochloride (1.89 g, 10.3 mmol). The mixture was heated at 65°C for 16 h, cooled and quenched by the addition of HO Ac (pH approx. 3). The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and saturated NaHCC . The organic layer was separated and washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography using 0-5% methanolic ammonia (0.07 N)/DCM to afford 1.117 g of the title compound as a purple solid. ¾ NMR (300 MHz, DMSO- d₆) δ 0.91-1.05 (m, 1 H), 1.28-1.43 (m, 1 H), 1.50-2.03 (overlapping m, 5 H), 2.08 (s, 3 H), 2.55-2.79 (m, 2 H), 3.78-3.87 (m, 2 H), 6.96-7.02 (m, 2 H), 7.06-7.13 (m, 2 H), 7.16-7.26 (m, 3 H); MS (ESI+) for C₉H2₁CIN₂S m/z 345.2 (M+H)⁺. Step 2 - Preparation of2-allyl-10-[(l-methylpiperidin-3-yl)methyl]-10H-phenothiazine

To a flame dried pressure tube was added bis(tri-tert-butylphosphine)palladium(0) (0.013 g, 0.026 mmol), cesium fluoride (0.291 g, 1.91 mmol) and 2-chloro-10-[(l-methylpiperidin-3-yl)methyl]-10H- phenothiazine (0.300 g, 0.87 mmol). 1,4-Dioxane (4.0 mL) was added and the mixture sparged with nitrogen for 10 min. To the mixture was added allyltributyltin (0.351 mL, 1.13 mmol). The tube was sealed and heated for 16 h at 80°C. The mixture was cooled, filtered through Celite and the filter pad washed with ethyl acetate. The combined filtrates were concentrated and the residue purified by flash chromatography using 0-1.5% methanolic ammonia (0.07 N)/DCM as eluent to afford 170 mg of the title compound as an oil. The HC1 salt was formed by dissolving the oil in methanol (5 ml) and adding IN HC1 (1 mL). Concentration from methanol (3 X) and drying in vacuo afforded the salt as a waxy solid. Ή NMR (300 MHz, CD₃OD) δ 1.28-1.32 (m, 1 H), 1.69-1.73 (m, 1 H), 1.96-1.98 (m, 2 H), 2.39- 2.43 (m, 1 H), 2.71-2.79 (overlapping m, 5 H), 3.38-3.40 (m, 3 H), 3.54-3.56 (m, 1 H), 3.84-4.09 (m, 2 H), 5.07-5.13 (m, 2 H), 5.90-6.02 (m, 1 H), 6.83-6.86 (m, 2 H), 6.98-7.05 (m, 1 H), 7.07-7.09 (m, 2 H), 7.17-7.25 (m, 2 H); MS (ESI+) for C22H26N2S m/z 351.2 (M+H)⁺.

Example 9 - Preparation of 5-(10H-phenothiazin-10-ylmethyl)-4-propyl-4H-l,2,4-triazole-3-thiol

Sodium hydroxide in water (10%, 3.00 mL, 16.0 mmol) was added to solid 2-(10H-phenothiazin-10- ylacetyl)-N-propylhydrazinecarbothioamide (51.0 mg, 0.137 mmol) and the reaction mixture heated at reflux for 1 h. The slurry was cooled to rt, the solid filtered, and washed with water. The white solid was dried under high vacuum at 70 °C for 48 h to afford 35.7 mg of the title compound. 'H NMR (300 MHz, CDCI3) δ 7.09-7.20 (m, 6H), 6.91-6.98 (m, 2H), 5.03 (s, 2H), 3.70-3.79 (m, 2H), 1.48-1.60 (m, 2H), 0.67 (t, J= 8.0 Hz, 3H); MS (ESI+) for Ci₈H₁₈N4S2 m/z 355.1 (M+H)⁺. Preparation of 2-[2-(10H-phenothiazin-10-yl)ethyl]-N-phenylhydrazine-

Sodium cyanoborohydride (84 mg, 1.3 mmol) was added to a stirring solution of (1E/Z)-10H- phenothiazin-10-ylacetaldehyde N-phenylsemicarbazone (100 mg, 0.27 mmol) and acetic acid (7.5μί, 0.13 mmol) in methanol (2 mL). After heating at reflux overnight, the mixture was cooled and additional sodium cyanoborohydride (84 mg, 1.3 mmol) and acetic acid (7.5μί, 0.13 mmol) were added. The reaction was heated at reflux for an additional 8 h and concentrated. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0-3% isopropanol in dichloromethane to afford 62 mg of the desired product. LCMS: ESI+ m/z of 377

(M+H) and ESI- m/z of 375 (M-H). Ή NMR (400 MHz, CDC1₃) δ (ppm) = 3.04-3.08 (m, 2H), 4.01- 4.04 (m, 2H), 6.88-6.94 (m, 3H), 7.06-7.08 (m, 2H), 7.13-7.21 (m, 6H), 7.32-7.34 (m, 2H), 7.74 (s, 1H),

8.47 (s, 1H).

Example 11 - Preparation of N-(3-methylisoxazol-5-yl)hydrazinecarboxamide (intermediate 1)

Step 1 - Preparation of phenyl (3-methylisoxazol-5-yl)carbamate

Phenyl chloro formate (0.919 mL, 7.33 mmol) was added drop wise to a stirring slurry of 5-amino-3- methylisoxazole (600 mg, 6.12 mmol) and potassium carbonate (1.27 g, 9.17 mmol) in THF (30 mL) at room temperature. After 16 h, the solids were removed by filtration and washed with water. Purification by flash chromatography using 0-40% ethyl acetate/hexanes afforded 594 mg of the desired compound as a white solid. ¾ NMR (400 MHz, DMSO) δ (ppm) = 3.15 (s, 3H), 5.95 (s, 1H), 7.24-7.32 (m, 3H), 7.43-7.47 (m, 2H), 11.86 (broad singlet, 1H); LCMS: ESI+ m/z of 219 (M+H). Step 2 - Preparation ofN-(3-methylisoxazol-5-yl)hydrazinecarboxamide

To a sealed tube containing phenyl (3-methylisoxazol-5-yl)carbamate in isopropanol was added hydrazine hydrate (0.1 16 mL, 2.38 mmol) and the reaction stirred for 45 minutes at 70°C. Solvent was removed under reduced pressure and ethyl acetate was added. This led to the precipitation of a white solid that was filtered and washed with ethyl acetate. This afforded 97 mg of the desired compound. ¾ NMR (400 MHz, DMSO) δ (ppm) = 2.13 (s, 3H), 5.88 (s, 1H). Example 12 - Preparation of 4-nitrophenyl hydrazinecarboxylate (intermediate 2)

Bis(4-nitrophenyl) carbonate (4.16 g, 13.7 mmol) was added portionwise to a stirring solution of hydrazine (430 μί, 13.7 mmol) and N,N-diisopropylethylamine (2.38 mL, 13.7 mmol) in dichloromethane (85 mL) at 0°C. The reaction was stirred overnight while warming to room temperature. Filtration of the solids that formed during the reaction followed by repeated washing of those solids with dichloromethane afforded 2.21 g of the desired product as a yellow solid. ¾ NMR (300 MHz, DMSO) δ (ppm) = 6.90-6.96 (m, 2H), 8.09-8.14 (m, 2H).

