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FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10/ rule 13)
"SUBSTITUTED TRIAZOLES USEFUL AS AXL INHIBITORS'
RIGEL PHARMACEUTICALS/ INC.
1180 Veterans Boulevard, South San Francisco, California 94080, United States of America.
The following specification particularly describes the invention and the manner in which it is to be performed.
SUBSTITUTED TRIAZOLES USEFUL AS AXL INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No, 60/983,352, filed November 15, 2007; U.S. Provisional Patent 5 Application No. 60/883,713, -filed January 5, 2007; and Provisional Patent Application No. 60/882,893, filed December 29, 2006, where these three provisional applications are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
This invention is directed to substituted triazoles and pharmaceutical
10 compositions thereof which are useful as inhibitors of the receptor protein tyrosine kinase known as Axl. This invention is also directed to methods of using the compounds and compositions in treating diseases and conditions associated with Axl activity, particularly in treating diseases and conditions associated with angiogenesis and/or cell proliferation.
BACKGROUND OF THE INVENTION
15 All of the protein kinases that have been identified to date in the human genome
share a highly conserved catalytic domain of around 30Q aa. This domain folds into a bibbed structure in which reside ATP-binding and catalytic sites. The complexity of protein kinase regulation allows many potential mechanisms of inhibition including competition wfth activating ligarids, modulation of positive and negative regulators,
20 interference with protein dimorization, and allosteric or competitive inhibition at the substrate or ATP binding sites.
Axl (also known as UFO, ARK, and Tyro7; nucleotide accession numbers NM_Q21913 and NM_001699; protein accession numbers NPJJS6713 and NP_Q01690} is a receptor protein tyrosine kinase (RTK) that comprises a C-terminal extracellular
25 frgand-binding domain and N-terminal cytoplasmic region containing the catalytic domain. The extracellular domain of Axl has a unique structure that juxtaposes Immunoglobulin and fibronectin Type Ill repeats and is reminiscent of the structure of neural cell adhesion molecules. Axl and its two close relatives, Mer /Nyk and Sky {Tyro3 / Rse I Dtk), collectively known as the Tyro3 family of RTK'sr alE bind and are stimulated
30 to varying degrees by the same ligand, Gas6 (growth arrest specific-6), a ~76kDa
secreted protein with significant homology to the coagulation cascade regulator, Protein
S. fn addition to binding to ligands, the Axl extracellular domain has been shown to undergo homophilic interactions that mediate eel! aggregation suggesting that one important function of Axi may be to mediate cell-cell adhesion,
Axl is predominantly expressed in the vasculature in both endothelial cells (EC's) 5 and vascular smooth muscle cells (VSMC's) and iri cells of the myeloid lineage and is also detected in breast epithelial cells, chondrocytes, Sertoli cells and neurons. Several functions including protection from apoptosis induced by serum starvation, TNF-a or the viral protein E1 A, as well as migration and cell differentiation have been ascribed to Axl signaling in cell culture. However, Axl -I- mice exhibit no overt developmental phenotype 10 and the physiological function of Axl in vivo is not clearfy established in the literature.
Angiogenesis (the 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 securing an adequate blood supply that feeds tumor growth and facilitates metastasis. Deregulated angiogenesis also a feature 15 of many other diseases (for example, psoriasis, rheumatoid arthritis, endometriosis and blindness due to age-related macular degeneration (AMD), retinopathy of prematurity and diabetes) and often contributes to the progression or pathology of the condition.
The overexpression of Ax! andfor its ligand has also been reported in a wide variety of solid tumor types including, but not limited to, breast, renal, endometrial, 2D ovarian, thyroid, non-small cell lung carcinoma, and uveal melanoma as well as in
myeloid leukemia's. Furthermore, it possesses "transforming activity in NIH3T3 and 32D cells. It has been demonstrated that loss of Axl expression in tumor cells blocks the growth of solid human neoplasms in an in vivo MDA-MB-231 breast carcinoma xenograft model. Taken together, these data suggest Axl signaling can independently regulate EC 25 angiogenesis and tumor growth and thus represents a novel target class for tumor therapeutic development.
The expression of Axl and Gas6 proteins is up regulated in a variety of other disease states including endometriosisr vascular injury and kidney disease and Axl signaling is functionally implicated in the latter two indications, Axl - Gas6 signaling 30 amplifies platelet responses and is implicated in thrombus formation. Axl may thus
potentially represent a therapeutic target for a number of diverse pathological conditions including solid tumors, including, but not limited to, breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma and uveal melanoma; liquid tumors, including but not limited to, feukemias (particularly myeloid leukemias) and lymphomas; 35 endometriosis, vascular disease / injury {including but not limited to restenosis,
atheroscSercsis 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; osteoporosis, osteoarthritis and cataracts.
5
SUMMARY OF THE INVENTION
This invention is directed to certain substituted triazoles which are useful as Axl inhibitors, methods of using such compounds in treating diseases and conditions associated with Axl activity and pharmaceutical compositions comprising such 10 compounds.
Accordingly, in one aspect this invention is directed to compounds of formula (I):
wherein:
R\ R4and R5 are each independently selected from the group consisting of hydrogen, 15 a Iky I, aryl, analkyi, -C(0)R® and -C(0)N(Re)R7;
R£ is aryl optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyS, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted hetenoarylalkyl, optionally substituted 20 heteroarylalkenyi, optionally substituted hetenocyclyl, optionally substituted
hetenocyclylalkyl, optionally substituted heterocyclylalkenyl, -R0-QRa, -R3-O-R10-OR5, -R*-0-R1c-0-RTO-0R5r -Rs-O-R10-CN, -R^-O-R^-CfOpR3, -R5-O-R10-C(O)N(R4)R7, -R^-O-Rl0-S(O)pRa {where p is 0, 1 or 2), -R9-O-R10-N(R6)R7r -R9-Q-R"-C(NR1,)N(R11)H, -R9-0C(0)-Rb, -R9-N(Rs)R7, 25 -R9-C{0)Rs, -Rfl-C(0)0Ra, -RS-C(Q)N(RG)R7, -R*-N(R6)C(0)0Rb,
"R^N{Re)C(O)R0, -Rs-N{Re)S(0),Rs (where t is 1 or 2), -R9-S{0)t0RB (where t is 1 or 2), -Re-S(0)pRa (where p is 0, 1 or 2), and -R^SfO^NfR^R7 (where t is 1 or 2);
R3 is selected from the group consisting of aryl and heteroaryir where the aryl and the heteroaryl are each independently optionally substituted by one or more 30 substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo,
haloalkyl, alkyf, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyciylalkyl, optionally substituted 5 heterocyclylalkenyl, -R9-ORB, -R*-O-R10-OR6, -R3-O-R10-O-R^-OR3,
-RS-O-R10-CN, -R9-O-R,0-C(O)ORS, -R9-O-Ri0-C(O)N(R6)R7, -Rs-0^R^-S(0)pR5 (where p is 0, 1 or 2), -R°-O-R10-N(Re)R'p -R'-O-R^-CtNR^JNfR^JH, -Rs-OC(Q)-Rfl, -Rb-N(R6)R7: -R3-C(0)Rs, -Rs-C(0)0R°, -Rs-C(O)N(R0)R7, -Re-N( R5)C(0)0Ra, -R9-lM(Re)C(0)Rs, -R'-N(R*)S(0),R* (where t is 1 or 2), 10 -R0-S(O):OR5 (where t is 1 or 2), -R9-S(0)pR* (where p is 0, 1 or 2), and
-RS-S(0),N(R6)R7 (where t is 1 or 2); each R6 and R7 Is independently selected from the group consisting of hydrogen, alky I, alkenyl, alkynyi, haloalkyf haloalkenyl, haloalkynyl, hydnoxyalkyl, optionally substituted ary3, optionally substituted aralkyl, optionally substituted aralkenyi 15 optionally substituted aralKynyl, optionally substituted cycloalkyl, optionally
substituted cycloalkyl a !kyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkyl a ikynyl, optionally substituted heterocyclyl, optionally substituted heterocydylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclyl alkynyl, optionally substituted heteroaryl, optionally 20 substituted heteroarylafkyl. optionally substituted heteroaryl a I kenyi, optionally
substituted heteroarylalkynyl, -R10-ORa, -R1°-CN, -Rlc-N02, -Rm-N(Re)2, -R^-CfOpR* and -R10-C(Q)N(RB)2l or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl; 25 each Re 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 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, 30 optionally substituted heterocyclyl, optionally substituted heterocydylalkyl,
optionally substituted heterocyclyl alkenyl, optionally substituted heterocyclyl a I kynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl;
35 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 R1d is independently selected from the group consisting of an optionally substituted 5 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 hydrogen, alkyl, cyano, nitro or -OR8;
as an isolated stereoisomer or mixture thereof, or a pharmaceutical^ acceptable salt 10 thereof.
In another aspect, this invention is directed to pharmaceutical compositions comprising a pharmaceutical^ acceptable excipientand a therapeutically effective amount of a compound of formula (I). as described above, as an isolated stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, 15 In another aspect, this invention is directed to methods of treating a disease or
condition associated with Axl activity in a mammal, wherein the methods comprise administering to the mammal a therapeutically effective amount of a compound of formula (!), as described above, as an isolated stereoisomer or mixture thereof, or a pharmaceuticaIly acceptable salt thereof, or a therapeutically effective amount of a 20 pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (1), as described above, as an isolated stereoisomer or mixture thereof, or a pharmaceutical^ acceptable salt thereof.
In another aspect, this invention provides assays to determine a compound of the invention effectiveness in inhibiting Axl activity in a cell-based assay.
25 DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: "Amino" refers to the -NHZ radical. 30 "Carboxy" refers to the -C(0}0H radical.
"Cyano" refers to the -CN radical. "Nitro" refers to the -NOa radical. "Oxa" refers to the -O- radical.
"Oxo" refers to the =0 radical.
"Thioxo" refers to the =S radical.
11 Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve 5 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 by a single bond, for example, methyl, ethyl, n-propyf, 1-methylethyl (fso-propyl), n-butyl, n-pantyi, 1,1-dimethylethyl (f-butyl), 3-methyIhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl radical may be optionally substituted by one or more of the 10 following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR20, -OC(O)-RJ0, -N(R£C')2, -C(0)R2D, -C(0)0R2°, -C(O)N(R20)2, -N(R^)C(0)0R2n, -NfR^OJR20, -NfR^SfO)^33 [where t is 1 or 2), -S^OR2*1 (where t is 1 or 2), -S(0)^R" (where p is 0, 1 or 2); and -SfO^NfR^)^ (where t is 1 or 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyf, cycloalkylalkyl, aryl, aralkyl, 15 heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl.
"Alkenyl" refers lo a sLraighl or branched hydrocarbon chain radical 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 molecule by a single bond, for example, ethenyl, prop-f-enyl, 20 but-1-enyl, pent-1-enyl, penta-1,4-dieny1r and the like. Unless stated otherwise
specifically in the specification, an alkenyl radical may be optionally substituted by one or more or Lhe following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^, -OQOJ-R20, -N(R2C)2, -C{0)R2C, -C(0)0R2°, -CTOJ^R^, ~N(R2D)C(0)0R^, -N(R20)C(O)R33: -N{R")S(0)TR23 (Where t IS 1 or 2), -S(0)L0R2° (where t is 1 or 2), 25 -S(0)PR"° (where p is 0,1 or 2), and -S(0)TN(R2U)2 (where t is 1 or 2) where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl orheteroarylalkyl.
"Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally 30 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 molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentyriyl. hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl radical may be optionally substituted by one or mora of the following substituents: halo, cyano, nitro, oxo, thioxo, 35 trimethylsilanyl, -OR20, -OQOJ-R2", -N(R2N)£, -C(0)R^, -C(0)0R20, -C{O)N(R20)2, -N(R2D)C(OPRM, -N(R2C)C(0)R23, -K(RM)S(0)1R2D (where t is 1 or 2), -S(0)L0R2° (where t is 1 or 2), -S(0)pR211 (where p is 0, 1 or 2), and -SfOhNtR23^ (where t is 1 or 2) where each R^ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl.
5 "Alkylene" or "alkylene chain" refers 1o a straight or branched divalent
hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, /r-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the io 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 through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heLerocyclyl, 15 heteroaryl, oxo, thioxo, trimethylsilanyl, -OR2C, -OCfOJ-R21', -N(R2D)2j -C(0)R2°,
-C(0)0R2Ci, -CCOJNfR^. -N(R£D)C(0)0RSC, -NTR^C^R20, -NfR^STO^R20 (where t is 1 or 2), -S(0)tQR2[> (where t is 1 or 2), -SfO^R31 (where p is 0, 1 or 2), and -S(O^N(R2C)2 (where t is 1 or 2) where each R30 is independently hydrogen, alkyi, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl. zo "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent
hydrocarbon chain linking the rest of the molecule to a radical group, consisting solefy of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like, The alkenyiene chain is attached to the rest of the molecule through a double bond or a 25 single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain, Unless stated otherwise specifically in the specification, an afkenylene chain may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, 30 heteroaryl, oxo, thioxo, trimethylsilanyi, -OR2:', -0C(0)-R2", -N(R*:,):, -C(0}RW,
-C(D)OR2C, -C(0)N(R2V -NtR^qOJOR*1, -N(R2D)qO}R2D, -NfR^StO^R20 (where t is 1 or 2), -S(OXORffl (where t is 1 or 2), -5(Q),R2D (where p is 0,1 or 2), and -S(0)lN(R^)2 (where t is 1 or 2) where each R™ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl. 35 "Alkynylene" or "alkynyteno chain" refers to a straight or branched divalent
hydrocarbon chain linking the rest of (he molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, for example, propynylene, n-butynylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical 5 group through a double bond or a single bond. The points of attachment of the
alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain may be optionally substituted by one or more of the following substituents; alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, 10 heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR20, -0C(0)-R23, -N(R^)2p
-C(0)R2D, -QOJOR®, -C(0)N(R^)2r -NCR^CtOJOR20, -N^CfOlR20, -N(R2CI)S(0)-R2Q (where t is 1 or 2), -S^OR30 (where t is 1 or 2), -S(0}pR2D (where p is D, 1 or 2\ and -S(O)LN(R20)z (where t is 1 or 2} where each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl 15 or hete roarylal kyI,
"Alkoxy" refers to a radical of the formula -QRg where Ra is an alkyl radical as defined above containing one to twelve carbon atoms. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.
"Alkoxyalkyl11 refers to a radical of the formula -Rb-O-R0 where F^ Is an alkyl 20 radical as defined above and RQ is an alkylene chain as defined above. The oxygen atom may bo bonded to any carbon in the alkyl radical or the alkylene chain. The alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl radical and the alkylene chain part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkylene chain. 25 "Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 14
carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical may be a monocyclic, bicyclic, or tricyclic system and which may include spino ring systems. An aryl radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the aryl radical. For purposes of this invention, an "aryl" 30 radical as defined herein can not contain rings having more than 7 members and cannot contain rings wherein two non-adjacent ring atoms thereof aro connected through an atom or a group ol" aLoms [i.e., a bridged ring system). Aryl radicals include, but are not limited to, aryl radicals derived from acenaphthylene, anthracene, azulene, benzene, 6,7,S,9-tetrahydro-5H-benzo[7]annulene, flu ore ne, as-indaconer s-indacene, indane, 35 indene, naphthalene, phenalene, and phenanthrene. Unless stated otherwise specifically in the specification, the term "optionally substituted aryl" is meant to include aryl radicals optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyf, halo, haloalkyl, haloalksnyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, 5 optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkyl, optionally substituted heteracydylalkenyl. optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted 10 heteroaryl a fkyl, optionally substituted hetenoarylalkenyl, optionally substituted
heteroarylalkynyl, -FT1-OR30, -Rai-OC(O>Ra0, -R21-N(Ra>>jr -R^-C^R20, -R^-CtOJOR*3, -Rs1-C(0)N(Rz:')2, -R'1-0-Raa-C(0)N{Ri3)2r -R^R^qOJOR23, -R^-NtR^JCtOJR20, 'R21-N(R2C}S(0)lR2° (where t is 1 or 2), -R^-StQMJR* (Where t is 1 or 2), -R^-StGJpR20 (where p is 0,1 or 2), and -R21-S(0)tN(RJ3)2 (where t is 1 or 2), where each R2C is 15 independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl. optionally substituted heterocycfyl, optionally substituted heterocyclyialkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two Rzo,s, together with the common nitrogen to which they are both 20 attached, may optionally form an optionally substituted W-heterocyclyl or an optionally substituted AMieteroaryl, each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and PF is a straight or branched alkylene or alkenylene chain,
"Aralkyl" refers to a radical of the formula -RirRt where Rt, is an afkylene chain as 25 defined above and R, is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like, The alkylene chain part of the aralkyl radical may be optionally substituted as described above for an alkylene chain, The aryl part of the aralkyl radical may be optionally substituted as described above for an aryl.
"Aralkenyl" refers to a radical of tho formula -Rd-Rc whero Rd is an alkenylene 30 chain as defined above and Rt is one or more aryi radicals as defined above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl. The alkenylene chain part of the aralkenyl radical may be optionally substituted as defined above for an alkenylene group.
"Aralkynyf" refers to a radical of the formula -ReRc where Re is an alkynylene 35 chain as defined above and R= is one or more aryl radicals as defined above. The aryl
part of the aralkynyl radical ma/ be optionally substituted as described above for an aryl. The alkynylene chain part of the aralkynyl radical may be optionally substituted as defined above for an alkynyfene chain.
"Aryloxy" refers to a radical of the formula -ORc where Rc is an aryl as defined 5 above. The aryl part of the aryloxy radical may be optionally substituted as defined above.
"Aralkyloxy" refers to a radical of the formula -OR where R4 is an aralkyl radical as defined above. The aralkyl part of the aralkyloxy radical may be optionally substituted as defined above.
10 "Cycloalkyl" refers to a stable non-aromatic monocyclic or poly cyclic hydrocarbon
radical consisting solely 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 len carbon atoms, more preferably from five to seven carbons and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. For 15 purposes of this Invention, a bridged ring system is a system wherein two non-adjacent ring atoms thereof are connected through an atom or a group of atoms. Monocyclic cycloalkyl radicals include non-bridged cycloalkyl radicals, for example, cyclopropyi, cyclo butyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include fused, spiro or bridged cycloalkyl radicals, for example, C,Q radicals such as 20 adarnantanyl (bridged) and decalinyl (fused), and C7 radicals such as
bicyclo[3.2.0]heptanyl (fused), norbomanyl and norbornenyl (bridged), as well as substituted polycyclic radicals, for example, substituted G? radicals such as 7,7-dimethylbicyclo[2.2,1]heptanyt (bridged), and the like. Unless otherwise stated specifically in the specification, cycloalkyl radicals defined herein may be "optionally 25 substituted" by one or more substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, 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 30 substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyf, optionally substituted heterocyclylalkenyl, optionally substituted heterocyciylalkynyl, oplionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl alkenyl, optionally substituted heteroarylaikyny!, -R^OR21, -R21-0C(0)-R2G, -R31-N(R2D)2, -R^-QOJR20, -RA1-C{0)0R30, 35 -R?1-C(0)N(R2CI)£, -R21-N(R:(J)C(0}0R2I], ^R2I-N(R23)C(0)R2Q, -R21~N(R2I])5(0}LR2Q (where t is 1 or 2), -R21-S(O)cOR (where 1 is 1 or 2), -RK1-S(0)pR™ (where p is 0,1 or 2), and -R21'S(0)[N(RaD)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 aryt, optionally substituted aralkyl, 5 optionally substituted heterocyclyl, optionally substituted heterocyclyl alkyl, optionally substituted heteroaryl and optionally substituted heteroarylaikyl, or two R20,s, together with the common nitrogen to which they are both attached, may optionally form an optionally substituted /V-helerocyclyl or an optionally substituted N-hetenoaryl, and each R21 is independently a direct bond or a straight or branched alkylena or alkenylene chain. 10 "Cycloalkylalkyl" refers to a radical of the formula -R|,RB where R^ is an alkylene
chain as defined above and Rg is a cycloalkyl radical as defined above. The alkylene chain and the cycloalkyl radical may be optionally substituted as defined above.
"CycloalkylaIkenyl" refers to a radical of the formula -R^Rg where R^ Is an alkenylene chain as defined above and Rg is a cycloalkyl radical as defined above. The 15 alkenylene chain and the cycloalkyl radical may be optionafly substituted as defined above.
"Cycloalkylalkynyl11 refers to a radical of the formula -ReRg where Re is an alky ny I ens radical as defined above and Rs is a cycfoalkyl radical as defined above. The alkynylene chain and the cycloalkyl radical may bo optionally substituted as defined 20 above.
"Halo" refers to bromo, chlono, fiuono or iodo.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, dlfluoromethyl, trichloromethyl, 2,2,2-trlfluoroethyl, l-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 25 l-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, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethoxy, difiuoromethoxy, trrchloromethoxy, 2,2,2-trlfluoraethoxy, and the like. The alkoxy part of 30 the haloalkoxy radical may be optionally substituted as defined above for an alkoxy radical,
"Haloalkenyl" refers to an alkanyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. The alkenyl part of the haloalkyl radical may be optionally substituted as defined above for an alkenyl radical. 35 "Haloalkynyf refers to an alkynyl radical, as defined above, that is substituted by
one or more halo radicals, as defined above. The alkynyl part of the hafoalkyl radical may be optionally substituted as defined above for an alkynyl radical.
