Polycyclic heteroaryl substituted triazoles useful as axl inhibitors

[0001] The invention is directed to triazoles substituted with polycyclic triazole heteroaryl and pharmaceutical compositions thereof that are useful as inhibitors of the receptor protein tyrosine kinase known as Axl. Also disclosed are methods of using compounds and compositions for the treatment of diseases and conditions associated with Axl activity, especially in the treatment of diseases and conditions associated with angiogenesis and / or cell proliferation.

BACKGROUND OF THE INVENTION [0002] All protein kinases identified to date in the human genome have a highly conserved catalytic domain of about 300 amino acids. This domain folds into a biplane structure in which ATP binding and catalytic sites are found. The complexity of regulation of protein kinase activity enables many potential inhibition mechanisms, including competition with activating ligands, modulation of positive and negative regulators, interference of protein dimerization, and allosteric or competitive inhibition at substrate sites or ATP binding.

[0003] Axl (also known as UFO, ARK and Tyro7; nucleotide accession numbers NMR_021913 and NMR_001699; protein accession numbers NP_068713 and NP_001690) is a receptor protein tyrosine kinase (RTK) that consists of the C-terminal extracellular ligand and N-binding domain - the terminal cytoplasmic region containing the catalytic domain. The extracellular domain of Axl has a unique structure that assembles immunoglobulin and type III fibronectin repeats and resembles the structure of neural cell adhesion molecules. Axl and its two closely related compounds, Mer / Nyk and Sky (Tyro3 / Rse / DTK), known collectively as the Tyro3 RTK family, all bind and are stimulated to varying degrees by the same ligand, Gas6 (specific growth inhibitory-6), ~ 76kDa secreted protein with significant homology to the blood coagulation regulator, protein S. In addition to ligand binding, the extracellular domain of Axl has been shown to undergo homophilic interactions that mediate cell aggregation, suggesting that one of the important functions of Axl may be mediation of cell-cell adhesion.

[0004] Axl is primarily expressed in the vascular system in both endothelial cells (EC) and blood vessel smooth muscle cells (VSMC), and in cells of myeloid origin, and is also detected in epithelial breast cells, chondrocytes, Sertoli cells and neurons . Some functions, including protection against serum-induced apoptosis, TNF-α or E1A viral protein as well as cell migration and differentiation have been assigned to Axl signaling in cell culture. However, Axl - / - mice do not show an overt developmental phenotype and physiological function of Axl in vivo not clearly established in the literature.

[0005] Angiogenesis (formation of new blood vessels) is limited to functions such as wound healing and the female reproductive cycle in healthy adults. This physiological process has been co-opted by tumors, thus ensuring an adequate blood supply that enhances tumor growth and facilitates metastasis. Deregulated angiogenesis is also characterized by many other diseases (e.g. psoriasis, rheumatoid arthritis, endometriosis and blindness due to age-related macular degeneration (AMD), retinopathy of prematurity and diabetes) and often contributes to the development or pathology of this condition.

[0006] Overexpression of Axl and / or its ligand has also been reported in a variety of solid tumor types, including but not limited to breast, kidney, endometrial, ovarian, thyroid, non-small cell lung cancer, and melanoma iris melanoma as well as leukemia leukemia. In addition, it has transforming activity in NIH3T3 and 32D cells. Loss of Axl expression in tumor cells has been shown to block the growth of solid human tumors in the in vivo MDA-MB-231 xenografted breast cancer model. Taken together, these data suggest that Ax1 signaling may independently regulate EC angiogenesis and tumor growth, and therefore constitute a new target class for tumor therapeutic development.

[0007] The expression of Axl and Gas6 proteins is increased in many other disease states, including endometriosis, vascular damage and kidney disease, and Axl signaling is functionally associated with these two assays. Axl -Gas6 signaling enhances platelet responses and is involved in clot formation. Axl may therefore potentially be a therapeutic target in a wide variety of pathological conditions, including solid tumors including, but not limited to, breast cancer, kidney cancer, endometrial cancer, ovary, thyroid, non-small cell lung cancer, iris melanoma; liquid tumors, including but not limited to leukemia (especially myeloid leukemia) and lymphomas, endometriosis, vascular disease / injury (including, but not limited to, restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; renal disease (including, but not limited to, glomerulonephritis, diabetic nephropathy, and renal transplant rejection), rheumatoid arthritis, osteoporosis, degenerative arthritis and cataracts.

[0008] WO2006 / 020767 discloses compounds based on 2-amido-thiazole having ATP inhibitory activity. The compounds disclosed therein differ from the compounds of the invention due to the thiazole core structure.

[0009] WO2004 / 046120 and WO2006 / 03416 disclose diaminotriazole compounds that are useful as protein kinase inhibitors. Such compounds differ from those of the invention in terms of the substituents designated R² and R³ in formula (I) below.

[0010] WO2007 / 030680 discloses triazole derivatives that are useful for inhibiting the receptor tyrosine kinase activity of Axl protein. However, such triazole derivatives differ from those of the invention due to the fact that R³ is not directly related to the triazole core structure.

SUMMARY OF THE INVENTION [0011] The invention is directed to certain polycyclic heteroaryl-substituted triazoles that are useful as Axl inhibitors, such compounds for use in the treatment of diseases and conditions associated with Axl activity and pharmaceutical compositions containing such compounds.

[0012] In connection with the above, in one aspect the invention relates to a compound of formula (I):

R¹

<img file="PL2078010T3_D0001.tif" />

wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (= NR⁶) N (R⁶) R⁷;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸,

R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰O = R¹⁰-OR⁸,

-R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰-C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2),

-R⁹-OR¹⁰-N (R⁶) R⁷,

C (O) R⁸, -R⁹-C (O) OR⁸,

-R⁹-OR¹⁰-C (NR¹⁰N (R¹¹) H,

-R⁹-C (O) N (R⁶) R⁷,

-R⁹-OC (O) -R⁸,

-R⁹-N (R⁶) R⁷, -R⁹-R⁹-N (R⁶) C (O) OR⁸, -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

or R² is polycyclic heteroaryl containing more than 14 ring carbon atoms as described above and R³ is selected from the group consisting of aryl and heteroaryl, wherein said aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkylalkyl -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) -R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²)², -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

or R³ is polycyclic heteroaryl having more than 14 ring carbon atoms as described above, and R³ is selected from the group consisting of aryl and heteroaryl, wherein said aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkylalkyl -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) -R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² where t is 1 or 2), -R¹³-S (O) t¹² where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or any R⁶ and R⁷, together with the common nitrogen, to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkylalkyl optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocycloalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, and an optionally substituted straight or branched alkenylene chain; and each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

as a single stereoisomer or mixture thereof, or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof.

[0013] In another aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of formula (I) as described above as a single stereoisomer or mixture thereof or as a tautomer or mixture thereof or a pharmaceutically acceptable salt or N-oxide thereof.

In another aspect, the invention relates to a compound of formula (I) as described above as a single stereoisomer or mixture thereof, or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof, or a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutically acceptable excipient and a compound of formula (I) as described above as a single stereoisomer or mixture thereof, or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of a disease or condition associated with Axl activity in a mammal.

[0015] This invention also provides assays to determine the effectiveness of a compound of the invention in inhibiting Axl activity in a cell-based assay.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS [0016] As used in this description and the appended claims, unless stated otherwise, the following terms have the meanings indicated:

"Amino" refers to the -NH2 radical.

"Carboxy" refers to the -C (O) OH radical.

"Cyano" refers to the -CN radical.

"Nitro" refers to the -NO2 radical.

"Oksa" refers to the radical -O-.

"Oxo" refers to the radical = O.

"Tioxo" refers to the radical = S.

"Alkyl" refers to a straight or branched chain hydrocarbon radical consisting only of carbon and hydrogen, not containing an unsaturated bond, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms ("lower alkyl "), and which is attached to the rest of the molecule through a single bond, for example, methyl, ethyl, npropyl, 1-methylethyl (iso-propyl) n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless specifically stated otherwise, the alkyl radical may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰,

-OC (O) -R²⁰, -N (R²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R²⁰) 2, -N (R²⁰) C (O) OR²⁰, 7

N (R²⁰) C (O) R²⁰, -N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) tN (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

"Alkenyl" refers to a straight or branched hydrocarbon radical consisting only of carbon and hydrogen, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms, and which is attached to the rest of the single molecule a bond, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specified specifically in the specification, the alkenyl radical may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R²⁰) 2, -C (O) R²⁰, C (O) OR²⁰, -C (O) N (R²⁰) 2, -N (R²⁰) C (O) OR²⁰, -N (R²⁰) C (O) R²⁰, -N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) tN (R²⁰)₂ (where t is 1 or 2), where each R²⁰ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

"Alkynyl" refers to a straight or branched radical with a hydrocarbon chain consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms, and which is attached to the rest of the single molecule a bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless specifically stated otherwise, the alkyl radical may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, C (O) N (R²⁰) 2, -N (R²⁰) C (O) OR²⁰, -N (R²⁰) C (O) R²⁰, -N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and S (O) tN (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group, consisting exclusively of carbon and hydrogen atoms, not containing unsaturation and having from one to twelve carbon atoms, for example methylene, ethylene, propylene, n-butylene and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be one carbon in the alkylene chain or through any two carbons contained in the chain. Unless otherwise specified specifically in the description, the alkylene chain may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R²⁰) 2, -N (R²⁰) C (O) OR²⁰, N (R²⁰) C (O) R²⁰, -N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) tN (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group, consisting exclusively of carbon and hydrogen atoms, containing at least one double bond and having from one to twelve carbon atoms, even ethylene, propenylene , n-butenylene, and the like. The alkenyl chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenyl chain to the rest of the molecule and to the radical group can be one carbon or through any two carbons contained in the chain. Unless otherwise specified specifically in the specification, the alkenyl chain may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, N (R²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R²⁰) 2, -N (R²⁰) C (O) OR²⁰, -N (R²⁰) C (O) R²⁰, N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰(where p is 0, 1 or 2), and -S (O) tN (R²⁰)₂ (where t is 1 or 2), where each R²⁰is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

"Alkynylene" or "alkynyl chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting exclusively of carbon and hydrogen atoms, containing at least one triple bond and having from one to twelve carbon atoms, for example propynylene, n -butynylene, and the like. The alkynyl chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynyl chain to the rest of the molecule and to the radical group can be one carbon or through any two carbons contained in the chain. Unless otherwise specified specifically in the specification, the alkynyl chain may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R²⁰) 2, -C (O) R²⁰, C (O) OR²⁰, -C (O) N (R²⁰) 2, -N (R²⁰) C (O) OR²⁰, -N (R²⁰) C (O) R²⁰, -N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), -S (O) tOR²⁰ (where t is 1 or 2), -S (O)_pR²⁰ (where p is 0, 1 or 2), and -S (O) tN (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

"Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above containing from one to twelve carbon atoms. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.

"Alkoxyalkyl" refers to a radical of the formula -Rb-O-Ra where Ra is an alkyl radical as defined above and Rb is an alkylene chain as described above. The oxygen atom can be attached to any carbon in the alkyl radical or alkylene chain. The alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl radical and the part comprising the alkylene chain of the alkoxyalkyl radical may be optionally substituted as defined above for the alkylene chain.

"Aryl" refers to a radical with a hydrocarbon ring system containing hydrogen, from 6 to 14 carbon atoms, and at least one aromatic ring. For the purposes of this invention, the aryl radical may be a monocyclic, bicyclic or tricyclic system and which may contain spiro ring systems. The aryl radical is usually, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl radical. For the purposes of this invention, the "aryl" radical as defined herein cannot contain more rings having more than 7 members and cannot contain rings in which two non-adjacent ring atoms are connected via an atom or group of atoms (i.e., bridged ring system). Aryl radicals include, but are not limited to, aryl radicals derived from acenaphthylene, anthracene, azulene, benzene, 6,7,8,9-tetrahydro-5Hbenzo [7] annulene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene and phenanthrene. Unless otherwise specifically specified in this specification, the term "optionally substituted aryl" means that it contains aryl radicals optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl aryl, optionally substituted heteroaryl optionally substituted heteroarylalkynyl, -R²¹-OR²⁰, -R²¹-OC (O) R²⁰, -R²¹N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹-OR²²-C (O) N (R²⁰) 2, R²¹-N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) t R²⁰ (where t is 1 or

2), -R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), 21 20 20

R -S (O) tN (R) 2 (where t is 1 or 2), where each R is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R²⁰ together with the common nitrogen to which they are attached, they can optionally form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, each R²¹ independently represents a direct bond or a straight or branched alkylene or alkenylene chain, and R²² means a straight or branched alkylene or alkenylene chain.

"Aralkyl" refers to a radical of the formula -Rb-Rc wherein Rb is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Part of the alkylene chain of the aralkyl radical may be optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl radical may be optionally substituted as described above for aryl.

"Aralkenyl" refers to a radical of the formula -Rd-Rc wherein Rd is an alkenyl chain as defined above and Rc is one or more aryl radicals as defined above. The aryl part of the aralkenyl radical may be optionally substituted as described above for aryl. Part of the alkenyl chain of the aralkenyl radical may be optionally substituted as described above for an alkenylene group.

"Aralkynyl" refers to a radical of the formula -ReRc where Re is an alkynylene chain as defined above and Rc is one or more aryl radicals as defined above. The aryl part of the aralkynyl radical may be optionally substituted as described above for aryl. A portion of the alkynylene chain of the aralkynyl radical may be optionally substituted as defined above for an alkynylene chain.

"Aryloxy" refers to a radical of the formula -ORc wherein Rc is aryl as defined above. The aryl part of the aryloxy radical may be optionally substituted as described above.

"Aralkyloxy" refers to a radical of the formula -ORf where Rf is an aralkyl radical as defined above. The aralkyl part of the aryloxy group may be optionally substituted as defined above.

"Cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting exclusively of carbon and hydrogen atoms, which may include spiro or bridged ring systems having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, more preferably from five to ten carbon atoms and which is saturated or unsaturated and attached to the rest of the molecule through a single bond. For the purposes of this invention, a bridged ring system is a system in which two non-adjacent ring atoms are connected through an atom or group of atoms. Monocyclic cycloalkyl radicals include non-bridged cycloalkyl radicals, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include fused, spiro or bridged cycloalkyl radicals, for example C10 radicals such as adamantanyl (bridged) and decalinyl (condensed), and C7 radicals such as bicyclo [3.2.0] heptanyl (condensed), norbornanyl and norbornenyl (bridged) as well as substituted polycyclic radicals, for example substituted C7 radicals such as 7,7-dimethylbicyclo [2.2.1] heptanyl (bridged), and the like. Unless otherwise specifically specified herein, the term "optionally substituted cycloalkyl" is intended to include cycloalkyl radicals which are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, aryl substituted optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R -OR, -R OC (O) -R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹N (R²⁰) C (O) OR²¹, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) t R²⁰ (where t is 1 or 2), R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where t is 0, 1 or 2), -R²¹S (O) t N (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl²⁰, together with the common nitrogen to which they are both attached, can optionally form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ independently represents a direct bond or a straight or branched alkylene or alkenylene chain.

"Cycloalkylalkyl" refers to a radical of the formula -RbRg where Rb is an alkylene chain as defined above and Rg is a cycloalkyl radical as described above. The alkylene chain and cycloalkyl radical may be optionally substituted as described above.

"Cycloalkylalkenyl" refers to a radical of the formula -RdRg where Rd is an alkenylene chain as defined above and Rg is a cycloalkyl radical as described above. The alkenylene chain and the cycloalkyl radical may be optionally substituted as described above.

"Cycloalkylalkynyl" refers to a radical of the formula -ReRg where Re is an alkynylene chain as defined above and Rg is a cycloalkyl radical as described above. The alkynylene chain and the cycloalkyl radical may be optionally substituted as described above.

"Halo" refers to bromine, chlorine, fluorine or iodine.

"Haloalkyl" refers to an alkyl radical as defined above which is substituted by one or more halogen radicals as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo- 2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl radical.

"Haloalkoxy" refers to an alkoxy radical as defined above which is substituted by one or more halogen radicals as defined above, for example trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, and the like. The alkoxy part of the haloalkoxy radical may be optionally substituted as defined above for an alkoxy radical.

"Haloalkenyl" refers to an alkenyl radical as defined above which is substituted by one or more radicals as defined above. The alkenyl part of the haloalkyl radical may be optionally substituted as defined above for an alkenyl radical.

"Haloalkynyl" refers to an alkynyl radical as defined above which is substituted by one or more radicals as defined above. The alkynyl portion of the haloalkyl radical may be optionally substituted as defined above for an alkynyl radical.

"Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that contains from one to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specifically specified in this specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring which may contain spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl radical may be partially or fully saturated. Such heterocyclyl radicals include, but are not limited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, octahydro-2H-pyri 1H-pyrrolo [2,3c] pyridinyl, octahydro-1H-pyrrolo [2,3-b] pyridinyl, octahydro-1H-pyrrolo [3,4b] pyridinyl, octahydropyrrolo [3,4-c] pyrrolyl, octahydro-1H- pyrido [1,2-] pyrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thienyl [1,3] dithanyl, trithanyl, tetrahydropyranyl, thiomorpholinyl, 1-thiamorolinyl thiomorpholinyl, azetidinyl, octahydropyrrolo [3,4-c] pyrrolyl, octahydropyrrolo [3,4-b] pyrrolyl, decahydroprazino [1,2] azepinyl, azepanyl, azabicyclo [3.2.1] octyl and 2,7diazaspiro [4.4] nonanyl. Unless otherwise specifically specified in this specification, the term "optionally substituted heterocyclyl" is intended to include heterocyclyl radicals as defined above which are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl , haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkylalkyl optionally substituted

twenty 21 heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R -OR, -R OC (O) R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O)_tR²⁰ (where t is 1 or 2), R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), -R²¹S (O) t N (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl²⁰, together with the common nitrogen to which they are both attached, can optionally form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ independently represents a direct bond or a straight or branched alkylene or alkenylene chain.

"N-heterocyclyl" means a heterocyclyl radical as defined above containing at least one nitrogen and where the attachment point of the heterocyclyl radical to the rest of the molecule is via a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical may be optionally substituted as described above for heterocyclyl radicals.

"Heterocyclylalkyl" refers to a radical of the formula -RbRh where Rb is an alkylene chain as defined above and Rh is a heterocyclyl radical as described above, and if the heterocyclyl is a nitrogen containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen. The alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl radical.

"Heterocyclylalkenyl" refers to a radical of the formula -RdRh where Rd is an alkylene chain as defined above and Rh is a heterocyclyl radical as described above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkenylene chain at the nitrogen atom. The alkenyl chain of the heterocyclylalkenyl radical may be optionally substituted as described above for the alkenylene chain. The heterocyclyl portion of the heterocyclylalkenyl radical may be optionally substituted as defined above for a heterocyclyl radical.

"Heterocyclylalkynyl" refers to a radical of the formula -ReRh where Re is an alkynylene chain as defined above and Rh is a heterocyclyl radical as described above, and if the heterocyclyl is a nitrogen containing heterocyclyl, the heterocyclyl may be attached to the alkynyl radical at the nitrogen atom. The alkynylene part of the heterocyclylalkynyl radical chain may be optionally substituted as defined above for an alkynylene chain. The heterocyclyl portion of the heterocyclylalkynyl radical may be optionally substituted as defined above for a heterocyclyl radical.

"Heteroaryl" refers to a 5- to 14-membered ring system radical containing hydrogen, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. The heteroaryl radical is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl radical. For the purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ring system which may contain spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom can optionally be quaternized. For the purposes of this invention, an aromatic heteroaryl radical ring need not contain a heteroatom as long as one heteroaryl radical ring contains a heteroatom. For example, 1,2,3,4-tetrahydroisoquinolin-7-yl is considered "heteroaryl" for the purposes of this invention. In addition to polycyclic heteroaryls containing more than 14 carbon atoms, as described above in the Summary of the Invention, the "heteroaryl" radical as defined herein does not contain rings having more than 7 members and cannot contain rings in which two non-adjacent members are connected via an atom or a group of atoms (i.e. a bridged ring system). Heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl, benzo [b] [1,4 ] oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno [3,2-d] pyrimidinyl, benzotriazolyl benzo [4,6] imidazo [1,2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] -pyrimidinyl, 6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidinyl .

5,6-dihydro-benzo [h] quinazolinyl, 5,6-dihydro-benzo [h] cinnolinyl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo [3,2-c] pyridinyl, 1,2,3,4,5,6-hexahydrobenzo [d] azocin-8-yl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, 2-oxazazinyl, oxazolyl, oxiranyl, 5,6,6a, 7,8,9,10,10a-octahydrobenzo [h] quinazolinyl,

1-phenyl-1H-pyrrolyl, phenynyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo [3,4-d] pyrimidinyl, pyridinyl, pyrido [3,2d] pyrimidinyl, pyrido [3,4- d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl,

5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydro-benzo [b] oxepin-7-yl, 3,4-dihydro2H-benzo [b] [1,4] dioxepin-7-yl , 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridinyl,

6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepinyl, 5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3d] pyrimidinyl, 6,7,8, 9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidinyl, 5,6,7,8-tetrahydropyrido [4,5-c] pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, 1,2, 3,4-tetrahydroisoquinolin-7-yl, triazinyl, thieno [2,3-d] pyrimidinyl, thieno [3,2d] pyrimidinyl, thieno [2,3-c] pyridinyl and thiophenyl (i.e., Thienyl). Unless otherwise specifically specified in this specification, the term "optionally substituted heteroaryl" is intended to include heteroaryl radicals as defined above which are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkylalkyl optionally substituted 21 heteroaryl alkenyl, optionally substituted heteroaryl alkynyl, -R -OR, -R OC (O) R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O)_tR²⁰ (where t is 1 or 2), R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), -R²¹16

S (O)_tN (R²⁰)₂ (where t is 1 or 2), where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl²⁰, together with the common nitrogen to which they are both attached, can optionally form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ independently represents a direct bond or a straight or branched alkylene or alkenylene chain. "Polycyclic heteroaryl containing more than 14 ring atoms"

refers to a radical with a 15- to 20-membered ring system containing hydrogen atoms, one to fourteen carbon atoms, one to eight heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. The "polycyclic heteroaryl containing more than 14 ring atoms" radical is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms". For the purposes of this invention, the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be a bicyclic, tricyclic or tetracyclic ring system which may contain fused or spiro ring systems; and nitrogen, carbon or sulfur atoms in the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be optionally oxidized and the nitrogen atom may also be optionally quaternized. For the purposes of this invention, the aromatic ring of a "polycyclic heteroaryl containing more than 14 ring atoms" need not contain a heteroatom as long as one ring of the "polycyclic heteroaryl containing more than 14 ring atoms" contains a heteroatom. Such "polycyclic heteroaryl radicals containing more than 14 carbon atoms in the ring" include at least, but not limited to, 6,7-dihydro5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7 , 8,9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-4 -yl, 6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) dibenzo [b, f] [1,4] thiazepin-11-yl , 6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3c] pyridazine-5,1'-cyclopentane] -3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7 ] canceled, 7.2 '- [1,3] dioxolane] -3-yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6.2' [1,3] dioxolane] -3-yl, 6,7-dihydro-5H-benzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-2- yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridin-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro5Hspiro [cycloocta [b] pyridine-7 , 2 '- [1,3] dioxane] -3-yl and 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-b] pyridin-2-yl. Unless otherwise specifically specified in this specification, the term "optionally substituted polycyclic heteroaryl containing more than 14 ring carbon atoms" is intended to include "polycyclic heteroaryl ring containing more than 14 ring atoms" as defined above which are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R²¹-OR²⁰, -R²¹-OC (O) R²⁰, -R²¹N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹-OR²²-C (O) N (R²⁰) 2, R²¹-N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) t R²⁰ (where t is 1 or

2), -R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), 21 20 20

R -S (O) tN (R) 2 (where t is 1 or 2), where each R is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R²⁰, together with the common nitrogen to which they are attached, can optionally form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ independently represents a direct bond or a straight or branched alkylene or alkenylene chain.

"N-heteroaryl" means a heteroaryl radical as defined above containing at least one nitrogen and where the attachment point of the heteroaryl radical to the rest of the molecule is via a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical may be optionally substituted as described above for heteroaryl radicals.

"Polycyclic heteroaryls containing more than 14 ring atoms" refers to a radical with a 15- to 20-membered ring system containing hydrogen atoms, one to fourteen carbon atoms, one to eight heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. The "polycyclic heteroaryl containing more than 14 ring atoms" radical is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" radical. For the purposes of this invention, the "polycyclic heteroaryl containing more than 14 ring atoms" radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain fused ring systems; and nitrogen, carbon or sulfur atoms in the "polycyclic heteroaryls containing more than 14 ring atoms" radical

may be optionally oxidized; the nitrogen atom may also be optionally quaternized. For the purposes of this invention, the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" need not contain a heteroatom as long as one ring of the "polycyclic heteroaryl containing more than 14 ring atoms" contains a heteroatom. Such "polycyclic heteroaryls having more than 14 ring carbon atoms" include, but are not limited to, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2c] pyridazin-3-yl, 6,7- dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z ) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro -5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl. Unless otherwise specifically specified in this specification, the term "optionally substituted polycyclic heteroaryls containing more than 14 ring atoms" is intended to include "polycyclic heteroaryls containing more than ring atoms" radicals as defined above which are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted 21 heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R -OR, -R OC (O) R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O)_tR²⁰ (where t is 1 or 2),

-R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2),

-R²¹-S (O) t N (R²⁰) 2 (where t is 1 or 2), where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl²⁰, together with the common nitrogen to which they are both attached, can optionally form an optionally substituted N-heterocyclyl or an optionally substituted N19 heteroaryl, and each R²¹ independently represents a direct bond or a straight or branched alkylene or alkenylene chain.

"Heteroarylalkyl" refers to a radical of the formula -RbRi where Rb is an alkylene chain as defined above and R1 is a heteroaryl radical as described above. The heteroaryl portion of the heteroarylalkyl radical may be optionally substituted as defined above for heteroaryl. The alkylene chain portion of the heteroarylalkyl radical may be optionally substituted as defined above for an alkylene chain.

"Heteroarylalkenyl" refers to a radical of the formula -RdRi where Rd is an alkylene chain as defined above and R1 is a heteroaryl radical as described above. The heteroaryl portion of the heteroarylalkenyl radical may be optionally substituted as defined above for heteroaryl. A portion of the alkenylene chain of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenylene chain.

"Heteroarylalkynyl" refers to a radical of the formula -ReRi where Re is an alkynylene chain as defined above and Ri is a heteroaryl radical as defined above. The heteroaryl portion of the heteroarylalkynyl radical may be optionally substituted as defined above for heteroaryl. A portion of the alkynylene chain of the heteroarylalkynyl radical may be optionally substituted as defined above for an alkynylene chain.

"Hydroxyalkyl" refers to an alkyl radical as defined above which is substituted by one or more hydroxy (-OH) radicals.

"Hydroxyalkenyl" refers to an alkenyl radical as defined above which is substituted by one or more hydroxy (-OH) radicals.

"Hydroxyalkenyl" refers to an alkynyl radical as defined above which is substituted by one or more hydroxy (-OH) radicals. [0017] Some of the chemical groups mentioned herein may be preceded by a shorthand notation indicating the total number of carbon atoms that are in the indicated group chemical. Even if; C7-C12alkyl describes an alkyl group as defined below having a total number of 7 to 12 carbon atoms, and C4-C12cycloalkylalkyl describes a cycloalkylalkyl group as defined below with a total number of 4 to 12 carbon atoms. The total number of carbon atoms in the abbreviation does not include carbon atoms that may be present in the substituents of this group.

[0018] "Stable compound" and "stable structure" is intended to indicate a compound that is sufficiently stable to survive isolation to a useful degree of purity from the reaction mixture, and formulation into an effective therapeutic agent.

[0019] "Mammals" include humans and domestic animals such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits and the like. Preferably, for the purposes of this invention, the mammal is a human.

[0020] "Optional" or "optional" means that the event or circumstances described subsequently may or may not occur, and that this description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and non-substituted aryl radicals. When a functional group is described as "optionally substituted", and in turn, the substituents on the functional group are also "optionally substituted", and so on, for the purposes of this invention, such iterations are limited to five.

[0021] "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / coloring agent, taste improving agent, superfactant, wetting agent, dispersant, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifier, which has been approved by the United States Food and Drug Administration as being acceptable for human or pet use.

[0022] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0023] "Pharmaceutically acceptable acid addition salt" refers to those salts that retain the biological effectiveness and properties of the free bases, which are not biologically or in any other undesirable form, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane acid -1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hipuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucous acid, naphthalene acid 1,5-disulfonic acid, naphthalene -2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, ptoluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0024] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or in any other form undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine , ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzatin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0025] "Pharmaceutical composition" refers to the formulation of a compound of the invention and an agent commonly accepted in the art for delivering a biologically active compound to mammals, even humans. Such an agent includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

[0026] A "therapeutically effective amount" refers to that amount of a compound of the invention that, when administered to a mammal, preferably a human, is sufficient for effective treatment, as defined below, of an existing disease or condition of interest in a mammal, preferably a human. The amount of a compound of the invention that is a "therapeutically effective amount" will vary depending on the compound, disease or condition and their severity, and age of the mammal being treated, but can be routinely determined by a person with ordinary skill in the art having regard to his own knowledge and this disclosure.

[0027] "Treat" or "treatment" as used herein refers to the treatment of a disease or condition of interest in mammals, preferably a human, having that disease or condition of interest, and includes:

(i) preventing or constituting the disease before it occurs in mammals, in particular when such a mammal is predisposed to such a condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting its development;

(iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) stabilizing the disease or condition.

[0028] As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular ailment or condition may not have a known causative agent (so that the etiology has not yet been developed) and therefore has not yet been recognized as a disease, but only as an undesirable condition or syndrome in which more or less specific set of symptoms has been identified by doctors.

[0029] The compounds of the invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thereby result in the formation of enantiomers, diastereomers and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R) - or (S) - , or as (D) - or (L) - for amino acids. The invention is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R) - and (S) -, or (D) - and (L) isomers can be prepared using chiral synthons or chiral reagents, or separated by conventional techniques such as HPLC using a column chiral. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, these compounds include both E and Z geometric isomers. Similarly, all tautomeric forms should also be included.

[0030] "Stereoisomer" refers to a compound consisting of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers" which are two stereoisomers whose molecules are their non-overlapping mirror images.

[0031] "Tautomer" refers to the transition of a proton from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of all such compounds.

[0032] "Atropoisomers" are stereoisomers resulting from impaired rotation around single bonds, where the rotation barrier is high enough to allow isolation of conformers (Eliel, EL; Wilen, SH Stereochemistry of Organic Compounds; Wiley &amp; Sons: New York, 1994 ; Chapter 14). Atropoisomerism is important because it introduces an element of chirality in the absence of stereogenic atoms. The invention is intended to include atropisomers, for example in the case of limited rotation around single bonds originating from the core of the triazole structure, atropisomers are also possible and are also specifically included in the compounds of the invention.

[0033] The test protocol and structural diagrams used herein are a modified form

IUPAC A nomenclature system in which the compounds of the invention are referred to in this description as derivatives of the main core structure, i.e. triazole structures. For the complex chemical names used here, the substituent group is listed before the group to which it joins. For example, cyclopropylethyl includes an ethyl backbone with a cyclopropyl substituent. In chemical structural schemes, all bonds were identified, except for some carbon atoms, which were assumed to be bonded to a sufficient number of hydrogen atoms to saturate valence.

[0034] For the purposes of this invention, a representation of the bond connecting the R substituent³ to the parent triazole moiety in formula (I) as shown below:

<img file="PL2078010T3_D0002.tif" />

it is intended to include only the two regioisomers shown below, i.e. compounds of formula (Ia) and (Ib):

<img file="PL2078010T3_D0003.tif" />

<img file="PL2078010T3_D0004.tif" />

[0035] The numbering system of the ring atoms in the compounds of formula (Ia) is shown below:

<img file="PL2078010T3_D0005.tif" />

For example, a compound of formula (Ia) wherein R¹, R⁴ and R⁵ each is hydrogen, R² is 4- (2- (pyrrolidin-1-yl) -ethoxy) phenyl, and R³ is 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2 c] pyridazin-3-yl; i.e. a compound with the following formula:

<img file="PL2078010T3_D0006.tif" />

is referred to in this description 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) N³- (4- (2- (pyrolidin-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0036] The numbering system of the ring atoms in the compounds of formula (Ib) is shown below:

<img file="PL2078010T3_D0007.tif" />

Compounds of formula (Ib) are similarly named herein.

EMBODIMENTS OF THE INVENTION [0037] Of the various aspects of the compounds of formula (I) as set out above in the Summary of the Invention, certain embodiments are preferred.

[0038] Accordingly, there is one embodiment of the compounds of formula (I) as set out above in the Summary of the Invention in which the compound of formula (I) is a compound of formula (Ia):

R³ /

N-N

<img file="PL2078010T3_D0008.tif" />

(la) in which:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (= NR⁶) N (R⁶) R⁷;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl,

-R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰-C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰N (R⁶) R⁷, -R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸,

-R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸,

-R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2),

-R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

or R² is polycyclic heteroaryl having more than 14 ring carbon atoms as described above and R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

or R³ is polycyclic heteroaryl having more than 14 ring carbon atoms as described above and R² is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are attached, they form an optionally substituted Nheteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl or heteroarylalkyl¹², together with the common nitrogen, to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

[0039] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (= NR⁶) N (R⁶) R⁷;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰-C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷, together with the common nitrogen, to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted Nheterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl , optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain; and each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸.

[0040] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ each is hydrogen;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰-C (O) N (R⁶) R⁷,

-R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸,

-R⁹-N (R⁶) R⁷, -R^9-C (O) R⁸, ⁶⁾C

-R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹N (R⁶⁾C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is or 2) or 2);

-R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

and each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸.

[0041] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ each is hydrogen;

R² and R³ are, independently of each other, a polycyclic heteroaryl containing more than 14 carbon atoms in the ring selected from the group consisting of 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta 1,2d] pyrimidin-4-yl, 6,7 -dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro -5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3c] pyridazine-5,1'-cyclopentane] -3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7 ] canceled, 7.2 '- [1,3] dioxolane] -3-yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' [1,3] dioxolane] -3-yl, 6,7-dihydro-5H-benzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2- yl, 5,6,8,9-tetrahydro-spiro [cyclohepta [b] pyridin-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro-5Hspiro [cycloocta [pyridine- 7.2 '- [1,3] dioxane] -3-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸(where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2) and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2) each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted , -R¹⁰-OR⁸, -R¹⁰CN, -R ¹⁰-NO 2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and R¹⁰-C (O) N (R⁸) 2 or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain; and each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and - OR⁸.

[0042] Another embodiment is the compound of formula (Ia) as described above which is 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (5 ', 5'-dimethyl-6,8,9,10tetrahydro-5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl) -1 H-1, 2,4-triazol-3,5diaminą.

[0043] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (NR⁶) N (R⁶) R⁷;

_R2 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸,

-R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰32

CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl; each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain; each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, and an optionally substituted straight or branched alkenylene chain; and each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain.

[0044] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are hydrogen;

_R2 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸-R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸,

-R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2),

-R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and

-R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each de R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0045] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are hydrogen;

_R2 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6, 7-dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro -5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3- yl, 6,8,9,10-tetrahydro-5Hspiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7 ] canceno-72 '- [1,3] dioxolane] -3-yl, 5,7,8,9-tetrahydro-spiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3 -yl, 6,7-dihydro-5Hbenzo [2,3] thiepino [4,5c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidine -2-yl,

5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10 tetrahydro-5H-spiro [cycloocta [b] pyridine -7.2 '- [1,3] dioxane] -3-yl and 6,7-dihydro-5H35 benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O)_tR⁸(where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR^12, -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0046] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are hydrogen;

_R2 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6 , 7-dihydro-5H-benzo [2,3] azepino [4,5c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7- dihydro5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl , 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7 ] cancelene-7.2 '- [1,3] dioxolane] -3yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl , 6,7-dihydro-5H-benzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2 yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridin-7.2 '[1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxane] -3-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹S (O) t N (R⁶) R⁷ (where t is 1 or 2);

_R3 is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, 4,5-dihydro-1H-benzo [b] azepine-2 (3H) -on-8-yl, benzo [d] imidazolyl, 6,7,8,9-tetrahydro5H pyrido [3,2-d] azepin-3-yl, 6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepin-3-yl,

5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 2,3, 4,5-tetrahydrobenzo [b] oxepin-7-yl, 3,4-dihydro-2Hbenzo [b] [1,4] dioxepin-7-yl, benzo [d] oxazol-5-yl, 3,4-dihydro -2Hbenzo [b] [1,4] oxazin-7-yl, benzo [b] thiophenyl, and 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, R¹³-N (R¹²) 2, -R¹³-C (O) R¹²,

-R¹³-C (O) OR¹²,

-R¹³-C (O) N (R¹²)₂, -R¹³-C (O) N (R¹²) -R¹⁴N (R¹²) R¹³,

-R¹³-C (O) N (R¹²) -R¹⁴-OR¹²,

-R¹³-N (R¹²) C (O) OR¹²,

-R¹³-N (R¹²) C (O) R¹²,

R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each de R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0047] Another embodiment is a compound of formula (Ia) as described above, which is selected from the group consisting of:

1- (6,7-dimethoxy-quinazolin-4-yl) -N³- (5,7,8,9-tetrahydrospiro [cyclohepta [b] pirydyno6,2 '- [1,3] dioksotan] -3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6,2 '- [1,3] dioxolan] -3-yl) -1H-1,2,4-triazolo3,5-diamine;

1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5,6,8,9tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolan] -3-yl) -1H-1,2,4-triazolo3,5-diamine; and

1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5 ', 5'-dimethyl-6,8,9,109tetrahydro-5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl) -1H-1,2- , 4triazolo-3,5-diamine.