Example 13 - Preparation of 1-methylhydrazinecarboxamide (intermediate 3)

O

^{H2 A}NH₂

I To a cooled (0-5°C) solution of N-methylhydrazine (0.200 mL, 3.68 mmol) in THF (6.00 g) was added trimethylsilyl isocyanate (0.587 mL, 3.68 mmol) over 5 min. After 1 h at 0-5°C methanol (3.00 mL) was added and the mixture heated at 40°C for 30 min. The solution was concentrated, concentrated several times from MeOH, then ethyl acetate. The resulting solid was slurried in MTBE, filtered, and washed with additional MTBE. Drying under high vacuum afforded 285 mg of the title compound as a white solid. Ή NMR (400 MHz, OMSO-d₆) δ 2.78 (s, 3 H), 4.34 (br s, 2 H), 5.83 (br s, 2 H).

Example 14 - Preparation of l-(2-hydroxyethyl)-N-(3-methylisoxazol-5-yl)hydrazinecarboxamide (intermediate 4)

To a solution of phenyl (3-methylisoxazol-5-yl)carbamate (0.200 g, 0.92 mmol) in THF (10.0 mL) and ethanol (1.00 mL) was added 2-hydroxyethylhydrazine (104 μί, 1.37 mmol). The reaction mixture heated at 50°C for 16 h and concentrated. Purification of the residue by flash chromatography (0-5% methanol in DCM as eluent) afforded 86 mg of the title compound as an oil. 'H NMR (300 MHz,

CDC1₃) δ 2.23 (s, 3 H), 3.01-3,24 (very br s, 1 H), 3.73 (t, J = 5 Hz, 2 H), 3.91 (t, J = 5 Hz, 2 H), 4.29 (br s, 2 H), 5.95 (s, 1 H), 9.35 (br s, 1 H);

Example 15 - Preparation of N-l,3-thiazol-2-ylhydrazinecarboxamide (intermediate 5)

O H H

Step 1 - Preparation ofN-l,3-thiazol-2-yl-lH-imidazole-l-carboxamide

To a solution of N,N-carbonyldiimidazole (0.818 g, 5.04 mmol) in chloroform (20.0 mL) was added l,3-thiazol-2-amine (0.500 g, 4.99 mmol). After 1 h at ambient temperature, the mixture was cooled to about 0°C and the solids collected by filtration, washed with chloroform and dried under high vacuum to afford the title compound which was used without further purification or characterization. Step 2 - Preparation ofN-l,3-thiazol-2-ylhydrazinecarboxamide

O

JJ

H H To a solution of N-l ,3-thiazol-2-yl-lH-imidazole-l -carboxamide (0.150g, 0.77 mmol) in isopropyl alcohol (10.0 mL) was added hydrazine hydrate (82 mg, 1.6 mmol). The reaction mixture was heated at 60°C for 1 h then cooled to 0-5°C. The solids were collected by filtration, washed with ethanol and MTBE, and dried under high vacuum to afford 123 mg of the title compound as a white solid. 'H NMR (400 MHz, CDC1₃) δ 7.03 (s, 1 H), 7.16 (d, J = 4 Hz, 1 H), 7.51 (d, J = 4 Hz, 1 H), 6.66 (s, 1 H), 8.30 (s, 1 H), 13.41 (br s, 1 H).

Example 16 - Preparation of l-amino-3-phenylimidazolidin-2-one (Intermediate 6)

Step 1 - Preparation of l-nitroso-3-phenylimidazolidin-2-one

Sodium nitrite (276 mg, 4.01 mmol) was added in portions to a stirring slurry of 1 -phenylimidazolidin- 2-one (500 mg, 3.08 mmol) in acetic acid (1 1.4 mL, 200 mmol) and water (1.14 mL, 63.3 mmol) at 0°C. The reaction mixture was stirred for 10 minutes before adding water (6.5 mL) and then the solids were filtered, washed with water, and dried to afford 530 mg of the product which was used in the next step without further purification.

Step 2 - Preparation of l-amino-3-phenylimidazolidin-2-one

Zinc (272 mg, 4.16 mmol) was added to a stirring solution of l-nitroso-3-phenyl-imidazolidin-2-one (530 mg, 2.77 mmol) in acetic acid (5 niL) at 10°C. After one hour HPLC showed approximately 50% conversion. Additional zinc (272 mg, 4.16 mmol) was added and the reaction mixture stirred overnight. The following morning the mixture was concentrated under reduced pressure, diluted with water and extracted with dichloromethane. The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product as a white solid. LCMS: ESI+ m/z of 278 (M+H).

Example 17 - Preparation of further phenothiazine derivatives

The following compounds of Table 1 were prepared using procedures and materials similar to those described above. The skilled person in the field of organic synthesis will recognize when starting materials, reaction conditions and/or protecting groups should be varied in order to obtain the desired compound. The compounds were analyzed by mass spectrometry (LCMS, ESI) and HPLC (Method A: Agilent 1100 HPLC, Zorbax Eclipse XDBC18 50 x 4.6 mm 1.8 micron column; solvent A: water (0.1% TFA); solvent B: acetonitrile (0.07% TFA); gradient: 6 min 95% A to 95% B, 1 min hold, then recycle; UV detection at 210 and 254 nm with no reference; Method B: Agilent 1100 HPLC, Zorbax Eclipse XDBC18 50 x 4.6 mm 1.8 micron column; solvent A: water (0.1% TFA); solvent B: acetonitrile (0.07% TFA); gradient: 5 min 95% A to 95% B, 1 min hold, then recycle; UV detection at 210 and 254 nm with no reference).

Table 1

pg. 508, Chart Example))

ylsemicarbazone

yl)semicarbazone

cco₀ 5 -methyl-N'-[( 1 E/Z)-2-( 10H- pheno-thiazin- 10-yl)- A (from 5-methylisoxazole-

387.0 4.21 (B) ethylidene] isoxazole-3 - 3 -carbohydrazide)

carbo-hydrazide oco₀ 3-amino-N'-[( 1 E)-2-( 1 OH-

B (from 3-amino-l ,2,4- phenothiazin- 10- triazole) 366.1 3.60 (A)

H ^NL ^NH> yl)ethylidene]-lH-l ,2,4- triazole- 1 -carbo-hydrazide

OCO„ „ A (using l-bromo-3,3-

( 1 E/Z)-3 -( 1 OH-phenothiazin- dimethoxypropane in place 411.2

10-yl)-propanal N- 4.77 (B) of bromoacetaldehyde (M+Na) phenylsemi-carbazone

diethyl acetal)

A (from (2E)-3-(phenyl- co (2E/Z)-N'-[(lZ)-2-(10H- o sulfonyl)acrylo-hydrazide

pheno-thiazin- 10-

(Gloria, M.C. et al., Bioorg.

yl)ethylidene]-3- 450.0 4.40 (B)

Med.Chem. 2011, 79, 7635- (phenylsulfonyl)acrylohydra

7642))

zide

Isolated in variable yields

0 N",N"'-bis[(lE/Z)-2-(10H- as a byproduct from the

phenothiazin-10- 535.0

preparation of certain 5.05 (A) yl)ethylidene] -carbono- semicarbazones from Chart

hydrazide

A and Chart B

Chart example Chart Example

(1 E/Z)-l OH-phenothiazin-10-

R⁵ = H yl-acetaldehyde A (from thiosemicarbazide) 337.2 3.95 (B) thiosemicarbazone

(1 E/Z)-l OH-phenothiazin-10-

A (from N-methyl

R⁵ = Me yl-acetaldehyde N- 351.1 4.31 (B) hydrazinecarbothioamide)

methylthiosemicarbazone

(lE/Z)-10H-phenothiazin-10- A (from Ν- yl-acetaldehyde N- propylhydrazine- 357.2 4.80 (B) propylthiosemicarbazone carbothioamide)