"Heterocyclyl" refers to a stable 3- to 1B-membened non-aromatic ring radical which comprises one to twelve carbon atoms and from one to six heteroatoms selected 5 from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical maybe optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical 10 may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited io: dioxoianyl, 1,4-diazepanyf, decahydroisoquinoiyi, imidazalinyi, imidazolidinyl, isothiazolidinyl, isoxazolidrnyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, octahydro-1 H-pyrrolo[3,2-cJpyridinyl, octahydro-1 W-pyrrolo[2,3- clpyridlnyLootanydro-lH-pyrrolot^^-^pyridlnyLoctahydro-l tf-pyrrolo [3,4-E>] p y rid i ny[, 15 octahydropynrolo[3,4-c]pyrrolyl, octa hydro-f H-pyrido[1,2-3]pyrazinyl, 2-oxgpiperazinyl, 2-oxopiperidinyl, 2-oxo pyrrol id inyl, oxazolidinyl, piperidinyl, piperazinyl. 4-piparidonyl, pyrTolidinyN pyrazalidinyl, quinuclidinyL thiazolidinyl. tetrahydrofuranyl, thienyl[1,3]dithianyl, trithianyl, tetrahydropyranyl, Lhiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-lhiomorpholinyl, azetidinyl, octa hyd ropy rrolo [3,4- 20 c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, decahydroprazino[1,2-a]azeplnyl, azepanyl, azabicycfo[3.2.1]octyl, and 2,7-diazaspiro[4.4]nonanyl. Unless stated otherwise specifically in the specification, the term " optionally substituted heterocyclyl" is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, 25 haloalkyl, baloalkenyl, haloalkynyi, oxo, thioxo, cyano, nitre, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyf, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyfalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl a I kyi optionally substituted 30 heterocyclylalkenyl, optionally substituted heterocyclyl alkynyl, optionally substituted
heteroaryf optionally substituted hete rear/la I kyF. optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R^-OR20 -R^-OCfOJ-R20, -R21-N(RaQ)z, -R21-CfO)Rmr -R^-CfOJOR® -R21-C(0)N(R"3)2j -R21-N(R2D)C(0)0R2°, -R21-N(RaD)C{0)R®, -Rai-N(Ri0)S(O)1Rw (where t is 1 or 2), -R2l-S(0)t0R2' (where t is 1 35 or 2), -R21-S(OVR23 (whera p fs 0, 1 or 2}, and -R21-S{0)tN(R2[l)2 (where t is 1 or 2),
where each R2C 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 heteracyclylalkyl, optionally substituted heleroaryl and 5 optionally substituted heteroarylalkyl, or two R20s, together with the common nitrogen to which they are both attached, may optionally form an optionally substituted N- heterocycfyl or an optionally substituted M-heteroaryl, and each R21 is independently a direct bond or a straight or branched alkylene or alkenylene chain.
"/V-heterocyclyl" refers to a heterocyclyl radical as defined above containing at 10 least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An 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 15 chain as defined above and Rh is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a
20 heterocyclyl radical,
"Heterocyclyialkenyl" refers to a radical of the formula -RflRh where Rj is an alkenylene chain as defined above and Rh is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl maybe attached to the alkenylene chain at the nitrogen atom. The alkenylene chain of the
25 heterocyclyialkenyl radical may be optionally substituted as defined above for an alkenylene chain, The heterocyclyl parL of Lhe heterocyclyialkenyl radical may be optionally substituted as defined above for a heterocyclyl radical.
"Heterocyclylalkynyr refers to a radical of the formula -RER-, where Re is an alkynylene chain as defined above and Rh is a heterocyclyl radical as defined above, and
30 if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkynyl radical at the nitrogen atom, The alkynylene chain part of the heterocyclylalkynyl radical may be optionally substituted as defined above for an alkynylene chain. The heterocyclyl part of the heterocyclylalkynyl radical may be optionally substituted as defined above for a heterocyclyl radical.
35 "Heteroaryl" refers to a 5- ic 14-membered ring system radical comprising
hydrogen atoms, 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. A heteroaryl radical is commonly, but not necessarily, attached to the parent molecule via an aromatic ring of the heteroaryl radical. For purposes of this invention, the heteroaryl 5 radical may be a monocyclic, bicyclic or tricyclic ring system, which may include spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. For purposes of this invention, the aromatic ring of the heteroaryl radical need not contain a heteraatom, as long as one ring of the heteroaryl radical contains a heteraatom, For example,
10 1.2,3,4-tetrahycf roisoq u i no I i n -7-y I is considered a "heteroaryl" for the purposes of this invention. For purposes of this invention, a "heteroaryl" radical as defined herein can not contain rings having more than 7 members and cannot contain rings wherein two non- adjacent ring atoms thereof are connected through an atom or a group of atoms {i.e., a bridged ring system). Examples of heteroaryl radicals include, but are not limited to,
15 azepinyl, acridinyl, benzimidazolyl, benzo[d]lmidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoyl ,4]dioxepinyl, benzo[b][1,4]oxaziny1, 1,4-benzodioxanyl, benzonaphthofuranyf, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-of]pyrimidinyl,
20 benzotriazolyl, benzo[4,6]imidazoI1,2-a]pyridinyl, carbazolyl, chromeno[4,3-c]pyridaziny[, crnn olinyI, cyclo penta [d] pyri m id i n yf
6,7-d i h yd ro-5tf-cy elope nta [4,5]thieno [2,3-dJpyrim idinyl, 5, B-d i hyd ro be nzo [fj]q u i nazo I i n y!,
5.6- dihydrobenzo[h]cfnnolinyl, T'.S'-dihydro-S'H-spiroItljSJdioxolane^.e'-quinolineJ-S'-yl,
6.7- dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyI, dibenzofuranyI,
25 dibenzothiophenyl, funanyl, furanonyl, furo[3,2-c]pyridiny|, furopyrimidinyl, furopyridazinyl, furopynazinyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazopyridazlnyl, imidazopyrazinyl, indazolyl, indolyl, Indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl (isoquinolyl), indolfzinyl, isoxazolyf, riaphthyridinyl, naphthyridinanyl, oxadiazolyl, 2-oxoazepinyl, oxazolyf, oxiranyl,
30 5,6,6ap7,3,9p10,1 Da-octahydrobenzo[li]quinazoliny1, 1-ptieny1-1H-pyrro!ylp phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-tfjpyrirnidinyl, pyridinyl (pyridyl), pyrido[3,2-cfJpyrinnidinyl, pyriclo[3p4-c(]pyrimidiriyl, pyrido[4,3-c]pyridaziny!, pyrazinyl, pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl, pyrrol opyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, quinazollnyl,
35 quinoxalinyf quinolinyl, quinuclidinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
2,3,4,5-tetrahydrobenzo[f)]oxepiny1r 3,4-dihydro-2H-benzo[f)][1,4]dioxepinyl, 6,7,Q,9-tetrahydro-5H-cyclohepta[£)]pyridinyl, 6,7,B,9-tetrahydro-5tf-pyrido[3,2-c]azepinyl, 5,6,7,8 -tetrahyd robenzo[4,5]thien o[2,3-tf] py ri m id in y I, 6,7, B, 9-tetrahyd ro-5 H-cyc k) he pta [4,5]th ie no [2,3-tf] py rimid ir y I, 5 5,6I71B-tetrahydropyrido[4,5-c]pyridazinyl1 thiazolyl, thiadiazolyl, triazolyi, tetrazoiyf, 1,2,3,4-tetrahydrocsoquinolin-7-yl, iriazinyl, thieno[2,3-c/]pyrirnidinyl, thienopyrimidinyl (e.g., thieno[3r2-t/|pyrimidinyl or thieno[2r3-tf]pyrimidinyl}, thiENo[2,3-G]pyriDINYL, thienopyridazinyl, thienopyrazinyl, and thiophenyl (thienyJ). Unless stated otherwise specifically in the specification, the term " optionally substituted heteroaryl" is meant to 10 include heteroaryl radicals as defined above which are optionally substituted by one or more substituent3 selected from the group consisting of alkyl, alkenyl, alkynyl, halo, 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, 15 optionally substituted cycioalkylalkenyl, optionally substituted cycloalkyl alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterccyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylaikenyl, optionally substituted heteroarylalkynyl, -FT-OFT1, -Rr-0C(0)-R3U, -R^-NfR^, ZO -R2f-C(0)R23, -R^-CTOJOR20, -R^-CfOJNfR^j, -R21-N(R2FL)C(O)ORi0,
-R^-NCR^CfOjR^0, -R^-N(Rzp)S(0)tR2D (where t is 1 or 2), -R21-S(0);QR2° (where t is 1 or 2), -R21-S(0),R^ (where p is 0, 1 or 2), and -R^-SfOfcNfR^fe (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, 25 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heLeroaryl and optionally substituted heteroarylalkyl, or two R£Dps, together with the common nitrogen to which they are both attached, may optionally form an optionally substituted N- heteinocyclyl or an optionally substituted JV-heteroaryl, and each R^'1 is independently a 30 direct bond or a straight or branched alkylene or alkenylene chair.
"N heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An /V-heteroaryl radical may be optionally substituted as described above for heteroaryl radicals, 35 "Heteroarylalkyl" refers to a radical of the formula -R^R, where Rt. is an alkylene
chain as defined above and R1 is a heleraaryl radical as defined above. The heleroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl. The alkylene chain part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkylene chain.
5 "Heteroaryfalkenyl" refers to a radical of the formula -RdR where Rd is ari
alkenylene chain as defined above and Ri is a heteroaryt radical as defined above. The heteroaryl part of the heteroarylalkenyl radical may be optionally substituted as defined above for a heteroaryl. The alkenylene chain part of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenylene chain. 10 'Heteroarylalkynyl" refers to a radical of the formula -RgR| where RH IS an
alkynylene chain as defined above and Rj is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkynyl radical may be optionally substituted as defined above for a heteroaryl. The alkynylene chain part of the heteroarylalkynyl radical may be optionally substituted as defined above for an alkynylene chain, '5 "Hydroxyalkyl" refers TD an alkyl radical as defined above which is substituted by
one or more hydroxy radicals {-OH}.
"Hydroxyalkenyl" refers to an alkenyl radical as defined above which is substituted by one or more hydroxy radicals (-QH).
"Hydroxyalkenyl" refers to an alkynyl radical as defined above which is 20 substituted by one or more hydroxy radicals (-OH).
Certain chemical groups named herein may be preceded by a shorthand notation indicating the tota! number of carbon atoms that are to be found in the indicated chemical group. For example; C7-C12alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C^C'jcycloalkylalkyl describes a cycloalkylalkyl group, 25 as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described,
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purfty from a reaction 30 mixture, and formulation into an efficacious therapeutic agent.
"Mammal" includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like. Preferably, for purposes of this invention, the mammal is a human.
"Optional" or "optionally11 means that the subsequently described event or 35 circumstances may or may not occur, and that the description Includes instances where
said event or circumstance occurs and instances in which 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 aryl radicals having no substitution. When a functional group is described as "optionally substituted,'" and in 5 turn, substitutents on the functional group are also "optionally substituted" and so on, for the purposes of this invention, such iterations are limited to five, preferably such iterations are limited to two.
"Pharmaceutical^ acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor 10 enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptabls tor use in humans or domestic animals.
"Pharmaceutically acceptable salt" includes both acid and base addition salts.
15 "Pharmaceutically acceptable acid addition salt" refers to those salts which retain
the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, 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-dlchloroacetlc 20 acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesutfonic acid, benzoic acid, 4-acetamidoben^oic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamlc acid, citric acid, cyclamic acid, dodecylsulfonic acid; ethane-1J2-disulforic acid, ethanesulTonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, 25 glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo- gfutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauricacid, maleicacid, malic acid, malonic acid, mandelicacid, methanesuifonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2- sulfonic acid, 1-hydroxy-2-naphLhoic acid, nicotinic acid, oleic acid, orotic acid, oxalic 30 acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-amlnosallcylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, Irifluonoacetic acid, undecylenic acid, and the like.
"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or 35 otherwise undesirable. These salts are prepared from addition of an inorganic base or
an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like, Prefened inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from 5 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, diethylamfne, tri ethyl am in a, tripropylamine, diethanoiamine, ethanofamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, 10 lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethyienediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, JV-elhylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamire, trimethylamine, dicyclohexylamine, choline
15 and caffeine.
A "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, for example, humans. Such a medium includes all pharmaceutical!/ acceptable carriers, diluents or excipients therefor,
20 "Therapeutically effective amount" refers to that amount of a compound of the
invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease or condition of interest In the mamma!, preferably a human. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease or
25 condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
"Treating" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of
30 interest, and includes:
(I) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;
(il) Inhibiting the disease or condition, i.e., arresting its development;
35 (iii) relieving the disease or condition, i.e., causing regression of the disease
or condition; or
(iv) stabilizing (he disease or condition.
As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular malady or condition may not have a known 5 causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centres and may thus give rise to anantiomers. 10 diastereomers, and other stereoisomer^ forms that may be defined, in terms of absolute stereochemistry, as [Ry or (S)- or, as (D)- or (L}- for amino acids. The present invention is meant 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 may be prepared using chiral synthons or chiral reagents, or resolved using conventional 15 techniques, such as HPLC using a chiral column. When the compounds described herein contain clofinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and 2 geometric isomers. Likewise, ail tautomeric forms are also intended to be included.
A "stereoisomer" refers to a compound made up of the same atoms bonded by 20 the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperiimposeable mirror images of one another.
A "tautomer" refers to a proton shift from one atom of a molecule to another atom 25 of the same molecule. The present invention includes tautomers of any said compounds.
"AtropIsomers" are stereoisomers resulting from hindered rotation about single bonds where the barrier to notation is high enough to allow for the isolation of the conformers (Eliel, E. L.; Wiien, S. H. Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994; Chapter 14). Atropisomerism is significant because it introduces 30 an element of chirality in the absence of stereogenic atoms. The invention is meant to encompass atropisomers, for example in cases of limited rotation around the single bonds emanating from the core triazole structure, atropisomers are also possible and are also specifically included in the compounds of the invention.
The chemical naming protocol and structure diagrams U3ed herein are a modified 35 form of the I.U.PAC. nomenclature system wherein the compounds of the invention are
named herein as derivatives of the central core structure, i.e., the triazole structure. For complex chemical names employed herein, a substituent group is named before the group to which It attaches. For example, cyciopropylethyi comprises an ethyl backbone with cyclopropyl substituent. In chemical sLructure diagrams, all bonds are identified, 5 except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
For purposes of this invention, the depiction of the bond attaching the R5 substituent to the parent triazole moiety in formula (I), as shown below:
10 is intended to include only the two regtoisomers shown below, i.e,, compounds of formula (la) and (lb):
The numbering system of the ring atoms in compounds of formula (la) is shown
below:
For example, a compound of formula (la) wherein RL R11 and R6 are each hydrogen, R2 is 4-(4-((1S,2Sf4/?)-bicycloI2.2.1]hept3n-2-yl)piperazin-1-yl)phenyl and R3 is 2-chloro-7-methylthieno[3,2-rf]pyrimidin-4-yl; i.e,, a compound of the following formula:
is named herein as A/J-(4-(4-((1SF2S]4/?)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)- 1 -(2-ch lo ro-7-nn ethy lthienoJ3, 2-c/Jpyri m i d in-4^y I )-1 H-1,2,4-triazole-3; 5-dia m i ne.
The numbering system of the ring atoms in compounds of formula (lb) is shown
5 below:
For example, a compound of formula (lb) wherein R1: R4 and R5 are each hydrogen, R2 is4-(4-cyclohexylpiperazin-1-yl)phenyl and R3 is 6.7-dimethoxyquinazolin- 4-yl; i.e., a compound of the following formula:
is named herein as A/s-{4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(6,7- dlmethoxyq uinazolin-4-yl)~1 H~ 1 ,2,4-triazole-3,5-diamlne.
EMBODIMENTS OF THE INVENTION
Of the various aspects of the compounds of formula (I), as set forth above in the 15 Summary of the Invention, certain embodiments are preferred.
Accordingly, one embodiment of the compounds of formula (I), as set forth above
wherein:
5 R1, R+ and R& are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)Ra and -C(0}N(R6)R7; R2 is aryl optionally substituted by one or more subslituents selected from the group consisting of oxo, thioxo, cyano, nitre, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally 10 substituted heleroaryl, optionally substituled heteroarylalkyl, optionally substituted
heteroaryl a I kenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, -RB-ORa, -Rs-O-R10-OR6, RB-0~R1D-OR10-OR5, -R9-0-R1d-CN, -R*-OR1°-C(0)0R3, -Rs-0-R1 °-C(0}N (Re)R7, -Rs-0- R1 (0)PR® (where p is 0, 1 or 2), 15 -R:'-0-R1C,-N(RS)R7, -RA-O-RL0-C(NR11)N(R11)HR -R*-0C(O)-RA, -R'-NfR6^
-Re-C(0)Ra, -Re-C(0)0RE, -R9-C(Q)N(R6)R7, -R9-N(Rg)C(0)QRs, -RS-N(RE)C(0}RE, -RB-N(R6)S{0),R8 (where t is 1 or 2), -R0-S(O).ORA (where t is 1 or 2), -R9-S(0)PRE (where p is 0, 1 or 2}, and -R?-S(0)TN(Re)R7 (where t is 1 or 2); Ra is selected from the group consisting of aryl and heteroaryl, where the aryl and the 20 heteroaryl are each independently optionally substituted by one or more
substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl a I kenyl, optionally substituted 25 heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted
heterocyclyialkenyl, -RH-ORw, -R*-0-R1D-0RB, -R^-O-R^-O-R^-OR*, ^0-R1Cl-CN, - Rs-O-R10-C( O }QRa, -R£-O-R"0-C(O)N(Rfi)R7, -Rfi-0-R'°-S(0)pR8 (where p is 0, 1 or 2), -R0-O-Ria-N{RS)R7, -R°-Q-R10-C[NR11)N(R11)H, -Rfi-0C(0)-Rs, -R0-N(Rfi)R', -R9-C(0)RK, -RH-C(0)0Rtt, -RM-C(0)N(RB)R7, 30 -R0-N{R3)C(O)ORa: -R3-N[R6)C(0)RB, -R9-N[Rs}S(0)tRe (where t is 1 or 2),
-R9-S(Q)LOR6 (where t is 1 or 2), -R9-S(0)BRA (where p is 0r 1 or 2), and -R3-S(OXN(Re)R7 (where t is 1 or 2); each and R? is independently selected from the group consisting of hydrogen, alkyk alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally 5 substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl,
optionally substituted aralkynyl, optionally substituted cyoloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted helerocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally 10 substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heferoarylalkynyl, -R1D-ORa, -R10-CN, -R1&-N02, -R,0-N(Re}2, -R^-CfOJOR* and -R13-C(0)N(Ra),, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted f 5 A^heteroa ryI or a n o pti ona I ly s u bstituted W-heterocyclyI;
each Rs is independently selected from the group consisting of hydrogen, alkyl, alkenyi. alkynyl haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 20 optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylaikyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted 25 heteroarylalkynyl;
each Rb 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; SO each R13 is independently selected from the group consisting of an optionally substituted straight or branched aikylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and
each R11 is hydrogen, alkyl: cyano, nitro or-OR6; 35 as an isolated stereoisomer or mixture thereof, or a pharmaceutical^ acceptable salt
thereof.
One embodiment of the compounds of formula (la), as set forth above, is a compound of formula (la) which is a compound of formula (Ia1}:
5 wherein:
RJ, R^ and R3 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)R* and -C(0)N(Rfi)R7;
R^is -R1Da-N(R6a)Rra where R^ and RTA, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an 10 opLionally subsLiLuted /V-heterocyclyl, and R1(ls is an optionally substituted straight
or branched alkylene chain;
R20 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^-OR65, -R9A-C(0)R^, -R"-C(0)0RKa, -R^-N(R^)R7a and -R?3-C(O)N(Rfi0)R7a, where each R69, R79 and R1^ is independently selected from the group consisting 15 of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R99 is independently
selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R5 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more 20 substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo,
haloalkyl, aikyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryialkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted 25 heterocyclyialkenyl, -RB-ORA, -RTF-0-R1u,-0RB, -Ru-0-RM-0-R1U-0RA,
-R3-O-R10-CN, -R9-O-R10-C(O)ORB, -R9-0-R1 °-Q(0)N( RE) R7 -R^-O-R'O-SICOPR0 (WHERE P IS 0, 1 OR 2), -RB-D-R10-N(RE)R7 -R9-0-R1D-CTNR11)N{R1,)H, -R4-0C(O)HRB, -RS-N(R6)R7, -R"-C(0)RBI -RB-C(0)0R4, -RS-C(0)N(R6)R7, -R9-N(RA)C(O)OR0, -RS-N(RB)C(0)RB, -R^NTR^SFO^R6 (WHERE T IS 1 OR2}: 30 -R3-S(OXORL1 (WHERE T IS 1 OR 2), -R'-S(0)PRB (WHERE P IS 0, 1 OR 2), AND
-R9-S(OXN(R"}R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haSoalkenyl, haloalkynyl, hydroxys Iky I, optionally substituted aryl, optionally substituted aralkyl optionally substituted aralkenyl, 5 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 10 substituted heteroarylalkyl, optionally substituted heteraarylalkenyl, optionally
substituted heteroarylalkynyl, -R1t,-ORs, -R'm-CN, -RJ(t-N02, -R1tl-N(R6)S, -R^-CtOJOR6 and -R1D-C(0)N(Rs)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocycIyi; 15 each Ra is independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, 20 opti on a lly s u bs tltuted heterocyclyl, o pti □ n a 11 y substituted heterocyclylalkyl,
optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl alkenyi, optionally substituted heteroarylalkynyl;
25 each R9 is independently selected from the group consisting of a dined 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 R13 Is independently selected from the group consisting of an optionally substituted 30 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 hydrogen, alkyl, cyano, nitro or-ORe.