[0048] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (NR⁶) N (R⁶) R⁷;

R² is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl , optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰-C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2),

-R⁹-OR¹⁰-N (R⁶) R⁷,

-R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H,

-R⁹-OC (O) -R⁸,

-R⁹-N (R⁶) R⁷, -R⁹C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, and an optionally substituted straight or branched alkenylene chain;

each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

[0049] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

R² is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) -R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰10

C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O)_tN (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each de R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0050] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkyalkyl¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷,

-R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸,

-R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O)_tN (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroalkyl, optionally substituted heteroalkyl , -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2 or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl and optionally substituted heteroaryl R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0051] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is aryl selected from the group consisting of phenyl and 6,7,8,9-tetrahydro5Hbenzo [7] annulen-2-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkylalkyl -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²⁾R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7- dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (2} -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7dihydro-5Hbenzo [6 , 7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'cyclopentane] -3-yl, 6 , 8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxolane] -3-yl, 5 6,8,9-tetrahydrospiro [benzo [7] annulen- 7.2 '- [1,3] dioxolane] -3yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl, 6, 7dihydro-5H benzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl, 5,6,8,9tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro5H-spiro [cycloocta [b] pyridine-7 , 2 '- [1,3] dioxane] -3-yl and 6,7-dihydro-5H45 benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O)_tR⁸(where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl and optionally each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0052] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralken, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²)₂ (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7- dihydro-5Hbenzo [2,3] azepino [4,5c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro5Hbenzo [6,7 ] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'cyclopentane] -3-yl, 6 , 8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7] canceled -72 '- [1,3] dioxolane] -3yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl, 6,7-dihydro -5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl, 5,6,8,9tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro5H-spiro [cycloocta [b] pyridine-7 , 2 '- [1,3] dioxane] -3-yl and 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸,

-R⁹-N (R⁶) R⁷,

-R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0053] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, cyano, optionally substituted heterocyclyl, wherein the optionally substituted heterocyclyl is selected from the group consisting of piperidinyl, pyrrolidinyl, piperazinyl, azepanyl, [decahydopyrazino1,2 ] azepinyl, octahydropyrrolo [3,4-c] pyrrolyl, azabicyclo [3.2.1] octyl, octahydropyrrolo [3,4-b] pyrrolyl, octahydropyrrolo [3,2c] pyridinyl, 2,7-diazaspiro [4.4] nonanyl and azetidinyl, each independently optionally substituted with one or two substituents selected from the group consisting of R⁹-OR⁸,

-R⁹-N (R⁶) R⁷, -R⁹-C (O) OR⁶, -R⁹-C (O) N (R⁶) R⁷-R⁹-N (R⁶) C (O) R⁷-R⁹-N (R⁶) C (O) OR⁷, alkyl, halogen, haloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [2,3] tiepino [4 , 5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, spiro [chromeno [4,3c] pyridazine-5.1 '-cyclopentane] -3-yl and 6,7-dihydro-5Hbenzo [6,7] cyclohepta [4,5c] pyridazin-3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl , halogen and -R⁹-OR⁸.

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR8, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

and each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0054] Another embodiment is a compound of formula (Ia) as described above selected from the group consisting of:

N³- (4- (4-cykloheksanylopiperazyn-1-yl) phenyl) -1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -1H-1, 2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methyl-3-phenyl-piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro- (4- (4-piperidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (indolin-2-on-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (morpholin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-cyklopentyl2-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyckohepta [1,2-c] pyridazin-3-yl) -N³- (4- (3,5dimetylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (pyrrolidin-1-yl) piperidin-1-yl) cyanophenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (diethylamino) pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine; 1 (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (diethylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine; 1- (6,7-dihydro-5H-9-methoxybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperdin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-10-fluoro-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-yl) piperdin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-10-fluoro-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (cyclohexyl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-9-methoxybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (cyclohexyl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine; 1 (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4metylopiperydyn-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine; 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4dimetyloaminopiperydyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-chloro-4- (4pirolidyn-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-trifluorometylo4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-9,10- dimethoxy-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-9,10,11-trimethoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (5metylooktahydropirolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3pirolidyn-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3pirolidyn-1-yl-azepan-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methylpiperidine-4-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (pyrrolidinyl) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (5propyloktahydropirolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (dekahydropyrazino [1,2-a] azepin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (5cyklopentylooktahydropirolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta (1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (pyrrolidin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl) phenyl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4pirolidyn-1-yl-azepan-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1metyloktahydropirolo [3,4-b] pyrrol-5-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (Nmetylocyklopentylamino) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine; 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (dipropylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1propylooktahydro-1H-pyrrolo [3,2-c] pyridin-5-yl) phenyl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (N- methylpiperazine-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (tert-butyloksykarbonylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4 aminopiperydyn-1-ylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (5cykloheksyloktahydropirolo [3,4-c] pyrrolyl) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (piperidin-4-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidin-1ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1-4pirolidyn ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-methyl-4- (1-4pirolidyn ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4cyklopentylopiperazynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methylpiperidine-4-ylopiperazynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (7-methyl-2,7-diazaspiro [4.4] nonan-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (Nizopropylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1-3pirolidyn yloazetidinylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-methyl-4- (4- (N- methylpiperazine-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4 - ((S) -3- (pyrrolidin-1-ylmethyl) pyrrolidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pirolidynylomethlo) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- ((4aR, 8aS) -dekahydroizoquinolin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro- (4- (3pirolidyn-1-yl) pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (5metylooktahydropirolo [3,4-c] pyrrolyl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydropyrrolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-Dihydro-9-chloro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-Dihydro-9-chloro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (N-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4-iodophenyl) -1H1,2,4-triazole-3,5-diamine;

1- (spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl) -N³- (3-fluoro-4- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4pirolidyn-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4pirolidyn-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (3R) dimethylaminopyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-YIp) -N³- (3-methyl-4- (4pirolidyn-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4pirolidyn-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (3-fluoro-4- (4-Cyclohexylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (1bicyklo [2.2.1] heptan-2-yl) piperidin-4-yl-phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (1cyklopropylmetylopiperydyn-4-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4cyklopropylometylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (4- (1bicyklo [2.2.1] heptan-2-yl) piperidin-4-yl-phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0055] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heterocyclylalkenyl, -R¹³-OR¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) -R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³C (O) N (R¹²) 2 and -R¹³-N (R¹²) C (O) R¹²;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2c] pyridazin-3-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [4 , 5-c] pyridazine-3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, halogen and -R⁹-OR⁸, each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸)2,

-R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷, together with the common nitrogen, to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0056] Another embodiment is a compound of formula (Ia) as described above selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (cyclopentyl) piperazin-1-ylcarbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c) pyridazin-3-yl) -N³- (4 - ((2-pyrrolidin-1-ylethyl) aminocarbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2,2,6,6-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((2- (dimethylamino) ethyl) aminocarbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] yridazin-3-yl) -N³- (4 - ((2- (methoxy) ethyl) aminocarbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((2- (pyrrolidin-1-yl) ethyl) aminocarbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4- (pyrrolidin-1-yl) piperidin-1-yl) carbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-chloro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-10-fluoro-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-9-methoxybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2- (Nmetylocyklopentylamino) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (N-methylpiperidine-4-yl-N-methylamino) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((N-butyl-Nacetoamino) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5diaminy; 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine-3-yl) -N³- (4- (4- (piperidin-1-yl) piperidin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (piperidin-1yloprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (pyrrolidin-1-1yloprop-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (3-dimethylaminopyrrolidin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (3dietyloaminopirolidyn-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidin-1ylopiperydyn-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-methylpiperazin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-isopropylpiperazin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4cyklopentylopiperazyn-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (morpholin-4-propyl-1-enyl) phenyl) -1H-1,2, 4-triazole-3,5-diamine and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (1-methylpiperidin-3-yl-oxy) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0057] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, cyano, optionally substituted heterocyclyl, wherein optionally substituted heterocyclyl selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, azepanyl, decahydopyrazino [1,2-a ] azepinyl, octahydropyrrolo [3,4-c] pyrrolyl, azabicyclo [3.2.1] octyl, octahydropyrrolo [3,4-b] pyrrolyl, octahydropyrrolo [3,2c] pyridinyl, 2,7-diazaspiro [4.4] nonanyl and azetidinyl, each independently optionally substituted with one or two substituents selected from the group consisting of -R⁹OR⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) OR⁶, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) R⁷, -R⁹N (R⁶) C (O) OR⁷, alkyl, halogen, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-4-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1 , 2-d] pyrimidin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, halogen and -R⁹-OR^8, each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted Nheteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

and each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0058] Another embodiment is the compound of formula (Ia) as described above is selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl) -N³- (4- (4- (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl) -N³- (3-fluoro-4- (4- (diethylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidine-2-yl) -N³- (4- (N- methylpiperazine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (3-fluoro-4- (4cykloheksylopiperazynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (4- (4- (2S) bicyclo [2.2.1] heptan-2-yl) -piperazynylofenylo) -1H-1,2,4-triazole-3,5-diamine.

[0059] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heterocyclylalkenyl, -R¹³-OR¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) -R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³C (O) N (R¹²) 2 and -R¹³-N (R¹²) C (O) R¹²;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-4-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1 , 2-d] pyrimidin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, halogen and -R⁹-OR⁸.

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain; and each

R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0060] Another embodiment is a compound of formula (Ia) as described above selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl) -N³- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0061] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, cyano, and optionally substituted heterocyclyl, wherein the optionally substituted heterocyclyl is selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, azepanyl, decahydopyrazino , 2-a] azepinyl, octahydropyrrolo [3,4-c] pyrrolyl, azabicyclo [3.2.1] octyl, octahydropyrrolo [3,4-b] pyrrolyl, octahydropyrrolo [3,2c] pyridinyl, 2,7-diazaspiro [4.4] nonanyl and azetidinyl; each independently optionally substituted with one or two substituents selected from the group consisting of -R⁹OR⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) OR⁶, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) R⁷, -R⁹N (R⁶) C (O) OR⁷, alkyl, halogen, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [2,3] azepino [4,5c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepine 11-yl, 6,7-dihydro5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, and 6,7-dihydro-5H-benzo [2,3] tiepino [4,5c] pyridazine -3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, halogen and -R⁹-OR⁸.

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl and optionally each de R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0062] Another embodiment is the compound of formula (Ia) as described above is selected from the group consisting of:

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (4- (N- methylpiperazine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-cykloheksylopiperazynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1 - ((Z) dibenzo [b, f] [1,4] thiazepin-11-yl) -N³- (4- (4-N-methylpiperazinyl) phenyl) -1H1,2,4-triazole-3,5-diamine;

1 - ((Z) dibenzo [b, f] [1,4] thiazepin-11-yl) -N³- (3-fluoro-4- (4-dietyloaminopiperydyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidine-1ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1-4pirrolidyn ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1-4pirrolidyn ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidine-1ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pirrolidynylometylo) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4 - ((4aR, 8aS) dekahydroizochinolin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0063] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heterocyclylalkenyl, -R¹³-OR¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) -R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³C (O) N (R¹²) 2 and -R¹³-N (R¹²) C (O) R¹²;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [2,3] azepino [4,5c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepine 11-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5Hbenzo [2,3] tiepino [4,5c] pyridazine-3- yyl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸(where t is 1 or 2), -R^9-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2) and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl,

-R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R^7, together with the common nitrogen to which they are attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each de R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0064] Another embodiment is the compound of formula (Ia) as described above is selected from the group consisting of:

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidine-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1 - ((Z) dibenzo [b, f] [1,4] thiazepin-11-yl) -N³- (4- (2- (pyrrolidine-1-yl) ethoxy) phenyl) -1H1,2,4-triazole-3,5-diamine.

[0065] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with a substituent selected from the group consisting of optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

R³ is selected from the group consisting of 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2c] pyridazin-3-yl and 6,7-dihydro-5H-benzo [2,3] tiepino [4 5-c] pyridazin-3-yl. each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl -R⁹-OR⁸,

R⁹-OC (O) -R⁸,

-R⁹-N (R⁶) R⁷,

-R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O)_tR⁸(where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2) and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂ or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl.

[0066] Another embodiment is the compound of formula (Ia) as described above is selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((5fluoroindolin-2-one-3-yl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4-pyrrolidine-1ylopiperydynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4cyklopentylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4izopropylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (isoindolin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0067] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 means 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo , thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, R¹³-N (R¹²) R¹⁴-N (R¹²)₂, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5 Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8 , 9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2d] pyrimidin-4-yl, 6 , 7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) dibenzo [b, f] [1,4] thiazepin-11-yl, 6.7 -dihydro-5Hbenzo [6,7] cyclohepta [4,5c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3- yl, 6,8,9,10-tetrahydro-5Hspiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7] annuleno -7.2 '- [1,3] dioxolane] -3-yl, 5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6 ​​2' - [1,3] dioxolane] -3-yl, 6, 7-dihydro-5 Hbenzo [2,3] tiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-2-yl . 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b ] pyridine-7.2 '[1,3] dioxane] -3-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2) and -R⁹S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, together with the common nitrogen to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0068] Another embodiment is a compound of formula (Ia) as described above selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (pyrrolidine-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine; 1 (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- ((bicyclo [2.2.1] heptan-2-yl) amino) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole 3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7 ((bicyclo [2.2.1] heptan-2-yl) (methyl) amino) 6,7,8,9-tetrahydro-5Hbenzo [7] annulen-2-yl) -1H-1,2,4- triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-piperidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-azetidin-1-yl) 6.7.8.9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7- (R) pirrolidyn1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5- diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-diethylamine 6.7.8.9- tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7cyklopentyloamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-pyrrolidine-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7- (2- (S) metylooksykarbonylo) pyrrolidine-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4 triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7- (2- (S) carboxy) pyrrolidine-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo 3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (8dietyloaminoetylo-9-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (S) fluoropirrolidyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2- (S) metylopirrolidyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (R) hydroksypirrolidyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine;

1- (6,7-dihydro-5H-benzo [6,7) cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2- (R) metylopirrolidyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (S) hydroksypirrolidyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (R) fluoropirrolidyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7cykloheksylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7cyklopropylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-hydroksy6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (4-methylpiperazin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (tetrahydrofuran-2-ylmethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7cyklobutylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (cyclopropylmethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pirtdazyn-3-yl) -N³- (7- (2- (diethylamino) ethyl) methylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (4-pyrrolidine-1ylopiperydin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3,5 diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (4- (piperidin-1-ylmethyl) piperidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4triazolo- 3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2- (dimethylamino) ethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (carboxymethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3,5-diamine.

[0069] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkenyl substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²)₂, -R¹³-N (R¹²) R14-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰10

C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR8 (where p is 0, 1 or 2), and -R⁹-S (O)_tN (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each de R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0070] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, 4,5-dihydro-1H-benzo [b] azepine-2 (3H) -on-8-yl, benzo [d] imidazolyl, 6,7,8,9-tetrahydro5H pyrido [3,2-d] azepin-3-yl, 6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepin-3-yl,

5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 2,3, 4,5-tetrahydrobenzo [b] oxepin-7-yl, 3,4-dihydro-2Hbenzo [b] [1,4] dioxepin-7-yl, benzo [d] oxazol-5-yl, 3,4-dihydro -2H69 benzo [b] [1,4] oxazin-7-yl, benzo [b] thiophenyl, and 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R13-N (R¹²)₂, -R¹³-C (O) R¹²,

-R¹³-C (O) OR^12,

-R¹³-C (O) N (R¹²)₂,

-R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³,

-R¹³-C (O) N (R¹²) -R¹⁴-OR¹²,

-R¹³-N (R¹²) C (O) OR¹²,

R¹³-N (R¹²) C (O) R¹²,

-R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²)₂(where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7- dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7dihydro-5Hbenzo [6 , 7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'cyclopentane] -3-yl, 6 , 8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7] annulen-7,2 '- [1,3] dioxolan] -3-yl,

5,6,8,9-tetrahydrospiro [benzo [7] annulene-7,2 '- [1,3] dioxolane] -3-yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6 ​​2' - [1,3] dioxolane] -3-yl, 6,7-dihydro-5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [ 6,7] cyclohepta [1,2d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 6 , 8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxane] -3-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR8, -R¹⁰-CN, -R¹⁰-WELL², -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0071] Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

R² is selected from the group consisting of pyridinyl and pyrimidinyl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl , optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5 Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8 , 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7 -dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7dihydro-5Hbenzo [ 6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'cyclopentane] -3-yl, 6 , 8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7] annulen-7,2 '- [1,3] dioxolan] -3-yl,

5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6.2 '- [1,3] dioxolane] -3-yl, 6,7-dihydro5H-benzo [2,3] tiepino [4,5 -c] pyridazin-3-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7 , 2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl and 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸-R ⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-WELL₂, -R¹⁰72

N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each de R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0072] Another embodiment is the compound of formula (Ia) as described above is selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) pyridin-3-yl) o-1H-1,2,4-triazol-3,5diaminy; 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4-cyclopentyl-1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (6 aminopirydyn-3-ylo) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-aminophenyl) pyridine-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-cyanophenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6 (benzo [d] [1,3] dioxol-6-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3metylosulfonamidylofenylo) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (2dietyloaminometylo) pyrrolidine-1-yl-pyridin-3-yl) -1H - 1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3dietyloaminopirrolidyn-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4- (N- methylpiperazine-4-yl) piperidin-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazolo-3,5-diamine ;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (pyrrolidine-1-yl) piperidin-1-yl) -5-methylpyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-piperidin-1ylo- (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (bicyclo [2.2.1] heptan-2-yl) -1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5diaminy ;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4- (pyrrolidine-1-yl) piperidin-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-piperidin-1-yl) -propanylopirydyn-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4- (piperidin-1-yl) piperidin-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4dimetyloaminopiperydyn-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazole-3,5diaminy;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (4-pyrrolidine-1ylopiperydyn-1-yl) pyrimidin-5-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (4- (piperidin-1-ylmethyl) piperidin-1-yl) pyrimidin-5-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6 - ((4-piperidin-1-ylpiperidin-1-yl) carbonyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (4cyklopropylometylopiperazyn-1-yl) pyridin-5-yl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (3- (S) -methyl-4cyklopropylometylopiperazyn-1-yl) piridyn-5-yl) -1H-1,2,4-triazole-3,5-diamine. Another embodiment is a compound of formula (Ia) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

R² is selected from the group consisting of 4,5-dihydro-1H-benzo [bj] azepin-2 (3H) -on-8-yl, benzo [d] imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido [ 3,2-d] azepin-3-yl, 6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepin-3-yl, 5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl,

5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 2,3,4,5-tetrahydrobenzo [b] oxepin-7-yl, 3,4-dihydro- 2H-benzo [b] [1,4] dioxepin-7-yl, benzo [d] oxazol-5-yl, 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl, benzo [b] thiophenyl, and 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7- dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,775 dihydro-5H benzo [6 , 7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'cyclopentane] -3-yl, 6 , 8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7] annulene -7.2 '- [1,3] dioxolane] -3yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl, 6 , 76.7-dihydro-5H5,6,8,9-tetrahydrospiro [

6,8,9,10-tetrahydro-5H6,7-dihydro-5Hdihydro-5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, benzo [6,7] cyclohepta [1,2- d] pyrimidin-2-yl, cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane ] -3-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl , alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸-R ⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl and optionally each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each de R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0073] Another embodiment is a compound of formula (Ia) as described above selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one-8-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (dimethylaminomethyl) -1H-benzo [d] imidazol-5-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-cyklopentylo6,7,8,9-tetrahydro-5H-pyrido [3,2-d] azepin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4-methylpiperazin-1-yl) carbonyl-5,6,7,8-tetrahydroquinolin-3-yl) -1H-1,2,4-triazolo-3,5-diamine, compound # 31, 1H-1, 2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2,3,4,5-tetrahydrobenzo [b] oxepin-7-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3,4-dihydro-2H-benzo [b] [1,4] dioxepin-7-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (2- (pyrrolidine-1-ylmethyl) benzo [d] oxazol-5-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2-dimethylamino) - (3,4-dihydro-2H-benzo [b] [1,4] oksazin-7-yl)) - 1H-1,2,4-triazolo3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (4- (2-dimethylamino) - (3,4-dihydro-2H-benzo [b] [1,4] oksazin-7-yl)) - 1H-1,2,4-triazolo3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (2- (1- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) oxomethyl) benzo [b] thiophen-5-yl) -1H-1,2,4-triazolo-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-cyclopentyl6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-pyrrolidine-1-yl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N 3 (2-cyklopentylo1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (pyrrolidine-1-yl) -5,6,7,8-tetrahydroquinolin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-cyklopentylo5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((S) -7- (pirrolidyn1-yl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl) -1H-1,2,4-triazole-3,5diaminy ;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (1,2,3,4- tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5diaminy; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (cyclopropylmethyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5diaminy.

[0074] Another embodiment of the compounds of formula (I) is wherein the compound of formula (I) is a compound of formula (Ib):

R^s

NN

<img file="PL2078010T3_D0009.tif" />

wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (= NR⁶) N (R⁶) R⁷;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰-C (O) N (R⁶) R⁷,

-R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷,

-R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

or R² is polycyclic heteroaryl containing more than 14 ring carbon atoms as described above and R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R12) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

or R³ is polycyclic heteroaryl containing more than 14 ring carbon atoms as described above and R² is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,

-R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, a substituted straight or branched alkenylene chain, and a substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, and an optionally substituted straight or branched alkenylene chain;

each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

[0075] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ -C (= NR⁶) N (R⁶) R⁷;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR^8, is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷,

-R⁹-OR¹⁰-C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p

-R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹N (R⁶) C (O) R^8, -R^N-9(R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, a substituted straight or branched alkenylene chain, and a substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain; and each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸.

[0076] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ all are hydrogen;

R² and R³ are independently of one another a polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸,

-R⁹-OR¹⁰-OR⁸,

R¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR⁹-OR¹⁰-S (O) pR⁸ (where p -R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-OR¹⁰-C (O) N (R⁶) R⁷,

-R⁹-OR¹⁰-N (R⁶) R⁷, means 0, 1 or 2),

R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R6 and R7 together with the common nitrogen to which they are both attached form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

and each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸.

[0077] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are hydrogen;

R² and R³ each independently is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7, 8,9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6, 7-dihydro-5Hbenzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7dihydro-5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5Hbenzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5.1'83 cyclopentane] -3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7 ] annuleno-7,2 '- [1,3] dioxolan] -3-yl,

5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6.2 '- [1,3] dioxolane] -3-yl, 6,7-dihydro5H-benzo [2,3] tiepino [4,5 -c] pyridazin-3-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7 , 2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl and 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2) and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2) each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-WELL₂, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁰ is an optionally substituted straight or branched alkylene chain.

[0078] Another embodiment is a compound of formula (Ib) as described above which is 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6,2 '[1,3] dioxolan] -3-yl) -1H-1,2,4-triazole-3,5diaminą.

[0079] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (= NR⁶) N (R⁶) R⁷;

_R2 is polycyclic heteroaryl containing more than 14 carbon ring atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl , optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, a substituted straight or branched alkenylene chain, and a substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, and an optionally substituted straight or branched alkenylene chain; and each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

[0080] Another embodiment is a compound of formula (Ib) as described above wherein: R¹, R⁴ and R⁵ are hydrogen;

_R2 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷,

-R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸,

-R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, t

or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo-thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, together with the common nitrogen to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0081] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are hydrogen;

_R2 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8, 9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl,

6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) dibenzo [b, f] [1,4] thiazepin-11-yl, 6, 7-dihydro-5H benzo [6,7] cyclohepta [4,5c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl , spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl, 6,8,9,10-tetrahydro-5Hspiro [cycloocta [b] pyridine-7,2 '- [1 , 3] dioxolane] -3-yl, 5,6,8,9tetrahydrospiro [benzo [7] annulen-7,2 '- [1,3] dioxolane] -3-yl, 5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6,2 '- [1,3] dioxolan] -3-yl, 6,7-dihydro5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,288

d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7.2 '[1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro- 5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxane] -3-yl and 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridine- 2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸-R ⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹S (O) t N (R⁶) R⁷ (where t is 1 or 2);

R³ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-WELL₂, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, together with the common nitrogen to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0082] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, C (O) R⁸, -C (O) N (R⁶) R⁷ and -C (= NR⁶) N (R⁶) R⁷;

R² is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³90

N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O)_tR¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸, 10

-R⁹-OR¹⁰67

C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹⁰-OR⁸, -R¹⁰CN, -R¹⁰-NO2, -R10-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, a substituted straight or branched alkenylene chain, and a substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, and an optionally substituted straight or branched alkenylene chain;

each R¹⁴ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain;

[0083] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

R² is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-O92

R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰C (O) N (R 6) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R 6) R⁷, R⁹-OR¹⁰-C (NR11) N (R11) H, -R⁹-OC (O) -R⁸, -R⁹-N (R 6) R⁷,

-R⁹-C (O) R⁸, -R⁹-C (O) OR⁸,

-R⁹-C (O) N (R 6) R⁷,

-R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R6) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰10

N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

and each R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0084] Another embodiment is a compound of formula (1b) as described above wherein: R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkyalkyl¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 ring carbon atoms, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OR¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰CN,

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, R⁹-OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, 94

R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O)_tR⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0 or 2), and -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-WELL₂, -R¹⁰10

N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0085] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is aryl selected from the group consisting of phenyl and 6,7,8,9-tetrahydro5Hbenzo [7] annulen-2-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkylalkyl R¹³-OR¹², -R¹³OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 carbon atoms consisting of 6,7-dihydro-5H 6,7,8,9-tetrahydro6,7-dihydro6,7-dihydro-5H ring selected from the group consisting of benzo [6,7 ] cyclohepta [1,2-c] pyridazin-3-yl, 5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidine -4-yl, benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro- 5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl , 6,8, 9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '[1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7 ] annulene-7.2 '- [1,3] dioxolane] -3yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl , 6,7-dihydro-5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl . 5,6,8,9tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 6,8,9,10-tetrahydro5H-spiro [cycloocta [b] pyridine-7 , 2 '- [1,3] dioxane] -3-yl and 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O)_tR⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0086] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralken, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5 Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8 , 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7 -dihydro-5H-benzo [2,3] azepino [4,5c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro- 5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl, Tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9tetrahydrospiro [benzo [7] annulen-7 , 2 '- [1,3] dioxolane] -3-yl, 5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl, 6,7 -dihydro-5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] 3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxane] -3-yl and 6.7dihydro-5H-benzo [6.7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹C (O) R⁸-R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸)₂, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted Nheteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl and optionally substituted heteroaryl R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0087] Another embodiment is a compound of formula (Ib) as described above selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4- (indoline-2-on-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4- (morpholin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4- (3,5dimetylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N⁵- (4- (N- methylpiperazine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((5fluoroindolino-2-on-3-yl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine-3-yl) -N⁵- (4- (4-pirrolidyn1-ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((4-pyrrolidine-1ylopiperydynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((4cyklopentylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((4izopropylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-Nmetylopiperyd-4-ylopiperazynyl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (7-methyl-2,7-diazaspiro [4.4] nonan-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (1-3pirrolidyn yloazetydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-methyl-4- (4- (N- methylpiperazine-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N⁵- (4- (4-pyrrolidin-1ylopiperydynylo) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl-N⁵- (3-fluoro- (4- (3pirrolidyn-1-yl) pyrrolidine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4cyklopropylometylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine.

[0088] Another embodiment is a compound of formula (Ib) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 means 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo , thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²)₂, 100

R¹³-N (R¹²) R¹⁴-N (R¹²)₂,

-R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³,

R¹³-N (R¹²)₂, -R¹³-C (O) R¹²,

-R¹³-C (O) OR¹²,

-R¹³-C (O) N (R¹²)₂,

R¹³-N (R¹²) C (O) R¹²,

-R¹³-C (O) N (R¹²) -R¹⁴-OR¹²,

-R¹³-N (R¹²) C (O) OR¹²,

-R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5 Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8 , 9-tetrahydro5H-cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro5Hbenzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl, 6,7 -dihydro-5H-benzo [2,3] azepino [4,5c] pyridazin-3-yl, (Z) -dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro- 5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl, Tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxolane] -3-yl, 5,6,8,9tetrahydrospiro [benzo [7] annulen-7 , 2 '- [1,3] dioxolane] -3-yl, 5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl, 6,7 -dihydro-5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] 3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxane] -3-yl and 6.7dihydro-5H-benzo [6.7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹C (O) R⁸-R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-WELL₂, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted

101 cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common m nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0089] Another embodiment is a compound of formula (1b) as described above selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵(7 ((bicyclo [2.2.1] heptan-2-yl) (methyl) amino) -6,7,8,9-tetrahydro-5H-benzo [7] annulen2-yl) -1H-1,2,4 triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1-2-c] pyridazin-3-yl) -N '- (7- (S) -pirrolidyn1-yl-6,7, 8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine.

[0090] Another embodiment is a compound of formula (1b) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkenyl substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally

102 substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴-N (R¹²) 2, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³C (O) N (R¹²) 2, -R¹³-C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³N (R¹²) C (O) OR¹², -R¹³-N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O) pR¹² (where p is 0, 1 or 2), and R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is polycyclic heteroaryl containing more than 14 carbon atoms in the ring, optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R9-OR⁸, -R⁹-OR¹⁰-OR⁸, -R⁹-OR¹⁰-OR¹⁰-OR⁸, -R⁹-OR¹⁰-CN, -R⁹-OR¹⁰-C (O) OR⁸, -R⁹-OR¹⁰C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R6) R7, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷,

-R⁹-N (R⁶) C (O) OR¹²,

-R⁹-N (R⁶) C (O) R⁸,

-R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O)_tN (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-WELL₂, -R¹⁰10

N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

103 each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR⁸;

each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain.

[0091] Another embodiment is a compound of formula (Ib) as described above wherein:

R¹, R⁴ and R⁵ are each independently hydrogen;

_R2 is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, 4,5-dihydro-1H-benzo [b] azepine-2 (H) -on-8-yl, benzo [d] imidazolyl, 6,7,8,9-tetrahydro5H pyrido [3,2-d] azepin-3-yl, 6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepin-3-yl,

5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 2,3, 4,5-tetrahydrobenzo [b] oxepin-7-yl, 3,4-dihydro-2Hbenzo [b] [1,4] dioxepin-7-yl, benzo [d] oxazol-5-yl, 3,4-dihydro -2Hbenzo [b] [1,4] oxazin-7-yl, benzo [b] thiophenyl, and 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, -R¹³-OR¹², -R¹³-OC (O) -R¹², -R¹³-OR¹⁴-N (R¹²) 2, -R¹³-N (R¹²) R¹⁴N (R¹²)₂, -R¹³-N (R¹²) 2, -R¹³-C (O) R¹², -R¹³-C (O) OR¹², -R¹³-C (O) N (R¹²) 2, -R¹³C (O) N (R¹²) -R¹⁴-N (R¹²) R¹³, -R¹³-C (O) N (R¹²) -R¹⁴-OR¹², -R¹³-N (R¹²) C (O) OR¹², -R¹³N (R¹²) C (O) R¹², -R¹³-N (R¹²) S (O) t R¹² (where t is 1 or 2), -R¹³-S (O) t¹² (where t is 1 or 2), -R¹³-S (O)_pR¹² (where p is 0, 1 or 2), and -R¹³-S (O) t N (R¹²) 2 (where t is 1 or 2);

_R3 is a polycyclic heteroaryl containing more than 14 ring carbon atoms selected from the group consisting of 6,7-dihydro-5H104 benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8 , 9-tetrahydro-5H cyclohepta [4,5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2 -d] pyrimidin-4 -yl, 6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) dibenzo [b, f] [1,4] thiazepin-11- yl, 6,7-dihydro-5Hbenzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3- yl, 6,8, 9,10-tetrahydro-5Hspiro [cycloocta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl, 5,6,8,9-tetrahydrospiro [benzo [7] canceled -7.2 '- [1,3] dioxolane] -3-yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6,2' - [1,3] dioxolane] -3-yl, 6 , 7-dihydro5Hbenzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridin-7,2 '- [1,3] dioxolane] 3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b ] pyridine-7.2 '- [1,3] dioxane] -3-yl and

6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl, each optionally substituted with one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halogen, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-OC (O) -R⁸, -R⁹-N (R 6) R⁷, -R⁹C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹-C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR¹², -R⁹-N (R⁶) C (O) R⁸, -R⁹N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹S (O) pR⁸ (where p is 0, 1 or 2), -R⁹-S (O) t N (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl heteroarylalkyl, -R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2, or each R⁶ and R⁷ together with the common nitrogen to which they are both attached, they form an optionally substituted Nheteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaryl;

each R⁹ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;

each R¹⁰ is an optionally substituted straight or branched alkylene chain;

105 each R¹² is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl¹², together with the common nitrogen, to which both are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;

each R¹³ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R¹⁴ is an optionally substituted straight or branched alkylene chain;

[0092] Another embodiment is the compound of formula (Ib) as described above is selected from the group consisting of:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (6- (4- (pyrrolidine-1-yl) piperidin-1-yl) -5-methylpyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4- (3,5dimetylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (1,2,3,4- tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine; and

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (2- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5diaminy.

[0093] Of the heteroaryls for R² and R³, preferred embodiments are selected from the group consisting of pyridinyl, pyrimidinyl, 4,5-dihydro-1H-benzo [b] azepine-2 (3H) -on-8-yl, benzo [d] imidazolyl, 6,7,8 , 9-tetrahydro-5H-pyrido [3,2-d] azepin-3-yl, 6,7,8,9-tetrahydro5H-pyrido [3,2-c] azepin-3-yl, 5,6,7 , 8-tetrahydro-1,6-naphthyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 2,3,4,5-tetrahydrobenzo [b ] oxepin-7-yl, 3,4-dihydro-2H-benzo [b] [1,4] dioxepin-7-yl, benzo [d] oxazol-5-yl, 3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl, benzo [b] thiophenyl, thieno [3,2-d] pyrimidinyl and 6,7,8,9-tetrahydro-5H -cyclohepta [b] pyridin-3-yl, each optionally substituted as described herein.

[0094] Of the polycyclic heteroaryls having more than 14 ring carbon atoms for R² and R³preferred embodiments are selected from the group consisting of 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl, 6,7,8,9-tetrahydro-5Hcyclohepta [4, 5] thieno [2,3-d] pyrimidin-4-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-4-yl, 6,7-dihydro-5H- benzo [2,3] azepino [4,5-c] pyridazin-3-yl, (Z) dibenzo [b, f] [1,4] thiazepin-11-yl, 6,7-dihydro-5H-benzo [ 6,7] cyclohepta [4,5-c] pyridazin-2-yl, 6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl, spiro [chromeno [4, 3106

c] pyridazine-5,1'-cyclopentane] -3-yl, 6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine 7.2 '- [1,3] dioxolane] -3-yl , 5,6,8,9-tetrahydrospiro [benzo [7] annulene-7,2 '- [1,3] dioxolane] -3yl, 5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine-6, 2 '- [1,3] dioxolane] -3-yl, 6,7-dihydro5H-benzo [2,3] thiepino [4,5-c] pyridazin-3-yl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2d] pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl,

6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7.2 '- [1,3] dioxane] -3-yl and 6,7-dihydro5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl.

[0095] In another embodiment of the invention, the compounds are according to formula (Ia1):

<img file="PL2078010T3_D0010.tif" />

where:

U is N or CR²⁵;

V and W are each independently selected from N and CH, wherein N 1 triazole can attach to C with V, W or a represented CH in the ring containing V and W;

X, Y and Z are each independently selected from C (R²⁶) 2, NR, O and S; as long as there are no adjacent heteroatoms in the X, Y, Z atomic chain;

each of R²⁵, R²⁶, R³⁰, R³⁵, and R⁴⁰ is selected from the group consisting of hydrogen, cyano, nitro, halogen, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -R⁹-OR⁸, -R⁹-O26

R¹⁰-OR⁸,

-R⁹-OR¹⁰-OR¹⁰-OR⁸,

-R⁹-OR¹⁰CN,

C (O) N (R⁶) R⁷, -R⁹-OR¹⁰-S (O) pR⁸ (where p is 0, 1 or 2),

-R⁹-OR¹⁰-C (O) OR⁸,

-R⁹-OR¹⁰-R⁹-OR¹⁰-N (R⁶) R⁷, -R⁹OR¹⁰-C (NR¹¹) N (R¹¹) H, -R⁹-OC (O) -R⁸, -R⁹-N (R⁶) R⁷, -R⁹-C (O) R⁸, -R⁹-C (O) OR⁸, -R⁹C (O) N (R⁶) R⁷, -R⁹-N (R⁶) C (O) OR⁸,

-R⁹-N (R⁶) C (O) R⁸, -R⁹-N (R⁶) S (O) t R⁸ (where t is 1 or 2), -R⁹-S (O) t⁸ (where t is 1 or 2), -R⁹-S (O) pR⁸ (where p is 0, 1 or 2), and -R⁹-S (O)_tN (R⁶) R⁷ (where t is 1 or 2);

each R⁶ and R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted

107 heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, - R¹⁰-OR⁸, -R¹⁰-CN, -R¹⁰-NO2, -R¹⁰-N (R⁸) 2, -R¹⁰-C (O) OR⁸ and -R¹⁰-C (O) N (R⁸) 2 or each R⁶ and R⁷, together with the common nitrogen, to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R⁸ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkinyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R⁹ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, a substituted straight or branched alkenylene chain, and a substituted straight or branched alkynylene chain;

each R¹⁰ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, and an optionally substituted straight or branched alkynylene chain;

each R¹¹ is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and -OR8^; two R²⁶ they can form oxo or thioxo on the same carbon;

R³⁰ and R³⁵ they may combine together with the atoms to which they are attached to form an optionally substituted C 3-5 alkylene in which one or two of the alkylene carbons is optionally replaced by O, S (O) 0-2 or N (R²⁶).

[0096] Among the various aspects of the pharmaceutical compositions of the invention, comprising a pharmaceutically acceptable excipient and a compound of formula (I) as outlined above in the Summary of the Invention, certain embodiments are preferred.

[0097] One embodiment of these pharmaceutical compositions is one wherein the compound of formula (I) is selected therein from any embodiment of the compound of formula (Ia) as defined above, or from any combination of embodiments of the compound of formula (Ia), as defined above, or the compound of formula (I) is selected therein from any embodiment of the compound of formula (Ib) as defined above, or from any combination of embodiments of the compound of formula (Ib) as defined above.

108 [0098] Among the various aspects of the compounds of formula (I), certain embodiments are preferred for use in treating a disease or condition associated with Axl activity in a mammal.

[0099] One embodiment of such uses is the use in which the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease, vascular damage, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, premature retinopathy, kidney disease , degenerative arthritis and cataracts.

[0100] One embodiment of these uses is a use in which the manifestation of the disease or condition is solid tumor formation in said mammal.

[0101] One embodiment of these uses is the use wherein the disease or condition is selected from the group consisting of breast cancer, kidney cancer, endometrial cancer, ovarian cancer, thyroid cancer, non-small cell lung cancer and iris melanoma.

[0102] One embodiment of these uses is a use in which the manifestation of the disease or condition is the formation of a liquid tumor in that mammal.

[0103] One embodiment of these methods is a method wherein the disease or condition is myeloid leukemia or lymphoma.

[0104] One embodiment of these uses is a use wherein the disease or condition is endometriosis.

[0105] One embodiment of these uses is the use in which the compounds of formula (I) used herein are selected from any embodiment of a compound of formula (Ia) as defined above or from any combination of embodiments of a compound of formula (Ia) as defined above or the compound of formula (I) therein is selected from any embodiment of the compound of formula (Ib) as defined above or from any combination of embodiments of the compound of formula (Ib) as defined above.

[0106] Another embodiment of the invention are those pharmaceutical compositions of the invention as defined above in the Summary of the Invention for use in treating a disease or condition associated with Axl activity in which the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease / vascular injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis, visual impairment due to macular degeneration, diabetic retinopathy or retinopathy of prematurity, kidney disease (including but not limited to glomerulonephritis, diabetic nephropathy and renal transplant rejection), degenerative arthritis and cataracts.

[0107] Another embodiment of the invention are those pharmaceutical compositions of the invention, as defined above in the Summary of the Invention, for use in treating a disease or condition associated with Axl activity in which the disease or condition is selected from the group consisting of breast cancer, kidney cancer , endometrial cancer, ovarian cancer, thyroid cancer, non-small cell lung cancer and iris melanoma.

109 [0108] Another embodiment of the invention are those pharmaceutical compositions of the invention as defined above in the Summary of the Invention for use in treating a disease or condition associated with Axl activity in which the disease or condition is endometriosis.