( 1 E/Z)-l OH-phenothiazin- 10-

A (from N-phenyl-

X- yl-acetaldehyde N- 391.1 4.96 (B) hydrazinecarbothioamide)

phenylthiosemicarbazone

( 1 E/Z)- 1 OH-phenothiazin-10-

A (from N-[3-(trifluoro- ylacetaldehyde N-[3- methyl)phenyl]hydrazine- 481.1 5.31 (B)

(trifluoro-methyl)phenyl] - carbothioamide)

thiosemicarbazone

( 1 E/Z)- 1 OH-phenothiazin-10-

A (from N-(3-methoxy- ylacetaldehyde N-(3- phenyl)hydrazinecarbothio- 421.1 4.97 (B)

R⁵ = *-^^OMe methoxy- amide)

phenyl)thiosemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-

A (from N-l,3-thiazol-2-yl- yl-acetaldehyde N-1,3- hydrazinecarbothioamide) 420.1 4.69 (B) thiazol-2-yl- thiosemicarbazone

"CC N NH

H fa

(2E/Z)-2-[2-(10H- phenothiazin-10- A (from aminoguanidine

R⁵ = H 298.1 3.32 (B) yl)ethylidene]hydrazine- hydrochloride)

carboximidamide

carboxamide

Example 18 - MALTl paracaspase exhibits proteolytic activity that is distinct from human caspases To screen for small molecular weight compounds that can inhibit MALTl protease activity, recombinant GSTMALTl was purified from E. coli to establish an in vitro protease cleavage assay suitable for high throughput screening (HTS). GSTMALTl was incubated for 1 h at 30°C in the presence of 50 μΜ of the tetrapeptide substrate Ac-LRSR-AMC, which is derived from the MALTl cleavage site in the C-terminus of BCL10 (Rebeaud, F., et al, Nat. Immunol. 2008, 9, 272-281). Proteolytic activity was determined by measuring the increase of fluorescence, which is emitted after cleavage and the accompanying release of the fluorophore AMC (Fig. 1A and B). MALTl catalyzed cleavage of Ac-LRSR-AMC is evident from a robust increase in fluorescence intensity over time. Mutation of the conserved cysteine (C453A) in the paracaspase domain of MALTl (Isoform B) completely abolished MALTl catalytic activity (Fig. 1A). Similar to arginine-lysine specific metacaspases, the MALTl protease has a high preference for cleaving after an arginine residue. Consistent with this Z-VRPR-FMK, which was initially designed as a metacaspase antagonistic peptide (Vercammen et al, J. Mol. Biol. 2006, 364, 625-636) also completely blocked MALTl cleavage activity at low nanomolar concentrations, emphasizing the high similarity of the paracaspase to plant metacaspases (Fig. IB and C). In contrast, the potent caspase inhibitory peptide Ac-DEVD-CHO which effectively blocked CASP8 activity even at picomolar concentrations (Fig. 11) only marginally reduced MALTl activity even when used at a concentration of 200 μΜ (Fig. ID).

The distinct substrate specificity of caspases and MALTl emphasizes the potential to identify small molecule inhibitors that interfere with MALTl dependent pro-survival signaling (Ferch J. Exp. Med. 2009, 206, 2313-2320; Hailfinger et al, PNAS USA 2009, 106, 19946-19951) without disturbing the caspase-dependent apoptotic machinery. As MALTl paracaspase is the only mammalian homologue to plant metacaspases (Uren et al, Mol. Cell 2000, 6, 961-967) the MALTl enzymatic activity and substrate preferences was further characterized. MALTl cleavage was assayed in the presence of protease inhibitors (Fig. IE) and compared the effects to the inhibitory profiles obtained for plant metacaspases AtMC4 and AtMC9 as summarized in Figure 9 (Vercammen et al, J. Biol. Chem. 2004, 279, 45329-45336). Just like AtMC4 and AtMC9, neither the aspartyl protease inhibitor Pepstatin A (100 μΜ) nor the serine protease inhibitor Aprotinin (5 μg/ml) strongly inhibited MALTl activity. Whereas the broad spectrum serine/cysteine protease inhibitor Chymostatin (100 μΜ) and Antipain (1 μΜ) inhibited MALTl and AtMC4/9 to a similar extent, Leupeptin (1 μΜ) was acting stronger on plant metacaspases. Interestingly, the cysteine protease inhibitor E-64 (100 μΜ) that was shown to have a mild effect on AtMC4 but not AtMC9, does not inhibit MALTl . In contrast, the serine/cysteine protease inhibitor TLCK (1 μΜ) that strongly inhibits AtMC9 and much weaker AtMC4, was only mildly affecting MALTl activity. As expected, tetra-peptide caspase inhibitors did not inhibit MALTl or AtMC4/9 activity. Taken together, substrate specificity and inhibitory profile indicate high similarity between the MALTl paracaspase to the plant metacaspases AtMC4/9. Example 19 - Identification of phenothiazine derivatives as selective MALT1 protease inhibitors

To identify small molecule inhibitors for the MALTl protease, approx. 18.000 compounds of the ChemBioNet collection were screened using an assay format as depicted in Figure 10. The primary screen was conducted by measuring the increase in AMC fluorescence in a 384 half-well format over an assay time of 20 min in the presence of 10 μΜ of each compound. 300 primary hits showed inhibitory potential and were chosen for secondary hit validation that was performed two times in the same format with increasing doses ranging from 0.7 to 90.9 μΜ of each compound. The validation yielded in 15 primary hits corresponding to -0.08 % of the primary screen.

When examining the structure of the 15 primary hits, it was noticed that three of the most efficient and selective compounds (Fig. 2A: compound A, B and C) are derivatives of the tri-cyclic phenothiazine that contains two outer benzene rings linked by a nitrogen and a sulfur atom in the inner ring. Also the heterocyclic core found in inhibitor D displays high structural similarities to phenothiazine, while the nitrogen is replaced by carbon. These initial results suggested that certain phenothiazines may act as MALTl inhibitors. To verify MALTl inhibition and to evaluate the specificity, the four identified phenothiazine compounds were tested for inhibition of MALTl and CASP8 activity. At 50 μΜ all four substances were reducing MALTl protease activity to less than 10% in a dose-dependent manner (Fig. 2B). In contrast, CASP8 activity was only modestly affected at the highest inhibitor concentrations of 50 μΜ, indicating that the four phenothiazine-related compounds are selectively acting on MALTl. These results suggested that phenothiazine derivatives (PDs) could be promising candidates as selective MALTl inhibitors. Example 20 - Phenothiazine derivatives act as potent and selective MALTl paracaspase inhibitors

Mepazine as well as 25 other commercially available phenothiazines were obtained to test their inhibitory potential. Whereas most compounds (12-26) had no or only very weak inhibitory potential (ICso > 20 μΜ), 8 compounds (4-11) inhibited MALTl activity with an IC₅₀ roughly between 5-20 μΜ. Only three phenothiazines had an IC50 below 5 μΜ. Thus, only a small subset of phenothiazines was capable of efficiently inhibiting MALTl. The three compounds having an IC50 below 5 μΜ represent promazine, thioridazine and mepazine, the latter initially identified in the screening (Fig. 3A). To define the inhibitory potential, the exact IC50 values for each compound on recombinant full length (FL) GSTMALTl and an enzymatically active truncated MALTl protein encompassing the amino acids of the paracaspase and C-terminal Ig-like (Ig3) domains from 325 to 760 was determined (Fig. 3B). Mepazine was most effective in inhibiting GSTMALT1 FL and GSTMALT1 325-760 with IC₅₀ values of 0.83 and 0.42 μΜ, respectively. Also thioridazine and promazine showed a dose dependent inhibition of GSTMALT1 FL and GSTMALT1 325-760, but the IC₅₀ values were approximately 4 (GSTMALTl FL) or 8 (GSTMALT1 325-760) fold lower when compared to mepazine. In contrast, promethazine, a drug that is still used in the treatment of certain psychiatric disorders and highly related to the three compounds promazine, thioridazine and mepazine did not cause any significant MALTl inhibition at concentrations up to 20 μΜ. These results indicate a high degree of specificity in MALT inhibition even within the group of phenothiazines.