One embodiment of the compounds of formula (Ia1), as set forth above, is a 35 compound of formula (Ia1) wherein:
RJ, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R^IS -R1DB-N(RGH)R7* Where RSa and R7b, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an 5 optionally substituted W-heterocyclyl, and R19a is an optionally substituted straight
or branched alkylene chain;
R^ is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R39-CR^, -R09-C(O)Ra9, -R9s,-C(O)OR0H, -R9l,-N(R?B)R7y and -R^-C(0)N(R^}R7^, where each R*9, R79 and R*9 is independently selected from the group consisting ID of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R99 is independently
selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each 15 optionally substituted by one or more substitjents selected from the group
consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R*-ORG, -R9-0C(0)-Ra, -R9-N(R6)R7, -R9-C[0)Rfl, -R^C(0)0Re, -R0-C(O)N(RG)R7, -Re-N(R0)C(O)OR*, -RS-N(R0)C(O)R*, 2D -R9-N(R0)S(O)|R8 (where t is 1 or 2), -R"-S(0)TOR* (where t is 1 or 2), -Ry-S(0)cR*
(where p is 0, 1 or 2), and -R9-S(0)TN(RG)R7 (where t is 1 or 2);
each Re and R7 is independently selected "from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 25 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1D-ORs, -R10-CM, -R^-NOj, -R1(J-N(R6}2, -Rm-C(0)0Ra and -R10-C(O)N(Rs)2, or any R* and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl; 30 each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; 35 each RH 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.
Another embodiment of the compounds of formula (la1), as set forth above, is a compound of formula (Ia1) wherein: 5 R1, R* and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2a is -R'^-NtR^JR73 where R15' and R73, together wiLh the common nitrogen to which they are both attached, form an optionally substituted W-hsteroaryl or an optionally substituted W-heterocyclyl, and R1Db is an optionally substituted straight 10 or branched alkylene chain;
R!G is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, _R9g_0Rag _R&3-C(0}R3B, -R"-C(0)0R^, -RB0-N(R*S)R73 and -RS9-C(0)N(R^)R7S, where each RE°, R70 and R60 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R0G is independently 15 selected from the group consisting of a direct bond and an optionally substituted
straight or branched alkylene chain; R3 is a monocyclic aryl optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted 20 heterocyclyialkenyl, -RB-ORA, -RA-0C(0}-R6, -RS-N(RS)R7, -RB-C(0)RR,
-R"-C(0)0R3, -RH-C(0)N(R')R7, -R9-N(RS)C(Q)ORB, -RB-NCRB)C(0)RS, -R5-N(RB)S(0)LRE (where t is 1 or 2), -R^-S^OR5 (where t is 1 or 2), -R9-S(O)PR0 (where p is 0, 1 or 2), and -R0-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, 25 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-ORE, -R1U-CN, -RIN-NO:, -R'°-N(RR)2, -RIRI-C(0)0RA and -R13-C{0)N(RA)Z, or any R6 and 3Q R7, together with the common nitrogen to which they are both attached, form an
optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl; each RA is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 35 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted hetenoaryf, 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 R13 is an optionally substituted straight or branched alkylene chain, 5 Of this embodiment, a preferred embodiment is wherein R2* is selected from the
group consisting of optionally substituted 2-(piperidinyl)ethyl and option ally substituted 2- (pyiTolidinyl)ethy! and R3 is optionally substituted phenyl.
One embodiment of this preferred embodiment is a compound of formula (Ia1), as set forth above, selected from the group consisting of: 1U L-PHENYL-^^^FZ-FPIPERIDIN-L-YIJETHOXYJPHENYLJ-IH-L^^-TRIAZOLE-S.S-DIAMINE;
1-{4-isopropylphenyl)-A/i-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3?5- diamine;
^l-{5-amino-3^(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-1H-1l2l4-triazol-1- y I) b e nzenesu ffo nam ide; 15 1-(2-fluorophenyl)-Ws-(4-(2-(2-methylpyrrolidin-1-yl)ethoxy)phenylJ-1H-1,2,4-triazo]e"3l5- diamine;
1-(2-f1uorophenyl)-/V;f-(4-(2-(piperidin-t-yl}etho)(y)phenyl)-1W-1p2,4~triazole-3r5-diaTnine; and
1-(2-ffuorophenyl)-/V3-(4-[2-(pyrrolidin-1-yl]ethoxy)phenyl)-1H-1,2,4-triazole-3l5-diamine. 20 Another embodiment of the compounds of formula (Ia1): as set forth above, is a
compound of formula (!a1) wherein:
R1, R*1 and Rs are each independently selected from the group consisting of hydrogen and alkyl;
R2a is -R10a-N(Rea)R?a where RBa and R7ar together with the common nitrogen to which 25 they are both attached, form an optionally substituted N-heteroaryl or an
optionally substituted N-heterocyclyl, and RJOi Is an optionally substituted straight or branched alkylene chain; Rae is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^-ORaa, -R*-C(0)RaB, -R"-C(0)0R*9, -RBg-N(R09)R79 and -R09-C(O}N(Re9)R79, 30 where each R6°r RTg and R65 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RSg i3 independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R5 i3 a monocyclic heteroaryl optionally substituted by one or more substituents selected 35 from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Ra-ORs, -R^-0C{0)-R8J -R9-N(R0)R7, -R*-C(0)R$, -RS-C(OJQR8, -R5-C(0)N(R6)R7, -R^-NFR^CCOJOR*, -R^-N^JCfOJR3. -RY-N(RS)S(0),RA (where t is 1 or 2), -R9-S(Q),ORFI (where t Is 1 or 2), -R9-S(0)PRA s (where p is 0, 1 or 2), and -Rs-S(O)TN(R0)R7 (where t is 1 or 2);
each Re and R7 is independently selected "from the group consisting of hydrogen, alkyl, haloalkyl, hydroxys Iky I, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclyfalkyl, 10 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR3,
-R10-CN, -RTO-N02, -R10-N(R6)2, -R10-C(O)ORs and -R"°-C(0)N(RE)Z, or any RE and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl; each RS is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, 15 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Rb is independently selected from the group consisting of a direct bond and an 20 opliunally substituted straight or branched alkylene chain; and
each RIA is an optionally substituted straight or branched alkylene chain.
Of this embodiment, a preferred embodiment is wherein R2A is selected from the group consisting of optionally substituted 2-(piperidinyl)ethyl and optionally substituted 2- (pyrrolidinyl)ethyl and R3 is selected from the group consisting of optionally substituted 25 pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl and optionally substituted pyrazinyl.
One embodiment of this preferred embodiment is a compound of formula (Ia1), as set forth above, solGctad from the group consisting of:
A^-(3-chloro-4-(2-( pyrrol id in-1-yl)ethoxy)phenyl }-1 -[pyridln-2-y|)^1/-M ,2,4-triazole-3,5- 30 diamine;
1 -(py rid i n -2-y I)-Af3-{4-( 2 -(pyrrolidi n-1 -y I Jet hoxy )p he n yl)-1 1,2,4-tri azole-3,5-d i a m i n e; A^-m ethyl-1 -(py ri d fn -2-y I >- Af'-t^f 2-( py rro I icl i ri -1 -y I Jethoxy >p h© nyr)-1 W-1,2,4-triazole-3,5- diamine;
W3-(4-(2-(pyrrolfdir>-1 -yl)ethoxy}phenyl)-H4-(trifluoromethyl)pyrimidin-2-yl)-1 H-1,2,4- 35 friazole-3,5-diamine;
diamine;
1-(6-chforopyridazin-3-yl)-/Vi!-(4-(2-(pyrrolidin-Vyl)etfioxy)phonyl)-1H-1,2,4-triazole-3l&- diamine;
5 1 -(pyrazin-2-yi)-/V3-{4-(2-(pyrnolidin-1 -yl)ethoxy )phenyl)-1 W-1 r2,4-triazole-3,5~diamine;
1 "(2-morpholinopyridin-4-yl)-/y3-(4-(2-(piperidin-l -yf}ethoxy)pheny1)-1 H-1,2,4-triazole-3,5- diarnine;
1 -(6-chlaropyridin'2'y!)-Ws-(4'(2'(pyrToBdin-1 -yf)ethoxy)phertyl)-1 tf-1 ,2,4-1^019-3,5- diamine;
10 1 -(S-ch I o ro py rid i n-2-yl 4-( 2-(pyrr o ftcfin-1 -yl )ethoKy )ph er yl)-1W-1,2,4-tr iazol e-3, diamine;
1 -(3-chloropyridin-2-yl)-/V3-(4-(2-(pyiTalidin-1 -yl}ethoxy }phenyi)-1 H-1,2,4-1rrazole-3,5- diamine;
1 -(6-c h I o ro py ridin-2-y I 4-( 2-(piperid irt-1 -yF )ethoxy)ph en yf)-1H-1,2,4-tri azo I e-3 r 5- 15 diamine;
1-(6-morpholinopyridin-2-yl)-W3-(^(2(piperidin-1 -yl }athoxy }pfienyl)-1 tf-1,2,4-tnaiDle-3,5- diamine;
/V3-(4-(2-(pyrroiidin-1-y!)ethoxy)phenyl)-1-(4-(trifluoromethyl)pyridin-2-yl)-1W-1r2!4- triazoie-3,5-dlamlne;
20 JV3-(4-( 2-(pyrrol i d i n-1 -yl )ethoxy )p heny I)-1 -(3-(trif I uo no nietliy I) p yrid in-2-yl)-1W-1,2:4- triazole-3,5-diamine:
1-(6-methij>^pyridin-2-y!)-A/J-(4-[2-(pyrrolidin-1-yl)ethDxy)phenyl)-1H-1l2I44riazole-3p5- diamine;
1 -{5-brorno py rid i n -2-y I )-/V3-(4-(2-( py rrolid i n-1 -yl )etti oxy }ph en y I)-1H-1,2,4-trrgzole-3,5- 25 diamine;
1"{6"(rneLhyiaminc})pyridin-2-yl)-W;!-(4-(2-(piperid]n-1'yl)ethoxy)phenyl)-1W-1l2,4-triazoi e- 3,5-diamine;
1-(6-(dimethy[amino)pyridin-2-yi^W3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1W-1,2,4- Lriazole-3,5-diam i ne;
30 2-(5-amino-3-(4-(2-(pyrrolfdin-1-yf)ethoxy)phenylamino)-1H-1,2,4-triazol'1'yl)-fi- methy I pyri m id i n-4-ol;
1-(pyrrmidin-2-y[)-W3-(4-(2-(pyrrolidirHl-yl)ethoxy)phenyi)-1 H-1 r2,4-triazoie-3,5-diamine; and
A/5-(3-fluorch4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl}-1 -(pyrfdin-2-y!)-1 H-1,2,4-triazole-3,5- 35 diamine.
Another embodiment of the compounds of formula (Ia1) is a compound of formula (I a1) wherein:
R\ R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
5 R^is -RINA-N(Rf:a)R7a where and RT*, together with the common nitrogen to which they are both attached, form an optionally substituted A/-heteroaryl or an optionally substituted A/-heterocyclyl, and R10a is an optionally substituted straight or branched alkylene chain; R23 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryf, aralkyl, 0 -R^-OR69, -R9s-C(Q)R^, -R0^C(O)OR89, -R^-NfR^JR79 and -R^-Cf0}N (R60}R7s,
where each RSg, R7' and R^ is independently selected from the group consisting of hydrogen, aikyl, haloalkyl, aryl and aralkyl. and each Raa is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; 5 Rs is selected from the group consisting of a bicyclic aryl and a bi eye lie heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Rs-ORs, D -R9-OC(0)-Re, -R^N(Re)R7, -R^-CtOJR6, -R^C(0)0R3, -R9-C(Q}N(R6)R7r
-R5-N(Re)C(0)0Rfl, -Rs-N(RB)C(0}Rs, -R9-N(R®)S(0}tRfl (where t is 1 or 2), -R9-S(0\0Re (where t is 1 or 2), -R9-S(0)fR* (where p is 0, 1 or 2), and -R9-S(0)tN(R6}R7 (where t is 1 or 2); each Ru and R7 is Independently selected from the group consisting of hydrogen, alkyl, 5 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^-OR®, -R1^CN, -R1U-N02, -R1U-N(R8)2j -R10-C(O)OR® and -RTO-C(0)N(R8)2, or any R0 and 3 R', together with the common nitrogen to which they are both attached, form an
optionally substituted /V-heteroaryl or an optionally substituted W-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 5 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, 5 Another embodiment of the compounds Df formula (la 1} is a compound of formula
(Ia1) wherein:
R1, R* and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2a is -R,0a'N(RG3)R7A where RSA and RTi\ together with the common nitrogen to which 10 they are both attached, form an optionally substituted W-heteroaryl or an
optionally substituted Af-heterocyclyl, and R1"5 is an optionally substituted straight or branched alkylene chain; R20 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^-ORAGR -R^-C(0)RAS, -R"~C{O)OR60, -Ra9-N(RE9)R73 and -R9S-C(0)N(R69)R79, 15 where each R6®, R7S and R6b is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R03 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkyfene chain; R" is a bicyclic aryl optionally substituted by one or more substltuents selected from the 20 group consisting of oxo, haio, haloalkyl, alkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -Rs-ORE, -R0-OC(O)-Ra, -R9-N(RE}R7, -R9-C(0)Ra, -Rs-C{0)ORa, -R9-C(0)N(R*)R7, -Rq-M(R')C(0)0R6, -R&-N(R®)C(0)R6, -R^NfR^SfOfcR5 (where t is 1 or 2), -RB-S(D)tOR6 (where t is 1 or 2}, -R^O^R15 25 (where p is 0, 1 or 2), and -R0-S{O),N(R5)R7 (where t is 1 or 2);
each Rfi and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally subsliluled heterocyclyl, optionally substituted heterocyclylalkyl, 30 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-OR4,
-R1tl-CN, -R10-NOA, -R*-N(Re)2, -R1°-C(O)0Rs and -R"-C(0)N(R8h, or any Re and R7, together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted W-heterocyclyl; each RA is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, 35 optionally substituted aryl, optionally substituted aralkyi, optionally substituted
aralkynyl, 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 5 optionally substituted straight or branched alkylene chain; and
each Rf° is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (1a1) is a compound of formula (Ia1) wherein:
RJ, R+ and R5 are each independently selected from the group consisting of hydrogen ID and alkyl;
R23 is -R'()a-N(RBa)Rra where RGa and R7a, together with the common nitrogen to which they are both attached, farm an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl, and R1tls Ss an optionally substituted straight or branched alkylene chain; 15 R29 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -RS9-OR^, -R39-C{0)Ra8, -R^-C(0)0R69, -R^-N(R^)R79 and -R^-CfOjNfR^R79, where each R^, R79 and R*9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R®9 is independently selected from the group consisting of a direct bond and an optionally substituted 20 straight or branched alkylene chain;
R3 is a bicyclic heteroaryl optionally substituted by ore or more substltuents selected
from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR#, -Rs-0C[0)-R3, -Ry-N(R0}R7, -Ra-C(0)Ra, 25 -R^C(Q)ORa, -R9-C(0)N{R6)R7. -R9-N(R6)G(0)0Rs, -Ra-N(Rs)C(0)Rs,
-R&-N(Rc)SfO)LRe (Where t is 1 or 2), -R^SfO^GR6 (where t is 1 or 2), -Ra-S(0)pRa (where p is 0, 1 or 2), and -R9-S(0}-N(R6)R7 (where t is 1 or 2); each R0 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyf, optionally substituted aryl, optionally substituted aralkyl, 30 optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-ORa, -R^CN, -RlQ-NO:, -R1D-N(Ra)a, -Rlc-C(0)0Re and -R"-qO}N(R!)s, or any R6 and R7, together with the common nitrogen to which they are both attached, form an 35 optionally substituted Af-heteroaryl or an optionally substituted N-heterocyclyl;
each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyi, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 5 optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each Ra is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1D is an optionally substituted straight or branched alkylene chain.
Of this embodiment, a preferred embodiment is wherein R2* is optionally 10 substituted 2-(pyrroiidinyl)ethyl and R3 is selected from the group consisting of optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted benzo[d]thiazo[yl, optionally substituted benzoMimidazolyl, optionally substituted phthalazinyl, optionally substituted isoquinolinyl, optionally substituted thieno[2,3-c]pyridinyl, optionally substituted furo[3,2-c]pyridinyl, optionally substituted 15 tetrahydroquinazolinyl, optionally substituted naphthyridinonyl, optionally substituted pyridof4l3-c]pyridazinyli optionally substituted thieno[2,3-tf]pyrimidinyl and optionally substituted th ieno[3,2- ofl pyrim i d i nyL
One embodiment of this preferred embodiment is a compound of formula (lal}, as set forth above, selected from the group consisting of: 20 1 -(7-(benzy1oxy )-6- methoxyq ui i n azo I i ri -4- y I )-A^-[4-( 2 -(py rrolid i n-1 -y I )ethoxy )phen yl)-1H- 1,2,4-triazole-3,5-diamine; A/i-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(quinoxalin-2-yl)-1tf-1,2,4-triazole"3I5-diamino; 1-(benzo[(/]thiazol-2-yl)-A/3-{4-(2"(pyrrolidin-1-yl)ethoxy)phenyl)-1W-1,2,4-triazole-3,5- diamine;
25 1 -(1 -methyl-1 H-ben^Mimidazol-2-yl}~A/!-(4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4- triazole-3,5-diamine;
/V3-(4-(2'(2-methylpyrrolidin-1 -yl)ethoxy)phenyl)-1 (quinoxalin-2-yl)-1 H-1,2,4-triazole-3,5- diamine;
1-(benzo[£/]thiazoJ-2-yl)-A/3-(4'(2-(2-methylpyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4- 30 triazole-3,5-diamine;
1 -(1 -methyl-1 H-ben zo[cflrm idazol^-yl)-/^ 4-(2-( 2-mothy I py rro I i d in -1 -y I )eth axy )p h e ny I )-
1H-1 r2,4-lriazole-3,5-diamlne; 1 -(1 H-ben zo[f/] im idazo l-2-y I 4-( 2-(2-m eth y I py rro I i d In -1 -y I Jethoxy )ph eny I}-1 tf-1,2,4- trlazole-3,5-diamine;
35 1-(phthalazin-1-yl)-A/3-{4-(2-(pyrriolidin'1-yl)ethoxy)phenyl)-1W-1,2l4-triazole-3l5-diamlre;
1 -(1 H-benzo [c/|im]dazD l-2-y I)- W"-{4-(2-( py rTolidi n-1 -yl )elhoxy }ph en yl)-1H-1,2,4-triazole-
3,5-diamine;
ineihyll-t2-C4-{5-airiino-l-(quinoxaliri-2-y,l)-lH-l,214-triazol-3- y lam i no) p he noxy )ethy I )py rro I id in a-2 - ca rboxy I ate;
1 -(2-chloroquinazolin~4-yl)-/Vs-(4-(2-(pyiTolidin-1 -yl)etho!(y)phenyl)-1 H-1 r2,4-triazole~3,5- diamine;
1-(2-morpholinoqulnazolin-4-y1)-W3-(4-(2-(pyrrolidln-1-yl )ethoxy )phe riy I1W-1,2,4-triazole- 3,5-diamine;
1 -(ben zoMthiazo!-2-y I 3-chloro-4-{2-( py rro I i d i n-1 -y1)ethoxy)phenyl)-1 HA ,2,4- triazole-3,5-d ia m i ne;
^-(3-c hlorc-4-(2-{pyrrol id in-1 -yi)ethoxy)phenyl)-1-(1 -methyl-1 H-benzo[d]i midazol-2-yl)- 1H-1,2r4-ti"iazoJe-3,5-diamine;
/V3-(4-{2-(pyrno1idln-1-yl)ethoxy)pheriy|)-1-(quinolin-2'yl)'1W-1I2I4-triazole-3l 5-diami ne;
methyl 1 -(2-(4-{5-amino-1 -(benzc[of]thiazol-2-yl)-1 H-1:2,4-triazol-3- y lam i no )p he noxy )ethy I )py rra I id in e-2 -ca rboxy I ate;
1 (2-chloro-e r7-dlmetrioxyquinaiOlin-4-yl)-/VJ-(4-(2-(pyrrolidin-1 -yf>ethoxy)phenyl)-l rt- 1,2,4-triazole-3,5-diainine;
1-(6,7-dimethoxyquinazolin-4-yl)-A/s-(4-(2-(pyrrolidin-1-yl)e'thoxy)phenyl)-1H-1,2.4- triazoie-3,5-d ia m i ne;
/V3-(4-(2-(2,5-dimelhylpyrroiidin-1-yl)ethoxy^ 3,5-diamine;
1 -(G-ch I oroq u i r a zolin-4-y IWs-(4-(2-( pyrrol id in-1 -y I )eth oxy )ph eny I}-1 HA ,2,4-triazoie-3,5- diamine;
1-(2-chloro-S,7-dihydrO"5/-^cydopenta[rf}pyrirnidin-4-y[)-A/3-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-1ff-1,2,4-triazo!e-3l5-diamirie;
1 -(isoquinolin-1 -yl)-fV3-(4-(2-(pyTrolidin-1 -yi)ethoxy)phenyl)-1 HA ,2,4-triazole-3,5-diamine;
/V3-(4-(2-(pyrrDlidin-1-yl)ethoxy)phenyl)-1-(tliierK)[2?3-i/|pyrirriidin-4-y I)-1 HA ,2,4-triazole- 3,5-diamine;
1 -(6 -pheny Ith ien o[3,2 -of] py ri m i d i n -4-y I > A/J-(4-(2-( py rrol id i n-1 -y I Jethoxy )p he nyl)-1H-'1,2,4- tria zole-3,5-d iami ne;
M7-(4-(2-(pyrrolidin-1-yl)ethoxy)ph8nyl)-1-(2-(trifluorornothyl}quinazoliri-4-yl)-1H-1,2,4- tria zole-3,5-d iamine;
4-( 2-{py rnol id i n-1 -y I Jethoxy )pheny I)-1 '(th ieno[3,py ri mid i n-4-y I1W-1,2,4'triazole- 3,5-diamine;
Wa-{3-fluorO'4-(2'( py rro I i d i n-1 -yl )ethoxy) p he ny I )-1 -(quinoxalin-2-yl)-1 H-1,2,4-iriazole-3,5- diamine;
1 -(ben zo[d]th iazol-2-y I}- N-( 3 -f I uoro-4-(2 -( pyrrolidin-1 -yl)ethoxy)pheny1)-1H-1,2,4- triaaole-3,5-diamine;
5 1 -(2-chloro-7-methylthieno[372-£/]pyrimidin-4-yl)-N3-(4-(2-(pyTTolid!n-1 -yl)ethoxy)phenyl)- 1H-112,4-triazole-3i5-di amino;
A^-(3-1luoro-4-[2-(pyrrolidin-1-yl)ethoKy)phenyl)-1-(isoqiiinolin-1-yl)-lH-1,2,4-triazole-3,5- dlamine;
3-ch!o ro-4-(2-t pyrnolidin-1-yl)9thoxy)phenyl)-1-(e,7-dfmethoxyquinaziolin^-yl)-1H- 10 1,2,4-triazole-3,5-diamine;
N3-chlon>4-(2-( pyrrolidin-1-yl)ethoxy)phenyl)-1-(isoqu]nolin-1-yl)-1H-1f2,4-triazole-3,5- diamine;
1 -(6-fIuoroquinazoIin-4-yl)-2-( pyrroladin-1-yl)ethoxy)phenyl)-1W-r1,2l 4-trl a e-3 r 5- diamine;
15 /V3-(4-(2-(pyrrolidin-1-y0ethoxy)phenyl)-1-(thieno[2,3-c]pyridin-7-y1)-lH-1,2,4-tnazole-3,5- diamine;
1-(2-methylquinazolin-4-yl)-/VJ-(4-(2-(pyrrolidin-1-yl)0thoxy)phenyl)-1H-1,2,4-triazole-3,5- diarnine;
1- (funo{3,2-c]pyridin-4-yl)- N3-(4-(2-(pyrrolldln-1 -yl)ethoxy}phenyl)-1 tf-1,2,4-triazDle-3,5- 20 diamine;
2- ( 5-aiTii no-3-( 4-(2-( py rrolid i n-1 -yl )ethoxy) phenyla m i n o)-1 H-1.2,4-tiiazo I-1 -y I )-5,6,7, B-
tetra hyd noq u i nasol i n-4-o I;
1-(6,7-dimethoxyisoquinolrn-1-yl)-/V'3-{4-(2-(pyrrQlidin-1-yl)ethoxy)pheny|)-.1H-1,2,4- triazo I &-3,5-d ia m i ne;
25 5-{5-amino-3-(4-(2-(pyrTOlidin-1-yl)ethoxy)phenylamino)-1H-1.2,4-triazoJ-1-yl)-1,e- na p h thy rid i n-2( 1 tt)-one;
benzyl3-(5-amino-3-(4-{2-(pyrrolidin-1-yl)ethoxy)phenylaminci)-1f-M,2,4-triazol-1-yl)-7,8- d i hyd ropy rido [4,3-c] py ridazi ne-6(5 tf)-carboxy late;
/V3-[4-(2-(pyrro]idin-1-yl)ethoxy)phenyl)-1-(5p6r7rS-t!etrahydropyrido[4,3-c)pyridazin-3-yl)- 30 1H-1 r2,4-triazole-3,5-diamine;
1-(2,6Hdiohlorothieno[3,2-c/]pyrimidin-4"yi)-A/3-(4--(2-pyrrolidin-1-ylethoxy)phenyl)-1 H- 1,2,4-triazole-3,5-diam!ne;
1-(2-chlorothi&no[2,3-d]pyTimidin-4-yl)-/V3-(4-(2-pyrnolidin-1 -ylethoxy)phenyl}-1 H-1,2,4- triazole~3,5-diamine; and 35 1-(2-chlQnolhieno[3?2-c^pyrimidin-4-yl)-/y3'{4-(2-pyrnolidin-1-ylethoxy)phQnyl)-1H-1r2r4- triazole-3,5-dIamine.