[0109] Particular embodiments of the invention are described in more detail in the following sections.

APPLICATION AND STUDY OF COMPOUNDS ACCORDING TO THE INVENTION [0110] Oncogenic RTK, Axl, has recently been identified using a retrovirus-based functional genetic screening protocol as a regulator of haptotactic migration, which is a key event in angiogenesis. Inhibition of Axl by RNAi-mediated silencing blocked endothelial cell migration, proliferation and tube formation in vitro. These observations, which were disclosed at the General Assembly of the American Cancer Research Association, 16-20. April, 2005, Anaheim, California, and at the 7th Annual Symposium on Anti-Angiogenic Agents, 10-13. February 2005, San Diego, California; (Requirement for The Receptor Tyrosine Kinase Axl in Angiogenesis and Tumor Growth, Holland, SJ Powell, MJ, Franci, C., Chan, E., Friera, AM, Atchison, R., Xu, W., McLaughlin, J., Swift, SE, Pali, E., Yam, G., Wong, S ., Xu, X., Hu, Y., Lasaga, J., Shen, M., Yu, S., Daniel, R., Hitoshi, Y., Bogenberger, J., Nor, JE, Payan, DG and Lorens, JB) were confirmed by an in vivo study which showed that stable, shRNAi-mediated Axl silencing impaired the formation of functional human blood vessels in a mouse model of human angiogenesis. These observations were published in a peer-reviewed journal (Holland SJ, Powell MJ, Franci C, Chan EW, Friera AM, Atchison RE, McLaughlin J, Swift SE, Pali ES, Yam g, Wong S, Lasaga J, Shen MR, Yu S, Xu W, Hitoshi Y, Bogenberger J, Nor JE, Payan DG, Lorens JB. "Multiple roles for the receptor tyrosine kinase axl in tumor formation." Cancer Res. (2005) Vol 65 pp 9294-303. These observations were also disclosed in the US Patent Application Published 2005/0118604 and European Patent Application 1 563 094, the disclosures of which are incorporated in their entirety by reference. Thus, Axl signaling affects many of the functions required for in vitro neovascularization and regulates angiogenesis in vivo. The regulation of these proangiogenic processes required the catalytic activity of Axl. Thus, Axl-mediated angiogenic stimulation would be sensitive to modulation by a small molecule inhibitor of Axl catalytic activity.

[0111] Accordingly, the compounds of the invention are small molecule inhibitors of Axl catalytic activity and are therefore useful in the treatment of diseases and conditions that are associated with Axl catalytic activity, including those diseases and conditions that are characterized by angiogenesis and / or cell proliferation. In particular, the compounds of the invention and the pharmaceutical compositions of the invention are useful in the treatment of diseases and conditions that are alleviated by modulation of Axl activity. For the purposes of this invention, diseases and conditions that are alleviated by "modulation of Axl activity" include diseases and conditions that are alleviated by a decrease in Axl activity and diseases and conditions that are alleviated

110 mitigated by an increase in Axl activity. Preferably such diseases and conditions are alleviated by a decrease in Axl activity. Diseases and conditions that are alleviated by modulation of Axl activity include, but are not limited to, solid tumors, including but not limited to breast, kidney, endometrial, ovarian, thyroid and non-small cell lung cancer, melanoma, prostate cancer, sarcoma , stomach cancer and iris melanoma; liquid tumors, including but not limited to leukemia (especially myeloid leukemia) and lymphomas; endometriosis, vascular disease / vascular injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular degeneration, diabetic retinopathy and retinopathy of prematurity; kidney disease (including, but not limited to, glomerulonephritis, diabetic nephropathy, and renal transplant rejection), rheumatoid arthritis; degenerative arthritis, osteoporosis and cataracts.

[0112] In addition to the above, the compounds of the invention are useful in the treatment of diseases and conditions that are affected by the following biological processes: invasion, migration, metastasis or drug resistance as manifested in cancer; stem cell biology as manifested in cancer; invasion, migration, adhesion or angiogenesis as manifested in endometriosis; vascular remodeling as manifested in cardiovascular disease, hypertension or vascular injury; bone homeostasis, as manifested in osteoporosis or degenerative arthritis; viral infection as manifested, for example, in Ebola virus infection; or differentiation as manifested in obesity. The compounds of the invention may also be used to modulate inflammatory processes by treating sepsis, acting as vaccine adjuvants, and / or enhancing the immune response in immunocompromised patients.

[0113] The following animal models provide guidance to a person of ordinary skill in the art in testing compounds of the invention for their use in the treatment of an indicated disease or condition.

[0114] Compounds of the invention can be tested for their use in the treatment of leukemia and lymphoma by testing compounds in xenograft on a SCID mouse model using human Axl-expressing cancer cell lines including, but not limited to HeLa, MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299, ACHN, A498 and Caki-1.

[0115] The compounds of the invention may be tested for their use in the treatment of xenograft leukemias on a mouse SCID or nu / nu model using human Axl-expressing leukemia AML and CML cell lines.

[0116] The compounds of the invention can be tested for their use in the treatment of endometriosis by using a syngeneic model of mouse endometriosis (see

Somigliana, E. et al., "Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis", Hum. Reprod. (1999), Vol. 14, NO. 12

111 pp. 2944-50). The compounds can also be tested for their use in the treatment of endometriosis by using a rat model of endometriosis (see Lebovic, DI et al., "Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis", Fertil. Steril. (2004), 82 Suppl 3, pp. 1008-13).

[0117] Compounds of the invention may be tested for their use in the treatment of restenosis using a rat carotid artery model after balloon trauma (see Kim, DW et al., "Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model ", Circulation (2004), Vol. 109, No. 12, pp. 1558-63, Epub 2004 Mar 8).

[0118] The compounds of the invention can also be tested for their use in the treatment of restenosis by the application of percutaneous coronary angioplasty on an apoE deficient mouse model (see von der Thusen, JH et al., "Adenoviral transfer of endothelial nitric oxide synthase attenuates lesion formation in a novel murine model of postangioplasty restenosis ", Arterioscler. Thromb. Vasc. Biol. (2004), Vol. 24, No. 2, pp. 357-62).

[0119] The compounds of the invention can be tested for their use in the treatment of atherosclerosis / thrombosis in an ApoE deficient mouse model (see Nakashima, Y. et al., "ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree ", Arterioscler. Thromb. (1994), Vol. 14, No. 1, pp. 133-40).

[0120] The compounds of the invention may also be tested for their use in the treatment of thrombosis using a collagen-epinephrine induced pulmonary thrombosis model and a stasis-induced venous thrombosis model (see Angelillo-Scherrer A. et al., "Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy ", J Clin Invest. (2005) Vol 115 pp237-46).

[0121] The compounds of the invention can be tested for their use in the treatment of psoriasis by using the mouse SCID model or the human psoriasis skin model (see Nickoloff, BJ et al., "Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model ", Am. J. Pathol. (1995), Vol. 146, No. 3, pp. 580-8).

[0122] The compounds of the invention can be tested for their use in the treatment of age-related macular degeneration or diabetic retinopathy by using a rat corneal angiogenesis model (see Sarayba MA, Li L, Tungsiripat T, Liu NH, Sweet PM, Patel AJ, Osann KE, Chittiboyina A, Benson SC, Pershadsingh HA, Chuck RS. Inhibition of corneal neovascularization of the cornea by a peroxisome proliferatoractivated receptor gamma ligand Exp Eye Res. 2005 Mar; 80 (3): 435-42) or a laser-induced mouse choroid neovascularization model (see Bora, PS, et al., "Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration", Proc. Natl. Acad. Sci. USA (2003), Vol. 100, No. 5, pp. 2679-84, Epub 2003 Feb 14).

112 [0123] The compounds of the invention can be tested for their use in the treatment of retinopathy of prematurity in a mouse model of premature retinopathy (see Smith, LE et al., "Oxygen-induced retinopathy in the mouse", Invest. Ophthalmol. Vis. Sci. ( 1994), Vol. 35, No. 1, pp. 101-11).

[0124] The compounds of the invention may be tested for their use in the treatment of glomerulonephritis or diabetic nephropathy in a rat proliferative model of the experimental anti-Thy1.1 induced glomerulonephritis (see Smith, LE et al. Cited above).

[0125] The compounds of the invention can be tested for their use in the treatment of renal transplant rejection by using a rat model of chronic renal transplant rejection (see Yin, JL et al., "Expression of growth arrest-specific gene 6 and its receptors in a rat model of chronic renal transplant rejection ", Transplantation (2002), Vol. 73, No. 4, pp. 657-60).

[0126] The compounds of the invention can be tested for their use in the treatment of rheumatoid arthritis by using the CAIA mouse model (see Phadke,

K. et al., "Evaluation of the effects of various anti-arthritic drugs on type II collagen-induced mouse arthritis model", Immunopharmacology (1985), Vol. 10, No. 1, pp. 51-60).

[0127] The compounds of the invention can be tested for their use in the treatment of degenerative arthritis by using the STR / ORT mouse model (see Brewster, M. et al., "Ro 32-3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR / ORT mouse model of osteoarthritis ", Arthritis. Rheum. (1998), Vol. 41, No. 9, pp. 1639-44).

[0128] The compounds of the invention can be tested for their use in the treatment of osteoporosis by using a ovariectomy rat model (see Wronski, TJ et al., "Endocrine and pharmacological suppressors of bone turnover protect against osteopenia in ovariectomized rats", Endocrinology (1989 ), Vol. 125, no. 2, pp. 810-6) or ovariectomy mouse model (see Alexander, JM et al., "Human parathyroid hormone 1-34 reverses bone loss in ovariectomized mice", J Bone Miner Res. (2001), Vol. 16, no. 9, pp. 1665-73; Fujioka, M. et al., "Equol, a metabolite of daidzein, inhibits bone loss in ovariectomized mice", J Nutr. (2004), Vol. 134, no. 10, pp. 2623-7).

[0129] Compounds of the invention can be tested for their use in the treatment of cataracts by using the H2O2-induced model (see Kadoya, K. et al., "Role of calpain in hydrogen peroxide induced cataract", Curr. Eye Res. (1993 ), Vol. 12, No. 4, pp. 341-6) or the mouse Emory model (see Sheets, NL et al., "Cataract- and lens-specific upregulation of ARK receptor tyrosine kinase in Emory mouse cataract", Invest. Ophthalmol. Vis. Sci. (2002), Vol. 43, No. 6, pp. 1870-5).

113

PHARMACEUTICAL COMPOSITIONS OF THE INVENTION AND ADMINISTRATION [0130] The administration of the compounds of the invention or their pharmaceutically acceptable salts, in pure form or in a suitable pharmaceutical composition, can be carried out by any of the accepted forms of administration for similar applications. Pharmaceutical compositions of the invention may be prepared by combining a compound of the invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, capsules, powders, granules, ointments, solutions , suppositories, injections, inhalants, gels, microspheres and sprays. Typical routes of administration for such pharmaceutical compositions include, without limitation, oral, superficial, transdermal, inhalation, parenteral, sublingual, oral, rectal, vaginal and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to bioavailability upon administration of the composition to a patient. The compositions that will be administered to the subject or patient take the form of one or more dosage units, wherein for example the tablet may be a single dosage unit and the container of the compound of the invention in aerosol form may contain multiple dosage units. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see at least Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition for administration will in any case contain a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition of interest according to the teachings of this invention.

[0131] The pharmaceutical composition of the invention may be in solid or liquid form. In one aspect, the carrier (s) are (are) solids, such that the compositions are, for example, in the form of tablets or a powder. The carrier (s) may (may) be fluid with liquid compositions that are, for example, an oral oil, injection fluid, or aerosol that is useful, for example, by inhalation.

[0132] If it is intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein the semi-solid, semi-liquid, suspension and gel forms are included in the forms contemplated herein as either solid or liquid.

[0133] As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granules, compressed tablet, pills, capsules, chewing gum, wafer or similar form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrants such as alginic acid, sodium alginate,

114

Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; a fragrance such as peppermint, methyl salicylate or an orange fragrance; and a coloring substance.

[0134] If the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0135] The pharmaceutical composition may be in the form of a liquid, for example an elixir, syrup, solution, emulsion or suspension. The fluid may be for oral administration or for delivery by injection as two exemplifications. If intended for oral administration, the preferred composition comprises, in addition to the present compounds, one or more sweeteners, preservatives, dyes / coloring agents and a flavor enhancer. One or more surfactant, preservative, wetting agent, suspending agent, buffer, stabilizer and isotonic substance may be included in the composition intended for administration by injection.

[0136] The liquid pharmaceutical compositions of the invention, whether they are solutions, suspensions or other similar forms, may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably saline, Ringer's solution, isotonic sodium chloride, non-volatile oils such as synthetic mono or diglycerides, which can serve as a solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial substances such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium disulfide; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and tonicity adjusting substances such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.

[0137] The liquid pharmaceutical composition of the invention intended for or for parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dose will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. If intended for oral administration, this amount may vary between 0.1 and about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 75% of the compound of the invention. Preferred pharmaceutical compositions and preparations according to the invention are prepared such that the parenteral dosage unit contains between 0.01 to 10% by weight of the compound before dilution of the invention.

[0138] The pharmaceutical composition of the invention may be intended for surface administration, in which case the carrier may suitably contain

115 solution, emulsion, ointment or gel base. The base, for example, may contain one or more of the following: paraffin, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in the pharmaceutical composition for surface administration. If intended for transdermal administration, the composition may contain a transdermal patch or an ionophoresis device. Surface formulations may contain a concentration of a compound of the invention from about 0.1 to about 10% w / v (mass per unit volume).

[0139] The pharmaceutical composition of the invention may be intended for rectal administration, for example in the form of a suppository that will melt in the rectum and release the drug. The composition for rectal administration may contain an oil base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

[0140] The pharmaceutical composition of the invention may contain various materials that modify the physical form of the solid or liquid dosage unit. For example, the composition may contain materials that form a coating sheath around the active ingredients. The materials that make up the coating shell are typically inert, and can be selected from, for example, sugar, shellac, and other enteric coating substances. Alternatively, the active ingredients may be embedded in a gel capsule.

[0141] The pharmaceutical composition of the invention in solid or liquid form may contain an agent that binds to the compound of the invention and thereby supports the delivery of the compound. Suitable substances that can act at this capacity include monoclonal or polyclonal antibody, protein or liposome.

[0142] The pharmaceutical composition of the invention may contain dosage units that can be administered as an aerosol. The term aerosol is used to mean a variety of systems ranging from colloidal to systems consisting of pressurized packaging. Delivery can take place via liquefied or compressed gas or via a suitable pump system that dispenses active ingredients. Aerosols of the compounds of the invention may be provided in single-phase, two-phase or three-phase systems to provide the active ingredient (s). The delivery of the aerosol includes the necessary container, activators, valves, sub-tank and the like which can together form the kit. A person with ordinary skill in the art without undue experimentation can determine the preferred sprays.

[0143] The pharmaceutical compositions of the invention may be prepared by techniques well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection may be prepared by combining the compound of the invention with sterile distilled water to form a solution.

A surfactant may be added to facilitate the formation of a homogeneous solution or

116 suspension. Surfactants are compounds that non-covalently interact with a compound of the invention such that they facilitate dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0144] The compounds of the invention, or a pharmaceutically acceptable salt thereof, are administered in a therapeutically effective amount that will vary depending on a variety of factors, including the activity of the particular compound employed; metabolic stability and duration of action of a compound; the patient's age, weight, general health, sex and diet; mode and time of administration; excretion rates; drug combinations; the severity of the particular disorder or condition; and the subject being treated. Generally, a therapeutically effective daily dose is (for 70 kg of mammal) from about 0.001 mg / kg (i.e. 0.07 mg) to about 100 mg / kg (i.e. 7.0 gm); preferably a therapeutically effective dose is (for 70 kg of mammal) from about 0.01 mg / kg (i.e. 0.7 mg) to about 50 mg / kg (i.e. 3.5 mg); more preferably the therapeutically effective dose is (for 70 kg mammal) from about 1 mg / kg (i.e. 70 mg) to about 25 mg / kg (i.e. 1.75 gm).

[0145] The compounds of the invention, or pharmaceutically acceptable salts thereof, may also be administered simultaneously with, before or after the administration of one or more other therapeutic substances. Such combination therapy includes administering a single pharmaceutical dose of the formulation that contains the compound of the invention and one or more additional active substances, as well as administering the compound of the invention and each active substance in its own separate pharmaceutical dosage formulation. For example, the compound of the invention and other active substance may be administered to a patient together in a single dose of a composition such as a tablet or capsule or each substance administered in separate oral doses of the formulation. Where separate dosages of formulations are used, the compounds of the invention and one or more additional active substances may be administered at the same time, i.e. simultaneously or at separate divergent times, i.e. sequentially; combined therapy is understood to include all of these schemes.

PREPARATION OF COMPOUNDS ACCORDING TO THE INVENTION [0146] The following Reaction Scheme illustrates methods for preparing compounds of the invention, i.e. compounds of formula (I):

R³

<img file="PL2078010T3_D0011.tif" />

where R¹, R², R³, R⁴ and R⁵ are described above in the Summary of the Invention for compounds of formula (I) as isolated stereoisomers or mixtures thereof, as tautomers or their

117 mixtures, or as pharmaceutically acceptable salts or N-oxides. In particular, the following Reaction Scheme illustrates methods for preparing compounds of formula (Ia):

R³ /

Ν-Ν

<img file="PL2078010T3_D0012.tif" />

where R¹, R², R³, R⁴ and R⁵ are as described above in the Summary of the Invention for compounds of formula (Ia), as isolated stereoisomers or mixtures thereof, as tautomers or mixtures thereof, or as pharmaceutically acceptable salts or N-oxides, and methods for preparing compounds of formula (Ib);

<img file="PL2078010T3_D0013.tif" />

where R¹, R², R³, R⁴ and R⁵ are as described above in the Summary of the Invention for compounds of formula (Ib) as isolated stereoisomers or mixtures thereof, as tautomers or mixtures thereof, or as pharmaceutically acceptable salts or N-oxides. It is understood that in the following Reaction Scheme and throughout this description, the combinations of substituents and / or variables of these illustrated formulas are permissible only if such actions result in stable compounds.

[0147] It will also be appreciated by those skilled in the art that in the methods described below, the functional groups of intermediates may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guanidino include benzyl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C (O) -R "(where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters.

[0148] Protecting groups may be added or removed according to standard techniques that are known to one of ordinary skill in the art as described herein.

[0149] The use of protecting groups is described in detail in Green, TW and PGM

Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As would be recognized by one of ordinary skill in the art, the protective group may also be a polymeric resin, such as Wang resin, Rink resin or 2-chlorotrityl chloride resin.

118 [0150] It will also be recognized by those skilled in the art, although such protected derivatives of the compounds of the invention may not have pharmacological activity as such that they may be administered to a mammal and then metabolized in the body to form compounds of the invention that are pharmacologically active. Such derivatives may therefore be described as "prodrugs".

[0151] It is understood that a person of ordinary skill in the art would be able to form compounds by methods similar to those described herein or by methods known to a person of ordinary skill in the art. It is also understood that a person of ordinary skill in the art would be able to prepare, as described below, other compounds of formula (I) not specifically described below by using appropriate starting components and modifying the synthesis parameters as needed. In general, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in the invention. ¹H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, acetone-d6 with trimethylsilane (TMS) as an internal reference using a Gemini 300 MHz instrument. Reagents and solvents were purchased from commercial sources and used without further purification. Flash column chromatography was performed using silica gel (230-400 mesh) under positive nitrogen pressure. LCMS spectra for purity and mass were recorded using Waters LCMS equipment. Deionized water was used to dilute the reaction and rinse the products. The brine used was prepared by dissolving sodium chloride in deionized water to the saturation point.

[0152] Compounds of formula (Ia) as outlined below in Reaction Scheme 1 below, where R¹, R² and R³ are as defined above in the Summary of the Invention for compounds of formula (I) and R⁴ and R⁵ are hydrogen, they are generally prepared as illustrated below in Reaction Scheme 1, where R¹, R² and R³ are as defined above in the Summary of the Invention for compounds of formula (I):

REACTION SCHEME 1

<td>ΧΝ</td><td></td><td>_t CN</td>

<td>Ν Λ</td><td>R³-N (R¹) H</td><td>Ν Λ</td>

<td>'OPh</td><td>in</td><td>R¹N OPh</td>

<td>(Α)</td><td></td><td> %</td>

κ³-νηνη₂ R³

Ν-Ν

Rf X Λ

Ν Ν NH_FROM

R * (Ιο) [0153] Compounds of formula (A), formula (B) and formula (D) are commercially available or can be prepared by methods known to a person skilled in the art or by methods disclosed herein.

119 [0154] Generally, compounds of formula (Ia) are prepared, as outlined in Reaction Schemes 1, by first treating a compound of formula (A) (where the phenyl groups therein can be replaced by other suitable groups or appropriately substituted groups known to a person skilled in the art ) (1.1 equivalents) with an equivalent amount of aniline of formula (B) in a polar solvent, including but not limited to isopropyl alcohol, at ambient temperatures overnight. The diaryllisourea product of formula (C) generally precipitates and isolation can be carried out by filtration, washing with a suitable solvent and drying. Hydrazine hydrate of formula (D) (2 equivalents) is added to a slurry of the compound of formula (C) in alcohol or other suitable solvent. Generally, the ring forming reaction occurs at ambient temperature and the triazole product of formula (Ia) can be isolated by standard isolation techniques. Compounds of formula (Ia) may then be treated with a suitably substituted alkylating or acylating substance under standard conditions to form compounds of formula (Ia) where R⁴ and R⁵ are as described above in the Summary of the Invention for compounds of formula (I).

[0155] Compounds of formula (Ib) may be prepared using the synthetic pathway outlined in Reaction Scheme 1 in varying amounts depending on the spatial and electronic nature of R¹, R² and R³as well as specific reaction conditions. In some cases, compounds of formula (Ib) are isolated as small isomers together with compounds of formula (Ia) as small isomers, e.g., during column chromatography as described herein.

[0156] Compounds of formula (C-1) are compounds of formula (C) as defined above in Reaction Scheme 1 where R¹ is hydrogen and R² means 7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl, i.e. where R² has the following structure:

<img file="PL2078010T3_D0014.tif" />

Compounds of formula (C-1) may be prepared according to the method described below in relation to Reaction Scheme 2:

120

REACTION SCHEME 2

<img file="PL2078010T3_D0015.tif" />

1CJ) [0157] Compounds of formula (Ca) and formula (A) are commercially available or can be prepared according to methods described herein or known to a person skilled in the art. Compounds of formula (Ba) are compounds of formula (B) as defined above in Reaction Scheme 1.

[0158] Generally, compounds of formula (C-1) are prepared, for example, as specified above in Reaction Scheme 2, by nitration of benzo [7] annulene of formula (Ca) followed by isolation of the ketone of formula (Cb1), even , by crystallization. Reductive amination of the keto group in the ketone of formula (Cb1) gives the pyrrolidine substituted compound of formula (Cc). The reduction of the nitro group of the pyrrolidine substituted compound of formula (Cc), for example, by catalytic hydrogenation, gives the aniline of formula (Ba). The reaction of aniline of formula (Ba) with, for example, diphenyl cyanocarbonimidate of formula (A), gives compound of formula (C-1). Compounds of formula (C-1) are enantiomeric. Enantiomers of (C-1) and similar compounds are separable by, e.g., a chiral HPLC phase. Enantiomers of compounds (C-1) were separated as follows. Each of the (C-1) enantiomers was used to synthesize compounds of formula (I) (see SYNTHESIS EXAMPLE 2 below). The following describes the method for producing aryl-linked cycloheptanone or cycloheptanone-linked cycloheptanone of formula (I):

121

<img file="PL2078010T3_D0016.tif" />

where Z is aryl or heteroaryl and each R¹ is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl and optionally substituted heteroarylalkyl. These compounds are useful as intermediates in the preparation of compounds of the invention and can be prepared as described below in REACTION SCHEME 2A in which Z is aryl or heteroaryl, each R¹ is independently selected from the group consisting of hydrogen, optionally substituted with alkyl, optionally substituted with aralkyl and optionally substituted heteroarylalkyl, each R² is independently selected from the group consisting of optionally substituted alkyl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl, and each LG is independently a suitable leaving group:

<img file="PL2078010T3_D0017.tif" />

[0159] In this method, the reagent of formula (ii) is first combined with a reagent of formula (iii) in the presence of a protic solvent, an aprotic solvent and a base to obtain an intermediate, for example, 8,9-dihydro-5H-benzo [7] annulen-7 (6H) -one substituted on the 6-, 8-, or 6- and 8-position or mixtures thereof with carboxyester groups. Suitable leaving groups for this method include, but are not limited to, quaternary ammonium, alkyl or aryl sulfonate salts (e.g. methanesulfonate, tosylate, triflate), alkyl or aryl sulfides, phosphonates and halogens (e.g. F, Cl, Br, I). In a particular embodiment, the leaving group LG is halogen. In a more particular embodiment, LG means bromo. Intermediate, e.g. 8,9-dihydro-5H-benzo [7] annulen7 (6H) -one, is then exposed to basic hydrolytic agents and then to acid to form compounds of formula (I). Intermediate, for example, 8,9-dihydro5H-benzo [7] annulen-7 (6H) -one, is exposed to acidic agents before exposure to basic hydrolytic agents. Also, intermediates, for example, 8,9-dihydro5H-benzo [7] annulene-7 (6H) -one, can be exposed to acidic agents and isolated before exposure to basic hydrolytic agents.

[0160] For example, Z is phenyl, R² is lower alkyl and R¹ means hydrogen.

Exemplary protic solvents include, but are not limited to, alcohols,

122 preferably alkanols, e.g., methanol, ethanol and the like. Exemplary aprotic solvents include, but are not limited to, ethers, e.g., THF, crown ethers and the like. For example, aprotic and protic solvents are in a volume ratio of about 1: 1. Exemplary bases include, but are not limited to, metal alkoxides, e.g., lithium, sodium, or potassium alkoxides. In one exemplary embodiment, the metal alkoxide is sodium methoxide. Exemplary acids and acidic agents include inorganic and organic acids, typically diluted with water. Such inorganic and organic acids are described above in the Definitions section, under "pharmaceutically acceptable acid addition salt" and "pharmaceutically acceptable base addition salt". Exemplary basic hydrolysis agents include, but are not limited to, alcohol solutions of metal hydroxides or metal alkoxides. For example, alkaline hydrolytic agents include an alcohol solution of metal hydroxide.

[0161] Preferably, the combination of the reagent of formula (ii) with the reagent of formula (iii) in the presence of a protic solvent, an aprotic solvent and the basic process described above is carried out in a temperature range between about -10 ° C and about 100 ° C, more preferably in a temperature range between about 0 ° C and about 50 ° C, even more preferably, in a temperature range between about 0 ° C and about 30 ° C.

[0162] Preferably, the first step process intermediate exposure to basic hydrolytic agents followed by acid to form compounds of formula (I) is carried out in a temperature range between about 40 ° C and about 150 ° C, more preferably in a temperature range between about 60 ° C and about 100 ° C, even more preferably in a temperature range between about 60 ° C and about 100 ° C.

[0163] Accordingly, an exemplary method for forming a compound of formula (Ca), i.e., dihydro-5H-benzo [7] annulene-7 (6H) -one, as described above in Reaction Scheme 2, is described below in a ratio to REACTION SCHEME 2B.

<img file="PL2078010T3_D0018.tif" />

[0164] Dimethyl-3-oxopentanedioesane and 1,2-bis (2-bromomethyl) benzene are commercially available or can be prepared according to methods disclosed herein or methods known to a person skilled in the art. The ester groups need not be methyl esters and the bromine groups need not be bromo groups in which any leaving group is sufficient.

123

Also, as described above, 3-oxopentanedioate may be substituted in the 2nd and 4th positions provided that there is at least one proton in each of the 2nd and 4th positions, assuming that at least one proton is required for deprotonation, and then forming a CC bond with the carbon bearing the leaving group.

[0165] Accordingly, the compounds of formula (Ca) are prepared as defined above in REACTION SCHEME 2B, first by combining the pentane-3dioesane shown, e.g. dimethyl-3-oxopentanedioesane with a 1,2-bismethyl aromatic compound having a suitable leaving group on each methyl group, e.g.

1,2-bis (bromomethyl) benzene, in a mixed protic / aprotic dissolving agent, e.g. THF-MeOH and a metal alkoxide, e.g. sodium methoxide. The metal alkoxide can be added as such or produced in situ by carefully adding (e.g. at low temperature) the appropriate metal to at least a protic solvent, preferably before combining with the remaining reagents. The intermediate benzo [7] annulene thus formed may be optionally isolated and may contain one or two carboxyester groups depending on the reaction conditions, e.g. methyl 7-oxo-6, 7,8,9-tetrahydro-5H-benzo [7] annulene -6,8-dicarboxylate as set out above.

Intermedia, dimethyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulene-6,8-dicarboxylate, is subjected to alkaline hydrolysis (saponification) followed by acidification to give compounds of formula (Ca ).

[0166] Compounds of formula (Da) are compounds of formula (D) as shown above in Reaction Scheme 1, where R³ is 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2c] pyridazin-3-yl, i.e. where R³ has the following structure:

Compounds of formula (Da) may be prepared according to the method disclosed below in Reaction Scheme 3:

124

REACTION SCHEME 3

<img file="PL2078010T3_D0019.tif" />

(D-1) [0167] Compounds of formula (Da) are commercially available or can be prepared by methods known to a person skilled in the art or by methods disclosed herein.

[0168] Generally, compounds of formula (D-1) are prepared, as specified above in Reaction Scheme 3, by first dissolving the compound of formula (Da) (1.0 equivalent) in an anhydrous aprotic polar solvent or a mixture of such solvents, for example , tetrahydrofuran with hexamethylphosphoramide (HMPA) (1.2 equivalents). The resulting solution is stirred at ambient temperature for about 10 minutes and then cooled to a temperature between about -10 ° C and about 5 ° C, preferably at 0 ° C. A strong base, lithium bis (trimethylsilyl) amide (Li-HMDS) (1.1 equivalents), is then added dropwise to the stirred mixture for a period of time between about 20 minutes and 40 minutes, preferably for 30 minutes, while the temperature of the resulting mixture is kept at between about -10 ° C and about 5 ° C, preferably at 0 ° C. Ethyl bromoacetate (2.5 equivalents) is then added to the resulting anion (Da) and the resulting mixture is stirred for an additional period of time between about 5 minutes and 15 minutes, preferably for about 10 minutes, and then allowed to warm to ambient temperature and stirring at ambient temperature for a period of time between about 30 minutes and 3 hours, preferably for about 2 hours. The compound of formula (Db) is then isolated from the reaction mixture by standard isolation techniques known to a person skilled in the art, such as solvent evaporation and purification by flash column chromatography.

125 [0169] The compound of formula (Db) is then subjected to basic hydrolysis conditions to form a compound of formula (Dc), which is isolated from the reaction mixture by standard isolation techniques known to a person skilled in the art.

[0170] The compound of formula (Dc) (1.0 equivalent) is then subjected to hydrazine hydrate (1.25 equivalent) in the presence of a polar protic solvent, such as ethanol, to obtain a compound of formula (Dd) which is isolated from the mixture reactive by standard isolation techniques known to those skilled in the art.

[0171] A mixture of the compound of formula (Dd) (1.0 equivalent) and anhydrous copper (II) chloride (2.0 equivalents) is then refluxed in acetonitrile to give the unsaturated compound of formula (De) which is isolated from the reaction mixture by standard isolation techniques known to those skilled in the art. [0172] A mixture of the compound of formula (De) and phosphoryl chloride is refluxed for a period of time between about 1 hour and 3 hours, preferably for about 2 hours for aromatizing and chlorination of the ring containing the NN bond. After cooling to ambient temperature, the compound of formula (Df) is isolated from the reaction mixture by standard isolation techniques known to a person skilled in the art. [0173] Those skilled in the art will recognize that a compound of formula (Df) may be used to prepare the corresponding 3-aniline, which may be used as the aniline of formula (B), as defined in Reaction Scheme 1 above, to produce embodiments of the invention. [0174] A mixture of the compound of formula (Df) (1.0 equivalent) and anhydrous hydrazine (19.8 equivalents) in a protic solution, such as ethanol, is refluxed for a period of time between about 4 hours and 24 hours, preferably for about 16 hours. After cooling to ambient temperature, water is added to the mixture and the compound of formula (D-1) is then isolated from the reaction mixture by standard isolation techniques known to a person skilled in the art.

[0175] Compounds of formula (C-2) are compounds of formula (C) as outlined above in Reaction Scheme, where R¹ is hydrogen and R² means 5 ', 5'-dimethyl-6,8,9,10-tetrahydro5H-spiro [cycloocta [b] pyridine-7.2' - [1,3] dioxane-3-yl, i.e. where R² has the following structure:

<img file="PL2078010T3_D0020.tif" />

Compounds of formula (C-2) can be prepared according to the method described below on

Reaction Scheme 4:

126

<img file="PL2078010T3_D0021.tif" />

[0176] Compounds of formula (Cd) and (Ce) are commercially available or can be prepared according to methods known to a person skilled in the art.

[0177] Generally, compounds of formula (C-2) are prepared, as specified above in Reaction Scheme 4, by first heating a mixture of a compound of formula (Cd) (1.0 equivalent) and a compound of formula (Ce) (0, 96 equivalents) and ammonia in a protic solvent such as methanol to maintain the temperature at reflux. The compound of formula (Cf) is then isolated from the reaction mixture by standard isolation techniques.

[0178] The compound of formula (Cf) is then reduced under standard reduction conditions known to a person skilled in the art to obtain a compound of formula (Cg).

[0179] A mixture of equivalent molar amounts of the compound of formula (Cg), diphenyl cyanocarboimidate and diisopropylethylamine in a protic solvent such as isopropyl alcohol is stirred at ambient temperature for a period of time between 8 hours and 16 hours, preferably for about 16 hours, to form the compound of formula (C-2), which is isolated from the reaction mixture by standard isolation techniques known to a person skilled in the art.

[0180] All compounds of the invention that exist in the form of the free base or free acid can be converted into their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid by routes known to those of ordinary skill in the art. Salts of compounds of the invention may be converted into their free base or acid form by standard techniques known to a person skilled in the art.

[0181] Specific Synthetic Preparations below (for intermediates) and Examples

Syntheses (for compounds of the invention) are provided as a guide to assist in practicing the invention and are not intended to limit the scope of the invention. The number following each compound below refers to its number in Table 1 and Table 2, as discussed in more detail below.

127

SYNTHETIC MANUFACTURE 1

Synthesis of 8,9-dihydro-5H-benzo [7] annulene-7 (6H) -one Compound of formula (Ca) [0182] A. Sodium methoxide (9.4 g, 174.2 mmol) was added to a 250 mL flask with dry methanol (100 ml) at 0 ° C. After dissolution of the solid, the resulting solution was warmed to ambient temperature and added dropwise to a solution of dimethyl acetone-1,3-dicarboxylate (15.2 g, 87.1 mmol) and o-xylene dibromide (20 g, 75.7 mmol) in 100 ml dry THF at 0 ° C for 30 min. After the addition, the reaction mixture was warmed to ambient temperature and stirred overnight. The volatiles were evaporated, the residue was poured into 40 ml of a 10% HCl solution and extracted with ethyl acetate (EtOAc) (200 ml × 2). The combined extracts were washed with water, saturated NaHCO3 solution and brine. After evaporation, the remaining oil was used directly in the next step.

[0183] B. Crude dimethyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulene-6,8-dicarboxylate was dissolved in 200 ml ethanol (EtOH) and then in 100 ml 2 N KOH . The resulting mixture was refluxed at 85 ° C and for 17 h. After cooling to ambient temperature, the volatiles were evaporated. 120 ml of 2N HCl was added to the residue at 0 ° C, the crude product was extracted with EtOAc (200 ml × 2). The combined extracts were washed with brine. After drying (MgSO4), filtration and concentration, the residue was purified by silica gel flash column chromatography (hexanes / EtOAc 8: 1) to obtain 6.6 g (57%) 8.9-dihydro-5H-benzo [7] annulene -7 (6H) -one as a white solid: mp 40-41 ° C; 1 H NMR (300 MHz, CDCl 3) δ: 7.21 (m, 4H), 2.94-2.90 (m, 4H), 2.63-2.60 (m, 4H); LC-MS: 161 (M + H) +.

SYNTHETIC MANUFACTURE 2

Synthesis of 2-nitro-8,9-dihydro-5H-benzo [7] annulen-7 (6H) -one Compound of formula (Cb1) [0184] To a cold (0 ° C) solution of concentrated sulfuric acid (15 ml) was added dropwise 70% nitric acid (15 ml) for 30 min. The addition was controlled to keep the internal reaction temperature below 5 ° C. After the addition, the resulting solution was transferred to an additional funnel and added dropwise to a solution of 8,9-dihydro-5H-7 (6H) -one (14 g, 87.5 mmol) in nitromethane (80 mL) at 0 ° C over a period of 40 min . After the addition, the reaction mixture was stirred at 0 ° C for 2 h. Then ice-water (-80 mL) was added to the reaction mixture, and the mixture was stirred for an additional 30 min. The mixture was then transferred to a separate funnel, where the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 80 mL). The combined layers were washed with cold water, saturated NaHCO3 solution and brine. After drying (MgSO4), filtration and concentration, the residue was purified by flash column chromatography on silica gel (hexanes / EtOAc = 3: 1 to 2: 1) to obtain a mixture of nitroregioisomers (~ 15 g), which was then purified by recrystallization from MTBE ( tert-butyl methyl ether, 180 ml)

128 to obtain 7.3 g of 2-nitro-8,9-dihydro-5H-benzo [7] annulen-7 (6H) -one (40% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ: 8.10-8.06 (m, 2H), 7.40-7.37 (m, 1H), 3.04-3.00 (m, 4H), 2.67-2.65 (m, 4H ); LC-MS: 206 (M + H) +.

SYNTHETIC MANUFACTURE 3

Synthesis of 1- (2-nitro-6,7,8,9-tetrahydro-5H-benzo [7] annulene-7-yl) pyrrolidine Compound of formula (Cc) [0185] Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.05 g, 10 mmol) were mixed in 1,2-dichloroethane (35 mL) and then treated with NaBH (OAc) 3 ( 3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under N2 overnight. The reaction mixture was quenched with saturated NaHCO3 and the product was extracted with EtOAc (3 x 30 mL). The organic layers were combined and dried on NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2 / DMA = 1/1 (DMA = CH2Cl2 / MeOH / 30% NH3 = 80/19/1) to give 1- (2-nitro-6,7,8,9 -tetrahydro-5H-benzo [7] annulen-7-yl) pyrrolidine, yellow oil (2.2 g, 85%); MS (m / e): 261 (M + H +). SYNTHETIC PRODUCTION 4

Synthesis of 7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulene-2-amine. Compound of formula (Ba) [0186] A mixture of 1- (2-nitro-6 , 7,8,9-tetrahydro-5H-benzo [7] annulen-7-yl) pyrrolidine (2.0 g;

7.69 mmol) and 10% palladium on carbon (0.2 g, ~ 50% water) in methanol (150 ml) was shaken under a hydrogen atmosphere (40 psi) for 1 h. After this time, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain 7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulene-2-amine as an oil (quantitative yield); MS (m / e): 231 (M + H +).