To test the mode of action, the effect of mepazine in Michaelis-Menten kinetics on basis of the fluorogenic MALTl cleavage assay was determined (Fig. 3C). GSTMALTl FL displayed a VMAX of ~ 170 RFU/min and the Michaelis-Menten constant (KM) was calculated to ~ 48 μΜ, which is in the range of what has been determined previously (Hachmann et al., Biochem. J. 2012, 443, 287-295). Addition of mepazine at a concentration around the IC50 (1 μΜ) strongly decreased the VMAX to ~ 58 RFU/min while the KM of 48 μΜ was not altered. Mepazine and other phenothiazines do not contain reactive groups. However, to confirm that mepazine acts as a non-covalent reversible inhibitor, washout experiments using GSTMALTl attached to glutathione sepharose beads were performed (Fig. 3D). Again, mepazine inhibited MALTl cleavage activity, but several cycles of washing the GSTMALTl beads resulted in complete loss of inhibition even at the highest concentration of the compound (50 μΜ). Thus, the effects of mepazine on MALTl enzymatic activity revealed a non-competitive and reversible mode of MALTl inhibition by phenothiazines.

Next the effects of phenothiazine compounds on caspases, which are structurally the closest relatives of MALTl in mammals (Uren et al., Mol. Cell 2000, 6, 961-967) were assayed. Importantly, promazine, thioridazine and mepazine did not significantly inhibit CASP3 or CASP8 activity, even at concentrations up to 50 μΜ (Fig. 3E), reflecting the selectivity of the compounds as MALTl inhibitors. Based on the above experimental results demonstrating that the phenothiazine compounds promazine, thioridazine and mepazine selectively inhibit MALTl, the present inventors conducted further experiments resulting in the preparation and finding of the PDs of the present invention; cf. also Table 1, above. Several compounds of the invention have been tested with respect to their ability to selectively inhibit MALTl using the reactions and conditions described above. The results of these tests are shown in Table 2, below (IC50: IC50 value determined by the in vitro MALTl cleavage assay; inhib.: maximum percental inhibition determined by the in vitro MALTl cleavage assay; IC50 cell.: IC50 value determined by the cellular MALTl cleavage assay; EC50 (IL-6): EC50 value determined by the IL- 6 production assay). Table 2

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.33 30

N- 1 , 3 -benzothiazol-2-ylsemicarbazone

1 -[3 -( 1 OH-phenothiazin- 10-yl)propyl] -3 -

0.69 40

phenylurea

phenyl [3 -( 1 OH-phenothiazin- 10-yl)propyl] -

0.41 50

carbamate

N-[3-(10H-phenothiazin-10-yl)propyl]-

0.96 40

benzenesulfonamide

l-[3-(10H-phenothiazin-10-yl)propyl)-3-

0.89 50

phenylthiourea

1 -methyl- 1 -[3-( 1 OH-phenothiazin- 10-yl)-

0.52 30

propyl] -3 -phenylthiourea

2-[(10H-phenothiazin-10-yl)carbonyl]-N-

0.69 15

phenylhydrazinecarbothioamide

(2E/Z)-N'-[( 1 E/Z)-2-( 1 OH-phenothiazin- 10- yl)ethylidene] -3 -(phenylsulfonyl)acrylo- 0.53 95

hydrazide

( 1 E/Z)-3-( 1 OH-phenothiazin-l 0-yl)propanal N-

0.7 20

phenylsemicarbazone

2-[2-( 1 OH-phenothiazin- 10-yl)ethyl]-N-

1.75 80

phenylhydrazinecarboxamide

5-methyl-N'-[( 1 E/Z)-2-( 1 OH-phenothiazin-10-

1.66 70

yl)ethylidene] isoxazole-3 -carbohydrazide

3 -amino-N'- [( 1 E/Z)-2-( 1 OH-phenothiazin- 10- yl)ethylidene]-lH-l ,2,4-triazole-l -carbo3.9 85

hydrazide

5 -[( 1 OH-phenothiazin- 10-yl)methyl] -4-propyl-

4.63 50

2,4-dihydro-3H-l ,2,4-triazole-3-thione

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin-10-yl)-

9.6 90

ethylidene]amino}imidazolidin-2-one

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)- ethylidene]amino}-3-phenylimidazolidin-2- 1.46 30

one

1 - { [( 1 E/Z)-2-( 1 OH-phenothiazin- 10-yl)-

12.5 60

ethylidene]amino}imidazolidine-2,4-dione

N-methyl-2-(10H-phenothiazin-10-ylacetyl)-

10.8 90

hydrazinecarbothioamide

2- [( 1 OH-phenothiazin- 10-yl)acetyl] -N-propyl-

5.9 90

hydrazinecarbothioamide

N-allyl-2-( 1 OH-phenothiazin- 10-ylacetyl)-

2.4 50

hydrazinecarbothioamide

( 1 E/Z) - 1 OH-phenothiazin- 10-ylacetaldehyde

5.43 95 5-10

N-[3-(dimethylamino)propyl]semicarbazone

10-[(l-methylpiperidin-3-yl)methyl]-2-propyl-

0.43 90 1.61 3.4 1 OH-phenothiazine

2-allyl- 10- [( 1 -methylpiperidin-3 -yl)methyl] -

0.48 80 1.78 5.5 1 OH-phenothiazine

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

N-(4,5,6,7-tetrahydro-[l,3]thiazolo[5,4-c]- 0.47 100 0.69 pyridin-2-yl)semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.66 100 1.29

Ν- {4-[2-(dimethylamino)ethoxy]phenyl} - semicarbazone

(1 E/Z)-[2-(methylthio)- 1 OH-phenothiazin- 10- yl]acetaldehyde N-(3 -methylisoxazol-5 - 0.84 80 3.18 yl)semicarbazone

1 OH-phenothiazin- 10-ylacetaldehyde N-(2-

0.73 80 1.54 fluoropyridin-4-yl)semicarbazone

2-ethyl- 10- [( 1 -methylpiperidin-3 -yl)methyl] -

0.52 60 1.47 1 OH-phenothiazine

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

1.20 95 5-10 thiosemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

1.03 75

N-methylthiosemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.98 60

N-propylthiosemicarbazone

(2E/Z)-2-[2-( 1 OH-phenothiazin- 10-yl)-

3.3 95

ethylidene]hydrazinecarboximidamide

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

2.51 80

N-methylsemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

N-(l,3-dimethyl-lH-pyrazol-5-yl)semi- 1.71 60

carbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.91 75 5-10 N-(3-methylisothiazol-5-yl)semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.71 60 5-10 N-phenylthiosemicarbazone

( 1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde

5 50 5-10 semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.56 50

NN-dimethylsemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.69 50

N-pyrimidin-2-ylsemicarbazone

4-methyl-N'-[( 1 E)-2-( 1 ΟΗ-phenothiazin- 10-

4.1 95

yl)ethylidene]piperazine- 1 -carbohydrazide

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

5.2 80

N-(l-methylpyrrolidin-3-yl)semicarbazone

( 1 E/Z)-[2-(methylthio)- 1 OH-phenothiazin- 10-

0.7 40

yl]acetaldehyde N-phenylsemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.93 50