Another embodiment of the compounds of formula (Ia1) is a compound of formula (Ia1) wherein:
R\ R4 and R5 are each independently selected from the group consisting of hydrogen 5 and alkyl;
R2s is where R6A and R7A, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted /V-heterocyclyl, and R'TE is an optionally substituted straight or branched alkylene chain; 10 R29 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^-OR09, -R^-C^R60, -RAG-C(0)0RS3R -R^-N^R79 and -R^-CFOMR^R73, where each R6H, R73 and R&9 is independently selected from the group consisting of hydrogen, alkyf, haloalkyl, aryl and aralkyl, and each R^ is independently selected from the group consisting of a direct bond and an optionally substituted 15 straight or branched alkylene chain;
R2, is selected from the group consisting of a tncyclic aryi and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally 20 substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R6-QRA,
-R9-OC(0)-R5, ~RS-N(RG)R7, -R9-C(0)RS, -RB-C(0)0R3R -R9-C(0)N(RB)R7, -R®-N(R3)C(0)0RS, -R9-N[RFI}C(0)R6, -RA-N(R6)S(0),RA {where t is 1 or 2), -R'-SFOJ.OR* (where t is 1 or 2), -R9-5(0)PR3 [where p is 0, 1 or 2), and -RA-S(0)-N(R6)R7 (where t is 1 or 2}; 25 each RS and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl. optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R™-QRAR 30 -R1(J-CN, -R10-NO2, -R10-N{RS>2, ~R1*-C(0)0RA and -R1&-C(0)N(R6}2, or any RS and
R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted /V-heterocyclyl; each RB is independently selecfed from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 35 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Rs is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and 5 each R1C is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ia1) Is a compound of formula (Ia1) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
10 R2A Is -R1Qa-N(R£A)R7A where RSa and R7A, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted /V-heterocyclyl, and R1Da is an optionally substituted straight or branched alkylene chain; R29 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, 15 -R^-OR69, -R^-C^R69, -RS9~C(0)0R^, -R"-N(R09)R79 and -RS3-C(O)N(RB9)R70,
where each RBS, R7g and R6* is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R93 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; 20 R3 is a tricyclic aryl optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R^OR*, -R3-QC(0)-R8, -R^-NfR^R7, -R9-C(0)R3, -Ra-C(0)0R3, -Ra-C(0)N(R6)R7, -R9-N(Re)C(0)0Rs, -R9-N(R3)C(0)RB, 25 -R9-N{Re)S{0)iR? (where t is 1 or 2), -R6-S(0)t0Rs (where t is 1 or 2), -R$-S(0)pR3
(where p is 0, 1 or 2), and -Rs-SfO)LN(RG)R7 (where t is 1 or 2); each R° and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 30 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORA, -R1D-CN, -R1D-NO:, -R10-N(RE}2, -R10-C(O)OR* and -R10-C(O)N(RA)2L or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted -heterocyclyl; 35 each RS is independently selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
5 each Rs 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.
Another embodiment of the compounds of formula (Ia1) is a compound of formula (Ia1) wherein:
10 R1, R*1 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2a is -R10a-N(RB*)R7a where R0* and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted W-heterocyclyl, and R1Ja is an optionally substituted straight 15 or branched alkylene chain;
R^ is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -Rqa-ORS0, -Rq0-C(O)R^, -RBa-C(0)0R3fl, -R
straight or branched alkylene chain; R* is a tricyclic heteroaryl optionally substituted by one or more substituents selected
from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally 25 substituted heterocyclylalkenyl, -R9-OR4, -Rs-0C(0)-Rs, -R9-N(R*)R7, -R9-C(0)Rs,
-R9-C(Q)ORE, -Rs-C(0)N(Re)R7, ^N(R0)C(O)OR3r -R9-N(R8)C[0)RB, -Ra-N(Re)S(0)tRe (where t is 1 or 2), -R9-S(0),0RB (where t is 1 or 2}, -R9-S(0)fRe (where p is 0,1 or 2), and -Rs-S(0)tN(RB)R7 (where t is 1 or 2); each Re and R7 is independently selected from the group consisting of hydrogen, alkyl, 30 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1LI-ORfc, -R1Ll-CN, -R1d-N02, -R10-N(R6)2, -R10-C(O)ORa and -Ric-C(0)N(RB)2| or any Rc and 35 R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted W-heterocyclyl; each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl optionally substituted cycloalkylalkyl,
5 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 is an optionally substituted straight or branched alkylene chain.
10 Of this embodiment, a preferred embodiment is wherein RZa is optionally
substituted 2-(pyrroiidinyl)ethyl and R3 is selected from the group consisting of optionally substituted 5,8,6a,7,6,9,10,f0a-octahydrobenior/)]quinazolinyf, optionally substituted 5,6-dihydrobenzo[h]quinazolinyl, optionally substituted 6,7,8,9-tetrahydro-5H- cydohepta[4,5]thieno[2,3-c^pyrimidinyl, optionally substituted 5r6,7,S- 15 tetrahydrobenzo[4,5]thieno[2,3-af]pyrimidinyfl optionally substituted phthalazinyl,
optionally substituted 6,7-dihydro-5H-cyclopenta[4,5]thieno[2.3-d]pyrimidinylp optionally substituted benzothieno[3,2-of]pyrimidinyi and optionally substituted 5,6- d i hydrobenzo[ft]cinnoIinyI.
One embodiment of this preferred embodiment is a compound of formula (Ia1), 20 as set forth above, selected from the group consisting of:
1-(5,6,6a,7,8,9,10,1 Oa-octahydrobenzo(h) Jq uinazol i n-2-yl)-4-( 2-[ py nolid in-1 -
yt)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5-diamine; 1 -(5,6-di hyd ro be nzo[/i]q ui nas^ I i n-2-yl)-A/^-(4-( 2-(py rrofidin-1 -y I )ethoxy) pheny I)-1H-'1,2,4- tri azole-3,5-d ia m i ne; 25 A/J-(4-[2-(pyrrclldin-1-yl)ethoxy)phenyl)-1-(6,7,S, 9-tetra hy d ro-5H-
cyclohepla[4,5]thieno[2 3cf|pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine; ■t -
yl)ethoxy}phenyl}-1 H-1,2,-4-t riazole-3,5-d iamine; 1-(6,7-dihydro-5H-cyclopenta[4l5]thieno[2l3-cflpynmidin-4-y1)-A/;?-(4-(2-(py,rrolidin-1- 30 yl)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5-diamine;
3-c h lo ra-4-(2 -(pyrrol idin-1-yl)ethoxy)pheny!)-f-(5,6,7,6-
tetrahydrobenzo[4,5]thienol2,3-c/]pyrimidin-4-yl)-1H-1,2,4-trla20le-3,5-diamine; ^-(S-fluoro^^-fpyrro lidin-1-yl )etho>fy) phenyl)-1-( 5,6,7, S- etrahydrobenzo[4,5]thieno[2,3
tf]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-d iamine;
l-fS-methyl-S.e./.a^etrahydrobenzc^SJthieno^^
1-yf)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; 1 -(benzcithieno[3I2-tflpyrimidin^-yl)-A/S'(4-(2-(pynolidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4- triazoie-3,5-diamine;
5 1-(7-fert-bLrty!"5I6l7JS-teti^hydrabenzoI4l5]thienol2l3-^pyrimidin-4-y!)-A/5l-(4-(2- (pyrrolidin-l-yl)ethoxy)phenyl]-lH-l ,2,4-triazole-3,5-diamine; and H5,6-dihydnobenzo[fi3cinnolin-3-yl)- W3-(4-(2-(pyiTo!Sdin-1 -yl)ethoxy)pheny1)-1 H-1,2,4- triazole-3,5-diamine.
Another embodiment of the compounds of formula (la), as set forth above, is a 10 compound of formula (la) which is a compound of formula (Ia2):
wherein:
R1, R* and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)Rb and -C(O)N(R0)R7; 15 R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R^-OR6b,
20
-R^-C(O)OR0b, -RSb-N(R3b)R7b and -R0b-C{O)N(RGb)R7b, where each Ra, R7b and R4b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each Reb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R^ is selected from the group consisting of -C(0)R6, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
R2k is selected from the group consisting of hydrogen and alkyl; 25 R3 is selected from the group consisting of aryl and heteroaryf, where the aryl and the
heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyario, nitre, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heteroarylaikenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkenyl, -R?-OR3, -R9-0-R1d-0R&, Rs-G-R10-O-R1&-OR*, -Rs-O-R10-CN, -R°-OR1u-C(0)0R*, 5 -R6-0-R1G-Q0)N(R6)R', -R3-0-R,Q-5{0)BR4 (where p is 0, 1 or 2},
-Rs-0-R1D-N(RG)R7, -R9-0-R13-C(NR' )N(R11 JH, -R9-0C(0}-Ra, -R9-N(Re)R7, -R^-CfOjR0, -Rs-C(0)0Rf, -Re-C(Q)N(Re)R7, -Rs-N(RB)C(D)ORB, ^^(R'jqOJR4, -R9-N(Rs)S(0)tRe (where t is 1 or 2), -Rfl-S(0)t0RB (where t is 1 or 2), -R^O^R® (where p is 0, 1 or 2); and ~R9-S(Q)iN(Rc)R7 (where t is 1 or 2); m each Re and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally 15 substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, opLionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted hetenoarylalkenyl, optionally substituted heteroarylalkynyl, -R-0-ORa, -R1°-CN, -R,u-N02, -R1u-N(RV 20 -RJ°-G(0)0R9 and -Rl0-C[O)N[RE)f, or any Rc and R7, together with the common
nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl; each RB is Independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally 25 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 3D heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl;
each R9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; 35 each R"° is an optionally substituted straight or branched alkylene chain; and
each R11 is hydrogen, alkyl, cyano, nitro or -OR*.
One embodiment of the compounds of formula (laZ), as set forth above, is a compound of formula (Ia2) wherein:
R , Ra and R5 are each independently selected from Lhe group consisting of hydrogen 5 and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9lJ-QRab,
-R9b-qO)ORebJ -R9b-N(Rab)R/3 and -RBb-C(0)N(RSt)R"p where each Reb, R7h and R3b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R-6 is independently selected finom the group 10 consisting of a direct bond and an optionally substituted straight or branched
alkylene chain;
R2c is selected from the group consisting of -C(0)R6, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
15 R2k is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally 20 substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted
heterocyclylalkenyl, -R°-ORa, -R'5-0C(0)-Ra, -R9-N(R6)Ry, -R9-C(0)R4, -R9-C(0)0Ra, -Ry-C(0)N(R5)R7, -Rs-N(R3}Q(Q)ORa, -R9-N[R6}C(0)R3, -Rs-N(RG)S(0)tRe (where t is 1 or 2), -RH-S(0)t0RR (where t is 1 or 2), -R9-S(0)pRa {where p is 0, 1 or 2), and -Ra-S(0)iN(Re)R7 {where t is 1 or 2): 25 each RB and R7 Is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substiLuLed heteroaryl, optionally substituted heteroarylalkyl, -R^-OR6, 30 -R10-CN, -R1D-NQ2, -R1fl-N(RB)01 -R10-C{O)ORs and -R13-C(0)N(Ra)2, or any R0 and
R7, together with the common nitrogen to which they are both attached, form an optionally substiluLed N-heteroaryl or an optionally substituted W-heterocyclyl; each Ra i3 independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 35 aralkynyl, optionally subslituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Rs is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and 5 each R1Cl is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ia2), as set forth above, is a compound of formula (!a2) wherein:
R\ R4 and are each independently selected from the group consisting of hydrogen and alkyl;
10 Rai) is selected from the group consisting of hydrogen, halo, haloalkyl, -RSb-OR3br
-RSh-C(0)0R*, -RSb-N(R6b,)R7j and -Rsb-C(0)N(Reb)R7>, where each R6b, R7t and R6b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each Reb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched 15 alkylene chain;
R2" is selected from the group consisting of -C(Q)Ra, hydrogen and alkyl;
R2k is selected from the group consisting of hydrogen and alkyl;
Ra is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each 20 optionally substituted by one or more substituents selected from the group
consisting of halo, haloalkyl, alkyl, opLionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R3-ORfi, -R3-0C(0)-Ra, -Rfl-N(RG)R7, -Rfl-C(0)Ra, -R5-C(0)0Ra, -Rs-C(0)N(R6)R7, -Rs-N(Re)C(O}QR0, -R^N(Rfi}C(Q}Re, 25 -R&-N(RB)S(0)tRs (where t is 1 or 2), -R9-S(0)-0R8 (where t is 1 or 2), -R9-S(0)pRa
(where p is 0, 1 or 2), and -R&-S(0},N(Rs}R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 30 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaiyl, optionally substituted heteroarylalkyl, -RlC-ORe, -R1t-CN, -R1t)-N02, -R1D-N(Ra)2, -RJ°-C(Q)OR0 and -R1D-C(0)N(R°)2, or any Re and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted /V-heterocyclyt; 35 each Rfi is independently selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted aryl, optionally substiLuLed aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted Heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
5 each R9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R1
Another embodiment of the compounds of formula (laZ), as set forth above, is a compound of formula (la2) wherein: 10 R\ R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-ORat,
-R0b-C(O)ORab, -R6b-N(REb)R7b and -R9t-C(0)N(RSb)R7s, where each R0b, R™ and RBtl is independently selected from the group consisting of hydrogen, alkyl, 15 haloalkyl, aryt and aralkyl, and each R9b is independently selected from the group
consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R£tis an optionally substituted non-bridged cycloalkyl; R2k is selected from the group consisting of hydrogen and alkyl; 20 is selected from Lhe group consisting of a monocyclic aryl and a monocyclic
heteroaryf, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted 25 heterocyclylalkenyl, -R^-OR6, -RB-QG(0)-Ra, -R5-N(RG)R7r -Rs-C(0}R6,
-R9-qO)ORe, -Ry-C(0)N(Rd)R', -R9-N(RB)C(0)0R8, -R3-N(R0)C(O)Rf, -Rfl-N(R9)5(0)LRa (where t is 1 or 2), -Ra-S(0),0R£ (where t is 1 or 2), -R9-S(0}pR!1 (where p i$ 0, 1 or 2), and -R^-SfOXNCR^R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, 30 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclyfalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R13-OR3, -RTO-CN, -R10-NOA, -R10-N(R3)a, -R1c-C(0)0Re and -Ria-C(0)N(RB)2, or any R6 and 35 R7, together with the common nitrogen to which they are both attached, form an
optionally substituted /V-heteroaryl or an optionally substituted W-heterocyclyl; each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 5 optionally su bstituted hetero cyclyl, o ptio na 11 y substituted hete rocycly lalky I,
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Rs is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each RT0 is an optionally substituted straight or branched alkylene chain, 10 Another embodiment of the compounds of formula (Ia2), as set forth above, is a
compound of formula (Ia2) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
RAB is selected from the group consisting of hydrogen, halo, haloalkyl, -R9B-ORAB, 15 -R9b-C{0)0Rab,-R9b-N(RCb)R7:)and-RSb-C(0)N(RGb)R73,whereeachReb,R7band
R8b is independently selected from tho group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R"b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; 20 Rae is an optionally substituted bridged cycloalkyl;
R2k is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group 25 consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-ORB, -R^OCFOJ-R?, -R^-NFR^R7, -R9-C(0)RB, -R^CTOJOR0, -R9-C(0)N(R6)R7, -RFT-N(R6)C{0}0RA, -R0~N(R6)C(G)RA, -R9-N(R6}S(0}LRs (where t is 1 or 2}, -R£-S(0):0RA (where t is 1 or 2), -R9-S(0},RB 30 (where p is 0, 1 or 2), and -R9-S{0}LN(R6)R7 (where t is 1 or 2);
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 35 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^-OR6,
-R °-CN, -R'°-NO?1 -R15-N{RBk, -R1D-C(0)QR3 and -R1G-C(0}N(R5}j, or any Re and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted /V-heterocyclyl; each Rb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, s optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyi, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R0 is independently selected from the group consisting of a direct bond and an 10 optionally substituted straight or branched alkylene chain; and
each R1D is an optionally substituted straight or branched alkylene chain.
Another embodiment otthe compounds of formula (Ia2), as set forth above, is a compound of formula (Ia2) wherein:
R", R4 and R5 are each independently selected from the group consisting of hydrogen 15 and alkyl;
Rsl1 is selected from the group consisting of hydrogen, halo, haloalkyl, -R9t-QRab,
-Rat-C(0)ORab, -RHt-N(RKb)R™ and -RHt>-C(0)N(Rtrj)R76, where each R^, R7h and Rafcl is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RDb is independently selected from the group 20 consisting of a direct bond and an optionally substituted straight or branched
alkylene chain; R^is optionally substituted bicyclo[2,2,1Jheptanyl; R2v is selected from the group consisting of hydrogen and alkyl; R3 is selected from the group consisting of a monocyclic aryl and a monocyclic 25 heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each
optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R9-ORB, -R9-0C(0)~R3, -R9-N(Rfi)R7, -R9-qO)Ra, 30 -R¥-C(0)0Ra, -R'-C(O}N(R0)R7, -RS-N(R6)C(0)0R3, -R9-N(R6)C(0)Ra,
-R*-N(Re)S(Q)iR3 (where t is 1 or 2), -R8-5(CtyORfl (where t is 1 or 2), -R9-S(0)pRa (where p is 0, 1 or 2), and -R9-S(0)iN{R3)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxys I kyl, optionally substituted aryl, optionally substituted aralkyl, 35 optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyf, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORS, -RLC-CN, -R1D-NOI, -RLC-N(R6)I, -R10-C(O)OR* and -R1D-C(Q)N(RV or any RB and R'P together with the oommon nitrogen to which they are both attached, form an 5 optionally substituted ^-heteroaryl or an optionally substituted W-heterocyclyl;
each RS is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, to 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,
Of this embodiment, a preferred embodiment is wherein R3 is optionally 15 substituted pyridinyl.