SYNTHETIC MANUFACTURE 5

Synthesis of phenyl N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) carbamimidate Compound of formula (C-1) [ 0187] A mixture of 7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulene-2-amine (1.7 g; 7.39 mmol) and diphenyl cyano carboimidate (1 , 76 g, 7.39 mmol) in 20 mL isopropanol was stirred at ambient temperature overnight. The solid was filtered, washed with isopropanol and ether and dried to give N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) phenyl carbamimidate as a white solid (2.2 g, 80%). MS (m / e): 375 (M + H +).

SYNTHETIC MANUFACTURE 6

129

Isolation of (S) -N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) carbamimide of phenyl and (R) - Phenyl N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) carbamimidate Enantiomers of the Compound of formula (C-1) [ 0188] Phenyl N'-cyano-7- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) carbamimidate (0.43 g, racemic) was eluted on the mobile phase of chiral column chromatography; ethanol / MeOH / triethylamine = 1/1 / 0.2% to obtain (S) -N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] Annulen-2-yl) carbamimidate of phenyl and (R) -N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] phenyl annulen-2-yl) carbamimidate: Chiral column: Chiralcel OJ, 21.2 x 250 mm. 10μΜ; loading material: cellulose tris- (4-methylbenzoate) coated on a 10 μm silica gel substrate. Flow rate 9.9 mL / min, sample solubility 30 mg / mL in methanol. Single enantiomers were isolated in amounts of 170 mg and 190 mg, respectively. The absolute configuration of each of the enantiomers has not been determined at this time.

SYNTHETIC MANUFACTURE 7

Synthesis of ethyl 2- (5-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulene-6-yl) acetate Compound of formula (Db) [0189] To a mixture of 1-benzosuberone (5.0 g, 31.2 mmol, Aldrich) in dry tetrahydrofuran (THF) (20 mL) was added hexamethylphosphoramide (6.5 mL, 37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambient temperature for 10 min and then cooled to 0 ° C with an ice-water bath, a 1.0 M solution of lithium bis (trimethylsilyl) -amide in THF (32.7 mL, 32.7 mmol) in dropwise was added dropwise. within 30 min After the addition, the reaction mixture was stirred at 0 ° C for 30 min. Then ethyl bromoacetate (8.7 mL, 78.1 mmol) was added. After stirring for a further 10 min, the reaction mixture was warmed to ambient temperature and stirred for 2 hours. The solvent was evaporated, the residue was diluted with ethyl acetate (EtOAc) (300 mL), and washed with water and brine. After drying (MgSO4), filtration and concentration, the residue was purified by flash column chromatography eluting with 6: 1 ethyl acetate 4: 1 tackles to obtain

6.6 g of the compound of formula (Db), ethyl 2- (5-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulen-6-yl) acetate as an orange oil (84%), 1H NMR (300 MHz, CDCl3) δ: 7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3 , 12-2.92 (m, 3H), 2.52-2.43 (m, 1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H ); LC-MS: purity: 91.8%; MS (m / e): 247 (MH +).

SYNTHETIC MANUFACTURE 8

Synthesis of 2- (5-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulene-6-yl) acetic acid Compound of formula (Dc) [0190] Compound of formula (Db), 2- Ethyl (5-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulen-6-yl) acetate (6.6 g, 26.8 mmol) was dissolved in ethanol (EtOH) (30 mL), then a 10% aqueous potassium hydroxide (KOH) solution (37.5 mL, 67 mmol) was added and the resulting mixture was refluxed for 2 h. After cooling to ambient temperature, it was removed

130

EtOh by evaporation. The residue was extracted twice with EtOAc (15 mL × 2). The aqueous layer was then transferred to a flask and cooled in an ice-water bath, concentrated HCl was added dropwise to adjust the pH to about 2.0. Then EtOAc (60 mL) was added, the layers separated and the aqueous layer extracted with EtOAc. The combined extracts were washed with brine. After drying (MgSO4), filtration and concentration, the compound of formula (Dc), 2- (5-oxo-6, 7,8,9-tetrahydro-5H-benzo [7] annulen-6-yl) acetic acid was obtained as orange oil (5.7 g, 97%); 1H NMR (300 MHz, CDCl3) δ: 7.71-7.68 (m, 1H), 7.41-7.20 (m, 3H), 3.37-3.31 (m, 1H) , 3.12-2.91 (m, 3H), 2.57-2.49 (m, 1H), 2.15-1.90 (m, 2H), 1.75-1.62 (m , 2H); LC-MS: purity: 100%; MS (m / e): 219 (MH +).

SYNTHETIC MANUFACTURE 9

Synthesis of 4a, 5,6,7-tetrahydro-2H-benzo [6,7] cyclohepta [c] pyridazin-3 (4H) -one. Compound of formula (Dd) [0191]

<img file="PL2078010T3_D0022.tif" />

[0192] A. A mixture of the compound of formula (Dc), 2- (5-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulen-6-yl) -acetic acid, (5.7 g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20 mL of ethanol was refluxed for 2 h, cooled and filtered (washed with a small amount of EtOH) to give the compound of formula (Dd), 4a, 5,6,7-tetrahydro2H -benzo [6,7] cyclohepta [c] pyridazin-3 (4H) -one as a white solid (4.7 g, 84%); 1H NMR (300 MHz, CDCl3) δ: 8.61 (bs, 1H), 7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58 ( dd, J = 15.3, 16.8 Hz, 1H), 2.31 (dd, J = 12.0, 16.8 Hz, 1H), 1.96-1.59 (m, 4H); LC-MS: purity: 100%; MS (m / e): 215 (MH +).

[0193] B. Alternatively, a mixture of benzosuberon (10.6 g, 66.2 mmol), glyoxylic acid monohydrate (6.08 g, 66.2 mmol), sodium hydroxide (10.6 g, 265 mmol), ethanol (40 ml) and water (100 ml) were stirred overnight at ambient temperature and then heated under reflux for 1 h. The mixture was cooled, then diluted with water and extracted twice with dichloromethane (then discarded). The acid layer was then acidified with 10% aqueous hydrochloric acid. Ice was added for cooling. The mixture was then filtered to give a pale yellow solid, 10.5 g (after air drying). The crude solid was then heated at 100 ° C for 1 h with a mixture of acetic acid (60 ml), water (30 ml) and zinc powder (6 g). The reaction mixture was cooled to ambient temperature and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed three times with saturated sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was heated with ethanol (25 mL) and hydrazine monohydrate (10 mL) at

131 reflux for 3 h. The solvent was removed in vacuo and the residue crystallized from benzene / ethanol, 1/1, to give 4a, 5,6,7-tetrahydro-2H-benzo [6,7] cyclohepta [c] pyridazine-3 (4H ) -one as a white solid, 2.31 g; 1H NMR (CDCl3, 300 MHz)

8.66 (s, 1H), 7.52 (d, 1H), 7.24-7.50 (m, 2H), 7.16 (d, 2H), 2.75-3.00 (m, 3H), 2.56 (dd, 1H),

2.31 (dd, 1H), 1.60-1.90 (m, 4H) ppm; MS (ES) 215 (M + H). This procedure followed the one reported by V. Peesapati and SC Venkata, Indian J. Chem., 41B, 839 (2002).

SYNTHETIC MANUFACTURE 10

Synthesis of 3-oxo-6,7-dihydro-5H [6,7] cyclohepta [1,2-c] pyridazine. Compound of formula (De) [0194]

<img file="PL2078010T3_D0023.tif" />

A. A mixture of the compound of formula (Dd), 4a, 5,6,7-tetrahydro-2Hbenzo [6,7] cyclohepta [c] pyridazin-3 (4H) -one (4.7 g, 22 mmol) and anhydrous copper (II) chloride (6 g, 44 mmol) were refluxed in acetonitrile (45 ml) for 2 hours. After cooling to ambient temperature, the mixture was poured into ice water (200 g) and the resulting solid was washed twice with 10% HCl solution (about 20 mL × 2) and twice with cold water (about 20 mL × 2). After lyophilization, the compound of formula (De), 3-oxo-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine (4.2 g, 90%) was obtained as a white solid, 1H NMR (300 MHz, CDCl3) δ: 10.80 (bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s, 1H), 2.66 (t, J =

6.9 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.14 (quantum, J = 6.9 Hz, 2H); LC-MS: purity: 100%; MS (m / e): 213 (MH +).

[0196] B. Alternatively, a solution of 4a, 5,6,7-tetrahydro-2H-benzo [6,7] cyclohepta [c] pyridazin-3 (4H) -one (2.31 g, 10.74 mmol), sodium nitrobenzene sulfonate ( 2.48 g, 11 mmol), sodium hydroxide (1.86 g, 46.5 mmol) in water (80 ml) was refluxed for 1.5 h. The solution was cooled to ambient temperature and then acidified with concentrated hydrochloric acid. The solid that precipitated was filtered off, washed with water and crystallized from ethanol to give 3-oxo-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine as tan crystals, 1.46 g; 1H NMR (DMSO-d6, 300 MHz) (s, 1H), 7.25-7.45 (m, 4H), 6.78 (s, 1H), 2.49 (m, 2H), 2 , 35 (m, 2H), 2.04 (m, 2H) ppm; MS (ES) 213 (M + H).

SYNTHETIC MANUFACTURE 11

Synthesis of 3-chloro-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine. Compound of formula (Df) [0197]

132

<img file="PL2078010T3_D0024.tif" />

A. A mixture of the compound of formula (De), 3-oxo-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine (4.0 g, 19.3 mmol) and POCl3 (20 ml) was refluxed for 2 h. After cooling to ambient temperature, the volatiles were evaporated. The residue was poured into a mixture of ice water and sodium bicarbonate, CH2Cl2 (200 mL) was added to dissolve the solid. The layer was separated and the aqueous layer was extracted with CH 2 Cl 2 once more. The combined organic layers were washed with brine. After drying (MgSO4), filtration and concentration, the compound of formula (Df) 3-chloro-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine was obtained as a yellow solid (4.3 g , 99%), 1H NMR (300 MHz, CDCl3) δ: 7.82 (m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m, 4H), 2.27 (quantum, J = 6.9 Hz, 2H); LC-MS: purity: 100%; MS (m / e): 231 (MH +).

[0199] B. Alternatively, 3-oxo-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine was heated with 20 ml phosphorus (III) oxychloride at 100 ° C for 4.75 h. The solvent was removed in vacuo. The remainder was treated with ice and saturated sodium bicarbonate solution. The solids that were formed were filtered off, rinsed well with water and air dried to give the corresponding 3-chloro-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine (1.6 g) ; 1H NMR (CDCl3, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H), 7.39 (s, 1H), 7.27 (m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES) 231/233 (M + H).

SYNTHETIC PRODUCTION 12

Synthesis of 3-hydrazine-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine. Compound of formula (D-1) [0200]

<img file="PL2078010T3_D0025.tif" />

[0201] A. A mixture of the compound of formula (Df) 3-chloro-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine, (4.3 g, 18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL of ethanol was refluxed for 16 h. After cooling to ambient temperature, 5 mL of water was added and then the volatiles were evaporated. Cold water (about 80 ml) was added to the solid residue. After sonication for 10 min, the resulting solid was collected by filtration and rinsed with cold water three times. After lyophilization, the compound of formula (D-1) 3-hydrazine-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine (4.14 g, 98%)

133 obtained as a slightly yellow solid, 1H NMR (300 MHz, CD3OD) δ: 7.59 (m, 1H), 7.339.26 (m, 3H), 7.04 (s, 1H), 2.54 ( t, J = 6.9 Hz, 2H), 2.47 (t, J = 6.9 Hz, 2H), 2.18 (quantum, J =

6.9 Hz, 2H); LC-MS: purity: 100%; MS (m / e): 227 (MH +).

[0202] B. Alternatively, 3-chloro-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazine (1.6 g) was heated with anhydrous hydrazine (4 ml) in ethanol ( 50 ml) at 100 ° C for 4.75 h. The solvent was removed in vacuo. The residue was partitioned between chloroform and 1 M saturated aqueous potassium carbonate solution. The organic layer was dried on anhydrous sodium sulfate and concentrated in vacuo to give 3-hydrazine-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine as a brown solid; 1H NMR (CDCl3, 300 MHz) 7.74 (m, 1H), 7.30 (m, 2H), 7.17 (m, 1H), 6.92 (s, 1H), 2.49 ( m, 2H), 2.39 (m, 2H),

2.12 (m, 2H) ppm; MS (ES) 227 (M + H).

EXAMPLE OF SYNTHESIS 1

Synthesis of 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4-2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine

<img file="PL2078010T3_D0026.tif" />

[0204] Diphenyl cyanocarbonoimidate (1.1 equivalent) and 4- (2- (pyrrolidin-1-yl) ethoxy) aniline (1 equivalent) were stirred in iso-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered off and washed with isopropyl alcohol and dried to give N'-cyano-N- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) carbamimidate (Z) -phenyl. 3-hydrazine-6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazine (82 mg, 0.36 mmol) and N'-cyano-N- (4- (2- (pyrrolidine (Z) -phenyl) ethoxy) phenyl) carbamimidate (Z) -phenyl (128 mg, 0.36 mMol) was suspended in isopropanol (3 ml) and subjected to microwave irradiation (150 ° C, 20 min). The precipitate that was prepared in the microwave vial was redissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2 (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 1, as a yellow body

134 solid, 23 mg. 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.83 (t, 1H), 7.43 (m, 3H), 7.29 (t, 1H), 6.93 (d, 1H), 6.83 (br s, 2H), 6.39 (s, 1H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2 , 80 (m,

8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M + H).

EXAMPLE OF SYNTHESIS 2

Synthesis of 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (S) (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3 5-diamines and 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (R) (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3 5-diamines [0205] (S) -N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) carbamide phenyl and ( R) -N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) carbamimidate phenyl was treated with 3-hydrazine-6 , 7-dihydro5H-benzo [6,7] cyclohepta [1,2-c] pyridazine as described above in Synthesis Example 2 to obtain 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (S) - (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3,5 -diamines and 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (R) (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3 5diaminy.

For example, a suspension of a single enantiomer of N'-cyano-N- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) phenyl carbamimidate (0.06 g, 0.16 mmol) and 3hydrazine-6,7-dihydro-5H-benzo [6.7] cyclohepta [1,2-c] pyridazine (0.036 g, 0.16 mmol) in 1 mL of IPA was stirred at 90 ° C for 18 h. After cooling to ambient temperature, it was evaporated and the residue purified by HPLC to provide enantiomerically pure 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (R) - (pyrrolidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3 5-diamine as a yellow solid (0.04 g, 50%). 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.94 (s, 1H), 7.85 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.72 (m, 4H), 2.61 (m, 3H), 2.25 (m, 5H), 2.09 - 1.82 (m, 5H) ppm; MS (ES) 507 (M + H).

EXAMPLE OF SYNTHESIS 3

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (5 ', 5'-dimethyl-6,8,9,10tetrahydro-5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl) -1 H-1, 2,4-triazole-3,5-diamine, compound # 247 [0206] A mixture of N'-cyano-N- (5 ', 5'-dimethyl-6,8,9,10-tetrahydro-5Hspiro [cycloocta [b] pyridine -7.2 '- [1,3] dioxane] -3-yl) carbamimidane (120 mg, 0.286 mmol) and (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) hydrazine (65 mg, 0.286 mmol) in isopropyl alcohol (2 ml) was heated in the microwave at 150 ° C for 20 min, filtered and washed with isopropanol to give 1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (5 ', 5'-dimethyl-6,8,9,10-tetrahydro-5H135 spiro [cycloocta [b] pyridine-7.2' - [1,3] dioxane] -3-yl) -1H-1 , 2,4-triazole-3,5-diamine, compound # 247 (55 mg, 35%); 1H NMR (DMSO-d6, 300 MHz) 9.22 (s, 1H), 8.72 (d, 1H), 7.94 (s, 1H), 7.88 (s, 2H), 7 , 13 (m, 1H), 7.62 (d, 1H), 7.44 (m, 2H), 7.36 (m, 1H), 3.42 (s, 4H), 2.82 (t, 2H), 2.71 (m, 2H), 2.25 (m, 2H), 1.97 (d, 2H), 1.69 (m, 2H), 1.52 (m, 2H) , 1.02 (d, 4H), 0.88 (d, 6H) ppm; MS (ES) 553.28 (M + H).

SYNTHESIS EXAMPLE 4 [0207] Similarly as described above, the following compounds of formula (Ia) were prepared using appropriately substituted starting materials and reagents:

N³- (4- (4-cykloheksanylopiperazyn-1-yl) phenyl) -1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -1H-1, 2,4-triazole-3,5-diamine, compound # 3, 1H NMR (CDCl3, 300 MHz) 7.89 (s, 1H), 7.81 (t, 1H), 7.58 (d, 1H), 7.42 (d, 2H), 7.30 (m, 1H), 6.97 (d, 2H), 6.80 (br s, 2H), 6.33 (s, 1H), 3.24 (m, 3H), 2.80 (m, 2H )

2.60 (M, 6H), 2.31 (m, 2H), 1.85 (m, 4H), 1.55-1.70 (m, 4H), 1.30 (m, 4H) ppm; MS (ES) 536.29 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 4, 1H NMR (300 MHz, DMSO): 9.19 (br.s, 1H), 7.91 (s, 1H), 7.86 (br.s, 2H), 7.72-7.69 (m, 1H),

7.45-7.43 (m, 2H), 7.38-7.33 (m, 3H), 6.96 (t, J = 9.3 Hz, 1H), 3.23-3.19 (m, 4H), 2.652.58 (m, 5H), 2.56 -2.53 (m, 2H), 2.10-2.00 (m, 1H), 1.94-1.90 (m, 3H), 1.67 (br.s, 6H),

1.60-1.48 (m, 2H), MS (ES): 540.33 (M + H);

Formic acid salt 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) -1H-1,2,4-triazole-3,5-diamine (formic acid salt of compound # 4); 1 - (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methyl-3-phenylpiperazin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine, compound # 5, 1H NMR (DMSO-d6, 300 MHz) 9.19 (s, 2H),

8.13 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.71-7.67 (m, 1H), 7.46-7.41 (m , 2H), 7.38-7.35 (m, 1H), 7.29 (d, 2H), 7.19-7.07 (m, 3H), 6.96 (t, 1H), 4.24 (d, 2H), 3.11 (d, 2H), 2.922,88 (m, 4H), 2.59-2.48 (m, 2H), 2.30-2.20 (m, 5H), 2.00 (t, 2H) ppm; MS (ES) 562.45 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (piperidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 6, 1H NMR (DMSO -d6, 300 MHz) 9.19 (s, 1H), 7.88 (d, 2H), 7.70 (s, 1H), 7.45-7.20 (m, 4H), 6.96 (t, 1H), 3.30 (s, 4H ), 2.62-2.40 (m, 9H), 2.20-2.16 (m, 2H), 1.87-1.80 (m, 2H), 1.59-1.48 (m, 8H) ppm; MS (ES) 554.20 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (indolin-2-one-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound

136 # 7.1H NMR (DMSO-d6, 300 MHz) 9.22 (s, 1H), 7.91 (s, 1H), 7.86 (s, 2H), 7.71-7.67 (m, 1H), 7.45-7.35 ( m, 4H), 7.28-7.15 (m, 3H), 7.08-6.94 (m, 2H), 4.26-4.18 (m, 1H),

3.55 (s, 2H), 2.85-2.76 (m, 2H), 2.61-2.46 (m, 4H), 2.30-2.20 (m, 2H), 2.75-2.48 (m, 2H) ppm; MS (ES) 602.48 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6 - (- 4 (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 8, 1H NMR (DMSO-d6, 300 MHz) 9.77 (s, 1H), 8.53 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.75-7.69 (m, 1 H), 7.48-7.35 (m, 2H), 6.96 (d, 1H), 4.27-4.14 (m, 2H), 3.60-3.41 (m, 2H), 3.23-3.10 (m, 3H), 2.60-2.40 (m, 10H), 2.39-2.31 (m, 2H), 2.08-1.95 (m, 1H), 1.63-1.51 (m, 2H), 1.39 (s, 1H), 1.22-1.18 (m, 1H ) ppm; MS (ES)

549.15 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (morpholin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 9, 1H NMR (DMSO -d6, 300 MHz) 9.79 (s, 1H), 9.23 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H),

7.77-7.68 (m, 1H), 7.45-7.38 (m, 4H), 7.00 (t, 1H), 4.01 (d, 2H), 3.72 (t, 2H), 3.50 (d,

2H), 3.47 (d, 2H), 3.20-3.08 (m, 2H), 2.70-2.57 (m, 6H), 2.25-2.09 (m, 4H), 1.80-1.76 (m, 2H) ppm; MS (ES) 556.17 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4 (cyclopropyl) piperazin-1-ylcarbonyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 10.1H NMR (DMSO-d6, 300 MHz) 9.51 ( s, 1H), 7.99 (s, 1H), 7.90 (br s, 2H), 7.69 (m, 6H), 7.41 (m, 2H), 3.48 (m, 8H), 2.58 (m, 3H), 2.22 (m, 4H), 1.75-1.32 (m, 8H) ppm; MS (ES) 550.2 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4,5-dihydro-1H-benzo [b] azepin-2 (3H) -on-8-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 11, 1H NMR (DMSO -d6, 300 MHz) 9.51 (s, 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7 - ((bicyclo [2.2.1] heptan-2-yl) (methyl) amino) -6,7,8,9tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2- , 4-triazole-3,5-diamine, compound # 24, 1H NMR (DMSO-d6, 300 MHz) 9.09 (s, 1H), 7.84 (br s, 2H), 7.72 (m, 2H). 7.40 (m, 5H),

7.05 (m, 1H), 3.84 (m, 1H), 3.54 (m, 1H), 3.25 (m, 1H), 2.77 (m, 3H), 2.53 (m, 7H), 2.30 (m, 6H ), 1.73-1.12 (m, 10H) ppm; MS (ES) 561.3 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4-cyclopentyl-1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 25.1H NMR (DMSO-d6 , 300 MHz) 8.32 (s, 1H), 8.17 (br s, 2H), 7.86 (m,

1H), 7.80 (s, 1H), 7.72 (m, 1H). 7.44 (m, 2H), 7.36 (m, 2H), 6.63 (m, 1H), 3.71 (m, 2H),

3.59 (m, 2H), 2.98 (m, 1H), 2.83 (m, 2H), 2.66 (m, 2H), 2.53 (m, 4H), 2.19 (m, 2H), 1.82 (m, 4H), 1.47 (m, 6H) ppm; MS (ES) 537.1 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-cyclopentyl6,7,8,9-tetrahydro-5H-pyrido [3,2-d] azepin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 26 , 1H NMR (DMSO-d6, 300 MHz) 9.73 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H),

137

8.08 (m, 1H), 7.94 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 2H), 7.39 (m, 1H), 3.54 (m, 3H),

3.16 (m, 3H), 2.54 (m, 5H), 2.25 (m, 2H), 1.85 (m, 2H), 1.69 (m, 4H), 1.49 (m, 4H) ppm; MS (ES) 508.2 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 27, 1H NMR (CDCl3, 300 MHz) 8.55 (d, 1H), 7.89 (s, 1H), 7.82 (m, 1H), 7.65 (m, 1H), 7.44 (m, 2H), 7.30 (m, 1H), 6.84 (br s, 2H) , 6.72 (d, 1H), 6.26 (s, 1H), 3.50 (m, 4H), 2.682.54 (m, 8H), 2.36 (s, 3H), 2.31 (m, 2H) ppm; MS (ES) 469.04 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 28, 1H NMR (DMSO- d6, 300 MHz) 9.27 (s, 1H), 8.60 (s, 1H), 7.94 (d, 1H), 7.88 (br s, 2H), 7.67 (m, 2H), 7.43 (m, 2H), 7.36 (m, 1H), 3.52 (s, 2H), 2.79 (m, 2H), 2.64 (m, 4H), 2.53 (m, 2H), 2.36 (s, 3H), 2.24 (m, 2H) ppm; MS (ES) 440.42 (M +);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 29, 1H NMR (DMSO- d6, 300 MHz) 8.88 (s, 1H), 8.46 (s, 1H), 7.92 (s, 1H), 7.82 (s, 2H),

7.79 (d, 1H), 7.70 (m, 1H), 7.43 (t, 2H), 7.36 (m, 1H), 6.80 (d, 1H), 4.05 (m, 2H),

3.15 (d, 1H), 2.77 (m, 2H), 2.60 (m, 2H), 2.55 (m, 2H), 2.25-2.10 (m, 4H), 1.87 (d, 2H), 1.66 (s, 4H ), 1.40 (m, 4H) ppm; MS (ES) 523.47 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 30, 1H NMR ( DMSO-d6, 300 MHz) 8.89 (s, 1H), 8.46 (s, 1H), 7.90 (d, 1H), 7.81 (s, 2H), 7.77 (s, 1H), 7.69 (m, 1H), 7.44 (d, 2H), 7.37 (t, 1H), 6.80 (d, 1H), 4.15 (d, 2H), 2.72-2.53 (m, 5H), 2.41 (s, 6H), 2.23 (d, 2H), 2.19 (s, 3H), 1.80 (m, 4H), 1.38 (m, 4H) ppm; MS (ES) 552.28 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4-methylpiperazin-1-yl) carbonyl-5,6,7,8-tetrahydroquinolin-3-yl) -1H-1,2,4-triazolo-3,5-diamine, compound # 31, 1H-1, 2,4-triazole-3,5-diamine; 1H NMR (DMSO-d6, 300 MHz) 9.24 (s, 1H), 8.58 (s, 1H), 7.94 (s, 1H), 7.87 (s, 2H), 7.71 (s, 2H), 7.44 (m , 2H),

7.36 (m, 1H), 3.52 (m, 4H), 2.78 (m, 2H), 2.61 (t, 2H), 2.42 (d, 2H), 2.32 (s, 2H), 2.25 (m, 4H), 2.18 (s, 3H), 1.95 (m, 2H), 1.75 (m, 2H) ppm; MS (ES) 551.54 (M +);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (diethylamino) pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 32, 1H NMR (DMSO-d6, 300 MHz) 9.06 (s, 1H), 7.89 (s, 1H), 8.84 (s, 2H), 7.69 (d, 1H), 7.47 (m, 3H), 7.38 (m, 1H), 7.30 ( d, 1H), 6.74 (t, 1H), 3.24 (m, 4H), 3.15 (d, 2H),

2.60-2.54 (m, 8H), 2.23 (t, 2H), 2.10 (m, 2H), 1.80 (s, 1H), 1.01 (s, 6H) ppm; MS (ES) 528.10 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine,

138 compound # 33, 1H-NMR (DMSO-d6, 300 MHz) 10.69 (s, 1H), 8.87 (s, 1H), 7.92 (s, 1H),

7.80 (m, 1H), 7.71 (m, 1H), 7.35-7.57 (m, 4H), 6.91 (d, 1H), 6.85 (d, 1H), 3.03 (m, 4H), 2.43 ( m, 10H), 2.20 (m, 4H), 1.69 (m, 2H), 1.17-1.40 (m, 5H) ppm; MS (ES)

548.20 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 34, 1H-NMR (CDCl3, 300 MHz) 7.89 (s, 1H) , 7.81 (m, 1H), 7.75 (m, 1H), 7.43 (m, 4H), 7.29 (m, 1H), 6.89-6.99 (m, 4H), 3.22 (m, 4H), 2.78 ( m, 4H), 2.58-2.79 (m, 4H), 2.46 (s, 3H), 2.32 (m, 2H) ppm; MS (ES) 468 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 35, 1H-NMR (CDCl3, 300 MHz) 7.91 (s, 1H), 7.81 (m, 1H), 7.44 (m, 3H), 7.26 (m, 4H),

6.85 (s, 2H), 6.59 (s, 1H), 3.51 (s, 2H), 2.59-2.69 (m, 9H), 2.34 (m, 8H) ppm; MS (ES) 482 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³-fluoro-4- (4- (diethylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 36, 1H-NMR (CDCl3, 300 MHz) 7.88 ( s, 1H), 7.82 (m, 1H), 7.44 (m, 3H), 7.40 (m, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.79 (s, 2H) , 6.42 (s, 1H), 3.46 (m, 2H), 2.98 (m, 1H),

2.88 (q, 4H), 2.40-2.75 (m, 9H), 2.36 (m, 2H), 1.91-2.05 (m, 5H), 1.25 (t, 6H) ppm; MS (ES) 540 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl) -N³- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 37, 1H-NMR (CDCl3, 300 MHz) 8.88 (s, 1H), 8.36 (s, 1H), 7.84 (m, 1H), 7.41 (m, 4H), 7.30 (m, 1H), 6.86 (d, 2H), 4.24 (t, 2H), 3.17 (t, 2H), 3.03 (m, 4H), 2.67 (m, 2H), 2.55 (m, 4H), 1.97 (m, 4H) ppm; MS (ES) 483 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl) -N³- (4- (4 (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 38, 1H-NMR (CDCl3, 300 MHz) 8.88 (s, 1H), 8.03 (s, 1H), 7.85 (m, 1H),

7.43 (m, 3H), 7.29 (m, 3H), 6.90 (d, 1H), 6.62 (s, 1H), 6.63 (s, 1H), 3.22 (m, 2H), 3.06 (m, 2H ), 2.55-2.70 (m, 6H), 2.38 (m, 1H), 2.24 (m, 1H), 1.73 (m, 11H), 1.40 (m, 4H) ppm; MS (ES) 548 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-4-yl) -N³- (3-fluoro-4- (4- (diethylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 39, 1H-NMR (DMSO-d6, 300 MHz) 8.92 (m, 1H), 7.76 (d, 1H), 7.42-7.53 (m, 4H), 7.37 (m, 1H), 7.14 (d, 1H), 6.90 (t, 1H), 3.26 (m, 2H), 3.13 (m, 2H), 2.88 (m, 2H), 2.49-2.62 (m, 9H), 1.73 (m, 2H), 1.60 (m, 2H), 0.99 (m, 6H) ppm; MS (ES) 542.28 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (4- (N-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 40, 1H-NMR (CDCl3, 300 MHz) 8.47 (s, 1H) , 7.69 (d, 1H), 7.35 (m, 4H), 7.25 (m, 3H), 7.08 (s, 1

139

H), 6.85 (d, 2H), 3.07 (m, 4H), 2.55 (m, 6H), 2.47 (m, 2H), 2.31 (s, 3H), 2.24 (m,

2H) ppm; MS (ES) 468.15 (M + H);

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (4- (N-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 41, 1H-NMR (CDCl3, 300 MHz) 7.89 (s, 1H) , 7.78 (d, 1H), 7.43 (m, 3H), 7.18 (t, 1H), 7.01 (broad s, 2H), 6.95 (d, 2H), 6.87 (s, 1H), 3.49 (m, 2H), 3.16 (m, 4H), 2.85 (m, 2H), 2.79 (s, 3H), 2.61 (m, 4H), 2.37 (s, 3H) ppm; MS (ES) 483.25 (M + H);

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4 (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 42, 1HNMR (CDCl3, 300 MHz) 7.86 (s, 1H), 7.78 (m, 1H), 7.58 (m, 1H), 7.45 (m, 1H),

7.25 (wide s, 2H), 7.18 (t, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.90 (t, 1H), 4.10 (m, 2H), 3.48 (m , 2H), 2.89 (m, 4H), 2.78 (s, 3H), 2.63 (m, 4H), 1.80 (m, 4H) ppm; MS (ES)

483.19 (M + H);

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-cyclohexylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 43,

1H-NMR (CDCl3 / MeOH-d4, 300 MHz) 7.83 (s, 1H), 7.69 (d, 1H), 7.37 (m, 2H), 7.057.15 (m, 3H), 6.90 (t, 1H) , 3.44 (m, 2H), 3.00-3.10 (m, 6H), 2.82 (m, 3H), 2.74 (s, 3H),

2.27 (m, 1H), 1.91 (m, 2H), 1.77 (m, 2H), 1.60 (m, 1H), 1.10-1.20 (m, 6H) ppm; MS (ES) 569.25 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 44, 1H-NMR (CDCl3, 300 MHz ) 8.53 (s, 1H), 7.24 (d, 1H), 7.43 (m, 2H), 7.31 (d, 1H), 7.04 (d, 1H), 6.90 (m, 3H), 4.20 (t , 2H), 3.08 (t, 2H), 2.89 (m, 4H), 2.59 (m, 2H), 2.52 (m, 2H),

2.32 (m, 2H), 1.89 (m, 4H) ppm; MS (ES) 501.30 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (3-fluoro-4- (4-cyclohexylpiperazinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 45, 1HNMR (CDCl3, 300 MHz) 8.55 (s, 1H), 8.46 (s, 1H), 7.74 (m, 1H), 7.43 (m, 2H), 7.31 (m, 1H), 7.06 (m, 1H), 6.97 (m, 1H), 6.86 (m, 3H), 3.26 (m, 4H), 2.98 (m, 4H), 2.95 (m, 1H), 2.60 (m, 2H), 2.52 (m, 2H), 2.32 (m, 2H), 2.13 (m, 2H), 1.91 (m, 2H), 1.39 (m, 4H), 1.16 (m, 1H) ppm; MS (ES) 554.25 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidin-2-yl) -N³- (4- (4- (2S) bicyclo [2.2.1] heptan-2-yl) piperazinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 46, 1H-NMR (CDCl3, 300 MHz) 8.54 (s, 1H), 7.74 (m, 1H), 7.43 (m, 2H),

7.36 (d, 2H), 7.30 (m, 1H), 6.90 (d, 2H), 6.78 (broad s, 2H), 6.46 (s, 1H), 3.12 (m, 4H), 2.45-2.60 (m , 6H), 2.32 (m, 4H), 2.19 (m, 1H), 2.05 (m, 2H), 1.78 (m, 2H), 1.51 (m, 1H), 1.30-1.40 (m, 4H), 0.98 (m, 1H) ppm; MS (ES) 547.28 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-chloro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 47, 1H-NMR (CDCl3, 300 MHz ) 7.84 (m, 1H), 7.75 (m, 1H), 7.60 (m, 1H), 7.38-7.48 (m, 3H), 7.27

140 (m, 1H), 6.93 (m, 1H), 4.33 (m, 2H), 3.42 (m, 2H), 2.60 (m, 8H), 2.28 (m, 2H), 2.01 (m, 4H) ppm; MS (ES) 517.15 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 48, 1H-NMR (CDCl3, 300 MHz ) 7.65 (m, 1H), 7.56 (m, 1H), 7.34 (m, 2H), 7.20 (m, 1H), 7.13 (m, 1H), 6.89 (t, 1H), 4.08 (t, 2H ), 2.89 (t, 2H), 2.64 (m, 4H), 2.50 (m, 4H), 2.19 (m, 2H),

1.76 (m, 4H) ppm; MS (ES) 501.17 (M + H);

1 - ((Z) dibenzo [b, f] [1,4] thiazepin-11-yl) -N³- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H1,2,4-triazole-3,5-diamine, compound # 49, 1H-NMR (CDCl3, 300 MHz) 11.15 (s, 1H), 7.62 (m, 1H), 7.48-7.58 (m, 4H), 7.42 (m, 1H), 7.36 (m, 1H), 7.33 (m, 1H), 7.29 (m, 1H) ), 7.11 (m, 1H), 6.93 (d, 2H), 4.16 (broad s, 2H), 4.12 (t, 2H), 2.92 (t, 2H), 2.66 (m, 4H), 1.83 (m, 4H) ppm; MS (ES) 498.17 (M + H);

1 - ((Z) dibenzo [b, f] [1,4] thiazepin-11-yl) -N³- (4- (4-N-methylpiperazin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine, compound # 50, 1H-NMR (CDCl3, 300 MHz) 11.10 (s, 1 H)

7.61 (m, 1H), 7.48-7.55 (m, 4H), 7.42 (m, 1H), 7.35 (m, 1H), 7.30 (m, 1H), 7.24 (m, 1H), 7.10 ( m, 1H), 6.95 (d, 2H), 4.24 (broad s, 2H), 3.19 (m, 4H), 2.60 (m, 4H), 2.36 (s, 3H) ppm; MS (ES) 483.09 (M + H); 1 - ((Z) dibenzo [b, f] [1,4] thiazepin-11-yl) -N³- (3-fluoro-4- (4-diethylaminopiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 51, 1H-NMR (CDCl3, 300 MHz) 11.26 (s , 1H), 7.59 (m, 1H), 7.45-7.55 (m, 3H), 7.42 (m, 1H), 7.27-7.38 (m, 2H), 7.18-7.25 (m, 2H), 7.11 ( t, 1H), 6.94 (t, 1H),

4.62 (s, 2H), 3.45 (m, 1H), 2.62 (m, 8H), 1.84 (m, 4H), 1.08 (t, 6H) ppm; MS (ES)

557.15 (M + H);

1- (6,7-dihydro-5H-9-methoxybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 52, 1H-NMR (CDCl3 , 300 MHz) 7.61 (s, 1H), 7.52 (d, 1H), 7.46 (m, 1H),

7.28 (m, 1H), 6.83-6.90 (m, 2H), 6.74 (m, 1H), 3.80 (s, 3H), 3.68 (m, 4H), 3.31 (m, 2H), 2.72 (m, 2H), 2.56 (m, 4H), 2.38 (m, 1H), 2.07 (m, 2H), 1.94 (m, 2H), 1.71-1.80 (m, 5H) ppm; MS (ES) 570.30 (M + H);

1- (6,7-dihydro-5H-10-fluoro-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 53.1H-NMR (CDCl3 , 300 MHz) 10.89 (s, 1H), 7.83 (s, 1H), 7.64 (dd, 1H), 7.54 (dd, 1H), 7.21-7.27 (m, 2H), 7.12 (dt, 1 H), 6.92 (t, 1H), 4.28 (br s, 2H), 3.45 (m, 4H), 2.84 (m, 2H), 2.46-2.75 (m, 5H), 2.26 (m, 2H), 2.03 (m, 2H), 1.90 (m, 6H) ppm; MS (ES)

558.38 (M + H);

1- (6,7-dihydro-5H-10-fluoro-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 54, 1HNMR (CDCl3 / MeOD4, 300 MHz) 8.40 (s, 1H), 7.83 (s, 1H), 7.39-7.46 (m, 2H), 7.16 (m, 1H), 7.04 (m, 2H), 6.93 (t, 1H), 4.15 ( m, 2H), 3.07 (m, 2H), 2.89 (m, 4H), 2.58 (m,

2H), 2.49 (m, 2H), 2.23 (m, 2H), 1.85 (m, 4H) ppm; MS (ES) 519.37 (M + H);

141

1- (6,7-dihydro-5H-10-fluoro-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro4- (4- (cyclohexyl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 55, 1H-NMR (CDCl3, 300 MHz) 10.91 (s, 1H), 7.83 (s, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.27 (m, 1H), 7.05-7.20 (m, 2H), 6.95 (m , 1H), 4.29 (s, 1H), 3.15 (m, 4H); 2.88 (m, 4H), 2.47-2.70 (m, 5H), 2.26 (m, 2H), 1.85-1.90 (m, 4H), 1.66 (m, 1H), 1.10-1.35 (m, 6H) ppm; MS (ES) 572.28 (M + H);

1- (6,7-dihydro-5H-9-methoxybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 56, 1H-NMR (CDCl3, 300 MHz) 8.52 (broad s, 1H), 7.77 (d, 1H), 7.71 (s, 1H),