N-(3-methoxyphenyl) semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

N-[4-(4-methylpiperazin- 1 -yl)phenyl] semi1.57 95

carbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

1.05 95

N-(2-methylpyridin-4-yl)semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.65 70

N-quinolin-7-ylsemicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

0.56 50

N,N'-dimethylthiosemicarbazone

2-(10H-phenothiazin-10-ylacetyl)-N-[3-(tri-

3.0 60

fluoromethyl)phenyl]hydrazinecarbothioamide

3-(10H-phenothiazin-10-ylmethyl)-N-phenyl-

0.65 60

4, 5 -dihydro- 1 H-pyrazole- 1 -carboxamide phenyl (2E/Z)-2- [2-( 1 OH-phenothiazin- 10-

0.42 70

yl)ethylidene]hydrazinecarboxylate

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo- 0.53 100 0.15

[4,5-c]pyridin-2-yl) semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde

N- [3 -(2-morpholin-4-ylethoxy)phenyl] semi0.23 100 1.31

carbazone

Example 21 - Phenothiazines inhibit MALT1 activity and IL-2 induction in T cells

Under physiological conditions the MALT1 protease has been shown to contribute to T cell responses. Mutation of the catalytic cysteine residue in the active cavity of MALT1 prevents optimal IL-2 production in response to anti-CD3/CD28 co-stimulation (Duwel et al., J. Immunol. 2009, 182, 7718- 7728). Therefore the effects of phenothiazines on MALT1 activity and IL-2 production in T cells were determined (Fig. 4). A MALTl cleavage assay after immunoprecipitation (IP) of the protein from Jurkat T cells was performed (Fig. 4A). Cells were left untreated or incubated for 3 h with 10 μΜ of mepazine or thioridazine and subsequently left unstimulated or stimulated with anti-CD3/CD28. MALTl protease activity was almost undetectable in the absence of stimulation and peaked at 30-60 min after CD3/CD28 treatment. Addition of either mepazine or thioridazine resulted in a strong reduction of MALTl protease activity in stimulated Jurkat T cells at all time-points (Fig. 4A). To confirm that both phenothiazines were inhibiting MALTl activity inside the cells, MALTl cleavage of RelB after stimulation of Jurkat T cells was monitored (Fig. 4B). RelB cleavage product RelBA could be detected when Jurkat T cells were incubated with proteasome inhibitor MG132 prior to P/I stimulation to prevent degradation of the unstable RelB truncation (Hailfinger et al., PNAS USA 201 1, 108, 14596-14601). As evident from decreased RelBA levels and a parallel increased expression of full length RelB, mepazine and thioridazine impaired RelB cleavage in a dose dependent manner (Fig. 4B). Similar to the situation with recombinant MALTl , mepazine was more efficient in inhibiting cellular MALTl cleavage activity and significantly reduced the appearance of RelBA between 2-5 μΜ, whereas thioridazine was effective above 5 μΜ. The ability to inhibit cellular MALTl cleavage has been tested for several compounds of the invention (exemplary data are shown in Figure 13) and the results are shown in Table 2, above.

To determine the effects of MALTl inhibition by phenothiazines on T cell activation, secreted IL-2 amounts were measured by ELISA after P/I or anti-CD3/CD28 stimulation of Jurkat T cells in the presence of absence of mepazine or thioridazine. Both compounds led to a decrease of IL-2 levels in the media of compound treated cells after T cell activation (Figure 4C). To verify that the inhibitory potential of the phenothiazines is also detectable in primary T cells, murine CD4⁺ Thl T cells were isolated and purified, and IL-2 mRNA induction by qPCR and protein levels by ELISA after anti- CD3/CD28 co-ligation in the presence or absence of 5 and 10 μΜ of mepazine or thioridazine were measured (Fig. 4D). Both, IL-2 mRNA induction and protein expression was reduced in a dose- dependent manner. Finally, primary human PBMCs from three donors were used to evaluate whether inhibition of MALTl activity also promotes a decreased IL-2 production in primary human T cells (Fig. 4E). Congruent with the previous results, mepazine and thioridazine treatment led to a significant decrease of IL-2 secretion in PBMCs from all three donors.

Example 22 - Phenothiazines inhibit MALTl activity and induction of NF-κΒ target genes in ABC-DLBCL cells

Coinciding with a constitutive cleavage of the MALTl substrates A20 and BCLIO, MALTl protease activity was enhanced as a characteristic feature of all ABC-DLBCL cells was previously shown (Kloo, B., et al, PNAS USA 2011, 108, 272-277). To determine the effect of phenothiazines on cellular MALTl activity, ABC-DLBCL cells were incubated for 4h with 5 or 10 μΜ of mepazine, thioridazine and promazine. An anti-MALTl IP was performed and MALTl protease activity was determined by adding the substrate Ac-LRSR-AMC to the precipitates. All three phenothiazines inhibited MALTl protease activity from ABC-DLBCL cells in a dose-dependent manner (Fig. 5 A and 12A). Even though inhibition of cellular MALTl activity varied depending on the individual cell lines and the compounds, mepazine had in general the strongest effects and at 10 μΜ it led to at least 75% reduction of MALTl activity in all ABC-DLBCL cells. Also thioridazine was inhibiting MALTl activity in all ABC- DLBCL cell lines. However, whereas 10 μΜ thioridazine inhibited MALTl by more than 80% in HBL1, U2932 and TMD8, only a -50% decrease was observed in OCI-Ly3 and OCI-LylO. Promazine was the weakest inhibitor of cellular MALTl activity.

Next, it has been evaluated whether MALTl inhibition by mepazine and thioridazine would also prevent the cellular cleavage of the known MALTl substrate BCLIO in ABC-DLBCL cells (Fig. 5B). MALTl is cleaving the very C-terminal five amino acids of BCLIO resulting in a truncated cleavage product (BCL10A5). ABC-DLBCL cells were treated for 20 h with increasing doses of each compound. Indeed, treatment with mepazine or thioridazine prevented the detection of BCL10A5 in a dose-dependent manner.

MALTl activity contributes to optimal NF-κΒ activation and target gene expression in ABC-DLBCL cells (Ferch, U., et al., J. Exp. Med. 2009, 206, 2313-2320; Hailfinger, S., et al, PNAS USA 2009, 106, 19946-19951). Therefore, it was determined if mepazine, which most strongly affected MALTl activity, is also imparing constitutive NF-κΒ DNA binding and subsequently NF-κΒ target gene expression in ABC-DLBCL cells (Fig. 6). To this end DLBCL cells were treated with 10 and 20 μΜ of mepazine for 20 hours and analyzed NF-κΒ DNA binding by EMSA (Fig. 6A). Increasing concentrations of mepazine resulted in reduced NF-κΒ target DNA binding in ABC-DLBCL cells. Congruently, mepazine treatment led to a dose-dependent decrease of anti-apoptotic BCL-XL and FLIP-L proteins. To further monitor the effects of mepazine on other NF-κΒ dependent genes, ABC- or GCB-DLBCL cells were treated with 10 μΜ mepazine for 20 h and secretion of the cytokines IL-6 and IL-10 was determined by ELISA (Fig. 6B). Whereas GCB-DLBCL cells are expressing low amounts of IL-6 or IL-10, ABC-DLBCL cells are secreting both cytokines even though to variable extends, which reflects the degree of heterogeneity between the different cell lines. Importantly, mepazine decreased expression of soluble IL-6 and IL-10 in all ABC-, but not GCB-DLBCL cells, demonstrating its direct effect on NF-κΒ target gene expression. The ability to inhibit expression of soluble IL-6 has been tested for several compounds of the invention (exemplary data are shown in Figure 13) and the results are shown in Table 2, above.