One embodiment of this preferred embodiment is a compound of formula (Ia2) selected from the group consisting of:
W3^ 4-(4-(bicycl o [2.2.1J he pta n-2-y I )pi pera zin-1 -yl}phsnyf)-1-(pyridin-2-yl)-1rt-1,2,4- triazole-3,5-diamine;
20 1-(6-pheny1pyndazin-3-y l)-yv3-(3-fluor^4-(4-(( 1 S,2S,4fi)-bicyclQ[2.2.1 ]heptan-2- yl)piperazin-1 -yl) phenyl)-1 ft-1,2,4-triazole-3,5-d iamine; and 1-(4-phenylpyridin~2-yf)-W3-C3-fluoro-4-(4-({2S)-bicyclo[2.2.1]heptan-2-yi)piperazin-1- yl)pheny|)-1 H-1,2,4-triazole-3,5-d iamine.
Another embodiment of the compounds of formula {Ia2); as set forth above, is a 25 compound of formula (Ia2) wherein:
R1, R'1 and Rs are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-OR6b,
-R9b-C(0)0RBt), -RYB-IM(Rao)R:'b and -R^-CfOjNfR^JR™, where each Ra, R7b and 30 Rst is independently selected from the group consisting of hydrogen, alkyl,
haloalkyl, aryl and aralkyl, and each R91, is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R3( is selected from the group consisting of -C(0)RA, hydrogen, alkyl, an optionally 35 substituted non-bridged cycloalkyl and an optionally substituted bridged
cycloalkyl;
R2K is selected from the group consisting of hydrogen and alkyl; R3 is selected From the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one 5 or more substituents selected from the group consisting of oxo, halo, haloalkyl,
alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -RS-QRFL, -R*-0C(0)-RB, -RS-N(R*>R7P -RS-C(0)RB, -RH-C(0)0R*, -RY-C(0)N(RE)R', - R9- N (RFI)C(0)0R&, -Rs-N(RG)C(0)RS, -R&-N(R£}S(0}LR6 (where t is 1 or 2), 10 -R3-S(0)TDRS (where t is 1 or 2), -R9-S(0}PRD (where p is 0,1 or 2), and
-R9-S(0\N(R6}R7 (where t is 1 or 2); each Rfi and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 15 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORa, -R^-CN, -R10-NOa, -R1D-N(R3)2, -R1(J-G(0)0R& and -R1D-C(0)N(R3)2, or any Re and Rr, together with the common nitrogen to which they are both attached, form an optionally substituted W-heferoaryl or an optionally substituted Af-heterocyclyl; 20 each Rs is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, oplignally substituted heteroaryl, and optionally substituted heteroarylalkyl; 25 each Ry is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each Rt0 is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (Ja2), as set forth above, is a compound of formula (Ia2) wherein: 30 R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-QRaD,
-R^-CfOJOR® -R0b-N(RSb)R75 and -R9b-C(0)N(Rst)R75, where each R6t, R7b and RBb is independently selected from the group consisting of hydrogen, alkyl, 35 haloalkyl, aryl and aralkyl, and each R"b is independently selected from the group
consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R2c is selected from the group consisting of -C(Q)R0, hydrogen and alkyl; Rai1 is selected from the group consisting of hydrogen and alkyl;
5 RJ is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocycfylalkenyl, ID -R0-OC(O)-R!1i -R9-N(Re)R7 -RS-C(Q)RB, -R9-C(0)0Rs, -R0-C(G}N(Rc)R7,
-Ru-N{R6)C(0)0RK, -R"-N(R6)C(0)R8, -RB-N(R6)S(0)tRR (where t is 1 or 2), -R0-S(O)vOR4 {where t is 1 or 2), -R^-S(0}pR5 (where p is 0, 1 or 2}, and -R9-S(0>N(Re)R7 (where t is 1 or 2); each Rfi and R7 is independently selected Iron the group consisting of hydrogen, alkyl, 15 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substiluLed helerocyclyi, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORS, -R1Q-CN, -R1D-NOJ, -Rf0-N(Rs)z, -R1°-C{Q)OR* and -R1u-C(0)N(R3)2l or any and 20 R7, together with the common nitrogen to which they are both attached, form an
optionally substituted N-heteroaryl or an optionally substituted W-heterocyclyl; each Rs is independently selected from the group consisting of hydrogen, alky!, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 25 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 R1D is an optionally substituted straight or branched alkylene chain, 30 Of this embodiment, a preferred embodiment is wherein R3 is selected from I he
group consisting of optionally substituted quinazolinyl, optionally substituted isoquinolinyl and optionally substituted naphthyridinonyl.
One embodiment of this preferred embodiment is a compound DF formula (la2), as set forth above, selected from the group consisting of: 35 1 -{isoq ui no I i n-1 -y] )-A/3-(4-t 4- methyl pipe razi n-1 -yl)phenyl)-1H-1,2,^triazole-3,5-diamine;
1 -(6-ch I o roq u i nazo I i ri -4-y I J-A/0-(4-(4-niettiy I pipe raa i n-1 -y!)phenyl)-1 H-l ,2,4-triazole-3,5- diarnine;
1 -(4-{4-(&-amino-1 -(isoquinoiin-1 -yl)-1 tf-1,2,-Hnazoi-3-ylamino)phenyl)piperazin-1 - yi)ethanone;
5 3-fluoro-4-{4-m ethy Ipipera zin-1 -y I) p he nyl)-1 -(isoq ui no I i n-1 -yl)-1H-1,2 r4-tria2ole-3,5- diamine;
1 -(6,7-d i methoxyq u i n azolin-4-yl y W^-fl uo ro-4-(4-melhy I pipe razi n -1 -y I }p he ny I1H-'1,2,4- triazole-3,5-d iamine;
1 -(4-{4-(5-a m in d-1 -(6,7-di methoxyq uinazolin-4-yl)-1 H-1,2,4-triazol-3- 10 yiami no )pheny I )pi pe razin-1 -y l)eth an on e;
5-(5-amino-3-(3-fluoro-4-(4-methylpiperazin-1-y1)phenyiamino)-1H-1,2,4-triazol-1-yl)-1,6- na ph th y ri d in-2 (1 H)-o n e;
4- (5-amino-3-(3-fluoro-4-(4-niethylpiperaari-'i-yi)phenyiamino)-iH-i,2I4-triazol-i- yl )q uinazol i ne-6,7-dio I;
15 4-(5-amino-3-(3-fluoro-4-(4-methy]piperazin-1-y1)phenytamino)-1W-1r2,4-triazol-1-yf)-6- rn eth oxyqu i nazoi i n- 7-ol;
JVT-(4-chloro-3-(4-ethyl pipe razin-1 -yl )pheriyl)-1 -{6,7-dimettioxyquinazolir>4-yl)-1 H-l ,2,4- triazole-3,5-diamine;
1 -(^(5-(5-amino-1 -(6,7-di methoxyq uinazolin-4-yl)-1 H-1,2,4-triazol-3-ylamino)-2- 20 chlorophenyl)piperazin-1 -yf)ethanone;
5- (5-amino-1 -(6,7-di methoxyq ui nazo I ln-4-yl)-1 N-1,2p4-triazoi-3-y1amino)-2-(4- methylpiperazin-1 -yl)benzamide; and
l-({j,7-dimethoxyqulnazolin-2-yl }-w3^4-(4-m ethyl plperazin-f-yl)p he n yl)-1 tf-1,2,4-trlazole- 3,5-d iamine.
25 Another embodiment of the compounds of formula (Ia2), as set forth above, is a
compound of formula (Ia2) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R4b-OR8b, 30 -R*b-C(0)0Rabr -R*b-N(RSh)R?b and -R9b-C(0)N(R6b)R7b, where each RGb, R'b and
RGb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RBb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
35 R21 is an optionally substituted non-bridged cycloalkyl;
R2lt is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, s alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R9-QRS, -RFT-0C(0)-R2, -Ra-N(Rt)R7, -R9-C(O)R0, -R3-C{0)0Rs, -R3-C(0}N(R6)R7, -Rs-N (RFI)C(0 )ORs, -RS-N(R6)C{0)RFLR -R9-N(Rfi)S(0)TRB (where t is 1 or 2), -R*-S(D)tOR6 (where t is 1 or 2}, -R3-S(O)PR0 (where p is 0, 1 or 2), and 10 -R9-S(0)LN(R6}Rt (whera t Is 1 or 2);
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 15 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^-OR6,
-R1t-CN, -R10-NQ,, -R10-N( R8)^, -R10-C(O)ORe and -R10-C(O)N(Rd)2l or any Rs and R'p together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted W-heterocyclyl; each Rs is indopandently selected from the group consisting of hydrogen, alkyl, haloalkyl, 20 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Ra is independently selected from the group consisting of a direct bond and an 25 optionally substituted straight or branched alkylene chain; and
each R1U is an optionally substituted straight or branched alkylene chain,
Of this embodiment, a preferred embodiment is wherein R3 is selected from the group consisting of optionally substituted quinazolinyl and optionally substituted isoquinolinyl.
30 One embodiment of this preferred embodiment is a compound of formula (Ia2),
as set forth above, selected from the group consisting of:
W5-(4-(4-cyclohexylpiperazin-1'-yl}phenyl>1-{6L7-dimQthoxyquinazoiin-4-yl)-1W-1,2,4- tri azole-3,5-dia m ine;
A^-(4-(4-{bicyclo[3.2.0]heptar-6-yl)piperazin-1 -yl)phenyl)-1-(6,7-dimethoxyquinazolin-4- 35 yl)-1H-1,2,4-triazole^3,5-diamine; AfI-(4-(4-cyclohexylpiperazin-1 -yl)phen yl)-1-(isoquinolin-1 -yl)-1 H-1,2,4-trlazofe-3,S- diamine;
4-(5-amino-3-(4-{4-cyclohexyfpiperazin-1-yl)pheny!amino)-1H-1,2F4~triazol-1-y1)-6- methoxyqu i nazol i n- 7-ol;
5 ^H-f^yclohexylpiperazin-l-ylJ-S-ruorophenyO-l-ti&oquinoliii-l-yO-IH-I.Z.^triazole- 3,5-diamine;
Af^-chlo ro-4-(4-cyclohexy I pi pera zin-1 -y ]}ph en yl)-1 -(isoq uinolin-1 -yl)-1H-1,2,4-triazo le- 3,5-diamine;
4-( 5-a m i no-3-( 4-(4-cyclohe pty I piperazin-1 -y I Jpheny I am ino)-1H-1,2,4-tria zol-1 -y I >6- 1d methoxyquinazolin-7-ol;
/Vs-(4-(4-cycloheptylpiperazin-1-yl)phenyl)-1-(6I7-dimethoxyquinazolin'4-yl]-1H-1,2,4- triazole-3,5-d iamine;
^3-(4-(4-cyclooctylpiperazin-1-yl)phenyl)-1-(6,7'dimethoxyquinazolin-4-yl)-1H-1,2f4- tiiazole-3,5-diamine;
15 ftf^3-chloro-4-(4-cyclohexyfpiperazin'1-yl)phenyl)'1-(6,7-dimethoxyquinazolin-4-yl)-1 w- 1,2,4-triazoie-3,5-diamine;
/V3-{4-(4-cy clohexy I p i pe razi n-1 -y I )-3-fluorophenyl)-1 ■ (6,7-d i methoxyq u in azol i n-4-y I)-1H- 1,2r4-triazole-3,5-diainine;
/V3- (4-{ 4-cydoheptyI pipe razi n-1 -yl) phenyl)-1 -(6 3 7-d i m eth a ?-1 1 r2,4- 2U triazole-3,5-diamine; and
1 -(GJ7-dime1hoxyquinazo!ln-2-yl)-/V:t-(3-fluoro-4-(4-cyclohexylpiperazin-1 -yl)phenyl)-1 H- 1,2,4-triazole-3,5-diamine.
Another embodiment of the compounds of formula (Ia2), as set forth above, fs a
compound of formula (Ia2) wherein: 25 R', R" and Rs are each independently selected from the group consisting of hydrogen and alkyl;
R?TL is selected from Lhe group consisting of hydrogen, halo, haloalkyl, -R^-OR36,
-R^-CTOJOR® -R9b-N(R^)R76 and -R9b-C(0)N(RET)R7B, where each R6B, R7b and Rafc is independently selected from the group consisting of hydrogen, alkyl, 3D haloalkyl, aryl and aralkyl, and each R¥b is independently selected Tram the group
consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R2c is an optionally substituted bridged cycloalkyf;
is selected from the group consisting of hydrogen and alkyl, 35 R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where
the bJcycNc aryl and the bicyclic heteroaryl aie each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -RB-ORs, 5 "R9-0C(0]-R3, -R9-N(Rb)R7, -Rs-C{O)R0, -Rs-C(Q)QRs, -R9-C(0}N(Rc)R7,
-RS-N(R6)C(Q}QR5, -R9-N(R0)c(o}Re, -Rff-N[Ra)S(0)tRfi (where t is 1 or 2), -RB-S{0)i0R* (where t is 1 or 2), -R"-S(0)PR* (wtiere p is 0, 1 or 2), and -R9-S
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1D-OR3, -R1D-CN, -R10-NO:, -Ria-N(Ra)2, -R1D-C(0)0Rfl and -R10-C(O)N(R3)2, or any R6 and 15 R7, together with the common nitrogen to which they are both attached, form an
optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 20 opti on a lly su bstituted hete racy cl yl, o pt io na 11 y subs I i tu led hete rocycl y la Iky I,
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R9 is independently selected from the group consisting of a direct bond and an
optionally substituted slraighL or branched alkylene chain; and each R1u is an optionally substituted straight or branched alkylene chain,
25 Another embodiment of the compounds of formula (Ia2), as set forth above, is a
compound of formula (Ia2) wherein:
R1, RJ and R^1 are each independently selected from the group consisting of hydrogen and alkyl;
is selected from the group consisting of hydrogen, halo, haloalkyl, -R^-OR^,
30 -R9t,-C(0)0RBb, -R9t,-N(Rfe)R7b and -RBb-C(0)N(Ra)Rrb, where each R6b, R7b and
Rat is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R5*1 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
35 R^is selected from the group consisting of optionally substituted bicyclo[2.2.1]heptanyl,
optionally substituted bicyclo[3.2.0]heptan-6-yl, optionally substituted bicyclo[3.3.1]nonanyl and optionally substituted adamantanyl; R3lt is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl. alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR0, -R9-0C(0)-RA, -R6-N(R6)R7, -R--C(0)R?, -RP-C(0)0RA, -R&-C(0)N(RFI)R7, -R9-N( RE)G( 0)QRA, -F^-N(R5)C(0)RB, -R'-NFR^STO^R" (where t is 1 or 2), -Rs-S(D)TORA (where t is 1 or 2), -R0-S(O)FR* (where p is 0, 1 or 2), and -R9-S(0)TN(R6)RY (where t is 1 or 2); each Reand R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10~ORA, -RT°-CN, -R1C-N02, -R10-N(RA)2L -R,F;-C(0}0RA and -R10-C(O)N(R*)A, oranyR8 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-hetenoaryf or an optionally substituted W-heterocyclyl; each RS is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, 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 R1u is an optionally substituted straight or branched alkylene chain.
Of this embodiment, a preferred embodiment is wherein RJ is selected from the group consisting of optionally substituted quinazolinyl, optionally substituted quinoxalinyl, optionally substituted benzotcflthiazolyl, optionally substituted isoquinolinyl, optionally substituted thienop.Z-djpyridazinyl, optionally substituted fmro[3,2-c]pyridiny1, optionally substituted thieno[2,3-d]pyrimidinyl and optionally substituted thieno[3,2-of]pyrimidinyL One embodiment of this preferred embodiment is a compound of formula (la2). as set forth above, selected from the group consisting of:
1 -(be nzo[tf)thiazol-2-yf )-/Vi'-(4-{4-(bicyclo[2.2.1]heptan'2-yf)piperazin-1-yl)phenyl)-1H- 1,2,4-triazole-3,5-d i a m irte;
Wff-(4-{4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1 -yl)phenyl)-1-(6,7~drmethoxyquinazolin-4- yl)-1 H-1 p2p4-triazole-3,5-diannine;
5 A^-(4-[4-(bicyclo[2.2.1 ]heptan-2-yl )pipsrazin-1 -yl) phenyl J-1 -(lsoquinolin-1 -yl)-1 HA ,2,4- tri azol e-3,5-dia m i ne;
1 -(be nzo [d]thiazol-2-yl)-Wa-(4-(4-(bicyclo[2.2.1 ] h epta n-2~y]) pi pe nazi n-1 -y I )p heny I)-1 tf- 1,2,4-triazole-3,5-diamine;
^-(4-[4^(bicyclo[2.2.1 ]heptan-2-yl)piparazin-1 -yl)phenyl>1 - f qu i noxa I i n -2-y I1 HA ,2,4- 10 triazol&-3,5-diamine;
JV3-(4-(4-( bicyclo [2.2.1 ]heptan-2-yl )piperazin-1 -yl)phenyl J-1 -{6,7-dimethoxyquinazDlin-4- yl]-1 HA ,2,4-triazole-3,5-dfamin^
A/J-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-{2-ch loro-7-methy Ith ieno [3,2- c^ py ri m i d in -4-y I}-1W p 2,4-triazole-3,5-d i a m In e; 15 JVa-(4-(4-Cbicyclo [2.2.1]heptan-2-yl)pi pera^i n-1 -y I) p heny I1 -{2-c h IOTO-Q , 7- d I m eth oxy q uinazol I ri-4-yl)-1H-1,2,4-tri azol e-3,5-d I a m i ne;
4-(5-amino-3-(4-(4-(bicyclo[2.2.1]heptari-2-yl)piperazin-1-yl)phenylarinmo)-1 H-1P2P4- triazol-1 -yl)-2-chlono-6~methoxyquinazolin-7-ol;
A/5-(4-[4-(blcyclO[2.2.1 ]heptan-2-yl)piperazir[-1 -yl)phenyl)-1 -(6-chloroquinazolin-4-y1)-1 H- 20 1,2,4-friazo!e-3,5-diamirie;
4-(5-amino-3-(4-(4-(bicyclo[2.2.1 ]heptan-2-yl)piperazin-1 -yl)-3-fluonQphenylainino)-1 H- 1,2,4-triazol-1 -y1)-0-metlxixyquir>azolin-7-ol;
jV1-(4-(4-adaimantar-2-yl)piperazin-1 -y1)pheriy1)-1 -(6:7-dimethoxy-qijiinazolin-4-y1)-1 H- 1 p2,4-triazole-3,5-diamine; 25 iV3-(4-(4-(bicyclo[3.3.1]nonan-9-yl)piperazin-1-yl)phenyl)-1-[6,7-dimethoxyquinazolin-4- yl)-1 HA ,2,4-triazcle-3,5-diamine;
A/3-(4-(4-fbicyclo[2,2.1]heptan-2-yl)piperazin-1-yl)-3-fluonophenyl)-1-{6J7- d i m eth oxy q uinazol i n-4-y I)-1 fM, 2,4-tri azol e^3,5 -d i a rm i in e;
A^-(4-(4-(bicyclo[2-2.1 ]heptan-2-yf )piperazin-1 -yl)phenyl)-1 -(6,7-dimethoxyisoquinolin-1 - 30 y I >'1H-1,2,44riazo1e-3,5-d iam ins;
W3-(4-(4-(bicyclo[2.2.1]heptan-2'y0piperazin-1-yl)phenyl)-1'(thieno[2,3-c^]pyrimidin-4-yl)- 1H-1,2,4-triazo I e-3,5-diami ne;
A^-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1 -yl)phenyl)-1 -{thieno[3r2-c/)pyrirnidin-4-yl)- 1H-1,2,4-triszo I e- 3,5-diami ne; 35 N3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-f6-phenylLhieno[3,2- (flpy rimld i n-4-y I)-1H-1,2,4-tri azote-3,5-d i a m i ns;
/V3-(4-(4-{bioycloI2.2.1 ]heptan-2-yl)piperazin~1 -yl) phenyl )-2-(6-phenylthieno[2,3- cflpyrimid i n-4-yI 1,2,4-trl azofe-3,5-d I a m i n e;
W3-(4-(4-{bicycloI2.2,1 Jheptan-2-y I )p i pe razi n-1 -yl) phenyl )-1 -(furo [3,2-c] py rid i n-4-y I)-1H- 5 1,2,4-tri aza ie-3,5-d ia m i ne;
Ns-(4-(4-{bicyclo[2.2,1]heptan-2-yl)piperazin-1 -yl)phenylM -(6-fluoroquinazolin-4-yl)-1 H- 1,2,4-tri azo I e-3,5-d ia m i ne;
4-( 1 (bicy clo[2.2,1 ]heptan -2-yl)pSperidin-4-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2- cfJpyrimidin^-ylJ-IH-l^^triazole-S.S-diamine; 10 W3-(4-(4-(bicyclo[2.2.1]h epta n-2-yl) pi pe razin-1 -y I )pheny I)-1 -(2-nethy |q u in a zol in -4-y I )-1 H- 1,2,4-triazole-3,5-d iamine;
A/J-(4-(4-(bicyclo[2.2. t]heptan-2-yl)piperazin-1 -yl)phenyl)-1 -(2-(trifluoromelhyl)quinazolin- 4-yl)-1 HA,.2,4-triazo le-3,5-d iam ine;
^^-^-(bicyclo^^. 1 ]heptan-2-yl)piperazin-1 -yi)phanyf)-T
W^(4*(4-(bicydo[2.2.1 ]hep1an-2-yl)piperazin-1 -yi)phenyl>1 -[5,6-dimethylthieno[2f3- d] py ri m id i n -4-y I)-1H-1,2,4-triazo le-3,5-diarn ine;
W3-(4-(4-((1S,25.4ff)-bicyclo[2.2.1]heptan-2-yl}pip(3razin-1-yi)phenyl)-1-(2-chloro-7- jneLhyllhienp[3,2-cf]pyrinnidin-4-yl)-1 W-1,2,4-triazole-S, 5-d famine; 20 Ns-{4-{ 4-( b i cyclo [2.2.1]heptan-2-yl)piperazin-1-yl)-3-f|ijorophenyl)-1-(£-chlciro-7- methylthieno[3,2-of]pyrimidin-4-yl)-1 HA,2 .^-triazolo-S, 5-d iamine;
A/^{4-(4-{(1 K,2R,4S)-bicydo[2.2,1]heptan-2-yl)piperazin-1 -yl)phenyl>1 -(2-chloro-7- methylthieno[3,2-d]pyrirnidin-4-y])-1 HA ,2,4-triazole-3,5-d iamine;
1-(2-chlorothieno[3,2-d]pyrimidin-^yl)-/V3-(4-(4-{(1S,2Sl4R)-bicyclo[2.2,1]heptan-2-yl)- 25 pipera zin -1 -y I )ph e n y I)-1H-1,2,4-triazo ie-3,5-d la m I ne;
1 -(B,7-dimethoxyquinazolin"2-yl)-W3-(4-(4-(( 1 S^S^-bicycIo^. 2.1]hep1an-2-y1)- pi pera zi n -1 -y I )ph e n y I)-1H-1,2,4-triazo le-3,5-d ia mi ne;
1-(5-(thiophen-2-yl)thi0no[2J3-d]pyrimidin-4-yi)-W3-[4-{4-(blcyclo[2.2.1]heptan-2-ylV pi perazi n-1 -y I) phe n y I)-1W-1,2,4-triazo le-3 r 5-d ia mi ne; 30 1-(6-(4-chlorophenyi)thieno[3,2'd]pyrimidin-4-yl)-/V3-(4-(4-(bicyclo[2l2l1]heptan-2-yl)- p i pe razi m 1 -yi) phe ny I)-1H-1,2,4-triazo le-3,5-dia mi ne;
1-{6-(1,1-dirnethylethyl)thieno[3,2-d]pyri[nidin-4-yl)-A/3-(4-[4-( bicyc lo [2.2.1 ] he pta n-2-y I }- p i pe razi n-1 -yl )pheny I) 1 ,2,4-triazole-3J 5-d iamine;
1-f7-methylthieno(3l2-c/]pyrlmidin-4-yl}-W3-(4-{4-((1S,2S,4R)'bi cyclo [2.2.1 ]h ep1an-2-y I)- 35 piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.