7.62 (d, 1H), 7.33 (m, 1H), 6.90-7.00 (m, 2H), 6.83 (s, 1H), 4.29 (m, 2H), 3.89 (s, 3H),

3.23 (m, 2H), 3.05 (m, 4H), 2.62 (m, 4H), 2.16 (m, 2H), 1.97 (m, 4H) ppm; MS (ES)

531.21 (M + H);

1- (6,7-dihydro-5H-9-methoxybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (cyclohexyl) piperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 57, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.71 (s, 1H), 7.61 (s, 1H), 7.437.53 (m, 2H), 6.99-7.08 (m, 2H), 6.78 (m, 2H), 6.67 (m, 2H), 3.70 (s, 3H), 2.95 (m, 4H), 2.71 (m, 4H), 2.25-2.50 (m, 4H), 2.12 (m, 1H), 1.82 (m, 2H), 1.62 (m, 2H ), 1.49 (m, 2H), 0.95-1.15 (m, 6H) ppm; MS (ES) 584.14 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 58, 1H-NMR (CDCl3, 300 MHz) 7.87 (s, 1H), 7.81 (m, 1H), 7.61 (wide s, 1H),

7.49 (m, 1H), 7.42 (m, 2H), 7.26 (m, 2H), 7.01 (m, 1H), 6.87 (t, 1H), 3.46 (m, 2H), 2.40-2.65 (m , 14H), 2.95-3.25 (m, 3H), 2.30 (s, 3H), 1.89 (m, 2H), 1.75 (m, 2H) ppm; MS (ES) 634 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine, benzenesulfonic acid salt, (benzenesulfonic acid salt of # 58 );

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 59, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.70 (s, 1H), 7.51 (m, 1H), 7.217.27 (m, 3H), 7.08 (m, 1H), 6.95 (m, 1H), 6.74 ( t, 1H), 3.19 (m, 2H), 2.73 (m, 2H), 2.30-2.45 (m, 5H), 2.00-2.25 (m, 5H), 1.72 (m, 2H), 1.40-1.60 (m , 4H), 1.00-1.20 (m, 4H), 0.72 (d, 3H) ppm; MS (ES) 634 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2- (N-methylcyclopentylamino) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 60,

1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.77 (s, 1H), 7.61 (m, 1H), 7.25-7.35 (m, 3H),

7.15 (m, 1H), 7.76 (d, 2H), 3.97 (m, 2H), 2.76 (m, 2H), 2.40-2.80 (m, 4H), 2.26 (s, 3H),

2.20 (m, 2H), 1.76 (m, 2H), 1.57 (m, 2H), 1.30-1.50 (m, 5H) ppm; MS (ES) 511.24 (M + H);

142

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-dimethylaminopiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 61, 1H-NMR (CDCl3, 300 MHz) 7.87 (m , 1H), 7.94 (m, 1H), 7.64 (m, 1H), 7.42 (m, 3H),

7.25 (m, 2H), 7.00 (m, 1H), 6.90 (m, 1H), 3.40 (m, 2H), 2.57-2.70 (m, 6H), 2.33 (s, 6H), 2.25.2.30 ( m, 2H), 2.19 (m, 1H), 1.90 (m, 2H), 1.72 (m, 2H) ppm; MS (ES) 514.42 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-chloro-4- (4- (pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 62, 1H-NMR ( CDCl3, 300 MHz) 7.86 (s, 1H), 7.80 (m, 1H), 7.61 (m, 1H), 7.43 (m, 2H),

7.29 (m, 2H), 7.16 (wide s, 2H), 7.05 (m, 1H), 6.99 (m, 1H), 3.31 (m, 2H), 2.55-2.65 (m, 9H), 2.30 (m , 2H), 2.18 (m, 2H), 1.98 (m, 2H), 1.82 (m, 6H) ppm; MS (ES) 556.13 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-trifluoromethyl4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 63, (CDCl3 / MeOD4, 300 MHz) 7.73-7.80 (m, 2H), 7.50-7.60 (m, 2H), 7.10-7.35 (m, 4H), 3.98 (m, 2H), 2.88 (m, 2H), 2.40-2.55 (m, 8H ), 2.16 (m, 2H), 2.06 (m, 2H), 1.83 (m, 2H), 1.50-1.75 (m, 5H) ppm; MS (ES) 590.29 (M + H);

1- (6,7-dihydro-5H-9,10- dimethoxy-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 64, 1H-NMR (CDCl3, 300 MHz) 7.81 (s, 1H), 7.65 (m, 1H), 7.37 (s, 1H),

7.25 (m, 1H), 6.88 (t, 1H), 6.79 (s, 1H), 3.96 (m, 6H), 3.80 (m, 2H), 3.51 (m, 2H),

3.17 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 2.45-2.73 (m, 4H), 2.00-2.35 (m, 9H) ppm; MS (ES) 600.21 (M + H);

1- (6,7-dihydro-5H-9,10,11-trimetoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³(3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 65, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.77 (s, 1H), 7.36 (m, 1H), 7.03 (m, 1H), 6.83 (m, 1H), 6.51 (s, 1H), 3.82 (m, 9H ), 3.68 (m, 2H), 3.37 (m, 2H), 3.22 (m, 4H), 3.00 (m, 1H), 2.57 (m, 4H), 1.96 (m, 9H) ppm; MS (ES) 631.00 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (5-methyloctahydropyrrolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 66, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.81 (s, 1H), 7.67 (m, 1H), 7.40 (m, 1H),

7.36 (m, 2H), 7.20 (m, 1H), 7.05 (m, 1H), 6.74 (t, 1H), 3.70 (m, 1H), 3.26 (m, 2H), 3.04 (m, 2H ), 2.84 (m, 2H), 2.72 (s, 3H), 2.70-2.75 (m, 3H), 2.58 (m, 2H), 2.53 (m, 2H), 2.24 (m, 2H) ppm; MS (ES) 512.21 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (N-methylpiperidin-4-yl-N-methylamino) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 67, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.87 (s, 1H), 7.71 (m, 1H), 7.36-7.48 (m,

3H), 7.26 (m, 1H), 7.12 (m, 1H), 7.02 (m, 1H), 3.31 (m, 3H), 2.80 (m, 2H), 2.55-2.70 (m, 9H), 2.30 (m, 2H), 1.94 (m, 4H) ppm; MS (ES) 514.24 (M + H);

143

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 68, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.88 (s, 1H), 7.70 (m, 1H), 7.35-7.45 (m, 3H),

7.26 (m, 1H), 7.16 (m, 1H), 6.99 (t, 1H), 3.55 (m, 1H), 3.31 (m, 4H), 3.17 (m, 2H), 3.02 (t, 1H), 2.55-2.80 (m, 6H), 2.30 (m, 2H), 2.05-2.15 (m, 4H), 1.92 (m, 1H), 1.79 (m, 1H) ppm; MS (ES) 540.29 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-yl-azepan-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 69, 1HNMR (CDCl3 / MeOD4, 300 MHz) 7.88 (s, 1H), 7.70 (m, 1H), 7.37-7.46 (m, 3H), 7.27 (m, 1H), 7.12-7.22 (m, 1H), 7.00 (m, 1 H), 3.40-3.55 (m, 4H), 3.30 (m, 4H), 3.10 (m, 1H), 2.57 (m, 4H), 2.28 (m, 2H), 2.05 (m, 4H), 1.60- 2.00 (m, 6H) ppm; MS (ES) 554.38 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-N-methylpiperidin-4-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 70, 1H-NMR ( CDCl3 / MeOD4, 300 MHz) 7.84 (s, 1H), 7.22 (m, 1H), 7.64 (m, 1H), 7.35-7.45 (m, 2H), 7.29 (m, 1H), 7.24 ( m, 1H), 7.16 (m, 1H), 3.45 (m, 2H),

3.30 (m, 1H), 2.90 (m, 1H), 2.74 (s, 3H), 2.61 (m, 4H), 2.29 (m, 1H), 2.13 (m, 1H),

1.55-1.95 (m, 10H), 1.34 (m, 3H) ppm; MS (ES) 568.18 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (pyrrolidinyl) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 71, 1HNMR (DMSO-d6, 300 MHz) 8.97 (s , 1H), 7.80 (m, 1H), 7.68 (s, 1H), 7.58 (m, 1H), 7.38-7.48 (m, 3H), 7.25 (m, 1H), 6.93 (t, 1H), 3.22 (m, 1H), 2.82 (m, 2H), 2.55-2.70 (m, 6H), 2.49 (m, 4H), 2.28 (m, 2H), 1.92 (m, 2H), 1.73 (m, 4H), 1.61 (m, 2H) ppm; MS (ES) 540.23 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (5-propyloctanehydropyrrolo [3,4-c] pyrrole) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 72, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.87 (s, 1H), 7.71 (m, 1H), 7.40 (m, 3H),

7.14 (m, 1H), 6.83 (t, 1H), 3.30-3.40 (m, 4H), 3.03-3.15 (m, 4H), 2.95 (m, 2H), 2.552.67 (m, 8H), 2.30 (m, 2H), 1.76 (m, 2H) ppm; MS (ES) 540.23 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4 (decahydropyrazino [1,2-a] azepin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 73, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.85 (s, 1H), 7.72 (m, 1H), 7.39 (m, 2H),

7.30 (m, 1H), 7.24 (m, 1H), 7.19 (m, 1H), 6.95 (t, 1H), 3.17-3.55 (m, 12H), 2.57-2.65 (m, 4H), 2.27 (m, 2H), 1.65-2.10 (m, 4H) ppm; MS (ES) 540.53 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (pyrrolidinyl) piperidinyl) phenyl) -1H1,2,4-triazole-3,5-diamine, formic acid salt, (formic acid salt of compound # 71);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (5cyklopentylooktahydropirolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine,

144 compound # 75, 1H-NMR (DMSO-d6, 300 MHz) 9.09 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H),

7.70 (m, 1H), 7.43 (m, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 6.78 (m, 1H), 3.19 (m, 1H),

2.89 (m, 2H), 2.48-2.68 (m, 9H), 2.32 (m, 4H), 1.35-1.70 (m, 9H) ppm; MS (ES) 566.17 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (pyrrolidin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl) phenyl) -1H-1,2,4-triazole-3,5- -diamine, compound # 76, 1H-NMR (DMSO-d6, 300 MHz) 9.38 (broad s, 1H), 9.15 (s, 1H), 7.88 (s, 1H), 7.70 (m, 1H) , 7.43 (m, 2H), 7.38 (m, 1H), 7.29 (m, 1H), 6.90 (t, 1H), 4.08 (m, 2H), 3.48 (m, 2H), 3.22 (m, 1H), 2.97 (m, 2H), 2.40-2.60 (m, 6H), 2.23 (m, 2H),

1.96 (m, 4H), 1.79 (m, 2H), 1.63 (m, 2H), 1.48 (m, 2H) ppm; MS (ES) 566.41 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-azepan-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 77, 1HNMR (CDCl3 / MeOD4, 300 MHz) 7.88 (s, 1H), 7.70 (m, 1H), 7.43 (m, 2H), 7.35 (m, 1H), 7.26 (m, 1H), 7.12 (m, 1H), 6.93 ( t, 1H), 3.39 (m, 1H), 3.15-3.45 (m, 4H), 2.95 (m, 2H), 2.66 (m, 1H), 2.58 (m, 4H), 2.32 (m, 4H) , 1.80-2.20 (m, 9H) ppm; MS (ES) 554.54 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine, compound # 78;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 80, 1H-NMR (DMSO-d6, 300 MHz) 9.24 (s, 1H), 7.91 (s, 1H), 7.71 (m, 1H), 7.46 (m, 3H), 7.34 (m, 2H), 7.00 (t, 1 H), 3.53 (m, 2H), 3.37 (m, 2H), 3.10 (m, 4H), 2.40-2.60 (m, 8H), 2.24 (m, 2H), 2.06 (m, 2H), 1.75 (m , 2H), 1.24 (d, 6H) ppm; MS (ES) 597.17 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³-fluoro-4- (1-methyloctahydropyrrolo [3,4-b] pyrrol-5-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 81, 1H-NMR (CDCl3 / MeOD4 , 300 MHz) 7.80 (s, 1H), 7.62 (m, 1H), 7.35 (m, 3H), 7.20 (m, 1H), 7.05 (m, 1H), 6.73 (t, 1H), 3.80 -3.85 (m, 2H), 3.30 (m, 1H), 2.90-3.20 (m, 4H), 2.83 (s, 3H), 2.56 (m, 2H), 2.51 (m, 4H), 2.24 (m, 2H ), 1.95 (m, 1H) ppm; MS (ES) 512.15 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-N-methylcyclopentylamino) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 82, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.91 (s, 1H), 7.71 (m, 1H), 7.41 (m, 3H), 7.29 (m, 1H), 7.16 (m, 1H), 6.92 (t, 1H), 3.40 (m, 2H), 3.31 (m, 1H), 3.05 (m, 1H), 2.90 (m, 1H), 2.50-2.70 (m, 6H), 2.34 (s, 3H), 2.29 (m, 1H) , 1.87 (m, 6H),

1.73 (m, 2H), 1.55 (m, 4H) ppm; MS (ES) 597.17 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (dipropylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 83,

145

1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.67 (s, 1H), 7.59 (m, 1H), 7.48 (m, 1H), 7.29 (m, 2H), 7.12 (m, 2H), 6.81 ( t, 1H), 3.37 (m, 2H), 3.27 (m, 1H), 2.96 (m, 2H), 2.85 (m,

2H), 2.64 (t, 2H), 2.46 (m, 4H), 2.14 (m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.68 (m, 4H) ppm; MS (ES) 570.38 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (1-propyloctahydro-1H-pyrrolo [3,2-c] pyridin-5-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 84, 1H- NMR (CDCl3 / MeOD4, 300 MHz) 7.78 (s, 1H), 7.61 (m, 1

H), 7.32 (m, 2H), 7.24 (m, 1H), 7.18 (m, 1H), 7.05 (m, 1H), 6.83 (m, 1H), 3.97 (m, 1

H), 3.50 (m, 1H), 3.19 (m, 2H), 2.80-3.05 (m, 4H), 2.45-2.65 (m, 7H), 2.23 (m, 2H),

2.19 (m, 2H), 1.65-1.80 (m, 3H), 0.90 (m, 3H) ppm; MS (ES) 555.40 (M + H); 1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (N-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 85, 1H-NMR (DMSO-d6, 300 MHz) 9.16 (s, 1H), 7.80 (s, 1H), 7.59 (m, 1H), 7.48 (m, 2H), 7.42 (m, 2H), 7.25 (m, 1 H), 6.92 (t, 1H), 2.80 (m, 1H), 2.40-2.50 (m, 12H),

2.28 (m, 6H), 2.13 (s, 3H), 1.76 (m, 2H), 1.53 (m, 2H) ppm; MS (ES) 569 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (tert-butyloxycarbonylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 86, 1H-NMR (CDCl3 / MeOD4, 300 MHz) 7.76 (s, 1H), 7.58 (m, 1H), 7.42 (m, 1H), 7.27 (m, 2H), 7.16 (m, 3H), 3.41 (m, 3H), 3.16 (m , 2H), 2.54 (m, 2H), 2.46 (m, 2H), 2.18 (m, 2H), 1.97 (m, 2H), 1.95 (m, 2H), 1.76 (m, 2H), 1.28 (s, 9H) ppm; MS (ES)

586.19 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-aminopiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 87, 1H-NMR (CDCl / 3MeOD4, 300 MHz) 7.83 (s, 1H), 7.65 (m, 1H), 7.36 (m, 3H), 7.21 (m, 1H),

7.12 (m, 1H), 6.98 (t, 1H), 3.36 (m, 2H), 3.13 (m, 1H), 2.79 (m, 2H), 2.60 (m, .2H),

2.53 (m, 2H), 2.28 (m, 2H), 2.04 (m, 2H), 1.83 (m, 2H) ppm; MS (ES) 486.15 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (5-cyclohexyloctahydropyrrolo [3,4-c] pyrrolyl) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo-3,5-diamine, compound # 88, 1H -NMR (CDCl3 / MeOD4, 300 MHz) 7.83 (s, 1H), 7.68 (m,

H), 7.40 (m, 2H), 7.24 (m, 2H), 7.07 (m, 1H), 6.86 (t, 1H), 3.30 (m, 4H), 3.08 (m,

2H), 2.88 (m, 2H), 2.45-2.65 (m, 8H), 2.26 (m, 2H), 1.97 (m, 8H), 1.82 (m, 2H), 1.61 (m, 2H), 1.45 (m , 2H), 1.18 (m, 4H) ppm; MS (ES) 666.30 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2,3,4,5tetrahydrobenzo [b] oxepin-7-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 89, 1H NMR (CDCl3, 300 MHz) 7.61 (d , 1H), 7.34 (s, 1H), 7.28 (t, 1H), 7.24 (d, 1H), 7.21 (t, 1H), 7.18 (s, 1H), 6.87 (d, 1H ), 6.78 (d, 1H), 5.42 (s, 2H), 4.05 (t, 2H), 3.31 (t, 2H),

2.85-2.60 (m, 4H), 2.05 (m, 2H), 1.71-1.55 (m, 2H), 1.45 (m, 2H) ppm; MS (ES) 440.07 (M + H);

146

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((N-butyl-Nacetoamino) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 90, 1H-NMR (CDCl3, 300 MHz) 7.85 (s, 1H), 7.60 (d, 2H), 7.55-7.19 (m, 6H), 5.55 (s, 2H), 4.61 (s, 1H), 3.34 (m, 2H), 2.76 (d, 2H), 2.1 (s, 2H), 2.05-1.85 (m, 2H), 1.42 (m, 2H), 1.12 (m,

3H) ppm, MS (ES) 497.53 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((5-fluoroindolin-2-one-3-yl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 91,

1H NMR (CDCl3, 300 MHz) 7.66 (d, 2H), 7.59 (d, 2H), 7.31 (s, 1H), 7.30-7.18 (m, 3H), 7.11 (d, 1H), 7.08-7.03 ( m, 3H), 7.00 (t, 1H), 5.93 (s, 2H), 3.71 (s, 1H), 3.58 (d, 1H), 3.33-3.18 (m, 2H), 3.14 (m, 2H), 2:55 (m, 2H), 2.10-1.96 (m, 2H) ppm; MS (ES)

533.14 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-iodopyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 92, 1H-NMR (CDCl3, 300 MHz) 8.73 (s, 1H), 7.61 (d, 1 H), 7.49 (d, 1H), 7.38 (s, 1H), 7.28-7.17 (m, 4H), 5.81 (s, 2H), 2.89 (m, 2H), 2.38 (m, 2H), 2.10 -1.89 (m, 2H) ppm; MS (ES) 497.09 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (pyridin-3-yl) 1H-1,2,4-triazole-3,5-diamine, compound # 93, 1H-NMR (CDCl3, 300 MHz) 8.77 (s, 1H), 8.13 (d, 1H ), 7.67 (d, 1H), 7.46 (d, 1H), 7.35 (s, 1H), 7.22-7.13 (m, 4H), 5.62 (s, 2H), 2.79 (m, 2H), 2.29 (m, 2H), 2.05-1.83 (m, 2H) ppm; MS (ES) 371.07 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (6-aminopyridin-3-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 94, 1HNMR (CDCl3, 300 MHz); 8.98 (s, 1H), 8.88 (s, 1H), 8.09 (d, 1H), 7.69 (d, 1H), 7.59 (d, 1H), 7.53 (s, 1H), 7.29- 7.18 (m, 2H), 6.51 (s, 2H), 5.38 (s, 2H), 2.93 (m, 2H), 2.42 (m, 2H), 2.11-1.92 (m, 2H) ppm; MS (ES) 463.11 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3aminophenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 95, 1H NMR (CDCl3, 300 MHz); 8.75 (s, 1H), 7.96 (d, 1H), 7.73 (d, 1H), 7.56 (d, 1H), 7.51 (s, 1H), 7.31-7.13 (m, 6H), 6.79 (d, 1H), 5.91 (s, 2H), 5.23 (s, 2H), 2.83 (m, 2H), 2.38-2.29 (m, 2H), 2.04-1.96 (m, 2H) ppm; MS (ES) 462.14 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-cyanophenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 96, 1H NMR (CDCl3, 300 MHz) 8.75 (s, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.66 (d, 1H), 7.52 (d, 1H),

7.36 (m, 1H), 7.31-7.17 (m, 6H), 5.73 (s, 2H), 2.79 (m, 2H), 2.31 (m, 2H), 2.06 (m,

2H) ppm; MS (ES) 472.08 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (benzo [d] [1,3] dioxol-6-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 97, 1H NMR ( CDCl3, 300 MHz) 8.89 (s, 1H), 8.02 (m, 1H), 7.57 (d, 1H), 7.38 (s, 1H), 7.34-7.17 (m, 4H), 6.83 (d, 1H), 5.98 (s, 2H), 5.88-5.83 (m, 3H), 2.88 (m, 2H), 2.45 (m, 2H), 1.98 (m, 2H) ppm; MS (ES) 491.10 (M + H);

147

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-methylsulfonamidylphenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 98, 1H NMR (CDCl3, 300 MHz) 8.88 (s, 1H), 8.02 (d, 1H), 7.91 (d, 1H), 7.63 (d, 1H), 7.49 (d, 1H), 7.34 (m, 1H), 7.29-7.15 (m, 6H), 5.53 (s, 2H), 3.08 (s, 3H), 2.83 (m, 2H), 2.29 (m, 2H), 1.97 (m, 2H) ppm; MS (ES) 540.01 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (methylpiperidin-4-yl) phenylyl) -1H-1,2,4-triazole-3,5-diamine, compound # 99, 1H NMR (DMSO-d6, 300 MHz) 9.11 (br s, 1H) , 7.95 (s, 1H), 7.84 (br s, 2H), 7.72-7.69 (m, 1H), 7.56 (d, 2H), 7.46-7.43 (m, 2H), 7.34-7.32 (m, 1H ), 7.12 (d, 2H), 3.01-2.92 (m, 4H), 2.62-2.59 (m, 1H), 2.47 (s, 3H), 2.43-2.24 (m, 4H), 1.76-1.67 (m, 6H) ppm; MS (ES) 467.17 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3,4-dihydro-2Hbenzo [b] [1,4] dioxepin-7-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 100, compound # 100, 1H NMR (DMSO-d6, 300 MHz) 9.05 (s, 1H), 7.83 (br s, 2H), 7.72-7.67 (m, 1H), 7.46-7.43 (m, 2H), 7.38-7.34 (m, 1 H), 7.25-7.18 (m, 3H), 6.85 (d, 2H), 4.08 (m, 2H), 4.01 (m, 2H), 2.59-2.52 (m, 4H), 2.25-2.23 (m, 2H) , 2.05 (m, 2H) ppm; MS (ES)

442.52 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidin-1-ylpiperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 101, 1H NMR (DMSO-d6, 300 MHz) 9.05 (br s, 1 H), 8.88 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.67 (br s, 2H), 7.50-7.43 (m, 2H) , 7.36-7.34 (m, 1H), 6.93-6.86 (m, 2H), 2.61 (m, 4H), 2.56 (m, 1H), 2.42 (m, 4H), 2.25-2.20 (m, 4H) , 2.08-2.04 (m, 2H), 1.97-1.92 (m, 2H), 1.70 (m, 4H), 1.55-1.51 (m, 2H) ppm; MS (ES) 522.37 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4-pyrrolidin-1-ylpiperidinyl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 103, 1H NMR (DMSO-d6, 300 MHz) 9.17 (br s, 1H), 7.96 (s, 1H), 7.84 (br s, 2H), 7.72-7.69 (m, 1H), 7.57 (d, 2H), 7.45-7.43 (m, 2H), 7.36- 7.35 (m, 1H), 7.15 (d, 2H), 3.37 (s, 2H), 2.81-2.78 (m, 2H), 2.66 (m, 4H), 2.46 (m, 2H), 2.21-2.20 (m , 4H), 2.09-2.07 (m, 1H), 1.93-1.81 (m, 4H), 1.71 (m, 4H), 1.50-1.38 (m, 2H) ppm; MS (ES) 536.45 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4-cyclopentylpiperazinyl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 104, 1H NMR (DMSO-d6, 300 MHz) 9.16 (br s, 1H) , 7.96 (s, 1H), 7.84 (br s, 2H),

7.72-7.65 (m, 1H), 7.57 (d, 2H), 7.45-7.43 (m, 2H), 7.37-7.35 (m, 1H), 7.15 (d, 2H),

3.36 (s, 2H), 2.62 (m, 1H), 2.53 (m, 4H), 2.43-2.38 (m, 4H), 2.26-2.23 (m, 4H), 1.73 (m, 2H), 1.58-1.46 (m, 6H), 1.30-1.24 (m, 2H) ppm; MS (ES) 536.59 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidinyl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 105, 1H NMR (DMSO-d6, 300 MHz) 10.22 ( br s, 1H), 9.25 (br s, 1H), 7.91 (s, 1H), 7.87 (br s, 2H), 7.70 (dd, 1H), 7.46-7.42 (m, 3H), 7.37- 7.35 (m, 2H), 6.99 (t, 1H), 3.56-3.51 (m,

148

2H), 3.21-3.18 (m, 1H), 3.07 (m, 2H), 2.66-2.59 (m, 4H), 2.54 (m, 4H), 2.26-2.22 (m,

2H), 2.15-2.11 (m, 2H), 1.99-1.98 (m, 2H), 1.86-1.79 (m, 4H) ppm; MS (ES) 540.29 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-methyl-4- (4-pyrrolidin-1-yl-piperidinyl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 106, 1H NMR (DMSO-d6, 300 MHz) 8.92 ( br s, 1H), 7.91 (s, 1H), 7.82 (br s, 2H), 7.70 (dd, 1H), 7.53 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.35 (m, 1H), 7.26 (d, 1H), 6.94 (d, 1H), 2.98-2.94 (m, 2H), 2.61-2.59 (m, 3H), 2.55 (m, 4H), 2.54 (m, 4H), 2.26 (m, 1H), 2.22 (s, 3H), 2.04 (m, 1H), 1.93-1.89 (m, 2H), 1.68 (m, 4H), 1.55-1.50 (m, 2H) ppm; MS (ES) 536.09 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-methyl-4- (4-pyrrolidin-1-ylpiperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, formic acid (formic acid salt of # 106, 1H NMR (DMSO-d6 , 300 MHz) 8.93 (br s, 1H), 7.91 (s, 1H), 7.82 (br s, 2H), 7.72-7.68 (m, 1H), 7.56-7.52 (m, 1H), 7.45 -7.42 (m, 2H), 7.38-7.34 (m, 1H), 7.25-7.27 (m, 1H), 6.95 (d, 2H), 2.95-2.93 (m, 4H), 2.59 (m, 4H), 2.56-2.46 (m, 5H), 2.28-1.96 (m, 2H), 2.22 (s, 3H), 1.95-1.91 (m, 2H), 1.72 (m, 2H), 1.70 (m, 4H), 1.60- 1.50 (m, 2H) ppm; MS (ES) 536.57 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-cyclopentylpiperazinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 107, 1H NMR (DMSO-d6, 300 MHz) 9.33 (br s, 1 H), 7.92 (s, 1H), 7.88 (br s, 2H), 7.71 (m, 1H), 7.51-7.38 (m, 5H), 7.04 (t, 1H), 3.37 (m, 4H), 3.24 -3.22 (m, 2H), 3.01-2.97 (m, 2H), 2.60 (m, 1H), 2.49 (m, 4H), 2.25 (m, 2H), 2.03 (m, 2H), 1.71 (m, 4H), 1.57 (m, 2H) ppm; MS (ES) 540.24 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4 - ((4isopropylpiperazinyl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 108, 1H NMR (DMSO-d6, 300 MHz) 9.32 (br s, 1H ), 7.96 (s, 1H), 7.87 (br s, 2H), 7.747.69 (m, 1H), 7.64 (d, 2H), 7.45 (d, 2H), 7.38-7.36 (m, 1H ), 7.27 (m, 2H), 3.45 (s, 2H), 3.05 (m, 4H), 2.72 (m, 1H), 2.55 (m, 4H), 2.40 (m, 4H), 2.26 (m, 2H) , 1.22 (d, 6H) ppm; MS (ES) 510.29 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-N-methylpiperidin-4-ylpiperazinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 109, 1H NMR (DMSO-d6, 300 MHz) 9.33 (br s, 1H), 7.91 (s, 1H), 7.88 (br s, 2H),

7.70 (dd, 1H), 7.51-7.35 (m, 5H), 7.04 (t, 1H), 3.25 (m, 4H), 3.02-2.96 (m, 4H), 2.78 (s, 3H), 2.62- 2.58 (m, 1H), 2.56-2.52 (m, 4H), 2.43-2.42 (m, 4H), 2.36-2.33 (m, 2H), 2.26-2.22 (m, 2H), 1.86-1.81 (m, 2H) ppm; MS (ES) 569.27 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (7-methyl-2,7-diazaspiro [4,4] nonan-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 110, 1H NMR (DMSO-d6, 300 MHz) 9.06 (br s, 1H), 7.86 (s, 1H), 7.83 (br s, 2H), 7.70-7.68 (m, 1H), 7.44-7.42 (m, 2H ), 7.37-7.35 (m, 2H), 7.29-7.26 (m, 1H), 6.69 (t, 1

149

H), 3.61-3.57 (m, 4H), 3.30 (m, 4H), 3.15-3.00 (m, 4H), 2.84 (s, 3H), 2.24-2.13 (m,

4H), 2.01-1.90 (m, 2H) ppm; MS (ES) 525.55 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (Nisopropylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 111, 1H NMR (DMSO-d6, 300 MHz) 9.31 ( br s, 1H), 7.91 (s, 1H), 7.87 (br s, 2H), 7.71-7.68 (m, 1H), 7.50-7.36 (m, 5H), 7.04 (t, 1H), 3.51-3.47 (m, 3H), 3.41-3.38 (m, 2H), 3.19 (q, 2H), 2.99 (t, 2H), 2.59 (m, 4H), 2.24-2.20 (m, 2H), 1.28 ( d, 6H) ppm; MS (ES)

514.26 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidinyl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, benzenesulfonic acid salt (benzenesulfonic acid salt # 4, 1H NMR (DMSOd6, 300 MHz) 9.24 (br s, 1H), 7.91 (s, 1H), 7.86 (br s, 2H), 7.72-7.69 (m, 1H), 7.587.54 (m, 2H), 7.47-7.42 (m, 3H), 7.38-7.34 (dd, 2H), 7.31-7.27 (m, 3H), 6.99 (t, 1H),

3.54 (m, 2H), 3.36-3.30 (m, 4H), 3.10 (m, 2H), 2.69-2.67 (m, 1H), 2.63-2.60 (m, 2H), 2.54-2.52 (m, 2H) , 2.26-2.22 (m, 2H), 2.15-2.11 (m, 2H), 2.02 (m, 2H), 1.88-1.82 (m, 2H), 1.78-1.70 (m, 2H) ppm; MS (ES) 538.37 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-ylazetidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 113, 1H NMR (DMSO-d6, 300 MHz) 9.16 ( br s, 1H), 7.90 (s, 1H), 7.85 (br s, 2H), 7.72-7.68 (m, 1H), 7.49-7.47 (m, 1H), 7.45-7.43 (m, 2H ), 7.38-7.29 (m, 2H), 6.59 (t, 1H), 4.154.07 (m, 2H), 3.94-3.92 (m, 2H), 3.80-3.76 (m, 2H), 3.60 (m, 2H), 2.03 (m, 1H), 2.602.54 (m, 4H), 2.26-2.22 (m, 2H), 2.05 (m, 2H), 1.89 (m, 2H) ppm; MS (ES) 512.50 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-methyl-4- (4- (N-methylpiperazin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 114, 1H NMR ( DMSO-d6, 300 MHz) 9.02 (br s, 1H), 7.91 (s, 1H), 7.84 (br s, 2H),

7.72-7.69 (m, 1H), 7.55 (d, 1H), 7.46-7.43 (m, 2H), 7.38-7.35 (m, 1H), 7.31 (m, 1H), 7.02-6.99 (m , 1H), 4.07 (m, 2H), 3.64 (m, 2H), 3.52 (m, 2H) , 3.12-2.95 (m, 4H), 2.78 (s, 3H), 2.71 (m, 1H), 2.61 (t, 2H), 2.56-2.54 (m, 2H), 2.43-2.41 (m, 2H), 2.25 (s, 3H),

2.24 (m, 2H), 2.02-2.00 (m, 2H), 1.72-1.68 (m, 2H) ppm; MS (ES) 565.29 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4 - ((S) - (3-pyrrolidin-1-ylmethyl) pyrrolidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 115, 1H NMR (DMSO- d6, 300 MHz) 9.18 (br s, 1H), 7.88 (s, 1H), 7.85 (br s, 2H),

7.72-7.68 (m, 1H), 7.53-7.51 (m, 1H), 7.46-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.31 (dd, 1H), 6.94 (t, 1H ), 3.99 (m, 2H), 3.13 (m, 4H), 3.01 (m, 4H), 2.60-2.52 (m, 2H), 2.43 (m, 2H), 2.26-2.22 (m, 4H), 2.20- 2.10 (m, 1H), 1.93-1.90 (m, 4H) ppm; MS (ES) 540.28 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidin-1-ylpiperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 116, 1H NMR

150 (CD3OD, 300 MHz) 9.04 (d, 1H), 8.03 (s, 1H), 7.84 (m, 2H), 7.60 (m, 2H), 7.35 (t, 1H), 7.20 (d, 1H), 6.99 (t, 2H), 4.57 (t, 2H), 4.47 (t, 2H), 3.70 (t, 4H), 3.40 (m, 4H), 2.99 (m, 2H), 2.73 (m, 2H), 2.23 ( m, 2H), 2.09 (br s, 4H), 1.84 (m, 2H); MS (ES) 524.12 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 117, 1HNMR (CD3OD, 300 MHz) 8.24 (s, 1 H), 8.00 (s, 1H), 7.82 (m, 1H), 7.48 (m, 2H),

7.35 (m, 1H), 7.20 (m, 1H), 6.98 (m, 1H), 4.61 (m, 4H), 3.48 (m, 4H), 3.02 (m, 4H),

2.76 (m, 4H), 2.21 (m, 2H), 2.10 (br s, 3H), 1.89 (m, 2H); MS (ES) 542.13 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] oxepino [4,5-c] pyridazin-3-yl) -N³- (2- (pyrrolidin-1-ylmethyl) benzo [d] oxazol-5-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 118, 1H NMR (CD3OD, 300 MHz) 8.13 ( s, 1H), 7.84 (m, 1H), 7.69 (m, 1H), 7.53 (m, 1H),

7.38 (m, 1H), 7.20 (m, 2H), 6.95 (d, 1H), 4.60 (m, 4H), 3.74 (s, 2H), 3.05 (m, 4H), 2.12 (m, 4H); MS (ES) 496.08 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidinyl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 119, 1HNMR (CD3OD, 300 MHz) 8.05 (s, 1 H), 7.78 (m, 1H), 7.70 (m, 1H), 7.61 (m, 1H),

7.53 (m, 2H), 7.25 (m, 1H), 7.02 (m, 1H), 3.70 (t, 2H), 3.47 (m, 4H), 3.20 (m, 4H),

2.97 (m, 2H), 2.80 (t, 2H), 2.30-1.80 (m, 8H); MS (ES) 558.18 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidin-1-ylpiperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 120, 1H NMR (CD3OD, 300 MHz) 8.07 (s, 1H), 7.80 -7.48 (m, 6H), 7.39 (m, 2H), 3.78 (t, 2H), 3.46 (m, 4H), 3.24 (m, 4H), 2.95 (m, 2H), 2.43 (m, 2H), 2.26-2.02 (m, 8H); MS (ES) 540.16 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (2-dimethylaminoethyl) - (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -1H-1,2,4-triazolo-3,5-diamine, compound # 121 , 1H NMR (CD3OD, 300 MHz) 8.41 (m, 1H), 7.93 (m, 1H),

7.73 (m, 1H), 7.52-7.23 (m, 3H), 7.20 (m, 1H), 7.02 (m, 1H), 6.79 (m, 1H), 4.24 (t, 3H), 3.53 (t , 2H), 3.29 (m, 6H), 2.93 (s, 3H), 2.92 (s, 3H), 2.60 (m, 4H), 2.28 (m, 2H); MS (ES) 498.18 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (4- (2-dimethylaminoethyl) - (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl)) - 1H-1,2,4-triazolo-3,5-diamine, compound # 122, 1H NMR (CD3OD, 300 MHz) 8.38 (m, 1H), 7.98 (m, 1H),

7.80 (m, 1H), 7.49 (m, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 6.97 (m, 1H), 6.76 (m, 1H),

4.60 (t, 2H), 4.23 (br s, 2H), 3.53 (br s, 2H), 3.28 (m, 6H), 2.94 (s, 3H), 2.92 (s, 3H); MS (ES) 500.13 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (isoindolin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 123, 1H NMR

151 (CD3OD, 300 MHz) 8.03 (s, 1H), 7.80-7.21 (m, 11H), 3.42 (t, 2H), 3.37 (s, 4H), 3.01 (t, 2H); MS (ES) 523.08 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cykloepta [1,2-c] pyridazin-3-yl) -N³-3-fluoro-4- (4-pyrrolidinylmethyl) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 124, 1H-NMR (CD3OD, 300 MHz) 7.88 (s, 1H) , 7.70 (m, 1H), 7.45 (m, 1H), 7.38 (m, 2H),

7.25 (m, 1H), 7.16 (m, 1H), 7.02 (m, 1H), 3.78 (m, 2H), 3.36 (m, 2H), 2.88 (m, 2H),

2.77 (t, 2H), 2.65 * m, 2H), 2.57 (m, 2H), 2.30 (m, 2H), 2.07 (m, 4H), 1.90 (m, 3H), 1.56 (m, 2H); MS (ES) 554.22 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidinylmethyl) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 125, 1H-NMR (CD3OD, 300 MHz) 7.93 (s, 1H ), 7.74 (m, 1H), 7.65 (m, 1H), 7.54 (m, 2H),

7.46 (m, 1H), 7.17 (m, 1H), 7.10 (m, 1H), 3.74 (m, 2H), 3.43 (m, 4H), 3.07 (m, 2H),

2.94 (m, 6H), 2.08 (m, 4H), 1.94 (m, 2H), 1.63 (m, 2H); MS (ES) 572.22 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4 - ((4aR, 8aS) decahydroisoquinol-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 126, 1H NMR (CD3OD, 300 MHz ) 8.02 (s, 1H), 7.80-7.32 (m, 7H), 3.62 (m, 1H), 3.44 (m, 4H),

3.14 (t, 1H), 2.96 (t, 2H), 2.64 (m, 1H), 2.02 (m, 1H), 1.95-1.58 (m, 6H), 1.36 (m, 2H), 1.11 (m , 2H); MS (ES) 543.17 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cykloepta [1,2-c] pyridazin-3-yl) -N³-3-fluoro-4 ((4aR, 8aS) decahydroisoquinol-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 127, 1H NMR (CD3OD, 300 MHz) 8.02 (s, 1H), 7.84 (m, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 7.58 (m, 1H), 7.46 (m, 2H), 7.37 (m, 1H), 3.67 (m, 2H), 3.53 (m, 1H), 3.37 (m, 2H), 2.65 (m, 4H), 2.33 (t, 2H), 1.95 (m, 1H), 1.74 (m , 6H), 1.40 (m, 3H), 1.15 (m, 1H); MS (ES) 525.16 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4 (octahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 128, 1H NMR (CD3OD, 300 MHz) 8.31 (s, 1H), 7.92 (s, 1H), 7.70 (m, 1H),