Example 23 - Selective toxicity and induction of apoptosis by phenothiazines in ABC-DLBCL cells

As the three phenothiazines are efficiently inhibiting MALTl protease activity in vitro and in vivo, their effect on the viability of ABC-DLBCL cells was tested (Fig. 7). As a control the three GCB- DLBCL cell lines BJAB, Su-DHL-6 and Su-DHL-4 were used, that were previously shown to be independent of MALTl proteolytic activity for their growth and survival (Ferch, U., et ai, J. Exp. Med. 2009, 206, 2313-2320). Cytotoxic effects were measured by MTT assays after two days of incubation (single treatment) using increasing concentrations of mepazine, thioridazine and promazine (Fig. 7A, C and Fig. 12B). All compounds promoted a decrease of cell viability measured by MTT reaction in the ABC-DLBCL cells HBL1, OCI-Ly3, U2932 and TMD8, without significantly affecting GCB-DLBCL cells. Further, cell viability was determined by cell counting after 4 days of treatment (Fig. 7B, D and Fig. 12C). Congruent with the MTT assay, the phenothiazines also decreased the overall number of viable ABC-DLBCL cells. Again, the reduced viability was much more pronounced in ABC-DLBCL cells, while GCB-DLBCL cells were only slightly impaired even at the highest concentration of the compounds. Consistent with the results obtained in the cellular MALTl cleavage assay (Fig. 11 A), promazine had in general the mildest effects on the viability of the ABC-DLBCL cells. To further validate that the decrease in viability of ABC-DLBCL cells after administration of distinct phenothiazines is linked to MALTl inhibition, DLBCL cells were treated with promethazine (Fig. 12E). Despite its close structural relation to promazine, promethazine was not inhibiting MALTl protease activity at concentrations up to 20 μΜ (Fig. 12D). Indeed, promethazine did not significantly inhibit viability of ABC- or GCB-DLBCL cells after 4 days of treatment, providing further evidence that the cellular effects of mepazine, thioridazine and promazine as well as PDs are dependent on MALT1 inhibition.

Finally, it has been determined whether mepazine is affecting the viability of ABC-DLBCL cells by enhancing apoptosis (Fig. 7D). To this end, DLBCL cells were treated for five days with 15 μΜ of mepazine and apoptotic cells were identified by FACS as AnnexinV-PE positive and 7-AAD negative cells. Mepazine provoked an enhanced apoptotic rate in all ABC-DLBCL cells, while apoptosis was not increased in the two GCB-DLBCL control cells. Thus, phenothiazines and PDs are selectively toxic to ABC-DLBCL cells and toxicity is partially due to enhanced apoptosis in the affected lymphoma cells, revealing a potential use of mepazine and structurally related compounds for ABC-DLBCL therapy. Example 24 - Phenothiazine derivatives impede growth of ABC-DLBCL in vivo

The long history of phenothiazine, especially thioridazine, in the treatment of psychiatric disorders as well as the detailed knowledge of their pharmacology and toxicology could facilitate an off-label use for the treatment of patients diagnosed with ABC-DLBCL. Therefore, it was determined whether mepazine and thioridazine could also exert effects on lymphoma growth in vivo in a murine DLBCL xenogeneic tumor model. For this purpose, the ABC-DLBCL cell line OCI-LylO and the GCB-DLBCL cell line Su-DHL-6 were injected as subcutaneous xenografts into NOD/scid IL-2Rg^nu11 (NSG) mice (Fig. 8A). Both tumor cell lines were engrafted simultaneously on opposite flanks of individual mice. Starting one day after injection, the mice were treated by intraperitoneal administration of solvent or either mepazine (12 mg/kg) or thioridazine (16 mg/kg). In control treated mice massive tumors grew from both DLBCL cell lines within three weeks of transplantation. Daily administration of mepazine or thioridazine strongly impaired the expansion of the ABC-DLBCL cell line OCI-LylO. In contrast, both compounds completely failed to exert any inhibitory effects on the progression of the GCB-DLBCL cell line Su-DHL-6 in the same animals.

To ascertain that mepazine and thioridazine were acting directly on the tumor cells, the induction of apoptosis in the tumor tissue was determined. Transplanted tumors were removed at the end of the treatment period and apoptotic cells were visualized by TUNEL staining on sections of the tumor tissue (Fig. 8B). Congruent with the selective in vivo toxicity, mepazine or thioridazine treatment increased the number of apoptotic cells in the xenografted ABC-DLBCL cell line OCI-LylO, while no induction of apoptosis was observed in the GCB-DLBCL cell line Su-DHL-6. Further, constitutive cleavage of the MALTl substrate RelB was impaired after mepazine and thioridazine treatment in specimens of xenografted OCI-LylO tumors, revealing that also in mice the compounds were indeed acting by inhibiting MALTl activity in the tumor cells (Fig. 8C). Thus, the murine tumor model provided evidence that MALTl inhibition by phenothiazines selectively kills MALTl -dependent DLBCL in vivo and indicates a potential therapeutic benefit for use of the known compounds in ABC-DLBCL therapy.

I l l

Claims

A compound selected from the group consisting of a phenothiazine derivative having

R¹ to R⁸ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azido, -N0₂, -OR¹¹, -N(R¹²)(R¹³), -ON(R¹²)(R¹³), -N⁺(-0 )(R¹²)(R¹³), -S(O)₀-2Rⁿ, -S(0)o-20R^U, -OS(O)₀-2R^u, -OS(0)o-20R^u, -S(O)₀-₂N(R¹²)(R¹³), -OS(0)o-₂N(R¹²)(R¹³), -N(R^u)S(0)o-2Rⁿ,

-C(=X)XR", -XC(=X)Rⁿ, and -XC(=X)XR", wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted;

R⁹ is -D-E-G-E'-R⁴⁰, wherein

D is -Li-Q_q-L'i_'-, wherein L and L' are independently selected from the group consisting of alkylene, alkenylene, and alkynylene; Q is selected from the group consisting of -NR¹¹-, -0-, -S(0)o-2-, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; and each of 1, q, and Γ is 0 or 1, wherein when q is 0, Γ is 0 and Q can only be -NR¹¹-, -O- or -S(0)o-2- if is 1 ; wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted;

E is selected from the group consisting of a covalent bond, -0-, -S(0)o-₂-, -C(=X)-, -NR²⁰-, -C(R²²)=N-, -N=C(R²²)-, -C(=X)-NR²⁰-, and -NR²⁰-C(=X)-; G is selected from the group consisting of

and -(NR³⁰)a-S(O)i.₂-(NR³¹)b-, wherein a is 0 or 1, b is 0 or 1, and a+b is 1 or 2;

E' is selected from the group consisting of a covalent bond, -0-, -S(0)o-2-, -C(=X)-, -NR²¹-, -C(R²³)=N-, -N=C(R²³)-, -C(=X)-NR²¹-, and -NR ¹-C(=X)-;

X is independently selected from O, S, and NR¹⁴;

R' ¹ is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R¹⁴ is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -OR¹¹, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

R¹⁵ and R¹⁶ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH_yR⁵⁰2-_y, or R¹⁵ and R¹⁶ may join together with the atom to which they are attached to form a ring which is optionally substituted, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted; R²⁰ and R²¹ are independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted;

or

y is an integer from 0 to 2; and

2. The compound of claim 1, wherein E is selected from the group consisting of -C(R²²)=N-, a covalent bond, -NR²⁰-, -C(=X)-, -N=C(R²²)-, -C(=X)-NR²⁰-, and -NR²⁰-C(=X)-, preferably from the group consisting of -C(R²²)=N-, a covalent bond, -NR²⁰-, and -C(=X)-NR²⁰-.