1 -(th ieno[3, 2-tf] py ri m id i n-4-y I)-fyp-(4-{ 4-({ 1S, 2S, 4tf)-bicy cl o[2.2.1 ] h epta n-2-y1)-piperazin- 1 -yl)phenyi)-1 W-1,2,4-triazo ie-3r5-diamine;
l-(thteno[2,3-c^pyiimidin^-yl)-A/3-(4-(4-(i1S,2S,4/?)-bicyclo[2,2.1]heptan-2-yl)-pipenazin- 1 -y l)ph en y I)-1H-1,2,4-triazo ie-3,5-dia m i ne;
1-(5'methylthieno[2p3-cjflpyrimidin-4-yi)-A/J-(4-(4-((1£p2Sl4R)-bicyclo[2.2.1]heptan-2-yl)- pi perazin-1 -y I )p h e n y I)-1H-1,2,4-triazo ie- 3 p 5-d ia m i ne;
1-(7'methyl-2-chlorolhieno[3,2-c/Ipyrimidin-4-yl)-A/3-(4"(4-{(1Sl2S,4R)-
bicyclo[2.2.1]heptan-2-yl)-piperazSn-1-y1)phenyl)-1H"1l2I4-triazDle-3,5-diamineI
1-(7-methylthieno[3.2-dlpyrimidin-4-yl)-N3-( 3-fluoro-4-(4-( bicyclo [2.2.1 ] heptan-2-y I )- piperazin -1 -y I )p he n y I)-1H-1,2,4-triazo ie- 3,5-d iam i ne;
1 -(thieno[3,2-rf|pyriiriidin-4-yJ)-Ns-(3-fluoro-4-(4-(bicyclo[2.2.1 ]heptan-2-yl)-piperazin-1 - yl)phenyl)-1 tf-1,2,4-triazo I e-3,5-diamine;
1 -(LhienD^^c^pyrimidirMl-ylJ-W3^ 3-f luoro-4-( 4-( bicyclo [2.2.1 ] he ptan-2-y l)-p i perazin-1 - yl)phenyl}-1 H-1,2,4-tri azoie-3,5-diamine;
1-(6-fluoroquiinazolin-4"yl)-/V3-(3-fluoro-4-(4-(bicycl0[2.2l1]heptan-2-yl)-piperazin-1- y[)phenyi}-1 tf-1,2,4-triazole-3,5-diamine;
1-(4-methylthienc3[3,2-djpyridazin-7-y!)-N3-(4-(4-(bicyclo[2.2,1]heptan-2-yl)-piperazin-1- yl)phenyl)-1 H-1,2,4-triazo 10-3,5-diamine;
1-(7-methyithieno[3l2-t/Jpyrrmidin-4-yS)-N3-C3-nnethyl-4-(4-(bicyclo[2l2l1]heptan-2-yl)- pi perazi n-1 -y I) pheny I)-1H-1,2,4-trig zole-3,5-d ra min e;
1-(7-methy1-2-ch broth ieno[3,2-of]pyhmidin-4-yl]-N3-[2-methy|-4-( A-(b icy clo[2.2.1 Jh epta n- 2-yi)-piperazin-1-yl)phenyl)-1H-1, 2,4-triszole-3,5-diamine;
H7-methy!thieno[3,2-^pyrimfdin-4-yih/V3-C3-fluoro-4-(4
bi cy clo [2.2.1 ]heptan-2-y I )-piperazin -1 -y I }p he ny I)-1H-1,2 p 4-triazo le-3,5-d jam i n e;
1 -(7-methyfthieno[3l2-of]pyrimidin-4-yl)-/V!-(2-niethyl-4-(4-(bicyc!o[2,2,1]heptan-2-yl)- p i pe raz i ri-1 -y I Jphenyl)- \H-1,2,4-tria zole-3,5-diamine;
1 -(4-methylthieno[3,2-c/]pyridazin-7-yl)-/V!-{3-fluoro-4-(4-9bicyclo[2,2,1 Jheptan-2-yi)- pi pe razi n-1 -y I )ph any I)-1H-1,2,4-trlazoie-3, i a m i n e;
1 -(4-methyithieno[3f2-of]pyridazin-7-yl)-NT-(3--methyl-4-(4-{bioyclo[2.211 ]heptan-2-y|)- pi pe razin-1 -y I )ph en y I)-1H-1,2,4-triazo le- 3,5-d ia m i ne;
1 -(7-methyi-2-chiorothieiio[3:2-£flpyrimidin-4-y!)-/VJ-(3-methyl-4-(4-(bicyGlo[2.2,1 ]heptan- 2-yl}piperazin-1-y!)phenyl)-t H-1,2,4-triazo le-3,5-diamine;
1-(4-methyithieno[3p2-d]pyTidazin-7-y1)-N?-(3-fluoro-4-(4-((lSI2S,4R)
bicyclo[2.2.1]heptan-2-yl)piperazin-1 yl)phenyl)-1 H-1,2,4-iriazo!e-3,5-diamine;
1 -(2-ch I o ro-6-m ethoxy-q u i n oxa I in-3-y I)-N3-(3-fluoro-4-( 4-(( 1S, 2 Sr4f?)-
bi cyclo [2.2.1 ] he pta n-2-y I )pipera zin-1 -y I )p he ny f)-1 H- T, 2,4-triazol e-3,5-d ia nil i ne;
1-(6l7-dimethoxy-1-rnethylphthalazin-4-yl)-W3-(3-fluoro-4-(4-((1S,2S,4R)-
bicyclo[2.2.l]heptan-2-yl)piperazin-l-yl)phenyl)-lH-,[,2,4-triazole^,5-diarnine;
1 -(4-methylth ie no [3 P2-d]pyrid azi n-7-y I)-W3^ 3-ch loro-4-( 4-( (2 S)- b i cy c lo[2.2.1 Jhepta n-2- 5 yl)piperazin-1-yl)phenyl}-1 H-1,2,4-triazole-3,5-d iamine;
H4-melhylthieno[3,2-d]pyridazin-7-yl)-/V3-(3-mefhyl-4-(4-((1S,2S,4R)-
bi cyclo [2.2,1 ] he pta n-2-yl Jpiperazin-1 -y I )phe ny I }-1 H-1,2,4-triazole^3,5-dia rn i ne;
1 -(7-methy]-2-m-toEylthieno[3,2-d]pyri midin-4-yl)-W3-(4-(4-(bi cyclo [2,2,1] hepta n-2- yl)piperazin-1 -yl)phenyf)-1 H-1,2,4-triazole-3,5-d iamine; 10 1^(7-me1hyl-2-( 3-cy a nophenyl)th leno[3,2-d] pyrimidin-4-yl)-AF-(4-( 4-[ bi cy clo[2.2.1 Jhepta n - 2-yl)piperazin-1 -yl)phenyl)-1 H-1 p2f4-triazole-3,5-diairriine;
1-(7-methyl-2-(2-chlorophenyl)thieno[3,2-d]pyrimidin-4-yl)-4-({ 25)-
bl cyclo [2.2.1] he ptan-2-yl)piperazin-1-yl)pheny!)-1H-1,2J4-triazole-3,5-d iamine;
1-(7-methyl-2-benzo[d]f1,3]dio>;ole-5-ylthieno[3l2-c/]pyrimidin-4-yl)-WJ-(4-(4-((2S)- 15 bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1p2,4-triazole'3p5'diamine;
H7-methyl-2-pyridin-4-ylthieno[3,2-(flpyrfmicfin-4-yn-A/3-(4-(4-((25)-b!Cyolo[2,2,1]heptan- 2-yl)piperazin-1-yl)phenyl)-1 HA ,2,4- triazo le-3,5-diamine;
1-(7-methyl-2-( 3-{met hylsulforiyl)aminopheryl)thieno[3J2-GfJpyrimidin-4-yl)-AAJ-(4-(4-((2S)- bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1/-/-1J2J4-triazole-3p5-diamine; 20 1-(7-methyl-2-(3-(pyrrolidin-1-yl)pi"op-1-enyl)thieno[3r2-d]pyrimidin-4-yl)-A/3-{4-(4-((2S)- bicyclo[2.2.1]heptan-2-Y1)piperazin-1-yl)phenyl)-1H-1,2J4-tnazole-3,5-diamine;
1-(7-methy1-2'(3-(4'methylpipeTiazin-1-yl)prop'1-enyl)thieno[3l2-d]pyrimidin-4-yl)-W5-(4- (4-((25)-bicyclo[2,2.1]heptan-2-yl)piperazin-1-yl}phenyl}-1H-1,2,4-triazole-3;5- diamine;
25 1 -{7-m ethy1-2-( 3 -{morpholin-4-y l)prop- 1 -enyl )ttiienop f2-d]pyrim idin-4-yl)-W*-( 4-(4-((2 S)- bicyclo[2,2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2J4-triazole-3,5-diamine;
H7-m eth y Ith ie no [3 r2-d]py rimidi n-4-y I)-3-ch lort>4-{ 4-((lS,2S,4R>
bi cy c lo [2 .£. 1 ] he pta n-2-yl Jpiperazin-1 -y I )pheny H-1,2,4-triazol e-3,5-d ia m i ne;
1 -th ie no [3r2-d]pyri m id i n-4-y l-N^-ch lo no-4-(4-( (1S, 2 5,4R)-b i eye lo[2,2.1 ] hepta n-2- 30 yl)piperazin-1 -yl}phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-thieno [2,3-d]pyrimidin-4-yl-/V3-(3-chloro-4-(4-((lS12S,4R)-bi cyclop,2.1]neptan-2- y I) p i pe razi n -1 -y I )p he ny I)-1M-1,2,4-triazo le-3,5-d iamine;
1-(7-methylthieno[3,2-t/J pyr(midin-4-yl)-W3-(3-fluoro-4-(4-[{1S,2S,4R)-
bicyclo[2,2.1 ]hoptan-2-yl)piporaziri-1 -yl)phonyl)-1 H-1,2,4-tnazole-3s5-diamine 35 1-(7-methylthieino[3l2-c/]pyrimidin-4-yl)-W;)-C3-fluoro-4-(3-(/?)-methyl-4- {bicy clo(2.2.1 ]heptan-2-y f )p i perazin -1 -y I )p he ny I H-1,2,4-triazo le-3,5-d iam in e;
1-(7-methylthieno[3l2-t/|pyrinnidin-4-yl)-WJ-C3-fluoro-4-(3-{S>nnethyJ-4-
(bicyclo[2.2 1 ]heptan-2-y I )p i perazi n-1 -y I }p he ny I >-1H-1.2,4-triazo le-3,5-d iam in e;
1-(7-methylthi9no[3,2-t/]pyrimidin-4-y!)-/V3-C3-fluoro-4-(3Kfl)'methyl-4-(C1S,25p4R)- 5 bicyclol2,2.1]heptan-2-yf)piperazin-1-yl)phenylJ-1 H~ 1,2,4-triazo le-3,5-diamine;
1-(7-methylthienoi3,2-t/jpyrimidin~4-yl)-WJ-(3-fluoro-4-(3-(S)-methy1-4-((lSi25,4RJ-
bicy cl o[2.2.1 ]heptan-2-y I )p i perazi n -1 -y I )p he ny I)-1 1,2,4-triazo le-3,5-diam in e;
1-(7-nnethylthieno[3,2-d]pyrinnidin-4-ylJ-/V:!-[3-methy1-4-(4-((1S,2Sp4R)-
bicycl o[2.2,1 ] heptan -2-y I )p i perazi n -1 -y I }p ho ny I)-1H-1,2,1-trjazo le-3,5-d iam in e; 1D 1 -(7-nie thy I th ieno[3,2-cf] py ri m i d i n-4-y I )- ^-(3- meth yl-4-( 3-( S)- methy l-4-(( 1S, ZS^ffJ- bicyclo^.llheptan-Z-ylJpiperazin-l -yl)phenyl)-1H-1,2r4-triazole-3,5-di amine;
1-(7-methylthieno[3,2-o(]pyrimidin-4-yl)-A/;!-(3-m0thy1-4-(3-(fl)-niethyl-4-({1SI2S,4R)- bicyclo[2.2,1]h epta n-2-yl)pi perazin-1 -yl)phenyj)-1 H-1,2,4-triazole-3J5-diamine;
1-thieno[3,2-c(]pyrimidin-4-yl-W3-(3-fluoro-4-(3-(S)-metliy|'4-((1Sl2Sp4R)- 15 bicyclo[2.2.1]heptan-2-yl)piperazin-1 -y|)phenyl)-1 H-1,2,4-triazole-3,5-diamine;
and
1 -(2-ch lo ro-7-m ethy Ith ieno [3,2-cflpyrim id i n-4-yl)-3-m ethy l-4-(3-( S)-m ethy I -4-
((1 S,2S,4R)-bicyc!o[2.2.1 ]heptan-2-y?)piperazin-1-yl)phenyl)-1 H-1,2,4-triazole- 3,5-diamine,
20 Another embodiment of the compounds of formula (Ia2)f as set forth above, is a
compound of formula (Ia2) wherein:
R1, R4 and R^1 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -RSb-ORCb, 25 -R"b-C(O)OR0b, -R"-N(RSb)R7b and -R9t-C(0)N(RSb)R7b, where each Rflb, RVb and
Rftb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl. and each R9I> is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
30 R2c is selected from the group consisting of -C(0}Re, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
R2k is selected from the group consisting of hydrogen and alkyl;
R- is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where 35 the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one
or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -Rs-ORs, -RB-0G(0)-RAP -Ra-N(RB)R', -RB-C(0)RA, -RY-C{0)0RE, -R"-C(0)N(R6)R'P 5 -R0-N(RG)QO)ORA, -R9-N(RC)C(0)RA: -R0-N(Rc)S(O)TRA (where t is 1 or 2),
-Rs-5(0)T0RA (where t is 1 or 2), -R3-5(0)PRS (where p is 0,1 or 2), and -R?-S(0)tN(Re)R7 (where t is 1 or 2); each RE and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, io optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-GRA, -R1D-CN, -R1D-N02, -RIA-N[RS)S, -R?15-C(G}GRE and -Rlc-C(0)N(RE)2, or any R5 and R7, together with the common nitrogen to which they are both attached, form an 15 optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl;
each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 20 optionally substituted heteroaryl, and oplionally subsliLuted heLemaryfalkyl;
each R" is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1C is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ia2), as set forth above, is a 2b compound of formula (Ia2) wherein:
R1, R4 and Rb are each independently selected from the group consisting of hydrogen and alkyl;
R2" is selected from the group consisting of hydrogen, halo, haloalkyl, -R3b-QR9b,
-RSb-C(0)0Rat, -RBb-N(RBb)R7b and -R^-C(0)N(Rbb)R7b, where each Rw, RTb and 30 Reb is independently selected from the group consisting of hydrogen, alkyl,
haloalkyl, aryl and aralkyl, and each RSb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R2tis selected from the group consisting of -C(0)Ra, hydrogen and alkyl; 35 R^ is selected from the group consisting of hydrogen and alkyl;
Rs is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally s substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Rs-ORa,
-R5-GC(0)-RB, -RS-N(RE)R7, -RD-C(0)R2, -R9-C(0)0RE, -R9-C(G)N(RG)R7, -R^N(R6)C(0)0R&, -R9-N( RB )C(0) RA, -R9-N(R6)S(0)TRE (where t IS 1 or 2), -R*-S(0)T0RB (where t is 1 or 2), -Rs-S(0)PRS (where p is 0,1 or 2), and -R5-S(0),N(RG}R7 (where t is 1 or 2); 10 each R5 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1(J-ORE, 15 -R1T-CM, -R1U-N02, -R1D-N(RA)2, -R1C-C(OJORg and -R1D-C(0)N(RA)2: or any RG and
R7 together with the common nitrogen to which they are both attached, form an optionally substituted /V-hetergaryl or an optionally substituted /V-heterocyclyf; each RE is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aiyl, optionally substituted aralkyl, optionally substituted 20 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyi, 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 25 each R10 is an optionally substituted straight or branched alkylene chain.
Of this embodiment, a preferred embodiment is wherein Rs is selected from the group consisting of optionally substituted 5,6-d i hyd ro be nzo[fi]qui nazo I in yl and optionally substituted 5,6-d ihyd roben zolfijci n no I i n -3-yL
One embodiment of this preferred embodiment is a compound of formula (Ia2), 30 as set forth above, selected from the group consisting of:
1 -(5,6-dihydrobenzo[/)]quinazolin-2-yl)-W3-(4-(4-methylpiperaz!n-f-yl)phenyl)-1 H-1,2,4-
triazole-3,5-d iamine; and 1-(5r6-dihydrobenzor^]cinnolin-3-yl)-/V3-(4-(4-methylpiperazin-1-yl)phenyi)-1H-1,2,4- triazole-3,5-diamins,
35 Another embodiment of the compounds of formula (Ia2), as set forth above, is a
compound of formula (Ia2} wherein:
R , Ra and R6 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen halo, haloalkyl, -R^-OR*15,
-RSB-C{0)0RSB, -R9B-N(RBB)R73 and -R5B-C(0)N(RGT)R7B, where each RGt, Rrb and RSB is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RAB is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; RZc is an optionally substituted non-bridged cycloalkyl, RKh is selected from the group consisting of hydrogen and alkyl; RA is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -RY-ORA, -R&-0C(0)-RB, -RS-N(R0)R7 -R9"C(0)RS, -R0-C(O)ORS, -RS-C(0)N(R6)RR7 -RE-N(RG)C{0)0R3, -R9-N(R6)C(0)RE, -RE-N(R*)S(0),R4 (where t is 1 or 2}, -Rs-S(0),0R6 (where t is 1 or 2), -R9-S(O)pR® (where p is 0,1 or 2), and -R^OXN^R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1(}-ORB, -R1D-CN, -R10-NO2, -R1Q-N{R% -R^C(0)0RA and -R10-C(O)N(RS)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryi or an optionally substituted fV-heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R3 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and
each R19 is an optionally substituted straight or branched alkylene chain.
Of this embodiment a preferred embodiment is wherein Ra is selected from the group consisting of optionally substituted 5,6-dihydrobenzo[h]quinazolinyl, optionally substituted 5,6-dihydrobenzo[/]]cinnolinyl and optionally substituted phenanthridinyl.
5 One embodiment of this preferred embodiment is a compound of formula (Ia2),
as set forth above, selected from the group consisting of:
N1- (4~(4-cyclohexylpiperazin-1-yl)ph en yl)-1 -(5,6-dihyd robenzo (h)quinazolin-2-yl)-f H-
1 ,2,4-triazole-3,5-diamine; /V3-{4-(4-cyclohexyl pi perazin-1-yl)phenyl)-1 -(5,6-dihyd robe nzo [fr]cinnolin-3-y1)-1H-1,2,4- 10 triazole-3,5-diamine; and
1-{phenanthridin-6-yl)-W3-(3-fluoro-4-(4-cyclopentylpiperazin-1-yl)phenyl)-1H-1,2I4- triazole-3, 5-diamine.
Another embodiment of the compounds of formula (Ia2), as set forth above, is a compound of formula (Ia2) wherein: 15 R\ Ra and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R^b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9t-OR6b,
-RSb-G(Q)OR0t?, -R*b-N(RBb)R7b and -R9b-C{Q)N{Rff',)R7b, where each R^, R7b and Rftb is independently selected from the group consisting of hydrogen, alkyl, 20 haloalkyl, aryl and aralkyl, and each R9b is independently selected from the group
consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R^ is an optionally substituted bridged cycloalkyl; R^ is selected from the group consisting of hydrogen and alkyl; 25 R" is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo. halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -RS-QRB, 30 -Ra-0C(0)-R^, -R~-N(R0)R7, -Ry-0(0)Rs, -R3-C(0)0RB, -R3-C(O)N(RB}R7,
-R0-N(RS}C(OJOR8, -R9-N(Rc}C(0)Rs, -R9-N{Rfi)S(0)|Ra {where t is 1 or 2), -RH-S(0)-0Re (where t is 1 or 2), -R9-S(a)pRe (where p is 0, 1 or 2), and -Rfl-S(0)-N(R6)R7 (where t is 1 or 2); each R0 and R7 is Independently selected from the group consisting of hydrogen, alkyl, 35 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rl0-ORa, -R C-CN, -RJ°-N02, -R10-N(RS)2, -R1D-C(0)0RA and -RLC-C(0)N(R4}i: or any RS and 5 R7, together with the common nitrogen to which they are both attached, form an
optionally substituted /V-heteroaryl or an optionally substituted Nheterocyclyl; each RA is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 10 optionally subsfituted 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 R1D is an optionally substituted straight or branched alkylene chain.