7.44 (m, 2H), 7.32 (m, 2H), 3.31 (m, 4H), 3.05 (m, 3H), 2.60 (m, 6H), 2.35 (t, 2H), 1.90 (m, 4H), 1.50 (m, 2H); MS (ES) 526.20 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4 (octahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 129, 1H NMR (CD3OD, 300 MHz) 8.38 (s, 1H), 7.97 (s, 1H), 7.77-7.40 (m,

4H), 7.23 (m, 1H), 6.99 (m, 1H), 3.42 (m, 7H), 3.20-2.78 (m, 6H), 1.92 (m, 4H), 1.60 (m, 2H); MS (ES) 544.14 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (2-diethylaminomethyl) pyrrolidin-1-yl-pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 130, 1H NMR (CD3OD, 300 MHz) 8.44 (m, 1H), 8.28 (m, 1H), 7.93 (m, 2H),

7.75 (m, 2H), 7.45 (m, 2H), 6.82 (m, 2H), 4.39 (m, 1H), 3.60-3.30 (m, 4H), 2.66-1.85 (m, 13H), 1.40 (m, 8H); MS (ES) 525.25 (M + H);

152

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (2- (1- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) oxomethyl) benzo [b] thiophen-5-yl) -1H-1,2,4-triazolo-3,5-diamine, compound # 131, 1H NMR (CD3OD, 300 MHz) 8.30 (s, 2H), 7.927.45 (m, 8H), 3.82 (m, 5H), 3.41 (m, 4H), 3.22 (s, 3H), 2.92 (m, 7H), 2.65 (m, 5H); MS (ES) 627.16 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, trifluoroacetic acid salt, compound # 132; 1H-NMR (DMSO-d6, 300 MHz) 9.17 (s, 1H), 7.89 (s, 1H), 7.86 (br. S, 2H), 7.73-7.69 (m, 1H), 7.50 -7.32 (m, 5H), 6.84 (t, J = 9.9 Hz, 1H), 4.00-3.90 (m, 4H), 3.45-3.40 (m, 4H), 3.19-3.10 (m, 4H), 2.71 (m , 1H), 2.62-2.58 (m, 2H), 2.26-2.24 (m, 2H), 2.06-2.02 (m, 2H), 1.89-1.85 (m, 2H) ppm; MS (ES) 525.43 (M);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3diethylaminopyrrolidin-1-yl) pyridin-3-yl) -1-H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 133;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (5-methyloctahydropyrrolo [3,4-c] pyrrolyl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 134;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4- (N- methylpiperazine-4-yl) piperidin-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazolo-3,5-diamine compound # 135, 1H-NMR (CDCl3, 300 MHz) 8.81 (s, 1H), 8.51 (s, 1H), 7.91-7.73 (m, 4H), 7.40 (m, 2H), 7.21 (m, 3H ), 6.51 (m, 2H), 3.25-2.81 (m, 9H), 2.65 (m, 4H), 2.45 (s, 3H), 2.32 (m, 2H), 2.15 (m, 6H), 1.97 (m, 2H), 1.82 (m, 2H), 1.51 (m, 2H) ppm; MS (ES) 592.55 (M + H), 590.30 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -5-methylpyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, trifluoroacetic acid salt, compound # 136; 1 (DMSO-d6, 300 MHz) 9.23 (s, 1H), 8.54 (s, 1H),

7.94 (s, 1H), 7.88 (br. S, 2H), 7.72-7.68 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.35 (m, 1H),

3.54 (m, 2H), 3.39-3.35 (m, 2H), 3.10-3.06 (m, 4H), 2.75-2.71 (m, 1H), 2.63-2.60 (m, 2H), 2.54-2.52 (m, 2H ), 2.26 (s, 3H), 2.26-2.22 (m, 2H), 2.15-2.11 (m, 2H), 2.02 (m, 2H), 1.88-1.82 (m, 2H), 1.76-1.72 (m, 2H ) ppm; MS (ES) 537.31 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydropyrrolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, trifluoroacetic acid salt, compound # 137;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-piperidin-1-yl (E) -propenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 138, 1HNMR (CDCl3, 300 MHz ) 8.85 (s, 1H), 8.53 (s, 1H), 7.95-7.77 (m, 4H), 7.42 (m, 2H),

7.25 (m, 3H), 6.56 (m, 2H), 3.05 (m, 2H), 2.54 (m, 4H), 2.24 (m, 4H), 1.94 (m, 2H),

1.52 (m, 6H) ppm; MS (ES) 494.38 (M + H), 492.29 (MH);

153

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-cyclopentyl6,7,8,9-tetrahydro-5H-pyrido [3,2-d] azepin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 139 , 1H NMR (DMSO-d6, 300 MHz) 10.96 (s, 1H), 9.94 (m, 1H), 9.08 (m, 1H), 8.18 (m, 1H), 7.86 (m, 1H), 7.72 (m, 1H), 7.40 (m, 4H), 4.54 (m, 3H), 3.16 (m, 2H), 2.49 (m, 2H), 2.25-1.51 (m, 16H) ppm; MS (ES) 508.4 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (4- (bicyclo [2.2.1] heptan-2-yl) -1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3 , 5-diamine, compound # 140, 1H NMR (DMSO-d6, 300 MHz) 9.40 (s, 1H), 8.72 (m, 1H),

7.97 (m, 4H), 7.71 (m, 1H), 7.41 (m, 3H), 7.14 (m, 1H), 4.13 (m, 1H), 3.86 (m, 1H), 3.57 (m, 4H), 3.19 (m, 2H), 2.60 (m, 6H), 2.24 (m, 5H), 1.97 (m, 1H), 1.54 (m, 3H),

1.37 (m, 3H), 1.20 (m, 1H) ppm; MS (ES) 563.3 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4- (pyrrolidin-1-yl) piperidin-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 141, 1H-NMR (CDCl3, 300 MHz) 8.91 (s, 1H), 8.33 (s, 2H), 7.97 (s, 1H), 7.83 (m, 2H), 7.61 (s, 1H), 7.50 -7.23 (m, 3H), 7.13 (s, 1H), 6.72-6.41 (m, 2H), 3.37 (m, 1H), 3.22 (m, 6H), 3.05 (m, 2H), 2.76-2.51 ( m, 5H), 2.33 (m, 4H), 2.03 (m, 6H) ppm; MS (ES) 563.25 (M + H), 561.68 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3-piperidin-1-yl) -propanylpyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 142, 1H-NMR (CDCl3, 300 MHz) 8.85 ( s, 1H), 8.53 (s, 1H), 7.95-7.77 (m, 4H), 7.42 (m, 2H), 7.25 (m, 3H), 3.05 (m, 2H), 2.54 (m, 4H), 2.24 (m, 4H), 1.94 (m, 2H), 1.52 (m, 6H), 1.42 (m, 4H) ppm; MS (ES) 496.13 (M + H), 494.17 (MH);

1- (6,7-Dihydro-9-chloro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 143;

1- (6,7-Dihydro-9-chloro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro4- (4- (N-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 144 ;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4- (piperidin-1-yl) piperidin-1-yl) - (E) -propenyl) -pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina. compound # 145, 1H-NMR (CDCl3, 300 MHz) 8.85 (s, 1H), 8.53 (s, 1H), 7.957.77 (m, 4H), 7.42 (m, 2H), 7.25 (m, 3H), 6.56 (m, 2H), 3.29-2.82 (m, 9H), 2.61 (m, 4H), 2.3 (m, 2H), 2.17 (m, 2H), 1.99 (m, 2H), 1.86 (m, 6H) , 1.54 (m, 2H) ppm; MS (ES) 577.27 (M + H), 575.40 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (3- (4-dimethylaminopiperidin-1-yl) - (E) -propenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 146; 1H NMR (CDCl3, 300 MHz) 8.85 (s, 1H), 7.97-7.73 (m, 4H),

7.53-7.21 (m, 6H), 6.53 (m, 2H), 3.22-2.95 (m, 4H), 2.66-2.47 (m, 4H), 2.37 (s, 6H),

154

2.29 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.62 (m, 3H) ppm; MS (ES) 537.51 (M + H), 535.33 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (4-pyrrolidin-1-ylpiperidin-1-yl) pyrimidin-5-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 147;

1H-NMR (CD3OD, 300 MHz) 8.62 (s, 2H), 8.19 (s, 1H), 7.83 (s, 1H), 7.70 (m, 1H),

7.40 (m, 5H), 7.49 (s, 1H), 4.78 (m, 2H), 4.03 (s, 3H), 3.30 (m, 4H), 3.18 (m, 4H), 2.86 (m, 2H), 2.60-1.70 (m, 13H); MS (ES) 524.25 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (4- (piperidin-1-ylmethyl) piperidin-1-yl) pyrimidin-5-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 148; 1H NMR (CD3OD, 300 MHz) 8.71 (s, 1H), 8.59 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.70 (m, 2H), 7.42 (m, 2H) , 7.30 (m, 2H), 4.72 (m, 2H), 3.59 (m, 2H), 3.00-2.52 (m, 10H), 2.38-1.80 (m, 9H), 1.50-1.23 (m, 4H); MS (ES) 552.27 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6 - ((4-piperidin-1-ylpiperidin-1-yl) carbonyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 149; 1H NMR (DMSO-d6, 300 MHz) 9.45 (s, 1H), 7.95 (s, 1H), 7.91 (s, 2H), 7.75-7.55 (m, 2H), 7.41 (m, 4H), 3.61 (m , 2H), 3.37 (m, 2H), 2.94 (m, 4H), 2.65-2.38 (m, 5H), 2.38-2.14 (m, 4H), 1.99-1.50 (m, 6H), 1.34 (m, 2H ) ppm; MS (ES) 565.21 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-piperidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl-1H-1,2,4-triazole-3,5-diamine, compound # 150, 1H NMR (DMSO-d6, 300 MHz) 9.03 (m, 1H), 8.20 (m, 1H), 7.91 (m, 1H), 7.84 (br s, 2H), 7.70 (m, 1H), 7.37 ( m, 5H), 6.99 (m, 1H), 2.54 (m, 6H), 2.22 (m, 5H), 2.03 (m, 4H), 1.36 (m, 10H) ppm; MS (ES) 521.3 (M + H );

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-azetidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl-1H-1,2,4-triazole-3,5-diamine, compound # 151, 1H NMR (DMSO-d6, 300 MHz) 9.21 (m, 1H), 8.03 (m, 1H), 7.70 (m, 1H), 7.60 (br s, 2H), 7.44 (m, 5H) , 7.03 (m, 1H), 2.77 (m, 3H), 2.55 (m, 6H), 1.98 (m, 8H), 1.12 (m, 4H) ppm; MS (ES) 493.6 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H - cyclohepta [b] pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, acid salt trifluoroacetic, compound # 152; 1 (DMSO-d6, 300 MHz) 8.87 (br. S, 1H), 8.04 (m, 2H), 7.99 (br. S, 2H), 7.72-7.70 (m, 1H), 7.46-7.44 (m , 3H), 7.38-7.36 (m, 1H), 3.50-3.46 (m, 4H), 3.18-3.16 (m, 1H), 3.14-3.00 (m, 4H), 2.71-2.55 (m, 4H),

2.26 (m, 4H), 1.98 (m, 2H), 1.84 (m, 2H), 1.59-1.53 ​​(m, 2H) ppm; MS (ES) 508.19 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2-cyclopentyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1H1,2,4-triazole-3,5-diamine, compound # 153;

155

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4-iodophenyl) -1H1,2,4-triazole-3,5-diamine, compound # 156; 1H NMR (DMSO-d6, 300 MHz) 9.40 (s, 1H), 7.97 (s, 1H), 7.89 (s, 2H), 7.70 (m, 1H), 7.61-7.31 (m, 7H), 2.69 -2.43 (m, 4H), 2.22 (m, 2H) ppm; MS (ES) 496.07 (M + H);

1- (spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 175; 1H-NMR (DMSO-d6, 300 MHz) 9.28 (s, 1H), 8.27 (d, 1H), 7.74 (s, 1H), 7.407.52 (m, 2H), 7.26 (m, 1H), 7.17 ( t, 1H), 6.95-7.05 (m, 2H), 3.47 (m, 2H), 3.34 (m, 3H), 2.99 (m, 2H), 2.78 (s, 3H), 2.65 (m, 2H), 2.12 (m, 2H), 1.80-2.10 (m, 9H), 1.68 (m, 2H); MS (ES) 611.30 (M + H);

1- (spiro [chromeno [4,3-c] pyridazine-5,1'-cyclopentane] -3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 176; 1H-NMR (DMSO-d6, 300 MHz) 9.68 (broad s, 1H), 9.28 (s, 1H), 8.27 (d, 1H), 7.74 (s, 1H), 7.40-7.53 (m, 2H), 7.26 (m, 1H), 7.17 (t, 1H), 6.95-7.03 (m, 2H), 3.54 (m, 2H),

3.32 (m, 2H), 3.22 (m, 1H), 3.10 (m, 2H), 2.64 (m, 2H), 1.65-2.30 (m, 16H); MS (ES)

582.31 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 177;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine (formic acid salt) compound # 178; 1H-NMR (DMSO-d6, 300 MHz) 10.76 (s, 1H), 8.21 (s, 1H), 7.77 (m, 1H), 7.76 (wide s, 1H), 7.54 (m, 1H), 7.46 (m , 2H), 7.39 (m, 1H), 7.24 (m, 1H), 7.02 (t, 1H), 3.28 (m, 2H), 2.82 (m, 2H), 2.70 (m, 2H), 2.45-2.60 ( m, 6H), 2.15-2.35 (m, 3H), 1.93 (m, 2H), 1.70 (m, 4H), 1.61 (m, 2H); MS (ES) 540.0 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine (benzenesulfonic acid salt) compound # 179;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (3 (3R) -dimethylaminopyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine (formic acid salt), compound # 180; 1H-NMR (DMSO-d6, 300 MHz) 9.66 (s, 1H), 9.15 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.73-7.70 (m, 1H), 7.49- 7.42 (m, 2H), 7.38-7.31 (m, 2H), 6.87 (t, 1H), 3.52-3.38 (m, 2H), 3.26-3.19 (m, 1H), 2.84 (s, 3H), 2.63- 2.58 (m, 3H), 2.57 (s, 6H), 2.40-2.20 (m, 4H) ppm; MS (ES) 500.71 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 181; 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.93 (s, 1H), 7.85 (br s, 2H), 7.71 (m, 1H), 7.45 (m, 3H), 7.38 (m, 2H), 7.05 (m, 1H), 2.76-2.46 (m, 10H), 2.221.76 (m, 13H) ppm; MS (ES) 507.6 (M + H);

156

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-methyl-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, formic acid salt, compound # 182;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, benzenesulfonic acid salt, compound # 183;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7- (R) pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] anulen-2-yl) -1H-1,2,4-triazole-3,5- diamine, compound # 184; 1 NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.93 (s, 1H), 7.85 (br s, 2H),

7.71 (m, 1H), 7.45 (m, 3H), 7.38 (m, 2H), 7.05 (m, 1H), 2.76-2.46 (m, 10H), 2.23-1.76 (m, 13H) ppm; MS (ES) 507.3 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-diethylamino6,7,8,9-tetrahydro-5H-benzo [7] cancen-2-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 185; 1H NMR (DMSO-d6, 300 MHz) 9.10 (s, 1H), 7.94 (s, 1H), 7.87 (br s, 2H), 7.70 (m, 1H), 7.44 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 2.88 (m, 2H), 2.55 (m, 8H), 2.25 (m, 3H), 1.92-1.24 (m, 12H) ppm; MS (ES) 509.3 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-cyclopentylamino-6,7,8,9-tetrahydro-5H-benzo [7] cancelen-2-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 186; 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.93 (s, 1H),

7.85 (br s, 2H), 7.71 (m, 1H), 7.45 (m, 3H), 7.35 (m, 2H), 7.04 (m, 1H), 3.66 (m, 1H), 3.34 (m, 1H), 2.74 (m, 4H), 2.57 (m, 7H), 2.25 (m, 4H), 1.99 (m, 2H), 1.71 (m, 2H),

1.54 (m, 4H) ppm; MS (ES) 521.3 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (4-cyclopropylmethylpiperazin-1-yl) pyridin-5-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 187; 1H NMR (DMSO-d6, 300 MHz) 9.45 (s, 1H), 8.41 (m, 1H), 8.02 (m, 1H), 7.93 (s, 1H), 7.95 (br s, 2H), 7.71 (m, 1H), 7.45 (m, 2H), 7.37 (m, 1H), 7.08 (m, 1H), 3.61 (m, 2H), 3.40 (m, 2H), 3.17 (m, 6H), 2.55 (m, 4H ), 2.25 (m, 2H), 1.08 (m, 1H), 0.65 (m, 2H), 0.38 (m, 2H) ppm; MS (ES) 509.3 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 188; 1 NMR (DMSO-d6, 300 MHz) 9.06 (s, 1H), 7.93 (s, 1H), 7.84 (br s, 2H), 7.71 (m, 1H), 7.45 (m, 3H), 7.35 (m, 2H), 7.02 (m, 1H), 2.86 (m, 2H), 2.55 (m, 8H), 2.22 (m, 3H), 1.89 (m, 3H), 1.68 (m, 4H), 1.50 (m, 3H ) ppm; MS (ES) 507.3 (M + H); [α] 20 +11.3 (c = 0.84, CH3OH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6- (pyrrolidin-1-yl) -5,6,7,8-tetrahydroquinolin-3-yl) -1H-1,2,4-triazole-3,5-diamine, (formic acid salt) compound # 189; 1H NMR (DMSO-d6, 300 MHz) 9.27 (s, 1H), 8.63 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.89 (s, 2H), 7.67 (m, 2H ), 7.43 (m, 2H), 7.36 (m, 1H),

157

3.38 (s, 2H), 3.02 (s, 2H), 2.75 (s, 4H), 2.60 (t, 1H), 2.23 (m, 4H), 1.73 (s, 4H), 1.48 (m,

1H), 1.21 (m, 2H), 0.83 (s, 1H) ppm; MS (ES) 494.22 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (6-cyclopentyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine, (formic acid salt) compound # 190; 1H NMR (DMSO-d6, 300 MHz) 9.28 (s, 1H), 8.62 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.89 (s, 2H), 7.69 (m, 1H ), 7.64 (s, 1H), 7.43 (m, 2H),

7.37 (m, 1H), 3.64 (s, 2H), 2.78 (s, 4H), 2.69 (t, 1H), 2.61 (t, 2H), 2.53 (t, 2H), 2.23 (t, 2H), 1.89 (s, 2H), 1.63 (d, 2H), 1.49 (m, 4H) ppm; MS (ES) 494.19 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((S) -7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina , compound # 191; 1H-NMR (CDCl3 / MeOD-4, 300 MHz) 8.55 (s, 1H), 7.88 (s, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 3.03 (m, 1H), 2.54-2.87 (m, 12H), 2.26 (m, 4H), 1.80 (m, 4H), 1.49 (m, 2H); MS (ES) 508.27 (M + H);

1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (3-fluoro-4- (4-cyclohexylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 192; 1H-NMR (DMSO-d6, 300 MHz) 8.86 (s, 1H), 7.67 (m, 1H), 7.36-7.56 (m, 10H), 7.22 (m, 1H), 6.89 (t, 1H), 2.88 (m, 4H), 2.62 (m, 6H), 2.46 (m, 2H), 2.17-2.27 (m, 4H),

1.73 (m, 4H), 1.55 (m, 1H), 1.19 (m, 4H); MS (ES) 629.27 (M + H);

1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 193; 1H-NMR (DMSO-d6, 300 MHz) 8.50 (s, 1H), 7.68 (m, 1H), 7.34-7.52 (m, 11H), 6.80 (d, 2H), 3.00 (m, 3H) , 2.65 (m, 2H), 2.49 (m, 1H), 2.43 (m, 4H), 2.14-2.26 (m, 4H), 2.21 (s, 3H); MS (ES) 543.16 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7- (2- (S) metyloksykarbonylo) pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4 triazole-3,5-diamine, compound # 194; 1H-NMR (CDCl3 / Me-OD-4, 300 MHz)

7.78 (s, 1H), 7.62 (m, 1H), 7.29 (m, 3H), 7.16 (m, 1H), 7.05 (m, 1H), 6.93 (d, 1H), 3.96 (s, 1 H), 3.58 (s, 3H), 3.40 (m, 1H), 2.89 (m, 1H), 2.63 (m, 3H), 2.44-2.58 (m, 7H), 2.19 (m, 2H), 1.93 (m, 2H), 1.65-1.80 (m, 3H), 1.27 (m, 2H); MS (ES) 565.33 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- ((7- (2- (S) carboxy) pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo -3,5-diamine (hydrochloric acid salt), compound # 195;

1H-NMR (DMSO-d6, 300 MHz) 8.83 (s, 1H), 7.89 (s, 1H), 7.72 (m 2H), 7.44 (m, 3H),

7.33 (m, 2H), 7.02 (d, 1H), 4.15 (m, 1H), 3.48 (m, 2H), 3.15 (m, 1H), 2.53-2.80 (m, 9H), 2.24 (m, 4H ), 2.02 (m, 1H), 1.89 (m, 1H), 1.79 (m, 1H), 1.42 (m, 2H); MS (ES)

551.25 (M + H);

158

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (bistrifluoroacetic acid salt), compound # 196 ; 1H NMR (DMSO-d6, 300 MHz) 9.47 (s, 1H), 7.97 (s, 1H), 7.91 (s, 2H), 7.77-7.59 (m, 3H), 7.52-7.30 (m, 5H),

6.72 (d, 1H), 6.14 (m, 1H), 3.83 (m, 2H), 3.55 (m, 2H), 3.21 (m, 3H), 3.01-2.69 (m, 9H), 2.66-2.41 (m, 6H), 2.35-1.96 (m, 4H), 1.67 (m, 2H) ppm; MS (ES) 591.31 (M + H),

589.53 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4- (piperidin-1-yl) piperidin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (bistrifluoroacetic acid salt), compound # 197 ; 1NMR (DMSO-d6, 300 MHz) 9.47 (s, 1H), 7.97 (s, 1H), 7.91 (s, 2H), 7.75-7.58 (m, 3H), 7.41 (m, 4H), 6.75 ( d, 1H), 6.13 (m, 1H),

3.86 (m, 2H), 3.61 (m, 2H), 3.37 (m, 2H), 2.94 (m, 4H), 2.65-2.38 (m, 5H), 2.33-2.14 (m, 4H), 1.99-1.52 ( m, 6H), 1.36 (m, 2H) ppm; MS (ES) 576.32 (M + H), 574.51 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (piperidin-1-propyl-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (bistrifluoroacetic acid salt), compound # 198; 1H NMR (DMSO-d6, 300 MHz) 9.46 (s, 1H), 8.03-7.84 (m, 3H), 7.77-7.59 (m, 3H), 7.40 (m, 4H), 6.73 (d, 1H), 6.14 (m, 1H), 3.79 (s, 2H), 3.42 (d, 2H), 2.86 (d, 2H), 2.66-2.41 (m, 4H), 2.23 (m, 2H), 1.80 (m, 2H) , 1.63 (m, 2H), 1.37 (m, 2H) ppm; MS (ES) 493.24 (M + H), 491.34 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (pyrrolidin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (bistrifluoroacetic acid salt), compound # 199; 1H NMR (DMSO-d6, 300 MHz) 9.38 (s, 1H), 8.09-7.81 (m, 3H), 7.71-7.43 (m, 3H), 7.34 (m, 4H), 6.69 (d, 1H), 6.08 (m, 1H), 3.74 (s, 2H), 3.33 (d, 2H), 2.85-2.41 (m, 6H), 2.28 (m, 2H), 1.74 (m, 2H), 1.59 (m, 2H) ppm ; MS (ES) 479.22 (M + H), 477.45 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (3dimethylaminopyrrolidin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (bistrifluoroacetic acid salt), compound # 200; 1H NMR (DMSO-d6, 300 MHz) 9.31 (s, 1H), 7.88 (s, 1H), 7.81 (s, 2H), 7.72 (m, 3H), 7.42 (m, 5H), 6.73 (d, 1H ), 6.18 (m, 1H),

3.90 (m, 2H), 3.64 (m, 2H), 3.17 (m, 5H), 2.74-2.42 (m, 8H), 2.18 (m, 2H), 1.07 (m, 2H) ppm; MS (ES) 522.30 (M + H), 520.51 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (3diethylaminopyrrolidin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine (bistrifluoroacetic acid salt), compound # 201; 1H NMR (DMSO-d6, 300 MHz) 9.48 (s, 1H), 7.97 (s, 1H), 7.92 (s, 2H), 7.71 (m, 3H), 7.40 (m, 5H), 6.75 (d , 1H), 6.14 (m, 1H),

3.95 (m, 2H), 3.69 (m, 2H), 3.18 (m, 5H), 2.70-2.41 (m, 8H), 2.23 (m, 2H), 1.17 (m, 6H) ppm; MS (ES) 550.31 (M + H), 548.55 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (3- (S) -methyl-4cyklopropylometylopiperazyn-1-yl) piperidin-5-yl-1H-1,2,4-triazole-3,5-diamine,

159 (bistrifluoroacetic acid salt), compound # 202; 1NMR (DMSO-d6, 300 MHz) 9.42 (s, 1H), 8.77 (s, 1H), 8.52 (s, 2H), 8.19-7.63 (m, 3H), 7.49-7.29 (m, 2H), 7.05 ( d, 1H), 4.31 (m, 2H), 4.08 (m, 1H), 3.78 (m, 1H), 3.54-2.87 (m, 4H), 2.67-2.38 (m, 5H), 2.27-1.97 (m, 2H), 1.28 (m, 3H), 1.08 (m, 1H), 0.65 (m, 2H), 0.38 (m, 2H) ppm; MS (ES) 523.27 (M + H), 521.39 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-pyrrolidin-1-yl-piperidin-1-yl-prop-1-enyl) -phenyl) -1H-1,2,4-triazole-3,5-diamine, (formic acid salt), compound # 203; 1H NMR (DMSO-d6, 300 MHz) 9.31 (s, 1H), 8.22 (s, 1H), 8.06-7.81 (m, 3H), 7.70 (m, 1H), 7.58 (d, 1H), 7.53-7.28 (m, 4H), 6.42 (d, 1H), 6.09 (m, 1H), 3.04 (d, 2H), 2.88 (m, 2H), 2.71-2.31 (m, 5H), 2.23 (m, 4H), 2.01-1.76 (m, 5H), 1.69 (m, 5H), 1.44 (m, 2H) ppm; MS (ES) 562.28 (M + H), 560.52 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-methylpiperazin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (formic acid salt), compound # 204; 1H NMR (DMSO-d6, 300 MHz) 9.28 (s, 1H), 8.15 (s, 1H), 8.12-7.89 (m, 3H), 7.75 (m, 1H), 7.52 (d, 1H), 7.55-7.22 (m, 4H), 6.45 (d, 1H), 6.05 (m, 1H), 3.04 (d, 2H), 2.26 (m, 4H), 2.46 (m, 4H), 2.27 (s, 3H), 1.95 (m, 2H) ppm; MS (ES) 506.42 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-isopropylpiperazin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (formic acid salt), compound # 205; 1H NMR (DMSO-d6, 300 MHz) 9.21 (s, 1H),

8.19 (s, 1H), 8.12-7.79 (m, 3H), 7.69 (m, 1H), 7.61 (d, 1H), 7.50-7.23 (m, 4H), 6.40 (d, 1H), 6.14 (m, 1H), 3.14 (d, 2H), 2.97 (m, 1H), 2.58 (m, 4H), 2.46-2.37 (m, 4H), 1.88 (m, 2H), 1.06 (m, 6H) ppm; MS (ES) 534.43 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (4-cyclopentylpiperazin-1-ylprop-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine (bismic acid salt), compound # 206; 1H NMR (DMSO-d6, 300 MHz) 9.24 (s, 1H), 8.11 (s, 1H), 8.12-7.85 (m, 3H), 7.74 (m, 1H), 7.51 (d, 1H), 7.53-7.21 (m, 4H), 6.39 (d, 1H), 6.12 (m, 1H), 3.23 (d, 2H), 2.81 (m, 2H), 2.78-2.22 (m, 5H), 2.12 (m, 4H), 2.051.68 (m, 5H), 1.62 (m, 5H), 1.41 (m, 2H) ppm; MS (ES) 562.28 (M + H), 560.32 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (morpholin-4-propyl-1-enyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (bismic acid salt), compound # 207; 1H NMR (DMSO-d6, 300 MHz) 9.46 (s, 1H), 8.03-7.84 (m, 3H), 7.777.59 (m, 3H), 7.40 (m, 4H), 6.73 (d, 1H), 6.14 (m, 1H), 3.82 (m, 4H), 3.65 (m, 2H), 2.64 (m, 4H), 2.37 (m, 4H), 1.87 (m, 2H) ppm; MS (ES) 495.21 (M + H), 493.36 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (8-diethylaminoethyl-9-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt) , compound # 208; 1H NMR (DMSOd6, 300 MHz) 9.35 (s br, 2H), 9.15 (s, 1H), 7.96-7.79 (m, 2H), 7.77-7.58 (m, 3H), 7.537.23 (m, 4H), 7.02 (d, 1H), 4.46 (m, 1H), 3.82-3.49 (m, 2H), 3.40-3.08 (m, 3H), 2.82

160 (m, 1H), 2.71-2.38 (m, 6H), 2.22 (m, 3H), 2.02-1.64 (m, 4H), 1.52 (m, 2H), 1.17 (m, 6H) ppm; MS (ES) 553.31 (M + H), 551.44 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 209; 1 H-NMR (DMSO-d6, 300 MHz) 9.31 (br. S, 1H),

7.91 (s, 1H), 7.88 (br. S, 2H), 7.72-7.69 (m, 1H), 7.51 (s, 1H), 7.46-7.43 (m, 2H), 7.397.36 (m, 2H), 7.04 (t, J = 8.7 Hz, 1H), 3.52-3.47 (m, 2H), 3.39-3.35 (m, 2H), 3.25-3.15 (m, 2H), 2.98-2.94 (m, 2H) , 2.85 (s, 3H), 2.60-2.54 (m, 4H), 2.26-2.22 (m, 2H) ppm; MS (ES) 485.57 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (1-methylpiperidin-3-yl-oxy) phenyl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 210; 1 H-NMR (DMSO-d6, 300 MHz) 9.09 (br. S, 1H),

7.92 (s, 1H), 7.84 (br. S, 2H), 7.72-7.69 (m, 1H), 7.59-7.57 (m, 2H), 7.45-7.42 (m, 2H),

7.37- 7.35 (m, 1H), 6.99-6.97 (m, 2H), 6.93-6.91 (m, 1H), 3.62-3.58 (m, 1H), 3.37-3.26 (m, 2H), 2.98-2.94 ( m, 2H), 2.78 (s, 3H), 2.60-2.54 (m, 4H), 2.25-2.22 (m, 2H), 1.941.89 (m, 2H), 1.72-1.57 (m, 2H) ppm; MS (ES) 483.61 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (1-bicyclo [2.2.1] heptan-2-yl) -piperidin-4-ylphenyl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 211; 1H-NMR (DMSO-d6, 300 MHz) 9.08 (br. S, 1H), 7.94 (s, 1H), 7.83 (br. S, 2H), 7.71-7.67 (m, 1H ), 7.54 (d, J = 8.4 Hz, 2H), 7.457.43 (m, 2H), 7.37-7.35 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 3.02-2.98 (m , 4H), 2.92-2.58 (m, 2H), 2.29-2.23 (m, 4H), 2.13 (m, 1H), 1.89-1.87 (m, 2H), 1.73-1.69 (m, 6H), 1.461.18 (m, 5H), 0.88-0.85 (m, 2H) ppm; MS (ES) 547.36 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (4- (1-cyclopropylmethylpiperidin-4-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 212; 1 H-NMR (DMSO-d6, 300 MHz) 9.18 (br. S, 1H),

7.95 (s, 1H), 7.85 (br. S, 2H), 7.72-7.69 (m, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.46-7.43 (m, 2H) , 7.38-7.35 (m, 1H), 7.12 (d, J = 8.7 Hz, 2H), 3.64-3.61 (m, 4H), 3.07-3.00 (m, 3H),

2.61-2.54 (m, 4H), 2.25-2.22 (m, 2H), 2.03-1.98 (m, 2H), 1.86-1.82 (m, 2H), 1.11-1.07 (m, 1H), 0.66 (d, J = 7.2 Hz, 2H), 0.38 (d, J = 5.1 Hz, 2H) ppm; MS (ES) 507.27 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 213; 1H-NMR (DMSO-d6, 300 MHz) 9.28 (br. S, 1H), 7.94 (s, 1H), 7.87 (br. S, 2H), 7.71-7.69 (m, 1H ), 7.53-7.51 (m, 1H), 7.45-7.43 (m, 3H),

7.38- 7.35 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.18 (m, 2H), 3.36 (m, 2H), 3.00 (m, 2H),

2.61 (m, 2H), 2.52 (m, 2H), 2.25-2.20 (m, 2H) ppm; MS (ES) 425.50 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-cyclopropylmethylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (acid salt

161 trifluoroacetic acid), compound # 214; 1 H-NMR (DMSO-d6, 300 MHz) 9.31 (br. S, 1H),

7.91 (s, 1H), 7.87 (br. S, 2H), 7.72-7.69 (m, 1H), 7.50-7.38 (m, 5H), 7.05 (t, J = 10.2 Hz, 1H ), 3.63 (m, 4H), 3.59 (m, 4H), 3.41-3.37 (m, 1H), 3.21-3.17 (m, 1H), 3.08-3.01 (m, 2H), 2.62-2.58 (m, 2H ), 2.26-2.22 (m, 2H), 1.09 (m, 1H), 0.66 (d, J = 8.1 Hz, 2H), 0.39 (d, J = 4.5 Hz, 2H) ppm; MS (ES) 526.32 (M + H), 524.33 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydroisoquinol-7-yl) -1H-1,2,4-triazole-3,5-diamine, (bistrifluoroacetic acid salt), compound # 215 ; 1 H-NMR (DMSO-d6, 300 MHz) 9.34 (br. S, 1H), 7.95 (s, 1H), 7.87 (br. s, 2H), 7.72-7.69 (m, 1H), 7.57-7.55 (m, 1H), 7.50 (s, 1H), 7.46-7.44 (m, 2H), 7.38-7.36 (m, 1H), 7.12 ( d, J = 8.4 Hz, 1H), 4.424.37 (m, 2H), 3.62 (m, 4H), 3.58 (m, 4H), 3.45-3.35 (m, 2H), 3.14 (m, 2H), 3.04 -3.02 (m, 1H), 2.78 (s, 3H), 2.62 (m, 2H), 2.26-2.23 (m, 2H), 1.93-1.90 (m, 2H) ppm; MS (ES) 522.30 (M + H), 520.12 (MH);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (2- (cyclopropylmethyl) -1,2,3,4-tetrahydroisoquinol-7-yl) -1H-1,2,4-triazole-3,5-diamine, (formic acid salt), compound # 216; 1H-NMR (DMSO-d6, 300 MHz) 9.05 (br. S, 1H), 7.91 (s, 1H), 7.84 (br. S, 2H), 7.72-7.68 (m, 1H ), 7.44-7.31 (m, 5H),

6.93 (d, J = 8.1 Hz, 1H), 3.59 (m, 2H), 2.82-2.75 (m, 4H), 2.60-2.58 (m, 2H), 2.40-2.36 (m, 4H), 2.25-2.23 ( m, 2H), 0.93 (m, 1H), 0.66 (d, J = 8.1 Hz, 2H), 0.39 (d, J = 4.5 Hz, 2H) ppm; MS (ES) 479.22 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (S) fluoropyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3. 5-diamine, (trifluoroacetic acid salt), compound # 217; 1H-NMR (DMSO-d6, 300 MHz) 9.11 (br. S, 1H), 7.93 (s, 1H), 7.84 (br. S, 2H), 7.71-7.69 (m, 1H ), 7.46-7.42 (m, 3H), 7.37-7.35 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 3.42-3.32 (m, 4H), 2.75-2.71 (m, 4H), 2.63-2.61 (m, 4H), 2.30-2.26 (m, 6H), 1.40 (m, 4H) ppm; MS (ES) 525.51 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2- (S) pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine, (trifluoroacetic acid salt), compound # 218; 1H-NMR (DMSOd6, 300 MHz) 9.10 (br. S, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.71-7.69 (m, 1H), 7.46-7.42 (m, 2H ), 7.37-7.33 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 3.28 (m, 2H), 3.16-3.15 (m, 2H),

2.78-2.70 (m, 4H), 2.63-2.59 (m, 2H), 2.56-2.52 (m, 2H), 2.26-2.12 (m, 6H), 1.88-1.83 (m, 2H), 1.61-1.40 (m , 2H), 1.34 (d, J = 5.7 Hz, 3H) ppm; MS (ES) 521.82 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (R) hydroxy-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine, (trifluoroacetic acid salt), compound # 219; 1H-NMR (DMSOd6, 300 MHz) 9.08 (br. S, 1H), 7.92 (s, 4H), 7.83 (m, 1H), 7.72-7.69 (m, 1H), 7.46-7.44 (m, 2H ), 7.36-7.34 (m, 2H), 7.03 (d, 1H), 3.42-3.32 (m, 4H), 2.75-2.71 (m, 4H), 2.632.61 (m, 4H), 2.30-2.26 ( m, 6H), 1.40 (m, 4H) ppm; MS (ES) 523.73 (M + H);

162

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2- (R) methyl-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine, (trifluoroacetic acid salt), compound # 220; 1H-NMR (DMSOd6, 300 MHz) 9.08 (br. S, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.71-7.69 (m, 1H), 7.46-7.42 (m, 2H), 7.37-7.33 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 3.28 (m, 2H), 3.16-3.15 (m, 2H),

2.78-2.70 (m, 4H), 2.63-2.59 (m, 2H), 2.56-2.52 (m, 2H), 2.26-2.12 (m, 6H), 1.88-1.83 (m, 2H), 1.61-1.40 (m , 2H), 1.35 (d, J = 5.7 Hz, 3H) ppm; MS (ES) 521.34 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (S) hydroxy-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3 5-diamine (trifluoroacetic acid salt), compound # 221; 1H-NMR (DMSOd6, 300 MHz) 9.08 (br. S, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.70-7.69 (m, 1H), 7.46-7.43 (m, 2H ), 7.36-7.34 (m, 2H), 7.03 (d, 1H), 3.42-3.32 (m, 4H), 2.75-2.71 (m, 4H), 2.632.61 (m, 4H), 2.30-2.26 (m , 6H), 1.40 (m, 4H) ppm; MS (ES) 523.73 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (3- (R) fluoropyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo3. 5-diamine, (formic acid salt), compound # 222; 1H-NMR (DMSO-d6, 300 MHz) 8.99 (br. S, 1H), 7.91 (s, 1H), 7.83 (br. S, 2H), 7.71-7.69 (m, 1H), 7.46-7.42 (m, 3H), 7.37-7.35 (m, 1H), 7.25 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.42-3.32 (m, 4H), 2.752.71 (m, 4H ), 2.63-2.61 (m, 4H), 2.30-2.26 (m, 6H), 1.40 (m, 4H) ppm; MS (ES) 525.15 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-oxo-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 223; 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.81 (m, 2H), 7.47-6.88 (m, 8H), 2.89 (m, 4H), 2.63 (m, 8H), 2.35 (m, 2H ); MS (ES) 452.22 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-cyclopentylamino-6,7,8,9-tetrahydro-5H-benzo [7] cancen-2-yl) -1H-1,2,4-triazole-3,5-diamine (bistrifluoroacetic acid salt), compound # 224; 1H NMR (CDCl3, 300 MHz)