3. The compound of claim 1 or 2, wherein E' is selected from the group consisting of -NR²¹-, a covalent bond, -0-, -S-, -C(R²³)=N-, -N=C(R²³)-, -C(=X)-NR²¹-, and -NR^2,-C(=X)-, preferably from the group consisting of -NR²¹-, a covalent bond, -0-, -S-, and -N=C(R²³)-.

4. The compound of any one of claims 1 to 3, wherein a+b is 1, wherein the moiety -E-G-E'- is preferably selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=X)-N(R²¹)-, -C(=X)-N(R³¹)-, -N(R³⁰)-C(=X)-, -N(R³⁰)-S(O)₂-, -S(0)₂-N(R³¹)-, -C(=X)-N(R²⁰)-N(R^3O)-C(=X)-N(R²¹)-, -N(R³⁰)- C(=X)-N(R²¹)-, -N(R³⁰)-C(=O)-O-, -N(R³⁰)-C(=O)-S-, -N(R³⁰)-C(=S)-O-, -N(R³⁰)-C(=S)-S-, -N(R²⁰)- N(R ⁰)-C(=X)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=X)-, and -C(R²²)=N-N(R³⁰)-C(=X)-.

5. The compound of any one of claims 1 to 3, wherein a+b is 2, wherein the moiety -E-G-E'- is preferably selected from the group consisting of -N(R²⁰)-N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)-, -N(R²⁰)- N(R³⁰)-C(=X)-N(R³¹)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)-, and -C(R²²)=N-N(R³⁰)- C(=X)-N(R^3,)-N=C(R²³)-.

6. The compound of any one of claims 1 to 3, wherein the moiety -E-G-E'- is selected from the group consisting of -C(R²²)=N-N(R³⁰)-C(=X)-N(R²¹)-, -S(0)₂-N(R³¹)-, -C(=X)-N(R²⁰)-N(R³⁰)-C(=X)- N(R²¹)-, -N(R³⁰)-C(=S)-N(R²¹)-, -N(R³⁰)-C(=NR¹⁴)-N(R²¹)-, -N(R³⁰)-C(=O)-S-, -N(R³⁰)-C(=S)-O-, -N(R³⁰)-C(=S)-S-, -N(R²⁰)-N(R³⁰)-C(=X)-N(R²')-, -N(R²⁰)-N(R³⁰)-C(=X)-, -C(R²²)=N-N(R ⁰)-C(=X)-, -N(R²⁰)-N(R³⁰)-C(=X)-N(R³¹)-N(R²¹)-, -N(R²⁰)-N(R³⁰)-C(=X)-N(R³¹)-N=C(R²³)-, -C(R²²)=N-N(R³⁰)- C(=X)-N(R³¹)-N(R²¹)-, and -C(R²²)=N-N(R³⁰)-C(=X)-N(R³¹)-N=C(R²³)-.

7. The compound of any one of claims 1 to 6, wherein L and L' are independently selected from the group consisting of Ci-6 alkylene, C₂-6 alkenylene, and C₂-6 alkynylene; and Q is selected from the group consisting of -NR¹¹-, 3- to 10-membered arylene, 3- to 10-membered heteroarylene, 3- to 10-membered cycloalkylene, and 3- to 10-membered heterocycloalkylene, wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted, wherein Q is preferably selected from the group consisting of phenylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, pyranylene, cyclopentadienylene, thiazolylene, isothiazolylene, oxazolylene, isoxazolylene, pyrazolylene, imidazolylene, pyrrolylene, furanylene, thienylene, thiadiazolylene, triazolylene, and hydrogenated forms of the forgoing groups, wherein each of the forgoing groups and hydrogenated forms thereof is optionally substituted.

8. The compound of claim 7, wherein D is selected from the group consisting of O-e alkylene, -(Ci-3 alkylene)-NRⁿ-(Ci-3 alkylene)-, -(C1-3 alkylene)-(5- to 6-membered arylene)-(Ci_3 alkylene)o-i-,

-(Ci-3 alkylene)-(5- to 6-membered heteroarylene)-(Ci-3 alkylene)o-i-, -(C1-3 alkylene)-(5- to 6-membered cycloalkylene)-(Ci-3 alkylene)o-i-, and -(C1-3 alkylene)-(5- to 6-membered heterocycloalkylene)-(Ci-3 alkylene)o i-, wherein each of the alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene groups is optionally substituted.

9. The compound of any one of claims 1 to 8, wherein R⁴⁰ is selected from the group consisting of -H, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted, wherein R⁴⁰ is preferably selected from the group consisting of -H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, morpholino, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, isoxazolyl, oxazolyl, benzothiazolyl, pyrazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, thiadiazolyl, triazolyl, phenoxazinyl, thiazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolothiazolyl, pyrrolooxazolyl, pyrrolopyrrolyl, phenothiazinyl, isoquinolinyl, imidazolyl, benzoimidazolyl, pyrrolyl, furanyl, thienyl, pyranyl, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, isothiazolyl, pyrazinyl, pyrrolizinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, quinolinyl, phthalazinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8- naphthyridinyl, 2,6-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, 1 ,7-phenanthrolinyl, 1 ,8-phenanthrolinyl, 1 ,10- phenanthrolinyl, 3,8-phenanthrolinyl, 4,7-phenanthrolinyl, phenazinyl, chromanyl, isochromanyl, and hydrogenated forms of the forgoing aryl/heteroaryl groups, wherein each of the forgoing alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups and hydrogenated forms thereof is optionally substituted.

10. The compound of any one of claims 1 to 9, wherein the ring formed by (i) R¹ and R², (ii) R² and R\ (iii) R³ and R⁴, (iv) R⁵ and R⁶, (v) R⁶ and R⁷, or (vi) R⁷ and R⁸ is a 3- to 7-membered ring, which is optionally substituted, wherein the ring preferably has 5 or 6 members and is an aromatic, cycloaliphatic, heteroaromatic, or heterocyclic ring, wherein the heteroaromatic / heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of O, S, and NK⁶⁰, wherein R⁶⁰ is selected from the group consisting of R", -OR¹¹, -NH_yR⁵⁰2-_y, and -S(0)o-2R^U, wherein R¹¹ and y are as defined above.

11. The compound of any one of claims 1 to 9, wherein R² and/or R⁷ are selected from the group consisting of -H, Ci-e alkyl, C₂.₆ alkenyl, C₂-₆ alkynyl, halogen, -CN, azido, -N0₂, -OR⁶¹, -N(R⁶²)(R⁶³), -SR⁶¹, -S(0)₂R⁶\ -S(0)₂N(R⁶²)(R⁶³), -N(R⁶¹)S(0)₂R⁶¹, -C(=X)R⁶¹, -C(=X)XR⁶¹, -XC(=X)R⁶¹, and -XC(=X)XR⁶¹, wherein R⁶¹, R⁶² and R⁶³ are independently selected from the group consisting of -H, Ci-₄ alkyl, C₂-₄ alkenyl, and C₂-₄ alkynyl, and wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -CN, azido, -N0₂, -OH, -0(Ci-₄ alkyl), -SH, -S(C,-₄ alkyl), -NH(Ci_₄ alkyl), -N(CM alkyl)₂, COOH, and COO(Ci-₄ alkyl).