15 Another embodiment of the compounds of formula (fa2), as set forth above, is a
compound of formula (Ia2) wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R*b is selected from the group consisting of hydrogen, halo, haloalkyl, -R,b-ORBb,
20 -Rab-C(Q)QRab, -R9b-N(RGb)R7b and 'R9i-C(Q)N(RCb)R?b, where each R6tp R7b and
Reb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RBfc is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
25 is optic naliy su bstituted bi cyclo[2,2,1 ] heptanyI;
R£k is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl,
30 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Re-ORs, -R3-0C(0)-Ra, -R*-N(RB)R7, -R^CfOJR6, -R9 C(0)0R3, -R*-C(0}N(R6)R7, -R9-N(RG)C(Q}QRe, -RA-N(Re)C(Q)Rs, -R8-N(R*)S(0)tR* (where t is 1 or 2), -R9-S(0),0R8 (where t is 1 or 2), -R8-S(0)BRe (where p Is 0, 1 or 2), and
35 -Rs-S(0)tN(RE,)R7 (where t is 1 or 2);
each Rs and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-ORs, -R1D-CN, -R1D-N01S -R10-N(RS)2, -R10-Q(O}ORA and -R,0-C(O)N(RS)2L or any R6 and R7, together with the common nitrogen to which they are bolh attached, form an optionally substituted N-heteroaryl or an optionally substituted N-hetenocyclyl; each RA is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, 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 R1D is an optionally substituted straight or branched alkylene chain.
Of this embodiment, a preferred embodiment is v/herein Ra is selected from the group consisting of optionally substituted 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3- cflpyrimidiny! and optionally substituted pyrido[2,3-b]pyrimido[4,5-d]thiopheneyf.
One embodiment of this preferred embodiment is a compound of formula (Ia2), as set forth above, selected from the group consisting of: A/J-(4-(4-(bicyclo[2.2.1]heptan-2'yl)pipera2in-1-yl)phenyl)-1-(6]7-dihydro-5^
cyclopenta[4,5]thieno[2,3-tf|pyrimidin-4-yl)-1 H-1,2,4-triazole-3,5-diamine; and 1-(pyrido[2l3-b]pyhmido[4,5-d]thiophene-4-yl)-/VJ-{4-( 4-(bicyclo[2. 2.1 ]heptan-2-y1 )- p i pe razi n-1 -yl )ph en yl)-1H-1,2,4-triazo I e-3,5-dia m i ne.
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen,
Another embodiment of the compounds of formula (la), as set forth above, is a compound of formula (la) which is a compound of formula (Ia3):
lhyJ, aryl, aralkyl, -C(0)Ra and -C(0)N(RB)R'; R2" is selected from the group consisting of halo, -ORa, -C(Q)R3, -C(0)0Ra,
-R1OE-N(R0)R7, -R10e-CfO)N(R9)R7, optionally substituted heterocyclyf and optionally substituted heteroaryl, where each RlLlE is an optionally substituted 5 straight or branched alkylene chain;
RZd and R2f are each independently selected from the group consisting of hydrogen, halo, alkyl and -ORs;
Rs is selected from the group consisting of aryt and heteroaryl, where the aryl and the heteroaryl are each optionally substituted by one or more substituents selected 10 from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl. optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl optionally substituted heterocyclylalkenyl, 15 -Rs-ORa. -R&-Q-R'°-QRa, -R9-0-Rlfl-0-RlC-0Re, -R9-0-R1c-CN,
-R*-Q-R1D-C[0)QR*, -R?-0-R1tl-C{0)N(Re)R7, -R0-O-R"°-S(O)pRa [where p is 0,1 or 2), -R3-0- R'°-N( RB )R7, -R^ORl0-C(NRl1)N(Rn)H, -R9-0C(0)-R3, -R3-N(R6)R7. -R^C(0)Ra, -Ra-C(0)0R?p -R9-C(0)N(R6)R', -R9-N(Rs)C(OJORa, -R*-N(RB)C{0)Ra, -R0-N(Rs)S(O)
each Ra and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionaily substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally 25 substituted cycloalkylalkyl, optionallysubstituted cycloaIkyIalkenyI, optionafly
substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryf, optionally substituted heteroarylalkyl, optionally substituted heteroarylafkenyl, optionally 30 substituted heteroarylalkynyl, -R"-ORa, -R,c-CN, -R10-NOI, -RfC-N(Ra)z,
-R1Q-C(0)0RB and -R^-CfOjNfR6};, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted Nhetfiroaryl or an optionally substituted N-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, alkenyi, 35 alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkyl alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl;
each Ry is independently selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; each R13 is an optionally substituted straight or branched aikylene chain; and each R11 is hydrogen, alkyl, cyano, nitro or -OR0
One embodiment of the compounds of formula (la3), as set forth above, is a compound of formula {Ia3) wherein:
R1, R" and R5, are each independently selected from the group consisting of hydrogen and alkyl;
R20 is selected from the group consisting of halo, -OR5, -C(0)R3r -C(0)0Rs,
-R1C*-N(R*}R7, -R1°0-C(O)N(RB}R7, optionally substituted heterocyclyl and optionally substituted heteroaryl, where each RTft; is an opLionally substituted straight or branched alkylene chain; Ric and R:R are each independently selected from the group consisting of hydrogen, halo, alkyl and -ORB;
R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and tho monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9^ORs, -R9-OCfO)-RA, -RY-N(R*)R7, -R3-C(0)R3, -R*-C(O)OR0, -Rs-C(0)N(R6)R7, -R9-N(R6 )C( Q)ORA, -R^N(R6)C(0)RE, -R0-N(R6)S(O)TR3 (where t is 1 or 2), R0-S(Q)TORE (where t is 1 or 2), -R9-S(O)PR0 (where p is 0, 1 or 2), and -R9-S(0)!N(R6)R7 (where t is 1 or 2); each R0 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR2, -R10-CN, -R10-NO2l -RiD-N(Ra)2, -R'fl-C(0)0Rfl and -R10-C(O)N(Re>z, or any RG and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl;
5 each R8 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
10 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,
Of this embodiment, a preferred embodiment is wherein R3 is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridinyl.
15 One embodiment of this preferred embodiment is a compound of formula (Ia3),
as set forth above, selected from the group consisting of: 1 -(4-isopropylphenyl)-W*-(4-morpholino phenyl )-1 HA, 2,4-triazole-3,5-diamine; /V3-(4-methoxypheny!)-1 -(pyridin-2-yI)-1 HA, 2,4-tri azol e-3,5-diamine, ethyl 4-(5-amino-1 -(2-chloropyridin-4-yl)-1 H-1,2,4-triazol-3-ylamino)benzoate;
20 CSJ-ethyl4-{5-amino-H2-(2-(pyrro!idin-1-ylmethyl)pyrrolidin-1-yl)pyridin-4-yl)-1H-1,2I4- triazol-3-y!amino)ben2oate; (S)-4-(5-am in o-1 -(2-(2-(pyrro I i din- 1-yl methyl }pyrrol id in- 1~yl)pyrid in-4-yl)-1H-1,2,4-triazo I-
3-yla mi no) benzoic acid; 1 -(4-(5-amino-1 -(2-fluorophenyl)-1 HA ,2,4-triazol-3-ylamino}phenyl )ethanone;
25 1 -(pyridin-2-yl)-W3-(3,4,&-trimethoxyphenyl)-l HA, 2,4-triazole-3,5-diamine; 1 -(pyridin^-ylJ-W3^ 3,4,5-trif I uoro phenyl)-1H-1,2,4-^32016-3,5-diamine; 3-(5-amino-1-(pyridin-2-y!)-1 H-1,2,4-triazo I-3-yla mi no) phenol; 1 -phenyl-N3-{4-(methylaminocarbonyl)phenyl )-Nf-methyl-1 H-1,2,4-triazole-3,5-diamine; 1-phenyl-N3-[4-(ethy[oxocarbonyl)phenyl)'N5-methyl-lH-1,2,4-triazole-3J5-diamine;
30 1 -(G-phenyIpyridazi n-3-yl)-N3-(3-fIuoro-4-(4-[pyn,ol id i n-1 -y l)piperidin-1 -yl )ph en yl)-1H- 1,2,4-triazole-3,5-diamine; and 1 -(4-phenylpyridln-2-y[)-A/3-(3-fluoro-4-(4-(pyrrolidin-1 -yl)piperidin-1 -yl)phenyl)-1 HA ,2,4- triazoIe-3:5-dia m i ne.
Another embodiment of the compounds of formula (Ia3}, as set forth above, is a
35 compound of formula (Ia3) wherein:
R', Raand R5 are each independently selected from the group consisting of hydrogen and alkyl;
is selected from the group consisting of halo, -OR6, -C(O)R0, -qQ)QR£, -RJ(*-N(R0)R7, -R1FT5-C(0)N (R6 )R7, optionally substituted heterocyclyl and 5 optionally substituted heteroaryl, where each R1Cfe is an optionally substituted
straight or branched alkylene chain; R™ and R2r are each independently selected from the group consisting of hydrogen, halo, alkyl and -ORa;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where 10 the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one
or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R6-ORFI, -R8-0C(0>R°, -RS-N(RD)R7, -RS-C(O}R0, -RS-C(0)0RA, -R9-C(0}N(RC)R7, 15 -R9-N{R6)C(O)OR0, -R--N{R3)G(0)R6, -R0-IM{RS)S(G];R3 (Where t is 1 or 2),
-R9-S(0)I0R4 (where t is 1 or 2), -R3-S(0)FRs (where p is 0, 1 or 2), and -RS-S(0]RN( RC')R7 (where t is 1 or 2}; each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, 20 optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^-OR6, -R1D-CN, -R1D-NOJ, -R10-M(R6)2, -R10-C(O)ORA and ~RL0-C(O)N(R3)2L or any RS and R', together with the common nitrogen to which they are both attached, form an 25 optionally substituted Af-h&teroaryl or an optionally substituted W-heterocyclyl;
each Ra is Independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, opLionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 30 optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each Ry is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain, and each R13 is an optionally substituted straight or branched aikyiene chain.
Of this embodiment, a preferred embodiment is wherein R3 is selected from the 35 group consisting of optionally substituted quinoxalinyl, optionally substituted quinazolinyl,
optionally substituted thieno[3,2-d]pyrimidinyl and optionally substituted isoquinolinyl. One embodiment of this preferred embodiment is a compound of formula [Ia3),
as set forth above, selected from trie group consisting of:
1 -(4-(5-amino-1 -(quinoxalin-2-yl)-1 H-1,2,4-triazcl-3-ylamino)phenyl)ethanone;
5 3-(4-(5-amino-1-(quinoxalin-2-yl)-1^-1l2l4-triazol-3-ylamino)phenyl)-1-(pyrrolidin-1- yl)propan-l-one;
1 "(5I7-dimethoxyquinazolin-4-yi)-A/,j!-(4-( 1 -methyl piperidin-3-yloxy)phery I )-1 H-1,2,4- triazole-3,5-diamine;
1 -(isoquinolin-1 -y I)-fV?-(4-( 1 -methylpiperidin-3-yloxy)phenyl)-1 H-1,2,4-triazole-3,5- 10 diamine;
1 -(isoquinolin-1 -yl^/V^-morp hoi inoph en yl )-1 H-1,2,4-triazo le-3,5-dia mine;
1-(6I7-dimethoxyquinazolin-4-y!)-A/3-(4-morpholinophenyl)-1H-l,2,4-triazole-3,5-diamino;
/VJ-{3-ctilorO"4-morpholinophenyl)-1 -(6,7-dimethoxyquinazolin-4-yl)-1 H-1,2,4-triazole-3P5- diamine;
15 /V3-(3-chloro-4-morpholinophenyl)-1-(6-chloroquinazolin-4-yl)-1H-1,2,4-triazole-3,5- diamine;
WJ-(3-fluoro-4-morpholinophenyl)-1-(isoquinolin-1-y1)-1H-1,2,4"triazole-3,5-diamine;
1 -(6,7-dimethoxyquinazolin-4-yl)-A/?-(3-fluoro-4-morpholinophenyl)-1 H-1,2,4-triazole-3,5- diamine;
20 1 -(isoquinolin-1 -ylJ-iV^-^in ethyl pi perazin-1 -yl) methyl )p he ny l)-1 H-1,2,4-triazole-3,5- diamine;
/V3-(4-{(R)-3-fdimethylamlno)pyrrolldin-l -yl)pheny |)-1 -(isoquinolin-1 -yl)-l H-1,2,4-triazole- 3,5-diamine;
W^-(4-{(S)-3-(dimethylamino)pyrrolidin-1 -yl)phenyl)-1 -(isoquinolin-1 -yl)-1 H-1,2,4-triazole- 25 3,5-diamine;
1 -(isoquinolin-1 -yl)-AP-(4-(oxazol-5-yl)phenyl)-1 H-1,2,4-triazole-3,5-diamine;
1-(isoquinolin-1-yl)-W3-(4-(1-methylpiperidin^-yl)phenyl)-1fJ-1,2,4-triazole-3I5-diamine;
1 -(Gj-dimethoxyquinazolin^-ylJ-A^-^ T -rnethylpiperidin-4*yl)phenyl)-1 H-1,2,4-triazole- 3,5-d iamine;
30 4-(5-amino-3-(4-(1 -rnethylpiperidin-4-yl)phenylamino)-1 H-1,2,4-triazoM -yl)-6- methoxyq u i nazo I i n - 7-o I;
1 -(6,7-d i methoxyq u i nazoli n-4-y| )-Ws-( 4-(( S)-3-( dim eth yla mi no) pyrrofid in-1 -yl)ph en yl )-1 H- 1,2,4-thazole-3,5-diamine;
4-(S-amino-3-(4-(1 -methylpiperidin-4-y!)phenylamino)-1 H-1,2,4-triazoM -yl)quinazoline- 35 6,7-diol;
1 -(6,7-dimeth oxyq uinazoli n-4-yl)-A/^4-( (4-m^ triazole-3,5-diamine;
1 -{6,7-dime1hoxyisoquino!in-1 -yl)-/V3-{4-( 1 -methyl pi peridln-4-yi)p he n yf)-1HA,2,4-triazole- 3,5-diamine;
5 1 -(6,7-dimethoxyqurnazolin-4-yl)-/VJ-(4-(4-{cyclopentyl)piperazin-1 -ylcarbonyl)phenyl}- 1 w-1,2,4-triazoie-3,5-d i a m ine; 1 -(7-m ethyl th ien o[3,2-cf] py ri m i d i n-4-y I)-4-( cy clopeniy I )piperazi n-1 -
y I ca rbo ny I }phe ny I)-1 fM ,2,4-triazo1e-3,5-dia mi ne; 1 -(7-m ethy I -2-ch loroth I e no [3:2-cflpyrf m Id i n-4-y I )-/V3-(4-({2-(py rrol id in-1 - 10 y I )ethy I Jam i noca rbonyl) p he ny I)-1H-1,2:4~triazole-3,5-dia mi ne;
1-(6,7-dimethoxyquinazolin-4-yl)-^-(3-ffuoro-4-(4-piperidfn-1-ylp[peridin-1-yl)phenyl)-1^-
1,2,4-triazole-3,5-diamine; 1 -(7-m ethy I -2-ch loroth i e no [3,2-c/|pyrim id i n-4-yl J-A^-t 3-Nuorcn4-( 4-piperi d in-1 -y I pi pe rid i n-
1 -yl )phen y I)-1H-1,2/4-triazo le-3,5-diamine;
15 1 -(7-methy l-2-ch lo roth i e no [3,2-cflpyrimid i n-4-yl 34i uoro-4-( 3-d ieth ylaminopyrrol i d i n - 1-yl)phenyl)-1 H-1,2,4-lriazole-3,5-diamine; 1 -(7-methy l-2-ch Ic rothieno [3,2-c/]pyrim id i n-4-yi)-W^f 3-f I uoren4-{ iso i ndo I i n-2-yl) pheny I )-
,2,4-triazofe-3,5-diannine: 1 -(e,7-dimethoxyquinazolin-4-y|)-W5-(3-fluoro-4"(isc}indolin-2-yl)phenyl)-1 H-1,2,4-triazo le- 20 3,5-diamine;
1 -(2-chloro-6-methoxy-quino!falin-3-y!)-iV3-(3-fluoro-4-{4-(pyrrolidin-1 -yl)piperidin-1 -
yl)phenyl)-1 H-1,2,4-tri azol e-3; 5-diamine; 1 -(7-methylthieno[3r2-d]pyrimidin-4-y1)-W5-(3-fluoro-4-(4-(2-azabicyclo[2.2.1 ]heptan-2- yt)piperidin-1 -yi)phenyl)-1 HA, 2,4-triazole-3,5-diamine; 25 1-(7-methylthieno[3r2-d]pyrimidin-4-yi)-W;i-(4-(1 -(bicyclo[2.2.1 ]heptan-2-yl)plperidln-4- yf)phenyl)-1 H-1,2,4-triazole-3; 5-diamine; and 1-(7-methy]thieno[3,2-ri|pyrimidin-4->4}-W5-(3-fluoro4-(1-([1SI2S,4Rhbicyclo[2.2.1]heptan-
2 -y I }p i perid i n^-y I )pheny I)-1 1,2,4-tri azote-3,5-d iam ine,
Another embodiment of the compounds of formula (Ia3), as set forth above, is a 30 compound of formula {Ia3} wherein:
R1, R4and R11 are each independently selected from the group consisting of hydrogen and alkyl;
R^ is selected from the group consisting of halo, -OR6, C(0)Raf -C^OJOR8,
-Rl0e-N(R6)R7, -R1Je-C(0)N(R*)R7, optionally substituted heterocyclyl and 35 optionally substituted heteroaryl, where each RICe is an optionally substituted
straight or branched alkylene chain; R!d and R* are each independently selected from the group consisting of hydrogen, halo, alkyl and -ORG;
R3 is selected from the group consisting of a tricyclic aryl or a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R'-OR15, -Rb-0C{0)-R8, -R'-NCR^R7. -R0-C(O)RS, -R0-C(O)ORE, -Rs-C(0)N(Rs)R7, -R6-N(RG)C(0)0R", -RH-N(Rfi)C(0)Rs, -R3-N(Rfi)S(0)tRB (where 1 is 1 Dr2), -R?-S(0)tORa (where t is 1 or 2), -R^S(0}pRe (where p is 0,1 or 2), and -R9-S(0)tM(R6)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionaliy substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-ORa, -R10-CN, -R:c'-NOr, -R10-N(Ra)?, -R'Q-C(0)0Rfi and -R1D'C(0)N(R6}2, or any and R7, together with the common nitrogen to which they are both attached, form an optionally substituted JV-heteroaryl or an optionally substituted W-heterocydyl; each R6 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Ra 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.
Of this embodiment, a preferred embodiment is wherein Ra is selected from the group consisting of optionally substituted 5,6-dihydrobenzo[ft]cinnoliny!, optionally substituted GH-chromeno^S-eJpyridazinyl and optionally substituted phenanthrldlnyl.
One embodiment of this preferred embodiment is a compound of formula (Ia3), as set forth above, selected from tho group consisting of: 1-(5,B-dihydrobenso[^]cinnolin-3-yl)-A/s-(3-fluoro-4-(4-(pyrrolidin'1-yl)piperldin-1- yl }p he ny I)-1H-1,2,4-tr iazo le-3,5-diamine;
1 -(8-m eth oxy-5,5-d i m elhyl-5H-ch rome no [4,3-c] py ri d azi n-3-y I)- AP-{3-fl uo ra-4-(4{4- methylpFperazin-l-ylJpiperidin-l-ylJphenylJ-IW-l^^-triazole-S.S-diamine; Hp he na nt hrid in-6-y I J-Z^-f 4-( 1 -met hy Ip i pe idi n-4-yl )ph en y I)-1H-1,2,.4-triazo I e-3,5- diamine; and
1 p he nanthrid in-6-y I)-3-methy I -4-{4-pyrrol id in-1 -yl piperi d i n-1 -y I )p he ny i)-1 H-1,2,4- tri azol e-3,5-diamine.