8.39 (s, 2H), 7.87 (s, 1H), 7.79 (m, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.42 (m, 2H), 7.34 (m, 1H), 7.05 (m, 2H), 3.28 (m, 1H), 3.03 (m, 1H), 2.61 (m, 8H), 2.30 (m, 4H), 2.05 (m, 2H), 1.83 (m, 2H), 1.57- 1.23 (m, 8H); MS (ES) 535.36 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-cyclopropylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazolo-3,5-diamine, (bistrifluoroacetic acid salt), compound # 225 ; 1H NMR (CDCl3, 300 MHz) 8.28 (s, 1H), 7.90 (s, 1H), 7.81 (m, 1H), 7.45-7.07 (m, 9H), 3.48 (m, 4H), 2.62 (m , 6H), 2.35 (m, 4H), 1.57 (m, 2H), 0.90 (m, 2H), 0.71 (d, J = 6.3 Hz, 1H); MS (ES)

493.31 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-hydroxy6,7,8,9-tetrahydro-5H-benzo [7] cancen-2-yl) -1H-1,2,4-triazole-3,5-diamine (acid salt

163 trifluoroacetic acid), compound # 226; 1H NMR (CDCl3, 300 MHz) 7.92 (s, 1H), 7.75 (m, 1H), 7.44 (m, 4H), 7.36 (m, 2H), 7.32 (m, 1H), 7.17 (m, 1H), 7.10 (m, 1H), 3.88 (m, 1H), 3.35 (m, 1H), 2.82 (m, 2H), 2.63 (m, 6H), 2.33 (m, 2H), 2.07 (m, 2H), 1.51 (m, 2H); MS (ES) 454.24 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (4-methylpiperazin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine (salt bistrifluoroacetic acid), compound # 227; 1H NMR (CDCl3, 300 MHz) 7.89 (s, 1H), 7.81 (m, 1H), 7.44 (m, 2H), 7.35 (m, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.07 (m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 2.98 (m, 8H), 2.86-2.58 (m, 8H), 2.55 (s, 3H), 2.33 (m, 5H) , 1.44 (m, 2H); MS (ES) 536.28 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (tetrahydrofuran-2-ylmethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine (salt bistrifluoroacetic acid), compound # 228; 1H NMR (CDCl3, 300 MHz) 8.41 (s, 1H), 7.87 (m, 1H), 7.80 (m, 1H), 7.44 - 7.04 (m, 9H), 4.46 (m, 6H), 3.87 (m, 2H ), 3.25 (m, 2H), 2.63 (m, 6H), 2.33 (m, 3H), 2.10 (m, 1H), 1.95 (m, 2H), 1.58 (m, 2H); MS (ES) 507.27 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-cyclopentylamino-6,7,8,9-tetrahydro-5H-benzo [7] cancen-2-yl) -1H-1,2,4-triazole-3,5-diamine (bistrifluoroacetic acid salt), compound # 229; 1H NMR (CDCl3, 300 MHz) 8.42 (s, 1H), 7.90 (s, 1H), 7.81 (m, 1H), 7.53 (m, 1H), 7.43 (m, 2H), 7.29 (m, 4H), 7.07 (m, 1H), 6.98 (m, 1H), 3.71 (m, 1H), 3.12 (m, 2H), 2.80 (m, 1H), 2.62 (m, 7H), 2.30 (m, 7H), 1.80 (m, 2H), 1.56 (m, 2H); MS (ES) 537.30 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (cyclopropylmethyl) amino-6,7,8,9-tetrahydro-5H-benzo [2] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine (salt of bistrifluoroacetic acid), compound # 230; 1H NMR (CDCl3, 300 MHz) 8.40 (m, 2H), 7.88 (s, 1H), 7.79 (m, 1H), 7.43 (m, 4H), 7.26 (m, 2H), 7.05 (m, 2H), 3.29 (m, 1H), 2.65 (m, 10H), 2.31 (m, 4H), 1.57 (m, 2H), 1.31 (m, 1H), 0.61 (m, 2H), 0.33 (m, 2H); MS (ES) 507.28 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2 (diethylamino) ethyl) methylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine ( bistrifluoroacetic acid salt), compound # 231; 1H NMR (CDCl3, 300 MHz) 8.38 (m, 1H), 7.92 (m, 1H), 7.76 (m, 1H), 7.46-7.10 (m, 8H), 4.04 (m, 8H), 3.02 (m, 6H ), 2.72 (m, 6H), 2.42 (m, 2H), 2.20 (m, 2H), 1.43 (m, 2H), 1.25 (m, 6H); MS (ES) 566.31 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (4-pyrrolidin-1ylopiperydyn-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] anulen-2-yl) -1H-1,2,4-triazolo3,5 -diamine (bistrifluoroacetic acid salt), compound # 232; 1H NMR (CDCl3 + CD3OD, 300 MHz) 7.93 (s, 1H), 7.76 (m, 1H), 7.47 (m, 4H), 7.36 (m, 2H),

164

7.25 (m, 1H), 7.14 (m, 1H), 3.35 (m, 10H), 2.64 (m, 8H), 2.39-2.09 (m, 11H), 1.55 (m,

3H); MS (ES) 590.36 (M + H);

1- (6,7-dihydro-5H- [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (4- (piperidin-1-ylmethyl) piperidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] anulen-2-yl) -1H-1,2,4triazolo- 3,5-diamine (bistrifluoroacetic acid salt), compound # 233; 1H NMR (CDCl3 + CD3OD, 300 MHz) 7.95 (s, 1H), 7.78 (m, 1H), 7.44 (m, 3H), 7.30-7.12 (m, 6H), 3.35 (m, 6H), 3.12-2.47 (m, 12H), 2.39 (m, 6H), 2.10-1.40 (m, 12H); MS (ES) 618.38 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7-Amino-6,7,8,9-tetrahydro-5H-benzo [7] cancen-2-yl) -1H-1,2,4-triazole-3,5-diamine (bistrifluoroacetic acid salt), compound # 234; 1H NMR (CD3OD, 300 MHz) 8.42 (m, 1H), 7.98 (s, 1H), 7.72 (m, 1H), 7.46 (m, 3H), 7.36 (m, 1H), 7.27 (m, 1H), 7.08 (m, 1H), 3.42 (m, 1H), 2.85 (m, 4H), 2.65 (m, 4H), 2.30 (m, 4H), 1.46 (m, 2H); MS (ES) 453.25 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (2-dimethylamino) ethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine (acid salt bistrifluoroacetic acid), compound # 235; 1H NMR (CD3OD, 300 MHz) 8.00 (m, 1H), 7.78 (m, 1H), 7.46 (m, 3H), 7.38 (m, 1H), 7.26 (m, 1H), 7.15 (m, 1H) , 3.55 (m, 5H), 2.98 (m, 6H), 2.86 (m, 4H), 2.64 (m, 4H), 2.31 (m, 4H),

1.49 (m, 2H); MS (ES) 524.31 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (4- (1-bicyclo [2.2.1] heptan-2-yl) -piperidin-4-ylphenyl) -1H-1,2,4-triazole-3,5-diamine (bistrifluoroacetic acid salt), compound # 236; 1H NMR (CD3OD, 300 MHz) 8.06 (m, 1H), 7.77-7.51 (m, 7H), 7.16 (m, 2H), 3.68 (m, 2H), 3.44 (m, 4H), 2.96 (m, 4H ), 2.69 (s, 1H), 2.39 (s, 1H), 2.08 (m, 4H), 1.55 (m, 6H), 1.29 (m, 2H); MS (ES) 565.33 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (7- (carboxymethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 237; 1H NMR (CDCl3 + CD3OD, 300 MHz) 8.09 (s, 1H), 7.95 (s, 1H), 7.43 (m, 3H), 7.33 (m, 2H), 7.09 (m, 2H), 3.48 (m, 1H ), 2.83 (m, 4H),

2.61 (m, 4H), 2.33 (m, 4H), 1.47 (m, 4H); MS (ES) 511.18 (M + H);

1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 238; 1 H-NMR (DMSO-d6, 300 MHz) 8.85 (s, 1H), 7.68 (m, 1H), 7.41-7.55 (m, 9H),

7.36 (m, 1H), 7.22 (m, 1H), 6.91 (t, 1H), 2.63 (m, 4H), 2.48-2.55 (m, 6H), 2.26 (m, 2H),

2.18 (m, 3H), 1.88 (m, 2H), 1.69 (m, 4H), 1.54 (m, 2H); MS (ES) 615.54 (M + H);

1- (6,7-dimethoxy-quinazolin-4-yl) -N³- (5,7,8,9-tetrahydrospiro [cyclohepta [b] pyridine6,2 '- [1,3] dioxolane] -3-yl) -1H-1,2,4-triazole-3,5-diamine ( trifluoroacetic acid salt), compound # 239; 1H-NMR (DMSO-d6, 300 MHz) 9.28 (br. S, 1H), 9.06 (s, 1H), 8.81 (d, J = 12.9 Hz, 1H), 8.18 (br. S, 2H), 7.53 (d, J = 17.4 Hz, 1H), 7.37

165 (d, J = 12.9 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.88-3.86 (m, 4H), 2.93 (m, 2H), 2.89 (m, 2H), 1.89 ( m, 2H), 1.62 (m, 2H) ppm; MS (ES) 491.19 (M + H);

1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6,2 '- [1,3] dioxolane] -3-yl) -1H-1,2,4-triazolo-3,5-diamine (acid salt trifluoroacetic acid), compound # 240; 1H-NMR (DMSO-d6, 300 MHz) 10.37 (br. S, 1H), 8.77 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.09 (br. S, 2H), 3.953.88 (m, 4H), 3.23 (s, 2H), 3.12-3.10 (m, 2H), 2.39 (s, 3H), 1.98-1.96 (m, 2H), 1.74 (m, 2H) ppm; MS (ES) 485.66 (M + H);

1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-7,2 '- [1,3] dioxolane] -3-yl) -1H-1,2,4-triazolo-3,5-diamine (acid salt trifluoroacetic acid), compound # 241; 1H-NMR (DMSO-d6, 300 MHz) 10.35 (br. S, 1H), 8.83 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.08 (br. S, 2H), 3.953.94 (m, 4H), 3.04 (m, 2H), 3.90 (m, 2H), 2.39 (s, 3H), 1.84 (m, 4H) ppm; MS (ES) 485.05 (M + H), 483.15 (MH);

1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5 ', 5'-dimethyl-6,8,9,10tetrahydro-5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl) -1 H-1, 2,4-triazole-3,5-diamine, compound # 246;

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (5 ', 5'-dimetylo6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pyridine-7,2' - [1,3] dioxane] -3-yl) -1H1,2. 4-triazole-3,5-diamine, compound # 247;

SYNTHESIS EXAMPLE [0208] Similarly as described above, the following compounds of formula (Ib) were prepared using appropriately substituted starting materials and reagents:

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4- (indolin-2-one-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 157, 1H NMR (DMSO-d6, 300 MHz) 10.90 (s, 1H), 7.93-7.81 (m, 2H), 7.77-7.71 (m, 1H), 7.52-6.98 (m, 9H), 5.91 (s, 2H) , 4.30-4.19 (m, 2H), 3.48-3.38 (m, 2H), 2.82 (t, 2H), 2.63-2.41 (m, 4H), 2.24-2.19 (m, 3H), 1.72 (d, 2H) ppm; MS (ES) 602.39 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4- (morpholin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 158, 1H NMR (DMSO -d6, 300 MHz) 10.95 (s, 1H), 7.84-7.80 (m, 2H), 7.75-7.70 (m, 1H), 7.47-7.41 (m, 2H), 7.38-7.35 (m, 1H), 7.12 (d, 1H), 7.01 (t, 1H), 5.96 (s, 2H), 3.58-3.55 (m, 4H), 3.38-3.23 (m, 4H), 2.68-2.42 (m, 7H), 2.29-2.18 (m, 4H), 1.86 (d, 2H), 1.611.49 (m, 2H) ppm; MS (ES) 556.55 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (2 ((simethylamino) methyl) 1H-benzo [d] imidazol-5-yl) -1H-1,2,4-triazole-3,5-diamine, compound # 159; 1H NMR (DMSO-d6, 300 MHz) 10.5 (s, 1H), 8.05 (s, 1H), 7.90 (m,

166

1H), 7.80 (br s, 2H), 7.70 (m, 2H), 7.38 (m, 5H), 3.64 (m, 2H), 2.56 (m, 4H), 2.15 (m,

8H) ppm; MS (ES) 467.1 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4- (3,5-dimethylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 160, 1H NMR (DMSO-d6, 300 MHz) 10.7 (s, 1H), 7.82 (br s, 2H), 7.72 (m, 1H), 7.58-7.36 (m, 6H), 6.96 (m, 2H), 3.55 (m, 5H), 2.99 (m, 3H), 2.21 ( m, 5H), 1.08 (d, 6H) ppm; MS (ES) 482.1 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (7- ((bicyclo [2.2.1] heptan-2-yl) (methyl) amino) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1 H-1, 2,4-triazole-3,5-diamine, compound # 161, 1H NMR (DMSO-d6, 300 MHz)

10.9 (s, 1H), 7.84 (br s, 2H), 7.72 (m, 2H). 7.42 (m, 5H), 7.16 (m, 1H), 3.88 (m, 1H),

3.55 (m, 1H), 3.23 (m, 1H), 2.77 (m, 3H), 2.57 (m, 7H), 2.25 (m, 6H), 1.74-1.13 (m, 10H) ppm; MS (ES) 561.3 (M + H);

1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N⁵- (4- (N-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 162, 1H-NMR (CDCl3, 300 MHz) 10.78 (s, 1H), 7.74 (m, 2H), 7.55 (d, 2H), 7.45 (t, 1H), 7.19 (t, 1H),

6.94 (d, 1H), 4.28 (s, 2H), 3.44 (m, 2H), 3.16 (m, 4H), 2.78 (m, 5H), 2.59 (m, 4H), 2.36 (s, 3H) ppm; MS (ES) 483.21 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((5-fluoroindolin-2-one-3-yl) methyl) phenyl) -1H1,2,4-triazole-3,5-diamine, compound # 163,

MS (ES) 533.08 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4- (4-pyrrolidin-1-ylpiperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 164, 1H NMR (DMSO-d6, 300 MHz) 10.71 (br s, 1H ), 7.81 (s, 1H), 7.74-7.72 (m, 1H), 7.55 (d, 2H),

7.45-7.43 (m, 2H), 7.38-7.35 (m, 1H), 6.94 (d, 2H), 5.84 (br s, 2H), 3.61-3.57 (m, 4H), 2.67 (m, 4H), 2.62 -2.60 (m, 1H), 2.57-2.52 (m, 4H), 2.22-2.18 (m, 2H), 1.97-1.92 (m, 2H), 1.72 (m, 4H), 1.60-1.50 (m, 2H) ppm; MS (ES) 522.66 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-4-yl) -N⁵- (4 - ((4-pyrrolidin-1-ylpiperidinyl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 165, 1H NMR (DMSO-d6, 300 MHz) 10.95 (br s, 1H), 7.84 (s, 1H), 7.72 (t, 1H), 7.67 (d, 2H), 7.57 (d, 1H), 7.45 (m, 1H), 7.36-7.35 (m, 1H), 7.25 (d, 2H), 7.15 (d, 1H), 5.89 (br s, 2H), 3.40 (s, 2H), 2.80-2.76 (m, 2H), 2.61 (m, 4H), 2.56 (m, 2H) , 2.42 (m, 1H), 2.252.21 (m, 4H), 1.98-1.80 (m, 4H), 1.69 (m, 4H), 1.40-1.36 (m, 2H) ppm; MS (ES) 536.47 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((4-cyclopentylpyerazinyl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 166, 1H NMR (DMSO-d6, 300 MHz) 10.94 (br s, 1H) , 7.84 (s, 1H), 7.73 (m, 1H), 7.66 (d, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.24 (d, 2H), 5.89 (br s, 2H) , 3.32 (s, 2H),

167

3.30 (m, 4H), 2.71 (m, 1H), 2.46 (m, 4H), 1.73 (m, 2H), 1.57-1.46 (m, 6H), 1.29 (m,

2H) ppm; MS (ES) 536.44 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (4 - ((4-isopropylpyerazinyl) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 167,

1H NMR (DMSO-d6, 300 MHz) 11.01 (br s, 1H), 7.85 (s, 1H), 7.78-7.70 (m, 2H), 7.487.44 (m, 2H), 7.40-7.30 (m, 4H ), 5.95 (br s, 2H), 3.45 (s, 2H), 3.08 (m, 4H), 2.72 (m, 1H), 2.56 (m, 4H), 2.42 (m, 4H), 2.26-2.22 (m , 2H), 1.21 (d, 6H) ppm; MS (ES) 510.18 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-N-methylpiperidin-4-ylpiperazinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 168, 1H NMR (DMSO-d6, 300 MHz) 10.92 (br s, 1H), 7.95 (d, 1H), 7.84 (s, 1H), 7.71 (dd, 1H), 7.48-7.44 (m, 2H), 7.38-7.32 (m, 2H), 7.10 (t , 1H), 3.61-3.58 (m, 4H), 3.27 (m, 2H), 3.10-3.00 (m, 2H), 2.78 (s, 3H), 2.72 (m, 1H), 2.59 (m, 4H), 2.43-2.41 (m, 4H), 2.40-2.36 (m, 2H), 2.26-2.20 (m, 2H), 1.92-1.82 (m, 2H) ppm; MS (ES) 569.22 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (7-methyl-2,7-diazaspiro [4,4] nonan-2-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 169, 1H NMR (DMSO-d6, 300 MHz) 10.73 (br s, 1H), 7.81 (s, 1H), 7.76 (d, 1H),

7.73-7.70 (m, 1H), 7.45-7.42 (m, 2H), 7.36-7.34 (m, 1H), 7.17 (d, 1H), 6.68 (t, 1H),

5.87 (br s, 2H), 3.19-3.16 (m, 4H), 2.56-2.53 (m, 4H), 2.43-2.40 (m, 4H), 2.26 (s, 3H), 2.21-2.17 (m, 2H) , 1.92-1.77 (m, 4H) ppm; MS (ES) 526.26 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (3-pyrrolidin-1-ylazetidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 170, 1H

NMR (DMSO-d6, 300 MHz) 10.82 (br s, 1H), 7.85 (m, 1H), 7.83 (br s, 2H), 7.70-7.66 (m, 1H), 7.46-7.44 (m, 2H), 7.38-7.36 (m, 1H), 7.28 (d, 1H), 7.65 (t, 1H), 5.89 (br s, 2H), 4.20-4.18 (m, 2H), 4.00-3.98 (m, 2H), 3.56 -3.54 (m, 4H), 3.03 (m, 1H), 2.55 (m, 2H), 2.44-2.42 (m, 2H), 2.25-2.20 (m, 2H), 2.05 (m, 2H), 1.89 (m , 2H) ppm; MS (ES)

512.21 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-methyl-4- (4-N-methylpiperazin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 171, 1H NMR (DMSO -d6, 300 MHz) 10.83 (br s, 1H), 7.83 (s, 1H), 7.72 (dd, 1H),

7.55-7.51 (m, 2H), 7.46-7.44 (m, 2H), 7.38-7.35 (m, 1H), 7.03 (d, 1H), 5.90 (br s, 2H), 3.48 (m, 4H), 3.13-3.11 (m, 2H), 3.00 (m, 2H), 2.78 (s, 3H), 2.71-2.69 (m, 1H), 2.632.55 (m, 4H), 2.42 (m, 4H), 2.27 ( s, 3H), 2.23-2.21 (m, 2H), 2.01 (m, 2H), 1.72-1.68 (m, 2H) ppm; MS (ES) 565.32 (M + H);

1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N⁵- (4- (4-pyrrolidin-1-ylpiperidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine, compound # 172, 1H NMR (CD3OD, 300 MHz) 8.01 (s, 1H), 7.80 -7.51 (m, 6H), 7.18 (m, 2H), 3.82 (m, 2H), 3.70

168 (m, 2H), 3.39 (m, 2H), 3.23 (m, 2H), 2.94 (m, 4H), 2.34-1.91 (m, 8H); MS (ES) 540.16 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -5-methylpyridin-3-yl) 1H-1,2,4-triazole-3,5-diamine, trifluoroacetic acid salt), compound # 173; 1 H-NMR (DMSO-d6, 300 MHz) 10.67 (br s, 1H),

8.45 (s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.75-7.70 (m, 1H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 1H), 5.82 ( br s, 2H), 3.60-3.40 (m, 4H), 3.12-3.08 (m, 4H), 2.78-2.71 (m, 3H), 2.552.52 (m, 2H), 2.27 (s, 3H), 2.21 -2.11 (m, 4H), 2.02 (m, 2H), 1.85-1.72 (m, 4H) ppm; MS (ES) 537.57 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (3-pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, trifluoroacetic acid salt, compound # 174; 1H-NMR (DMSO-d6, 300 MHz) 10.81 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.72-7.70 (m, 1H), 7.45-7.43 (m, 2H), 7.37-7.35 (m, 1H), 7.287.26 (m, 2H), 6.85 (t, J = 10.2 Hz), 5.93 (br. s, 2H), 4.00-3.92 (m, 4H), 3.60 (m, 2H), 3.52-3.48 (m, 4H), 2.28-2.26 (m, 1H), 3.12 (m, 2H), 2.40-2.36 ( m, 2H), 2.26-2.20 (m, 2H), 2.08-2.04 (m, 2H), 1.89-1.85 (m, 2H) ppm; MS (ES) 526.34 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine, (trifluoroacetic acid salt), compound # 242; 1 H-NMR (DMSO-d6, 300 MHz) 10.92 (br. S, 1H),

7.92 (d, J = 16.5 Hz, 1H), 7.84 (s, 1H), 7.74-7.71 (m, 1H), 7.46-7.43 (m, 2H), 7.377.30 (m, 2H), 7.11 (t, J = 9.6 Hz, 1H), 3.53-3.42 (m, 4H), 3.24-3.18 (m, 2H), 3.01-2.93 (m, 2H), 2.86 (s, 3H), 2.59-2.54 ( m, 4H), 2.25-2.19 (m, 2H) ppm; MS (ES) 485.57 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine (trifluoroacetic acid salt), compound # 243; 1 H-NMR (DMSO-d6, 300 MHz) 11.03 (br. S, 1H),

7.85 (s, 1H), 7.70-7.67 (m, 2H), 7.58 (s, 1H), 7.47-7.43 (m, 2H), 7.38-7.36 (m, 1H), 7.21-7.19 (d, J = 8.7 Hz, 1H), 5.95 (br. S, 2H), 4.25-4.21 (m, 2H), 3.39-3.36 (m, 2H), 3.02-2.98 (m, 2H), 2.58-2.55 (m, 4H) , 2.26-2.22 (m, 2H) ppm; MS (ES) 425.50 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-cyclopropylmethylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine (trifluoroacetic acid salt), compound # 244; 1 H-NMR (DMSO-d6, 300 MHz) 10.91 (br. S, 1H),

7.95-7.91 (m, 1H), 7.84 (s, 1H), 7.71 (m, 1H), 7.45-7.31 (m, 4H), 7.11 (t, J = 9.0 Hz, 1H), 5.90 (br s, 2H), 3.64-3.60 (m, 2H), 3.21-3.17 (m, 4H), 3.08-3.04 (m, 4H), 2.51 (m, 4H), 2.24-2.21 (m, 2H), 1.10 -1.08 (m, 1H), 0.66 (d, J = 8.1 Hz, 2H), 0.39 (d, J = 4.5 Hz, 2H) ppm; MS (ES) 526.32 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (2- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydroisoquinol-7-yl) -1H-1,2,4-triazole-3,5-diamine (bistrifluoroacetic acid salt), compound # 245; 1 H-NMR (DMSO-d6, 300

169

MHz) 11.07 (br. S, 1H), 7.85 (s, 1H), 7.73-7.71 (m, 2H), 7.65 (s, 1H), 7.46-7.44 (m, 2H), 7.39-7.37 (m , 1H), 7.22 (d, J = 9.0 Hz, 1H), 5.92 (br. S, 2H), 4.47-4.43 (m, 2H),

3.45-3.35 (m, 4H), 3.14 (m, 2H), 3.02 (m, 2H), 2.78 (s, 3H), 2.59 (m, 4H), 2.45-2.35 (m, 1H), 2.23-2.21 (m, 4H), 1.94 (m, 2H) ppm; MS (ES) 522.30 (M + H);

1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (5,7,8,9tetrahydrospiro [cyclohepta [b] pyridine-6.2 '[1,3] dioxolane] -3-yl) -1H-1,2,4-triazolo-3,5-diamine (trifluoroacetic acid salt ), compound # 248; 1H-NMR (DMSO-d6, 300 MHz) 11.14 (br. S, 1H), 9.04 (s, 1H), 8.41 (s, 1H), 7.88 (s, 1H), 7.75-7.71 (m, 1H ), 7.477.44 (m, 2H), 7.38-7.36 (m, 1H), 5.98 (br. S, 2H), 3.98-3.94 (m, 2H), 3.87-3.83 (m, 2H),

3.19 (s, 2H), 3.09-3.07 (m, 2H), 2.60-2.53 (m, 4H), 2.24-2.20 (m, 2H), 197-1.95 (m, 2H), 1.75-1.71 (m, 2H ) ppm; MS (ES) 497.51 (M + H); and 1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N⁵- (7- (S) -pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine , compound # 249; 1H NMR (DMSO-d6, 300 MHz) 10.90 (s, 1H, NH), 7.83 (s, 1H), 7.73 (s, 1H), 7.537.28 (m, 5H), 7.07 (d, 1H), 5.89 (s, 2H), 3.31 (s, 4H), 2.91 (m, 2H), 2.66-2.36 (m, 7H),

2.19 (m, 2H), 1.87 (m, 2H), 1.68 (s, 4H), 1.52 (m, 2H) ppm; MS (ES) 507.32 (M + H).

INVESTIGATION OF COMPOUNDS ACCORDING TO THE INVENTION [0209] Compounds of the invention were tested in the following analysis for their ability to inhibit Axl activity.

Analysis of phosphoactivity in a WESTERN ASSAY cell

REAGENTS AND BUFFERS [0210]

Cell culture plate: 96-well analysis plate (Corning 3610), white, with transparent bottom, treated with tissue culture.

Cells: Hela cells.

Fasting medium: For Axl stimulation: 0.5% FCS (fetal bovine serum) in DMEM, plus Axl / Fc (extracellular AXL domain attached to immunoglobulin Fc region) (R&amp;D, 154-AL) 500ng / mL.

For EGF (epithelial growth factor) stimulation: 0.5% FCS in DMEM (Eulles with Dulbecco's modification).

0.01% poly-L-lysine solution (working solution): 10mg / ml, diluted in PBS (phosphate buffered saline).

Cross-linking of the Axl antibody:

1st: mouse anti-Axl (R&amp;D, MAB154).

2nd: goat-conjugated biotin-SP AffiniPure anti-mouse IgG (H + L) (Jackson ImmunoResearch # 115-065-003).

170

Fixation buffer: 4% formaldehyde in PBS.

Wash buffer: 0.1% TritonX-100 in PBS.

Quenching buffer: 3% H2O2, 0.1% azide in the washing solution, azide and hydrogen peroxide (H2O2) are added fresh.

Blocking buffer: 5% BSA in TBST (saline buffered tris plus 0.1% Tween 20).

Primary antibody: Phospho-Akt rabbit anti-human antibody (Cell Signaling 9271): diluted 1 x 250 in blocking buffer.

Secondary antibody: goat HRP (horseradish peroxidase conjugated) secondary anti-rabbit, mother liquor: Jackson ImmunoResearch (Goat anti-Rabbit HRP, # 111-035-144) diluted 1: 1 in glycerol, stored at 20 ° C. Working solution: dilution 1x 2000 dilution of the mother liquor in blocking buffer.

Chemiluminescent working solution (Pierce, 37030): SuperSignal ELISA (enzyme linked immunosorbant assay) Pico Chemiluminescent substrate.

Crystal violet solution: mother liquor: 2.5% crystal violet in methanol, filtered and stored at ambient temperature. Working solution: dilute 1:20 PBS mother liquor immediately before use.

10% SDS: working solution: 5% SDS (sodium dodecyl sulfate), dissolved in PBS

WAYS:

Day 1:

[0211] A 96 well TC plate (cell culture treated) was coated with 10 μg / mL poly-L-lysine at 37 ° C for 30 min, washed twice with PBS, and air dried for 5 minutes before adding the cells. Hela cells were seeded at a density of 10,000 cells / well and the cells were starved in 100 Pl starvation medium containing Axl / Fc for 24 hours.

Day 2:

[0212] Cells were pre-treated with test compounds by adding 100 μL of 2X test compound to the starvation medium on the cells. Cells were incubated at 37 ° C for 1 hour before stimulation.

[0213] Cells were stimulated as follows by cross-linking of Axl antibodies: A 5X 1 / 2g Axl antibody mixture (37.5 μg / mL 1/100 μg / mL 2gie) was prepared in starvation medium and vibrated at 4 ° C with thorough mixing for 1 -2 hours for clustering. The resulting mixture was heated to 37 ° C. 50 μL 5X Axl 1st / 2nd antibody cluster was added to the cells and the cells were incubated at 37 ° C for 5 min.

171 [0214] After 5 minutes of stimulation, the plate will be flicked off to remove the nutrient and the plate tapped on paper towels. Formaldehyde (4.0% in PBS, 100 μL) was added to fix the cells and the cells were incubated at ambient temperature for 20 min without shaking.

[0215] Cells were washed with plate wash buffer to remove formaldehyde solution. The plate was flicked to remove excess wash buffer and knocked onto paper towels. Quenching buffer (100 μL) was added to each well and the cells were incubated at ambient temperature for 20 min without shaking.

[0216] Cells were washed with plate wash buffer to remove quenching buffer. Blocking buffer (100 μL) was added to each well and the cells were incubated at ambient temperature for at least one hour with gentle shaking.

[0217] Cells were washed with plate wash and diluted primary antibody (50 PL) was added to each well (blocking buffer added instead to the wells with negative control). Plates were incubated overnight at 4 ° C with gentle shaking.

Day 3 [0218] Wash buffer was removed, secondary antibody (100 μL) was diluted and cells were incubated at ambient temperature for 1 hour with gentle shaking. During incubation, the chemiluminescent reagent was brought to ambient temperature.

[0219] Secondary antibody was removed by washing the cells 1X with washing buffer, 1X PBS through a plate washer. PBS was removed from the plate and chemiluminescent reagent (80 μL: 40 μL A and 40 μL B) was added to each well at ambient temperature.

[0220] The chemiluminescence obtained was read with a Luminomitor within 10 minutes to minimize changes in signal intensity. After reading the chemiluminescence, the cells were washed 1X with wash buffer and 1X PBS through a plate washer. The plate was knocked on paper towels to remove excess liquid from the wells and air dried at ambient temperature for 5 minutes.

[0221] Crystal violet working solution (60 μL) was added to each well and the cells were incubated at ambient temperature for 30 min. The crystal violet solution was removed and the wells were washed with PBS, then washed 3X with PBS (200 μL) each for 5 minutes.

[0222] A 5% SDS solution (70 μL) was added to each well and the cells were incubated on a shaker for 30 min at ambient temperature.

[0223] Absorbance was read at 590 nM on a Wallac photospec photospectrometer.

Readings at 590nM indicated the relative number of cells in each well. This relative number of cells was then used to normalize each luminescence reading.

172 [0224] The results of the ability of the compounds of the invention to inhibit Axl activity, when tested in the above analysis, are presented in Tables 1-2 below, where the activity level (eg IC50) for each compound is indicated in each Table. The compound numbers in the Tables refer to the compounds disclosed herein prepared by the methods disclosed herein:

173

IC50 activity:

Table 1

<img file="PL2078010T3_D0027.tif" />

A = &lt;1 μΜ B = 1 to 10 μΜ C =&gt; 10 to 20 μΜ D =&gt; 20 μΜ

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 1</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (2 (pyrrolidin-1-yl) ethoxy) phenyl) 1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 3</td><td>N³- (4- (4-cyclohexanyl-piperazin-1-yl) phenyl) -1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -1H-1,2,4-triazole-3 5-diamine</td><td>H</td><td>gp TR</td><td>FLF Κ'Ν '</td><td>H</td><td>H</td><td>AND</td>

174

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>_R4</td><td>R⁵</td><td>IC50</td>

<td> 4</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2o c] pyridazin-3-yl) -N - (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>and</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 5</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (3-fluoro-4- (4-methyl-3-phenyl-piperazin-1-yl) -phenyl) 1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^η^ 'Ν' '_Ί f</td><td>&gt; BS</td><td>H</td><td>H</td><td>D</td>

<td> 6</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (3-fluoro-4- (4-piperidin-1-yl) piperidin-1-yl) phenyl) 1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>θ "Ρ and</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 7</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (3fluoro-4- (4- (indolin-2-one-1-</td><td>H</td><td>.0 Pi A Pi</td><td>fa APN</td><td>H</td><td>H</td><td>D</td>

175

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>yl) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 8</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4bicyklo [2.2.1] heptan-2-yl) piperazin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>N Uy</td><td>&lt;V y ^ N '</td><td>H</td><td>H</td><td>B</td>

<td> 9</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (morpholin-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>about</td><td>&lt;V &gt; The</td><td>H</td><td>H</td><td>B</td>

<td> 10</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4cyklopentylo) piperazin-1ylokarbonylo) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>about nVI</td><td>&lt;Λ</td><td>H</td><td>H</td><td>B</td>

176

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 11</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (4,5-dihydro-1H-benzo [b] azepin2 (3H -) -on-8-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>0 Λ, X</td><td>fa Αν '</td><td>H</td><td>H</td><td>AND</td>

<td> 12</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((2-pyrrolidin-1-ylethyl) aminocarbonyl) phenyl ) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 13</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (2 ((dimethylamino) methyl) -1Hbenzo [d] imidazol-5-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>H₃C h₃c An "AND</td><td>fV AND^N'</td><td>H</td><td>H</td><td>B</td>

<td> 14</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (4- (2,2,6,6-tetramethylpiperidin-1-yl) ethoxyphenyl) -1H-1,2,4-</td><td>H</td><td>H₃c ch₃CAA ch₃</td><td>(\ Ά '</td><td>H</td><td>H</td><td>B</td>

177

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>_R4</td><td>R⁵</td><td>IC₅0</td>

<td></td><td>triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 15</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>ck: o ,.</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 16</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4-cyclopentyl-2metylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>Cip ch₃</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 17</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (3,5dimetylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>CH, HTA V /</td><td>&lt;V</td><td>H</td><td>H</td><td>AND</td>

178

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 18</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4pirolidyn-1-yl) piperidin-1-yl) -3-cyanophenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>Y γγ</td><td>FY Κ'Ν '</td><td>H</td><td>H</td><td>AND</td>

<td> 19</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((2- (dimethylamino) ethyl) aminocarbonyl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>CH₃ 0 H₃C " ^N N "\ y^H vx</td><td></td><td>H</td><td>H</td><td>B</td>

<td> 20</td><td>1- (6,7-dihydro-3Hbenzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((2- (methoxy) ethyl) aminocarbonyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>CH % about Y</td><td>FY X = N</td><td>H</td><td>H</td><td>B</td>

<td> 21</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((2-pyrrolidin-1-yl) ethyl) aminocarbonyl) -</td><td>H</td><td>^αΥχ</td><td>FY \&gt; = N '</td><td>H</td><td>H</td><td>AND</td>

179

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>_R3</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td></td><td>phenyl) -1 # -1,2,4-triazol-3,5diamina</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 22</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((4- (pyrrolidin-1-yl) piperidin-1-yl) carbonyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td> 0 _οο^Λα</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 23</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- ((bicyclo [2.2.1] heptan-2-yl) amino) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazol-3 5-diamine</td><td>H</td><td>-CO.</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 24</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2₃c] pyridazin-3-yl) -N³- (7 ((bicyclo [2.2.1] heptan-2-yl) (methyl) amino) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4- triazole-3,5diamina</td><td>H</td><td>ηλΟΟα</td><td></td><td>H</td><td>H</td><td>B</td>

180

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 25</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4-cyclopentyl-1,4-diazepan-1-yl) pyridin-3-yl) -1 H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td> 00</td><td>H</td><td>H</td><td>AND</td>

<td> 26</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7cyklopentylo-6,7,8,9-tetrahydro-5H-pyrido [3,2-d] azepin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>c&gt; OCX</td><td>(Λ 00</td><td>H</td><td>H</td><td>B</td>

<td> 27</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1-H-1,2,4-triazole-3,5diamina</td><td>H</td><td>k ^ -NN Ux</td><td> 00</td><td>H</td><td>H</td><td>AND</td>

<td> 28</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6-methyl-5,6,7,8-tetrahydro-1,6naftyrydyn-3-yl) -1H-1,2,4</td><td>H</td><td> „,=.00</td><td>&lt;V 00</td><td>H</td><td>H</td><td>AND</td>

181

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 29</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridin-3-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>B</td>

<td> 30</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>^HSC'on^atxX</td><td>Κ = Ν</td><td>H</td><td>H</td><td>AND</td>

<td> 31</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4-methylpiperazin-1yl) carbonyl-5,6,7,8-tetrahydroquinolin-3-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>_Ογαχ about Ν ch₃</td><td></td><td>H</td><td>H</td><td>AND</td>

182

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 32</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (diethylamino) pyrrolidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>^hiV_N^^CH3^t?'about.</td><td>&lt;V ^ N</td><td>H</td><td>H</td><td>AND</td>

<td> 33</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4- (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>&lt;Λ y = N '</td><td>H</td><td>H</td><td>B</td>

<td> 34</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>and</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 35</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-1,2,4</td><td>H</td><td>AA</td><td>&lt;Λ Ά</td><td>H</td><td>H</td><td>AND</td>

183

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 36</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (diethylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>^CH3 χΑ ^ '</td><td>&lt;Λ K = N</td><td>H</td><td>H</td><td>AND</td>

<td> 37</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyrimidin-4-yl) -N³- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>/ A- ° '/' i vx</td><td>l&gt; = N X^N</td><td>H</td><td>H</td><td>AND</td>

<td> 38</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyrimidin-4-yl) -N³- (4- (4- (bicyclo [2.2.1] heptan-2-yl) piperazin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>uu</td><td>/ Λ = Ν</td><td>H</td><td>H</td><td>AND</td>