12. The compound of claim 1, wherein the phenothiazine derivative is selected from the group consisting of:

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-phenylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-4-ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-3 -ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- (4-[2-(dimethylamino) ethoxyjphenyl} semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(3-methylisoxazol-5-yl)semicarbazone

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(3 ,4-dimethylisoxazol-5-yl)semicarbazone;

( 1 E/Z)-l OH-phenothiazin-l 0-ylacetaldehyde N'-(2-hydroxyethyl)-N-(3-methylisoxazol-5- yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-isoxazol-3-ylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(3-methyl-lH-pyrazol-5-yl)semicarbazone;

(1 E/Z)- 1 OH-phenothiazin-l 0-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[5,4- c]pyridin-2-yl)semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(4-pyridin-3 -yl-1 ,3 -thiazol-2-yl)semicarbazone;

N-(3 -methylisoxazol-5 -yl)-3 -( 1 OH-phenothiazin- 10-ylmethyl)-4,5 -dihydro- 1 H-pyrazole- 1 - carboxamide;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3 -benzoxazol-2 -ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 ,3 -benzodioxol-5-ylsemicarbazone;

N",N"'-bis[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]carbonohydrazide; ( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N- 1 , 3 -benzothiazol-2-ylsemicarbazone;

1- [3-(10H-phenothiazin-10-yl)propyl]-3-phenylurea;

phenyl [3 -( 1 OH-phenothiazin- 10-yl)propyl] carbamate;

N- [3 -( 1 OH-phenothiazin- 10-yl)propyl]benzenesulfonamide;

1 - [3 -( 1 OH-phenothiazin- 10-yl)propyl)-3 -phenylthiourea;

1 -methyl- 1 -[3 -( 1 OH-phenothiazin- 10-yl)propyl] -3 -phenylthiourea;

2- [( 1 OH-phenothiazin- 10-yl)carbonyl]-N-phenylhydrazinecarbothioamide;

( 1 E/Z)-3 -( 1 OH-phenothiazin- 10-yl)propanal N-phenylsemicarbazone;

2-[2-(l OH-phenothiazin- 10-yl)ethyl]-N-phenylhydrazinecarboxamide;

3- amino-N'-[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]-lH-l ,2,4-triazole-l-carbohydrazide; 5-[(10H-phenothiazin-10-yl)methyl]-4-propyl-2,4-dihydro-3H-l,2,4-triazole-3-thione;

l-{[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]amino}imidazolidin-2-one;

1- {[(lE/Z)-2-(10H-phenothiazin-10-yl)ethylidene]amino}imidazolidine-2,4-dione;

N-methyl-2-( 1 OH-phenothiazin- 10-ylacetyl)hydrazinecarbothioamide;

2- [(10H-phenothiazin-10-yl)acetyl]-N-propylhydrazinecarbothioamide;

N-allyl-2-(10H-phenothiazin-10-ylacetyl)hydrazinecarbothioamide;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-[3 -(dimethylamino)propyl] semicarbazone;

10-[(l -methylpiperidin-3-yl)methyl]-2-propyl-10H-phenothiazine;

2-allyl- 10-[(l -methylpiperidin-3 -yl)methyl] - 1 OH-phenothiazine;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde Ν- {4-[2-(dimethylamino)ethoxy]phenyl} semicarbazone; (lE/Z)-[2-(methylthio)-10H-phenothiazin-10-yl]acetaldehyde N-(3-methylisoxazol-5- yl)semicarbazone;

(2E/Z)-2-[2-(10H-phenothiazin-10-yl)ethylidene]-N-(3-methylisoxazol-5- yl)hydrazinecarboximidamide;

N-(3 -methylisoxazol-5 -yl)-6-[( 1 OH-phenothiazin- 10-yl)methyl]piperidine-2 -carboxamide;

2,3-dihydrocyclopenta[b]phenothiazin-10(lH)ylacetaldehyde N-(3-methylisoxazol-5- yl)semicarbazone;

N-(3 -methylisoxazol-5 -yl)-6-[( 1 OH-phenothiazin- 10-yl)methyl]pyridine-2 -carboxamide;

(1 E/Z)-(2-propyl-l OH-phenothiazin- 10-yl)acetaldehyde N-(3 -methylisoxazol-5 -yl)semicarbazone; 1 OH-phenothiazin- 10-ylacetaldehyde N-(2-fluoropyridin-4-yl)semicarbazone;

2-ethyl- 10- [( 1 -methylpiperidin-3 -yl)methyl] - 1 OH-phenothiazine; ( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde thiosemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-methylthiosemicarbazone;

( 1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde N-propylthiosemicarbazone;

(2E/Z)-2-[2-(10H-phenothiazin-10-yl)ethylidene]hydrazinecarboximidamide;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-methylsemicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(l,3-dimethyl-lH-pyrazol-5-yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(3-methylisothiazol-5-yl)semicarbazone;

( 1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde N-phenylthiosemicarbazone;

( 1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde semicarbazone;

(1 E/Z)-l OH-phenothiazin-10-ylacetaldehyde NN-dimethylsemicarbazone;

( 1 E/Z)-l OH-phenothiazin- 10-ylacetaldehyde N-pyrimidin-2-ylsemicarbazone;

4-methyl-N-[(l E/Z)-2-( 1 OH-phenothiazin- 10-yl)ethylidene]piperazine- 1 -carbohydrazide;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(l-methylp}TTolidin-3-yl)semicarbazone;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(3-methoxyphenyl) semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-[4-(4-methylpiperazin- 1 -yl)phenyl] semicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-quinolin-7-ylsemicarbazone;

( 1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde NN'-dimethylthiosemicarbazone;

3-( 1 OH-phenothiazin- 10-ylmethyl)-N-phenyl-4,5-dihydro- lH-pyrazole- 1 -carboxamide ;

phenyl (2E/Z)-2-[2-( 1 OH-phenothiazin- 10-yl)ethylidene]hydrazinecarboxylate;

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]- pyridin-2-yl) semicarbazone; and

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[3-(2-mo holi -4-ylethoxy)phenyl]semicarbazone, preferably from the group consisting of:

1 OH-phenothiazin- 10-ylacetaldehyde N-pyridin-4-ylsemicarbazone;

10H-phenothiazin-10-ylacetaldehyde N-(5-methylisoxazol-3-yl)semicarbazone;

10H-phenothiazin-10-ylacetaldehyde N-(3,4-dimethylisoxazol-5-yl)semicarbazone;

lOH-phenothiazin-l 0-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l ,3]thiazolo[5,4-c]pyridin-2- yl)semicarbazone;

(1 E/Z)- 1 OH-phenothiazin- 10-ylacetaldehyde N-(5-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[4,5-c]- pyridin-2-yl) semicarbazone; and

(lE/Z)-10H-phenothiazin-10-ylacetaldehyde N-[3-(2-morpholin-4-ylethoxy)phenyl]semicarbazone.

13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

14. The compound of any one of claims 1 to 12 or the pharmaceutical composition of claim 13 for inhibiting a paracaspase.

15. The compound of any one of claims 1 to 12 or the pharmaceutical composition of claim 13 for use in therapy or for use in a method of treating or preventing a disease or disorder which is treatable by an inhibitor of a paracaspase, wherein the disease or disorder preferably is (i) cancer, more preferably a lymphoma, most preferably diffuse large B-cell lymphoma (DLBCL), or (ii) a paracaspase-dependent immune disease, more preferably an allergic inflammation.

16. The compound or pharmaceutical composition of claim 14 or 15, wherein the paracaspase is mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).