184

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 39</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyrimidin-4-yl) -N³- (3-fluoro-4- (4- (diethylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>h₃C^CH3 k / N_ ^._fAJL /</td><td>ί Λ = Ν ^ kk / N</td><td>H</td><td>H</td><td>AND</td>

<td> 40</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyrimidin-2-yl) -N³- (4- (N- methylpiperazine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^H’^C'_Nx&gt;^ljv \ oz</td><td>N^/\ / 0nkk)</td><td>H</td><td>H</td><td>B</td>

<td> 41</td><td>1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4.5₃c] pyridazin-3-yl) -N - (4- (N-methylpiperazin-1-yl) phenyl) 1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^H3CABOUT . k ^ yy uu</td><td>ch₃/ N \ ^ Ίμ '^Ν</td><td>H</td><td>H</td><td>B</td>

<td> 42</td><td>1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>O0U</td><td>ch₃</td><td>H</td><td>H</td><td>AND</td>

185

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 43</td><td>1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4.5₃c] pyridazin-3-yl) -N - (3-fluoro-4- (4-cyclohexylpiperazinyl) phenyl o) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td></td><td>ch₃/ N Χ ^ Ν '^</td><td>H</td><td>H</td><td>B</td>

<td> 44</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃d] pyrimidin-2-yl) -N - (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>N^/ \ /</td><td>H</td><td>H</td><td>AND</td>

<td> 45</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃d] pyrimidin-2-yl) -N - (3-fluoro-4- (4-cyclohexylpiperazinyl) phenyl o) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>"X".</td><td>^{n / a} \ / \ ^ NjQ)</td><td>H</td><td>H</td><td>AND</td>

<td> 46</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyrimidin-2-yl) -N³-(4-(4-</td><td>H</td><td>ou</td><td>Ν^/Λ / {Tj</td><td>H</td><td>H</td><td>AND</td>

186

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>(2S) bicyclo [2.2.1] heptan-2-yl) -piperazynylofenylo) -1H1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 47</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-chloro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>Ύ '</td><td>H</td><td>H</td><td>B</td>

<td> 48</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>Ya</td><td>(Λ Y = n '</td><td>H</td><td>H</td><td>B</td>

<td> 49</td><td>1 - ((Z) dibenzo [b, f] [1,4] tiazepin11-yl) -N³- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>?! " • Yo</td><td>H</td><td>H</td><td>B</td>

187

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 50</td><td>1 - ((Z) dibenzo [b, f] [1,4] tiazepin11-yl) -N³- (4- (N- methylpiperazine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>'-"AT</td><td>Ο- »,</td><td>H</td><td>H</td><td>B</td>

<td> 51</td><td>1 - ((Z) dibenzo [b, f] [1,4] tiazepin11-yl) -N³- (3-fluoro-4- (4dietyloaminopiperydyn-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>h₃C Γ^ΝΥΊ CH₃</td><td>Y ί-O</td><td>H</td><td>H</td><td>B</td>

<td> 52</td><td>1- (6,7-dihydro-5H-9metoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>h₃c (Λ Ø^N</td><td>H</td><td>H</td><td>AND</td>

<td> 53</td><td>1- (6,7-dihydro-5H-10fluorobenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^€· Y,_FAA</td><td>ABOUT?</td><td>H</td><td>H</td><td>AND</td>

188

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 54</td><td>1- (6,7-dihydro-5H-10fluorobenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>H / P</td><td>H</td><td>H</td><td>AND</td>

<td> 55</td><td>1- (6,7-dihydro-5H-10fluorobenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (cyclohexyl) piperazin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>Y0A</td><td>0 / N = 3 /AND'</td><td>H</td><td>H</td><td>C</td>

<td> 56</td><td>1- (6,7-dihydro-5H-9metoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>h₃c id p</td><td>H</td><td>H</td><td>B</td>

189

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 57</td><td>1- (6,7-dihydro-5H-9metoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (cyclohexyl) piperazin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>gp</td><td>H₃c ppp ° hf and</td><td>H</td><td>H</td><td>D</td>

<td> 58</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^{H, C}ABOUT AND^Np nay</td><td>fi Χ = ν '</td><td>H</td><td>H</td><td>AND</td>

<td> 59</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-metylopiperydyn1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^VYG</td><td>fi y = N</td><td>H</td><td>H</td><td>AND</td>

190

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 60</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (2- (Nmetylocyklopentyloamino) phenyl o) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>«./n about</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 61</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4dimetyloaminopiperydyn-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>ch₃h₃c 'ⁿY ^_FV / s</td><td>Y^N</td><td>H</td><td>H</td><td>AND</td>

<td> 62</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-chloro-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>Ύ τα</td><td>&lt;Λ Y</td><td>H</td><td>H</td><td>AND</td>

191

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 63</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N- (3-trifluoromethyl-4- (4-pyrrolidin-1-yl-piperidin-1-yl) phenyl) 1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>0Χ ; 0G</td><td>(Λ 00</td><td>H</td><td>H</td><td>B</td>

<td> 64</td><td>1- (6,7-dihydro-5H-9,10dimetoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>θΥΊ nay</td><td>H₃C bbbo^zCH3mb b^N'</td><td>H</td><td>H</td><td>B</td>

<td> 65</td><td>1- (6,7-dihydro-5H-9,10,11trimetoksybenzo [6,7] cyclohepta [1,2-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>G "yx ,thirty</td><td>h₃c Cfc ° '^m30Ή ° 'CH₃ 0^N'</td><td>H</td><td>H</td><td>AND</td>

<td> 66</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (5-metylooktahydropirolo [3,4-c] pyrrolyl) phenyl) -</td><td>H</td><td>ABOUT,</td><td>&lt;V 00</td><td>H</td><td>H</td><td>AND</td>

192

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td> 1_Jff-1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 67</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (N-methylpiperidin-4-yl-N-methylamino) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>ch₃_HJC, N, J _faaa</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 68</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>n &lt;Χχν</td><td>ρΑ Α</td><td>H</td><td>H</td><td>AND</td>

<td> 69</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-yloazepan-1-yl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>CA σ _fxa</td><td>ο /</td><td>H</td><td>H</td><td>AND</td>

193

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 70</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-N-methylpiperidin-4-yl-piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^h’^c'nX op</td><td>fV X&gt; = N</td><td>H</td><td>H</td><td>AND</td>

<td> 71</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (pyrrolidinyl) piperidinyl) phenyl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td></td><td>s ^N</td><td>H</td><td>H</td><td>AND</td>

<td> 72</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (5-propylooktahydropirolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>(Λ &gt; T = n '</td><td>H</td><td>H</td><td>AND</td>

194

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 73</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (dekahydropirazyno [1,2-a] azepin-2-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>pP y ^ N</td><td>H</td><td>H</td><td>AND</td>

<td> 75</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (5cyklopentylooktahydropirolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^α"φ</td><td>PP y == N '</td><td>H</td><td>H</td><td>AND</td>

<td> 76</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-yl) -8-azabicyclo [3.2.1] oct-8-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>^G'td γα</td><td>pP y ^ N</td><td>H</td><td>H</td><td>AND</td>

195

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 77</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-yloazepan-1-yl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>f ~ c &gt; TN '</td><td>H</td><td>H</td><td>AND</td>

<td> 78</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^h’^c'N ^ ^ "ΥΊ cn</td><td>fc</td><td>H</td><td>H</td><td>AND</td>

<td> 80</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-isopropylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>ch₃Cn.</td><td>Ή^Ν'</td><td>H</td><td>H</td><td>AND</td>

196

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 81</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (1-metylooktahydropirolo [3,4-b] pyrrol-5-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>.Qa h₃c</td><td> &lt;00</td><td>H</td><td>H</td><td>AND</td>

<td> 82</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (N-metylocyklopentyloamino) piperidinyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>CH₃Cpk_fAJU</td><td>&lt;00 • H ^ N '</td><td>H</td><td>H</td><td>AND</td>

<td> 83</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (dipropylamino) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>h₃C because.</td><td>) Tn '</td><td>H</td><td>H</td><td>B</td>

197

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 84</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (3-fluoro-4- (1-propyloctahydro-1H-pyrrolo [3,2-c] pyridin-5-yl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>h₃c s_FAJy-</td><td> 00</td><td>H</td><td>H</td><td>AND</td>

<td> 85</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4- (N- methylpiperazine-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>α</td><td>fi 0</td><td>H</td><td>H</td><td>AND</td>

<td> 86</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (tertbutyloksykarbonyloamino) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>H^H0». _Fxf</td><td>0? y = N</td><td>H</td><td>H</td><td>B</td>

198

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 87</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-amino-piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>h₂n_x-^</td><td>PC AND'</td><td>H</td><td>H</td><td>AND</td>

<td> 88</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (5-cykloheksylooktahydropirolo [3,4-c] pyrrolyl) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>% AND", CA</td><td>&lt;V • ^ pN</td><td>H</td><td>H</td><td>AND</td>

<td> 89</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2,3,4,5-tetrahydrobenzo [b] oxepin-7-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>Ca</td><td></td><td>H</td><td>H</td><td>B</td>

199

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 90</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((n-butyl Nacetoamino) methyl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>γχα</td><td>fV Y '</td><td>H</td><td>H</td><td>B</td>

<td> 91</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N- (4 - ((5fluoroindolin-2-on-3-yl) methyl) phenyl) -1H- 1,2,4-triazolo-3,5-diamine</td><td>H</td><td> 0</td><td>&lt;Λ Y '</td><td>H</td><td>H</td><td>D</td>

<td> 92</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6jodopirydyn-3-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>'AT</td><td>(Λ Y '</td><td>H</td><td>H</td><td>D</td>

<td> 93</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>Ox</td><td>(V Y '</td><td>H</td><td>H</td><td>D</td>

200

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 94</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (6 aminopirydyn-3-ylo) pyridin-3-yl) -1 H-1,2,4-triazol-3,5diamina</td><td>H</td><td>H₂NN</td><td>(Λ AND^N'</td><td>H</td><td>H</td><td>D</td>

<td> 95</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3-aminophenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>«χΑχ Μ-χ</td><td>fi AND*'</td><td>H</td><td>H</td><td>D</td>

<td> 96</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3-cyanophenyl) pyridine-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>IA Οχ</td><td>&lt;1 AND</td><td>H</td><td>H</td><td>D</td>

<td> 97</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (benzo [d] [1,3] dioxol-6-yl) pyridin-3-yl) -1 H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>/ - ° o i. ga</td><td>fV &gt; A '</td><td>H</td><td>H</td><td>D</td>

201

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 98</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3metylosulfinamidylofenylo) pyridin-3-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>H₃CX P.</td><td>&lt;V y = N '</td><td>H</td><td>H</td><td>D</td>

<td> 99</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (4- (methylpiperidin-4-yl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td>&lt;Λ pr</td><td>H</td><td>H</td><td>AND</td>

<td> 100</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (3,4-dihydro-2Hbenzo [b] [1,4] dioxepin-7-yl) 1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>CM</td><td>Pⁿ'</td><td>H</td><td>H</td><td>B</td>

<td> 101</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4pirolidyn-1ylopiperydynylo) phenyl) -1H-</td><td>H</td><td>cp^L'AT,</td><td>&gt; M^N</td><td>H</td><td>H</td><td>AND</td>

202

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td></td><td>1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 103</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((4pirolidyn-1ylopiperydynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>&lt;V</td><td>H</td><td>H</td><td>AND</td>

<td> 104</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((4cycklopentylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>and^N^ ^AT/</td><td>0N '</td><td>H</td><td>H</td><td>AND</td>

<td> 105</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1ylopiperydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td> % _F-uu</td><td>ABOUT/ 0N</td><td>H</td><td>H</td><td>AND</td>

203

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 106</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-methyl-4- (4-pyrrolidin-1ylopiperydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>p γη</td><td>Υ ν ^ '</td><td>H</td><td>H</td><td>AND</td>

<td> 107</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4cyklopentylopiperazynylo) phenyl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>Υ'Ί Yu</td><td>\ Jn / &lt;Λ y ^ N</td><td>H</td><td>H</td><td>AND</td>

<td> 108</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4 - ((4izopropylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>H₃CyN ^ J ΥΛχ ch₃</td><td>y ^ '</td><td>H</td><td>H</td><td>AND</td>

204

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 109</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-N-methylpiperidin-4-ylopiperazynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>^h'°' on ap_fAA &lt;</td><td>pN AND</td><td>H</td><td>H</td><td>AND</td>

<td> 110</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (7-methyl-2,7-diazaspiro [4,4] nonane-2-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>^hAND % YCI f-AA</td><td>(Λ AND¹⁴'</td><td>H</td><td>H</td><td>AND</td>

<td> 111</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (Nizopropylopiperazyn-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>ch₃h₃c ^ n ^ AND</td><td>fV and.</td><td>H</td><td>H</td><td>AND</td>

205

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 113</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1yloazetydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>XX</td><td>&lt;V Κ'Ν '</td><td>H</td><td>H</td><td>AND</td>

<td> 114</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-methyl-4- (4- (N- methylpiperazine-4-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td> ^^ΝΥΊ^c"n</td><td>&lt;Λ Κ'ν '</td><td>H</td><td>H</td><td>AND</td>

<td> 115</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4 - ((S) -3- (pyrrolidin-1-ylmethyl) pyrrolidinyl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>about f ^ A</td><td>&lt;Λ χ⁵*'</td><td>H</td><td>H</td><td>B</td>

206

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 116</td><td>1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (4- (4pirolidyn-1ylopiperydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>O-NYY AT/</td><td>WHAT \ '^N 00</td><td>H</td><td>H</td><td>B</td>

<td> 117</td><td>1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1ylopiperydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>nay</td><td>00 \ N 00</td><td>H</td><td>H</td><td>AND</td>

<td> 118</td><td>1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (2- (pyrrolidin-1-ylmethyl) benzo [d] oxazol-5-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>about HU</td><td>0N-</td><td>H</td><td>H</td><td>B</td>

<td> 119</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-</td><td>H</td><td>nay</td><td> \ '^N 0'</td><td>H</td><td>H</td><td>AND</td>

207

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>ylopiperydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 120</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (4- (4pirolidyn-1ylopiperydynylo) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>^ ΥΊ Y</td><td> \ '^NΎ</td><td>H</td><td>H</td><td>AND</td>

<td> 121</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (2-dimethylamino) - (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl)) 1 H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>h₃c._nxh₃s γΛΛ</td><td>&lt;V Y '</td><td>H</td><td>H</td><td>AND</td>

<td> 122</td><td>1- (6,7-dihydro-5H-benzo [2,3] oxepino [4,5-c] pyridazin-3-yl) -N³- (4- (2-dimethylamino) - (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl)) 1 H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>h₃c._n, ch₃s Γ^ΝΎι</td><td>(V Y '</td><td>H</td><td>H</td><td>AND</td>

208

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 123</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (isoindolin-2-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>ca n</td><td>\ 'n n</td><td>H</td><td>H</td><td>D</td>

<td> 124</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidinylmethyl) piperidinyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>ΟΆ</td><td>Ά '</td><td>H</td><td>H</td><td>AND</td>

<td> 125</td><td>1- (6,7-dihydro-5H-benzo [6,7] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (pyrrolidinylmethyl) piperidinyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td></td><td> \ 'ⁿAND'</td><td>H</td><td>H</td><td>AND</td>

209

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 126</td><td>1- (6,7-dihydro-5H-benzo [6,7] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4 - ((4aR, 8aS) dekahydroizochinolin-2-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>P</td><td> \ '^N</td><td>H</td><td>H</td><td>D</td>

<td> 127</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4 - ((4aR, 8aS) dekahydroizochinolin-2-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>P</td><td></td><td>H</td><td>H</td><td>B</td>

<td> 128</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydro-1Hpirydo [1,2-a] pyrazin-2-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>p n</td><td></td><td>H</td><td>H</td><td>B</td>

210

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 129</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydro-1Hpirydo [1,2-a] pyrazin-2-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>AND an</td><td>&gt; r^N'</td><td>H</td><td>H</td><td>AND</td>

<td> 130</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (2dietyloaminometylo) pyrrolidin-1-yl-pyridin-3-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>r^Nv% π ^ Ύ- 'LA M</td><td></td><td>H</td><td>H</td><td>B</td>

<td> 131</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (2- (1- (4- (2-dimethylamino) ethyl) piperazin-1-yl) oxomethyl) benzo [b] thiophen-5-yl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>H₃C Ν-Χ / -_x about H₃Æ sil</td><td>\ p = N</td><td>H</td><td>H</td><td>B</td>

211

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 132</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3-pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>pN</td><td>H</td><td>H</td><td>AND</td>

<td> 133</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3dietyloaminopirolidyn-1-yl) pyridin-3-yl) -1 H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>h₃c- \ / a^ch3 wyt</td><td>ANDⁿ</td><td>H</td><td>H</td><td>AND</td>

<td> 134</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (5metylooktahydropirolo [3,4-c] pyrrolyl) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>^H,'"AND ha.</td><td>f \ Ά &lt; '</td><td>H</td><td>H</td><td>AND</td>

212

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 135</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3- (4- (N-methylpiperazin-4-yl) piperidin-1-yl) - (E) propenyl) pyridin-3-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>H₃WHAT</td><td>fb 0N '</td><td>H</td><td>H</td><td>AND</td>

<td> 136</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -5-methylpyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^Gp k ^ NN 11</td><td>(Λ 0N</td><td>H</td><td>H</td><td>AND</td>

<td> 137</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (octahydropyrrolo [3,4-c] pyrrolyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>"φ n</td><td>0 / 0N</td><td>H</td><td>H</td><td>AND</td>

<td> 138</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3-piperidin-1-yl) - (E) -</td><td>H</td><td>Ο'ΌΟ ,.</td><td>0 / 0N-</td><td>H</td><td>H</td><td>AND</td>

213

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td></td><td>propenyl) pyridin-3-yl) -1H1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 139</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6cyklopentylo-6,7,8,9-tetrahydro-5H-pyrido [3,2-c] azepin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>WHAT, 0</td><td></td><td>H</td><td>H</td><td>D</td>

<td> 140</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (4- (bicyclo [2.2.1] heptan-2-yl) 1,4-diazepan-1-yl) pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>AND</td><td>OO &gt; Y^N</td><td>H</td><td>H</td><td>AND</td>

<td> 141</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3- (4- (pyrrolidin-1-yl) piperidin-1-yl) - (E) -propenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td></td><td>CC</td><td>H</td><td>H</td><td>B</td>

214

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 142</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3-piperidin-1-yl) -propan</td><td>H</td><td>he</td><td>AND</td><td>H</td><td>H</td><td>AND</td>

<td> 143</td><td>1- (6,7-Dihydro-9-chloro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-1ylopiperydyn-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>AND AND</td><td>z ^ bb "⁰¹fc</td><td>H</td><td>H</td><td>AND</td>

<td> 144</td><td>1- (6,7-Dihydro-9-chloro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (N- methylpiperazine-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>n&gt; an nay</td><td>bbb ^⁰¹b^N'</td><td>H</td><td>H</td><td>B</td>

<td> 145</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3- (4 (piperidin-1-yl) piperidin-1-yl) - (E) -propenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-</td><td>H</td><td>_ABOUT.he</td><td>AND</td><td>H</td><td>H</td><td>AND</td>

215

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 146</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6- (3- (4dimetyloaminopiperydyn-1-yl) - (E) -propenyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>AND ch₃</td><td>fV</td><td>H</td><td>H</td><td>AND</td>

<td> 147</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2- (4pirolidyn-1-ylpiperidin-1-yl) pyrimidin-5-yl) -1 H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>gp</td><td>pP Χ = Ν</td><td>H</td><td>H</td><td>AND</td>

<td> 148</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2- (4- (piperidin-1-ylmethyl) piperidin-1-yl) pyrimidin-5-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>Oty</td><td>pY y = N</td><td>H</td><td>H</td><td>B</td>

216

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 149</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (6 - ((4-piperidin-1-ylpiperidin-1-yl) carbonyl) pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>0 υΎί</td><td></td><td>H</td><td>H</td><td>B</td>

<td> 150</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- ((7piperydyn-1-yl) -6,7,8,9tetrahydro-5H-benzo [7] annulen2-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>Q .</td><td>fV Y '</td><td>H</td><td>H</td><td>AND</td>

<td> 151</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- ((7azetydyn-1-yl) -6,7,8,9tetrahydro-5H-benzo [7] annulen2-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>and.</td><td>(V Y '</td><td>H</td><td>H</td><td>AND</td>

217

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 152</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- ((7pirolidyn-1-yl) -6,7,8,9tetrahydro-5H-cyclohepta [b] pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>Q</td><td>Ά '</td><td>H</td><td>H</td><td>AND</td>

<td> 153</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2cyklopentylo-1,2,3,4- tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>_σατ</td><td>rV AN</td><td>H</td><td>H</td><td>AND</td>

<td> 156</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4-iodophenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>'Tc</td><td>TC X</td><td>H</td><td>H</td><td>D</td>

<td> 175</td><td>1- (spiro [chromeno [4,3-c] pyridazin-5,1'-cyclopentane] -3-yl) -N³- (3-fluoro-4- (4- (4metylopiperazyn1ylo) piperidin-1-yl) phenyl) -</td><td>H</td><td>; ®a</td><td>? T IN</td><td>H</td><td>H</td><td>C</td>

218

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>1? -1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 176</td><td>1- (spiro [chromeno [4,3-c] pyridazin-5,1'-cyclopentane] -3-yl) -N³- (3-fluoro-4- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>B</td>

<td> 177</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (3-fluoro-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>ABOUT -</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 178</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-₃c] pyridazin-2-yl) -N - (3-fluoro-4- (4-pyrrolidin-1-ylpiperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td> %-</td><td> 0^</td><td>H</td><td>H</td><td>AND</td>

219

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 179</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>HAp -Μ '</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 180</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (3- (3R) dimethylaminopyrrolidin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>/ -N_fAA</td><td>fV P = N</td><td>H</td><td>H</td><td>AND</td>

<td> 181</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- ((7-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>Q from</td><td>fy</td><td>H</td><td>H</td><td>AND</td>

220

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 182</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-methyl-4- (4-pyrrolidin-1-1ylopiperydyn-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>r) ch₃-at</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 183</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [4,5-c] pyridazin-2-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-1ylopiperydyn-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td> 0</td><td> 00</td><td>H</td><td>H</td><td>AND</td>

<td> 184</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- ((7 (R) pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>Ο'ΟΟλ</td><td> &gt;0^N</td><td>H</td><td>H</td><td>AND</td>

221

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 185</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7-diethylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>ch₃ &lt;ⁿpoa ch₃</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 186</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7-cyclopentylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 187</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2- (4cyklopropylometylopiperazyn1-yl) pyridin-5-yl) -1 H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>Αγγ</td><td>&gt; P</td><td>H</td><td>H</td><td>B</td>

222

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 188</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - ((7-pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3 , 5diamina</td><td>H</td><td>OYO,</td><td>fV Ύ</td><td>H</td><td>H</td><td>AND</td>

<td> 189</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2o c] pyridazin-3-yl) -N - (6- (pyrrolidin-1-yl) -5,6,7,8-tetrahydroquinolin-3-yl) -1-H1,2,4-triazole-3,5-diamine</td><td>H</td><td>_σΧΧι,</td><td>ΥΝ</td><td>H</td><td>H</td><td>AND</td>

<td> 190</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2o c] pyridazin-3-yl) -N- (6-cyclopentyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>_andox</td><td>fV</td><td>H</td><td>H</td><td>AND</td>

223

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>_R5</td><td>IC50</td>

<td> 191</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- ((S) -7 (pyrrolidin-1-yl) -6,7,8,9tetrahydro-5H-cyclohepta [b] pyridin-3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>c-CGA</td><td>pN</td><td>H</td><td>H</td><td>AND</td>

<td> 192</td><td>1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (3-fluoro-4- (4-Cyclohexylpiperazin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>Υϊ</td><td>^^ "Y ^ Y</td><td>H</td><td>H</td><td>C</td>

<td> 193</td><td>1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>B</td>

224

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 194</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- ((7- (2 (S) metyloksykarbonylo) pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5- diamine</td><td>H</td><td>h₃c_s 0 0</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 195</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- ((7- (2 (S) carboxy) pyrrolidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazol-3 5-diamine</td><td>H</td><td>OH C0 = 0</td><td> 0 00</td><td>H</td><td>H</td><td>B</td>

<td> 196</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4- (4-methylpiperazin-1-yl) piperidin-1yloprop-1-enyl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>H, Cⁿ0</td><td>N = 0</td><td>H</td><td>H</td><td>AND</td>

225

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 197</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4- (piperidin-1-yl) piperydyn1yloprop-1-enyl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>αάχα q_nGJ him</td><td>fc fn</td><td>H</td><td>H</td><td>B</td>

<td> 198</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4- (piperidin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>ΟΆλ</td><td>fc n^N</td><td>H</td><td>H</td><td>AND</td>

<td> 199</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (4- (pyrrolidin-1-ylprop-1-yl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>he.</td><td>Ob &gt; AN</td><td>H</td><td>H</td><td>AND</td>

<td> 200</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (3-dimethylaminopyrrolidin-1yloprop-1-enyl) phenyl) -1H-</td><td>H</td><td>ΡΆ H₃CN ch₃</td><td>&lt;c</td><td>H</td><td>H</td><td>AND</td>

226

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 201</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (3dietyloaminopirolidyn-1yloprop-1-enyl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>) H₃C</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 202</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2- (3- (S) -methyl-4cyklopropylometylopiperazyn1-yl) pyridin-5-yl) -1 H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>Τ Λ³</td><td>&lt;00 He'</td><td>H</td><td>H</td><td>AND</td>

<td> 203</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (1-4pirolidyn ylopiperydyn1 = yl-prop-1-enyl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>AND</td>

227

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 204</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4-methylpiperazin-1-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>_H3pU Va</td><td>AND"</td><td>H</td><td>H</td><td>AND</td>

<td> 205</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4-isopropylpiperazin-1-yloprop1-enyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>H₃Cp, NM Ua ch₃</td><td>AND^N'</td><td>H</td><td>H</td><td>AND</td>

<td> 206</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (4cyklopentylopiperazyn-1yloprop-1-enyl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>pa.</td><td>fV AND^J'</td><td>H</td><td>H</td><td>AND</td>

<td> 207</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (morpholin-4-yl-prop-1-enyl) phenyl) -1H-1,2,4-triazolo</td><td>H</td><td> »9^0.</td><td>fv A = N '</td><td>H</td><td>H</td><td>AND</td>

228

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 208</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N- (8-diethylaminoethyl-9-hydroxy6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>ch₃&lt; For example, / ch₃α</td><td></td><td>H</td><td>H</td><td>B</td>

<td> 209</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>Η, α AT 1 pc</td><td>pN</td><td>H</td><td>H</td><td>AND</td>

<td> 210</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (1-methylpiperidin-3-yloxy) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>h₃c_saa</td><td></td><td>H</td><td>H</td><td>AND</td>

229

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 211</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (1bicyklo [2.2.1] heptan-2-yl) piperidin-4-yl-phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>uu</td><td>γγ γ</td><td>H</td><td>H</td><td>D</td>

<td> 212</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (4- (1cyklopropylometylopiperydyn4-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>Υγ Y</td><td>γΥ Y '</td><td>H</td><td>H</td><td>AND</td>

<td> 213</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (1,2,3,4- tetrahydroisoquinolin-7-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>ca</td><td>FY</td><td>H</td><td>H</td><td>AND</td>

<td> 214</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (3-fluoro-4- (4cyklopropylometylopiperazyn1-yl) phenyl) -1H-1,2,4-triazolo</td><td>H</td><td>ί Y</td><td></td><td>H</td><td>H</td><td>AND</td>

230

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 215</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydroisoquinoline-7-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>YCO * h₃c^{z N}C</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 216</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (2- (cyclopropylmethyl) -1,2,3,4-tetrahydroisoquinoline-7-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>P.O0</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 217</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7- (3- (S) fluoropyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>F Q and</td><td>OC</td><td>H</td><td>H</td><td>AND</td>

231

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 218</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (2- (S) pyrrolidin-1-yl) -6,7,8,9tetrahydro-5H-benzo [7] annulen2-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>&lt;P .. «CH₃'' -N and,</td><td>p = N</td><td>H</td><td>H</td><td>AND</td>

<td> 219</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (3- (R) -hydroxypyrrolidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>OH G</td><td>fG</td><td>H</td><td>H</td><td>AND</td>

<td> 220</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (2- (R) -methyl-pyrrolidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>pride₃PN G</td><td></td><td>H</td><td>H</td><td>AND</td>

232

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 221</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (3- (S) hydroxy-pyrrolidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>OH 0</td><td>fa</td><td>H</td><td>H</td><td>AND</td>

<td> 222</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (3- (R) fluoropyrrolidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>F</td><td>ANDⁿ'</td><td>H</td><td>H</td><td>AND</td>

<td> 223</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N - (7-oxo, 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>AND</td><td>H</td><td>H</td><td>AND</td>

233

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>_R4</td><td>R⁵</td><td>IC50</td>

<td> 224</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7-cyclohexylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>(Vnh and</td><td> 00</td><td>H</td><td>H</td><td>AND</td>

<td> 225</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7-cyclopropylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>0-NH</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 226</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>HO 0</td><td>00 Y^N</td><td>H</td><td>H</td><td>AND</td>

234

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 227</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2c] pyridazin-3-yl) -N³- (7- (4-methylpiperazin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>H₃C about NN</td><td>ot AND</td><td>H</td><td>H</td><td>AND</td>

<td> 228</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2₃c] pyridazin-3-yl) -N- (7- (tetrahydrofuran-2-ylmethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3 , 5diamina</td><td>H</td><td>and nh »</td><td>fc AND</td><td>H</td><td>H</td><td>AND</td>

<td> 229</td><td>1- (6,7-dihydro-5Hbenzo [6,7] cyclohepta [1,2₃c] pyridazin-3-yl) -N - (7-cyclobutylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>&lt;Aⁿand c</td><td>fc AND</td><td>H</td><td>H</td><td>AND</td>

235

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 230</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-₃c] pyridazin-3-yl) -N- (7- (cyclopropylmethyl) amino6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>&lt;L ^ -NH</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 231</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (2- (diethylamino) ethyl) methylamino-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>ch₃&lt; N "\ CH₃AND</td><td>OG AND</td><td>H</td><td>H</td><td>AND</td>

<td> 232</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (4pirolidyn-1-ylpiperidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>Q 0 r.</td><td>&lt;GG ga AND</td><td>H</td><td>H</td><td>AND</td>

236

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 233</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (4- (piperidin-1-ylmethyl) piperidin-1-yl) 6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5- diamine</td><td>H</td><td></td><td>fV</td><td>H</td><td>H</td><td>AND</td>

<td> 234</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7 amino-6,7,8,9-tetrahydro-5Hbenzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>h₂n c</td><td>Ό</td><td>H</td><td>H</td><td>AND</td>

<td> 235</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (2- (dimethylamino) ethyl) amino6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>h₃c N-. h₃c ^ -nh X</td><td>He</td><td>H</td><td>H</td><td>AND</td>

237

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 236</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N³- (4- (1bicyklo [2.2.1] heptan-2-yl) piperidin-4-yl-phenyl) 1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>&lt;A Y</td><td>γ'ώ \ '^NY</td><td>H</td><td>H</td><td>AND</td>

<td> 237</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (7- (carboxymethyl) amino-6,7,8,9-tetrahydro-5H-benzo [7] annulen2-yl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>about Hoy yh and.</td><td>γγ Ύ</td><td>H</td><td>H</td><td>D</td>

<td> 238</td><td>1- (4-phenyl-6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridin-2-yl) -N³- (3-fluoro-4- (4-pyrrolidin-1-ylopiperydyn1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td></td><td></td><td>H</td><td>H</td><td>B</td>

238

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 239</td><td>1- (6,7-dimethoxy-quinazolin-4-yl) -N³- (5,7,8,9tetrahydrospiro [cyclohepta [b] pir ydyno-6,2 '- [1,3] dioxolane] -3ylo) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>&lt;O Pa</td><td>ch₃d h₃c V P</td><td>H</td><td>H</td><td>B</td>

<td> 240</td><td>1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5,7,8,9tetrahydrospiro [cyclohepta [b] pir ydyno-6,2 '- [1,3] dioxolane] -3ylo) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>oP Όλ</td><td>ch₃^s^ Ppc &gt; P</td><td>H</td><td>H</td><td>AND</td>

<td> 241</td><td>1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5,6,8,9tetrahydrospiro [cyclohepta [b] pir ydyno-7,2 '- [1,3] dioxolane] -3ylo) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>p 'G.</td><td>ch₃cg</td><td>H</td><td>H</td><td>AND</td>

<td> 246</td><td>1- (2-chloro-7-methyl-thieno [3,2-d] pyrimidin-4-yl) -N³- (5 ', 5'dimetylo-6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pirydyno7,2' - [1,3] dioxane] -3-yl) -1H-</td><td>H</td><td>H₃c</td><td>ch₃G.</td><td>H</td><td>H</td><td>AND</td>

239

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 247</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N³- (5 ', 5'dimetylo-6,8,9,10-tetrahydro-5H-spiro [cycloocta [b] pirydyno7,2' - [1,3] dioxane] -3-yl) -1H1,2,4-triazole -3,5-diamine</td><td>H</td><td>h₃c</td><td>mb Cⁿ'</td><td>H</td><td>H</td><td>D</td>

Table 2 IC activity₅₀: A = &lt;1 μΜ

B = 1 to 10 μΜ C =&gt; 10 to 20 μΜ D =&gt; 20 μΜ

<img file="PL2078010T3_D0028.tif" />

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 157</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4- (indolin-2-on-1-yl) piperydyn1ylo) phenyl) -1H-1,2,4-triazolo</td><td>H</td><td>ABOUT %</td><td>&lt;10 0N</td><td>H</td><td>H</td><td>D</td>

240

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 158</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4- (morpholin-4-yl) piperydyn1ylo) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td> 0</td><td>AND^N'</td><td>H</td><td>H</td><td>D</td>

<td> 159</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (2- ((dimethylamino) methyl) -1Hbenzo [d] imidazol-5-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>h₃c N-; m₃c&gt; = n M.</td><td>MA AND^N”</td><td>H</td><td>H</td><td>D</td>

<td> 160</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (4- (3,5dimetylopiperydyn-1-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>ch₃^hM * &lt;X</td><td>&lt;AM AND^N’</td><td>H</td><td>H</td><td>AND</td>

<td> 161</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (7- ((bicyclo [2.2.1] heptan-2-yl) (methyl) amino) -6,7,8,9-</td><td>H</td><td>ηζΑΧα</td><td>&lt;V AND^N'</td><td>H</td><td>H</td><td>B</td>

241

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>tetrahydro-5H-benzo [7] annulen-2-yl) -1H-1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 162</td><td>1- (7-methyl-6,7-dihydro-5H-benzo [2,3] azepino [4,5-c] pyridazin-3-yl) -N⁵- (4- (N- methylpiperazine-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>uz</td><td>ch₃c^N ON '^</td><td>H</td><td>H</td><td>D</td>

<td> 163</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (4 - ((5fluoroindolin-2-on-3-yl) methyl) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>0 f</td><td>fo ABOUT^N</td><td>H</td><td>H</td><td>D</td>

<td> 164</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (4- (4pirolidyn-1ylopiperydynylo) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>uz</td><td>ABOUT^N'</td><td>H</td><td>H</td><td>B</td>

<td> 165</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (4- (1-4pirolidyn</td><td>H</td><td>ΓΎΎΊι uz</td><td>&lt;a ABOUT^N'</td><td>H</td><td>H</td><td>AND</td>

242

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>ylopiperydynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 166</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (4- (4cycklopentylopiperazynylo) methyl ) Phenyl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>σ^{Νχ&gt; Uz}</td><td>fc AND"</td><td>H</td><td>H</td><td>B</td>

<td> 167</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (4 - ((4izopropylopiperazynylo) methyl) phenyl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>H₃CpwH CJy ch₃</td><td>FGG AN</td><td>H</td><td>H</td><td>B</td>

<td> 168</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-N-methylpiperid-4ylopiperazynylo) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>an about · · Χ.</td><td></td><td>H</td><td>H</td><td>B</td>

243

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>_R3</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 169</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (7-methyl-2,7-diazaspiro [4,4] nonane-2-yl) phenyl) -1H-1,2,4-triazole-3,5diamina</td><td>H</td><td>ABOUT ,AND</td><td>&lt;c AND^{N &lt;}</td><td>H</td><td>H</td><td>B</td>

<td> 170</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (3-pyrrolidin-1yloazetydynylo) phenyl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>f-AAA</td><td>(C AND^N‘</td><td>H</td><td>H</td><td>B</td>

<td> 171</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-methyl-4- (4- (N-methylpiperazin-4-yl) piperidin-1-yl) phenyl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>^HLC'AND ^^NAND</td><td>fc AND'</td><td>H</td><td>H</td><td>D</td>

<td> 172</td><td>1- (6,7-dihydro-5H-benzo [2,3] tiepino [4,5-c] pyridazin-3-yl) -N⁵- (4- (4-pyrrolidin-1ylopiperydynylo) phenyl) -1H-1,2,4</td><td>H</td><td>° Α^VAND</td><td>fc AND^N'</td><td>H</td><td>H</td><td>D</td>

244

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>_R2</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 173</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -5-methylpyridin-3-yl) -1H-1,2,4-triazolo-3,5-diamine</td><td>H</td><td>° ΥΊ</td><td>Y</td><td>H</td><td>H</td><td>B</td>

<td> 174</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (3-pyrrolidin-1-yl) pirolidyn1ylo) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>5x °.</td><td>Y</td><td>H</td><td>H</td><td>B</td>

<td> 242</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>^H!° 'O i Y</td><td>&gt; y</td><td>H</td><td>H</td><td>B</td>

<td> 243</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (1,2,3,4- tetrahydroisoquinolin-7-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td></td><td>Y^N</td><td>H</td><td>H</td><td>B</td>

245

<td>Relationship #</td><td>Relationship Name</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td> 244</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (3-fluoro-4- (4-cyklopropylometylopiperazyn1-yl) phenyl) -1H-1,2,4-triazolo3,5-diamine</td><td>H</td><td>^ pi n</td><td></td><td>H</td><td>H</td><td>AND</td>

<td> 245</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (2- (1-methylpiperidin-4-yl) -1,2,3,4-tetrahydroisoquinoline-7-yl) -1H1,2,4-triazole-3,5-diamine</td><td>H</td><td>^ CCZ h₃Pⁿ^</td><td>pP •&gt; P</td><td>H</td><td>H</td><td>B</td>

<td> 248</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (5,7,8,9tetrahydrospiro [cyclohepta [b] pyrid yne-6,2 '- [1,3] dioxolane] -3-yl) -1H-1,2,4-triazole-3,5-diamine</td><td>H</td><td>oP PVO "PU</td><td>^ λ0</td><td>H</td><td>H</td><td>D</td>

<td> 249</td><td>1- (6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- d] pyridazin-3-yl) -N⁵- (7- (S) -pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl) -1H-</td><td>H</td><td>Q FROM,</td><td></td><td>H</td><td>H</td><td>AND</td>

246

<td>Relationship #</td><td>Relationship Name</td><td>_R1</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>1,2,4-triazole-3,5-diamine</td><td></td><td></td><td></td><td></td><td></td><td></td>

247