Another embodiment of the compounds of formula (la), as set forth above, is a compound of formula (la) which is a compound of formula (Ia4):
R* R£J
R'
wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)R8 and -C{0)N(Re}R7;
R2h is selected from the group consisting of hydrogen, -N(Rfih)R7hr optionally substituted heterocyclyl and optionally substituted heteroaryl, where RGh is hydrogen or alkyl and R7h is an optionally substituted bridged cycloalkyl;
Rza is independently selected from the group consisting of hydrogen, halo, -OR" and -RS-N(RC)R7;
RZf, R2' and Rai are each Independently selected from the group consisting of hydrogen,
halo and -ORe;
Rs is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R*-ORe, -R9-0C(0)-R3, -Re-N(Rfi}Rr, -R9-C(0)R3, -R*-C(Q)QR0, -R9-CtO)N£R6)R', -R9-N(R6)C(0}0Re, -R9-N(R*)C(Q)R6, -R'-NCR^StOJtR6 (where t is 1 or 2), -R8-S(0)t0Ra (where t is 1 or 2), -R?-S(0)PRE (where p is 0. 1 or 2), and -R9-S(0):N(Re)R7 (where t is 1 or 2};
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substiLuLed heteroaryl, optionally substituted heteroarylalkyl, -RLL!-ORE, -RT0-CN, -R1C-N02, -R1D-N(RS)2L -R1TT-C(0)0RB and -R10-C(O)N(RB>i or any R6 and 5 R7, together with the common nitrogen to which they are both attached, form an
optionally substituted W-heteroaryl or an optionally substituted N-hettsrocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 10 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl: each Rs 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. f 5 One embodiment of the compounds of formula (Ia4), as set forth above, is a
compound of formula (Ia4) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2h is selected from the group consisting of hydrogen, -N(RFLH)R7TL, optionally substituted 20 heterocyclyl and optionally substituted heteroaryl, where Rth is hydrogen or alkyl
and R7h is an optionally substituted bridged cycloalkyl; R2d is independently selected from the group consisting of hydrogen, halo, -OR6 and -R9-N(R6)R7;
R2*, R2' and Rai are each independently selected from the group consisting of hydrogen, 25 halo and -OR*;
R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally subsLituLed by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally 30 substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted
heterocyclyialkenyl, -RS-OR0, -R0-OC{O)-RA, -R9-N(R6)R7, -R*-C(0)R* -RA-C(0)0R*, -RB-C(0)N(RE)R7, -R3-N(R6)C(0)0RA, -R9-N(R6)C(0)RS, -R°-N[RC)S(0)IRA (where t is 1 or 2), -R'-SFOJTOR® [where t is 1 or 2), -RS-S(0}3RJ (where p is 0, 1 or 2), and -R9-S(0}LN[R6)R7 (where t is 1 or 2); 35 each Rfl and R7 is independently selected from the group consisting of hydrogen, alkyl,
haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORA, 5 -R c-CN, -R!0-NOaj -R10-N(Ra)2, -R10-C(O)OR6 and -R1D-C(0)M{Rs)£, or any Rs and
R7, together with the common nitrogen to which they are both attached, form an optionally substituted JV-heteroaryl or an optionally substituted N-heterocyclyl; each RD is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 10 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each RY is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and 15 each R10 is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (la4), as set forth above, is a compound of formula (Ia4) wherein:
R', R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
20 R2" is selected from the group consisting of hydrogen, -N{Rfih)R7h, optionally substituted heterocyclyl and optionally substituted heteroaryl, where R6h is hydrogen or alkyl and R7h is an optionally substituted bridged cycloalkyl; R2d is independently selected from the group consisting of hydrogen, halo, -ORB and -R9-N{RE)R7;
25 R2f, R2' and R:i are each independently selected from the group consisting of hydrogen, halo and -ORfl;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or mpre substituents selected from the group consisting of oxo, halo, haloalkyl, 30 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R*-OR6, -R0-OC(Q)-RA, -R9-N(RB)R', -Rs-qO}RS, -R"-C(0)0RA, -R9-C(0)N(R6)R', -Rs-N(Re)C(0}0R5, -R9-N(Rs)C(0)RB, -RB-N(R6)S(0)TRA (where t is 1 or 2), -R6-S(0)t0Ra (where t is 1 or 2), -Ra-S(0)FR* (where p is 0,1 or 2), and 35 - R9-S(0)tN( R6 )R7 (■whe re t i s 1 or 2};
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR3, -R'm-CN, -Rm-N02, -R10-N(RS)2, -R10-C(O)OR3 and -R1C,-C(0)N(R6}£, or any Rs and R', together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl; each Rtt is independently selected from the group consisting of hydrogen, alkyl, haloalkyl. optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted helerccyclyl, 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 R1D is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ia4), as set forth above, is a compound of formula (Ia4) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R:h is selected from the group consisting of optionally substituted heterocyclyl and
optionally substituted heteroaryl: R2d, R2", R2' and R2j are each independently hydrogen;
R"1 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -RB-ORR, -R9-0C(0>Ra, -R9-N(R6)R7 -R3-C(0)Rb, -R9-C(0)0Rs, -Re-C(0)N(Rc)R7, -Re-N(R€)C(0)0RS, -R^NCR^CfQJR6, -R9-N[R6}S(0),Rs (where t is 1 or 2), -Ra-S(0):0Rs (where t is 1 or 2), -RH-S(0)pR* (where p is 0, 1 or2), and -Rs-S(Q):N(R6)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R™-OR3, -R1u-CN, -R1t;,-N02l -R10-N{Rfi)2, -Rl0-C(O)OR* and -R'°-C(0)N(R2)2l or any Re and R', together with the common nitrogen to which they are both attached, form an 5 optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl;
each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, to optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each Rs is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1(J is an optionally substituted straight or branched alkylene chain,
Of this embodiment, a preferred embodiment is wherein R3 is selected from the 15 group consisting of optionally substituted thieno[3,2-tf)pyrimidinyl and optionally substituted quinazolinyf.
One embodiment of this preferred embodiment is a compound of formula {Ia4}, as set forth above, selected from the group consisting of:
1 -(7-methy |-2-chlo roth ienoI3,2-cfJpyri m i d in-4-y I >-Af'-t 7- py rroiid i n-1 -yl-G, 7,8,9-tetra h y d ro- 20 5H-benzo[7]annulene-2-yl)-1tf-1 r2,4~triazole-3,5-diamine; and
1-(6,7-dimethoxyquinazolirH4"yl)-/V3-(7-pyrrolidin-1-yl-6,7lfll9-tetrahydro-5W- benzo[7]annulene-2-yl)-l HA ,2r4-trlazole-3,5-diamine,
Another embodiment of the compounds of formula (Ia4), as set forth above, is a compound of formula (Ia4) wherein: 25 R1, R1 and R5 are each independently selected from the group consisting of hydrogen and aikyl;
R7[l is -N(R6ll)R7h where R&l is hydrogen or alkyl and R7h is an optionally substituted bridged cycloalkyl;
R2d is independently selected from the group consisting of hydrogen, halo, -OR6 and 30 -R9-N(RB)R7;
R2*, Ra and R2" are each independently selected from the group consisting of hydrogen, halo and -OR6;
R5 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one 35 or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -RB-OR\ -R*-0C(0)-RA, -FTH-N(RE)R'P -R"-C(0)RH, -RY-C(0)0RA, -RB-C(0)N(R6)R', -R9-N(R6)C(0)0RS, -R^N(RA)C(0)RE, -R^-NCR^SFOJIR6 (where t is 1 or 2>, 5 -R^-S(0)TORE (Where t is 1 or 2), -Ra-S(G)PR* (where p is 0, 1 or 2), and
-R--S(0)TN(RE}R7 (where t is 1 or 2); each Rg and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 10 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1CL-ORA, -R °-CN, -R^-NOJ, -R10-N(R3)2I -R10-C(O)OR6 and -R10-C(O)N(R4}2; or any RS and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted Nheterocyclyl; 15 each R0 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substiluted heteroarylalkyl; 20 each RB is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R13 is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ia4), as set forth above, is a compound of formula (Ia4) wherein: 25 R , R11 and R6 are each independently selected from the group consisting of hydrogen and alkyl;
R2h is -N(R^)R7h where Reh' is hydrogen or alkyl and R71" is optionally substituted
bicycl o[2,2.1 ]heptanyl; RZd is independently selected from the group consisting of hydrogen, halo and -OR6; 30 R2f, Ra and are each independently selected from the group consisting of hydrogen, halo and -ORa;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, 35 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R3-ORB, -R9-0C(0>R$, -R9-N(R6)R7, -R--C(0)RE, -R0-C(O)ORfl, -R9-C(0)N(RE)R7, -R9- N{ Re)C( 0)0Ra, -Rf-N(Rs)C(0)Rs, -Rs-N(Re)S(0)LRA (where t is 1 or 2), -R9-S(0),0Rfl (where t is 1 or 2), -R9-S(Q)PRG (where p is 0, 1 or 2), and -R9-S(0),N(Re)R7 (where t is 1 or 2); each R6 and R' is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxys Iky I, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R'm-ORft, -R1D-GN, -R1Cl-NQa, -R10-N(RBk, -R10-C(O)OR£ and -R10-C(O)N(Rfl)2l or any Rc and R', together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted W-heterocyclyl; each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl. optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Ra is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1D is an optionally substituted straight or branched alkylene chain,
Of this embodiment, a preferred embodiment is wherein R3 is selected from the group consisting of optionally substituted thieno[3,2-rf]pyrrmidinyl and optionally substituted quinazolinyl.
One embodiment oF this preferred embodiment is a compound of formula (Ja4), as set forth above, selected from the group consisting of:
1-{7-methyl-2-chlorothieno[3,2-Df]pyrimidin-4-yl)-/y:!-(7-(/V-methyl-/V-bicyclo[2,2,1]heptan- 2-yl)amino-6,7,S,9-tetrahydro-5W-benzor7]annuJene-2-yl)-1H-1l2l4-triazole-3,5- diamine;
1-{7-methyl-2-chlorothieno[3,2-ri]pyrimidin-4-yl)-/V;!-(7-(W-bicyclo[2.2-1]heptan-2-
yiJamino-fi^.S.Q-tetrahydro-SW-benziolJlannulene^-ylJ-IH-l^^-tri azol e-3,5- diamine;
1-(6,7-dimethoxyquinazolin-4-yl)-W;f-(7-{A/Lbicyclol2.2.1]heptan-2-yl}amino-6,7,B,9-
tetrahydro-5W-benzo[7]annu!ene-2-yl)-1 HA ^^-trrazole-S.S-diamine; and 1-(S,7-dirnethoxyquinazolin-4-yl)-A/3-(7-(Nmethyl-W-bicyclo[2r2-1]heptan-2-yl)amrno- 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1 H-1,2,4-triazole-3p5-diarnine. Another embodiment of the compounds of formula (Ia4), as set forth above, is a compound of formula (Ia4) wherein:
R\ R4 and Rs are each independently selected from the group consisting of hydrogen 5 and alkyl;
Rah is hydrogen; R^ is -R9-N(R6)R7;
R3, R2' and R2i are each independently selected from the group consisting of hydrogen, halo and -ORa;
10 R'1 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R'-ORB, 15 -R9-QC(0)-R8, -R9-N(R6)R7, -R9-C(0)Ra, -Rs-C(OpRa, -R9-C{0)N(R6)R7,
-R9- N( R6)C( O)OR0, -R9-N(R9)C(0)RS, -R3-N(R6)S(0)[RA (where t is 1 or 2), -R^S^OR* (where t is 1 or 2), -R0-S(O)FRe (where p is 0, 1 or 2), and -R9-S(0)1N(RG)R7 (where t is 1 or 2); each R6 and R7 is independently selecled from the group consisting of hydrogen, alkyl, 20 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1D-ORs, -R10-CN, -R1D-N02, -R1,l-N(R£;k, -R10-C(O)ORa and -Riy-C(O)N(R0),, or any Re and 25 R7, together with the common nitrogen to which they are both attached, form an
optionally substituted iV-heteroaryl or an optionally substituted N-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl a I kyi, 30 optionally substituted hotorocyclyl, 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 R1D is an optionally substituted straight or branched alkylene chain, 35 One embodiment of this preferred embodiment is the compound of formula (Ia4),
as set forth above, which is 1 T-meth yl -2-cfi I a rot hleno[3yrim id] n-4-yl J-iV^-i 8-[2- diethylaminoethy1)-9-hydroxy-6,7,B,9-tetrahydro-5J^benzo[7]annulene-2-yl)-1 H-1,2,4- triazo le-3,5-dia mine.
Another embodiment of the compounds of formula (Ia4), as set forth above, is a 5 oo m po u nd of formula (I a4) wherei n:
RJ, R" and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2h is selected from the group consisting of hydrogen, -N(R61l)R7h, optionally substituted heterocyclyl and optionally substituted heteroaryl, where R6h is hydrogen or alkyl 10 and R7h is an optionally substituted bridged cycloalkyl;
Rm is independently selected from the group consisting of hydrogen, halo, -ORa and -R9-N{R6)R7;
R2f, Ra and R2J are each independently selected from the group consisting of hydrogen, halo and -OR*,
15 R3 is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R°-ORe, 20 -Ry-0C(0]-R8, -RY-N(RB)R7, -R--C(0)RB, -RB-C(0)0Ra, -R*-C(0}N(R*)R7,
-R9-N(RG)C(0)0Ra, -R£-N(R3)C(0}Ra, -R&-N(R6)S(0)tRa (where t is 1 or 2), -R0-S(Q>ORs (where t is 1 or 2), -Ra-5(0)r,R6 (where p is 0,1 or 2), and -Ru-S(0>N(Re)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, 25 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^-OR^, -R1D-CN, -R1CI-N02, -R10-N(Ra}2, -R10-C(O)ORe and -R10-C(O)N(Ra)2l or any R6 and 30 R', together with the common nitrogen to which they are both attached, form an
optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl; each Ra Is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 35 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R0 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.
Another embodiment of the compounds of formula (I), as set forth above in the Summary of the Invention, is wherein the compound of formula (I) is a compound of formula (lb):
(lb)
N—N
wherein:
R1r R4 and RD are each independently selected from the group consisting of hydrogen, alkyl, alyl, aralkyl, -C(0)R6 and -C(0)N(RS)R7;
R2 is aryl optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl. optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -R9-ORE, -R5-O-R10-ORB, -Rs-O-R,IJ-O-R10~ORa, -R9-0-R™-CN, -R*-O-R10-C(O)OR8, -Rs-O-R10-C(O)N(Re)R7, -R3-0R'°S(0)pR3 (where p is 0,1 or 2), -R8-O-R10-N(R6)R7, -R9-0- R1 C( N R11 )N( R11 )H, -Rd-QC(Q)-Re, -RD-N(R6)R7, -R9-C(0)Rs, -R^C(0)0Ra, -R9-C(0)N(RB)R7, -R^N(RB}C(0)0Rfl, -R9"N(Rfl)C(0)R6, -R0-N(Re)S(O}1Ra (where t is 1 or 2), -R^SfOKOR6 (where t is 1 or 2), -R'-S(0)pRa (where p is 0, 1 or 2}, and -R3-S{0)1N(R6)R7 (where t is 1 or 2);
R2 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substituents solected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted
heterocyclyialkenyl, -RB-ORa, -R9-0-RT°-ORs, -R9-t)-Rl0-O-R1D-ORa, -R"-0-R1D-CNs -RS-OR10-C(0)QR3, -Rs-O-R10-C(O}N(R6)R7, -R9-0-R^-S(0)pRb (where p is 0, 1 or 2), -RQ-OR1Q-N(Re)R7, -Rs~0-R1D-C(NR11|NfR1')H, -R*-QC(0)-RB, -R9-N(R6)R7, -Rs-C(0)Rb, -R^C(0)0Rs, -R9-C(0)N(R6)R7, 5 -R5-N(RB)C(Q)OR'!: -R9-N(R6)C(O)R0, -R9-N(R6)S(0)tR'1 (where t is 1 or 2),
-R^-S(0)t0R6 (where t is 1 or 2), -R^SfOJpR® (where p is D, 1 or 2), and -R*-S(0)tN(RG)R' (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 10 substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl,
optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloaIkyfalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally 15 substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R^-QR6, -R,c-CN, -R10-NO;, -R1D-N(Rs)2l -R1°-C(0)0R3 and -R1,5-0(0)N(REk or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted 20 W-heteroaryl or an optionally substituted W-heterocyclyl;
each Ra 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 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 25 optionally substituted cycloalky[alkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted helerocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted 30 heteroarylalkynyl;
each Rs 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; 35 each R13 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 hydrogen, alkyl, cyano, nitro or-ORs; 5 as an isolated stereoisomer or mixture thereof, or a pharmaceutical^ acceptable salt thereof.
One embodiment of the compounds of formula (lb), as set forth above, is a compound of formuia (lb) which is a compound of formula (Ib1):
10 wherein:
R1, R4 and R& are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)RA and -C(0}N(Ra)R"';
R^is -R'^-NfR^JR73 where R,:aand R7a, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an 15 optionally substituted W-heterocyclyl, and R1Ua is an optionally substituted straight
or branched alkylene chain;
R29 is selected from the group consisting of hydrogon, halo, alkyl, haloalkyl, aryl, araikyl, -RF)a-ORBa, -R"-C(0)R^, -RBs-C(0)0Rfls, -RBB-N(RBB)R'fl and -R^-CtOMR^JR70, where each Reg, R79 and Res is independently selected from the group consisting 20 of hydrogen, alkyi, haloalkyl, aryl and aralkyl, and each R53 is independently
selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
RJ is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each Independently optionally substituted by one or more 25 substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo,
30
haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -R9-ORs, -R9-0-R13-0Ra, -R"-C%Rf^O-R1u-ORa,
-RB-0-R10-CN, -RH-0-R1U-C(0)0RB, -RS-0-R1D-G(0}N(RB)R7, -R9-Q-R1G-S(0)CR° (WHERE P IS 0, 1 OR 2), -RB-0-R1
each and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkyl alkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R1°-ORa, -R10-CN, -R^-N02l -R10-N(R% -R10-C(O)OR3 and -Rlc,-C(Q)N(RE)2, or any RG and R/, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl;
each Ra 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 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, 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 R1"1 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 R" is hydrogen, alkyl, cyano, nitro or -0Ra.
One embodiment of the compounds of formula (Ibl), as set forth above, is a 5 compound of formula (!b1) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R23 is -R^-NfR^JR73 where R6a and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an 10 optionally substituted W-heterocyclyl, and R1Db is an optionally substituted straight
or branched alkylene chain; R2g is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^OR*5, -RB0-C(O)Raa, -R"-C(0}0R6g, -R"-N{RG9)R73 and -R8s-C(0)N(RE5)R7* where each R09, and Ras is independently selected from the group consisting 15 of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R09 is independently
selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; RJ is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each 20 optionally substituted by one or more substituents selected from the group
consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -RB-ORa, -R9-0C(0)-R4, -R^N(R6)R7, -R3-C(0>Re, -R*-C(0}0Ra, -R9-C(0)N(RG)Rr, -R9-N(Rg)C(0)0R4, -R0-N(R5}G(O)Rb, 25 -Rs-N(RG)S(0}.Ra (where t is 1 or 2), -R*-S(Q)tORB (Where t is 1 or 2), -Ry-S(0)PRa
(where p is 0, 1 or 2), and -R0-S(O)-N(RB)R7 (where t is 1 or 2)\ each Re and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 30 optionallysubstituted heterocyclyl, optionally substituted heterocyclyl a Ikyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1Cl-QRa, -R-°-CN, -R'°-NOj, -R10-N{Rfl)2> -R10-C(O}OR6 and -R1D-C(0)N{Rs)2, or any Ra and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl; 35 each Ra is Independently selected from the group consisting of hydrogen, alkyl, haloalkyt,
optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
5 each R0 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,
Another embodiment of the compounds of formula (Ib1), as set forth above, is a compound of formula (Ib1) wherein: "10 R\ R" and R3 are each Independently selected from the group consisting of hydrogen and alkyl;
R^ is -R1Da-N(Rea)R7a where R5a and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted Nheteroaryl or an optionally substituted W-heterocyclyl, and R10a is an optionally substituted straight 15 orbranchedalkylenechain;
R?A is selected from Lhe group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R"-ORE9, -R3G-C(0)RFE, -R9B-C(O)OR0«, -R^-N(RFJA)R7B and -R"-C(0)N(RB9}R?9, where each R60, R79 and R43 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R09 is independently 20 selected from the group consisting of a direct bond and an optionally substituted
straight or branched alkylene chain; R3 is a monocyclic aryl optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted 25 heterocyclyialkenyl, -R"-ORB, -RY-0C(0)-R*, -R9-N(R*}R7, -R*-C(0)RFL,
-RB-C(0)0RFL, -R9-C(0)N(R6)RJ'P -RS-N(RC)C[0)0RA, -RS-N(RS)C(0)RK, -Rs-N(R&)S(OJiR8 (where t is 1 or 2), -RS-S(0)|0RA (where t is 1 or 2), -R9-S(0)FRs (where p is 0, 1 or 2), and -R9-S(O)RN(R0}R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, 30 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1Q-OR3, -R10-CN, -RTC-N02L "R10-N(R6)2S -R1D-C(0}0RA and -R10-C[O)N(RV or any RG and 35 R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted /V-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 5 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. 10 Of this embodiment a preferred embodiment is wherein R^ is optionally
substituted 2-(piperidinyl)ethyl and R3 is optionally substituted phenyl.
One embodiment of this preferred embodiment is a compound of formula (Ib1), as set forth above, which is 1-phenyl-/Vi-{4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-1,2,4-- triazole-3,5-diamine.
15 Another embodiment of the compounds ot formula (Ib1), as set forth above, is a
compound of formula (Ib1) wherein:
R", R" and Rb are each independently selected from the group consisting of hydrogen and alkyl;
R2a is -R1Da-N(Re!l)RF9 where R63 and RTa, together with the common nitrogen to which 20 they are both attached, form an optionally substituted N-heteroaryl or an
optionally substituted W-heterocyclyl, and R10* is an optionally substituted straight or branched alkylene chain; R^ is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^-OR69, -R"-C(0)R^, -R99-C(0)0Rto, -R99-N(RGn)R7g and -R3a-C(O)N(R60)R70, 25 where each Reg, R7s and Res is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each Ra0 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R3 is a monocyclic heteroaryl optionally substituted by one or more substituents selected 30 from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R'-OR6, -R9-OC(O)R#, -R9 N(RB)R7, -R^-C(0)Ra, -R*-C(0)0R3, -R9-C(0)N(R6)R7, -R3-N(R6)C(0)0Rs, -R"-N(R6)C(0)Rs, -R^N(R6)S(0),Ra fwhere t is 1 or 2), -R8-S(0)i0Ra (where t is 1 or 2), -R3-S(0)PRa 35 (where p Is 0, 1 or 2), and -R^S(O)^R^jR7 (where t is 1 or 2);
each RE and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted hetenocyclylalkyl, 5 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR3,
-R10-CN, -R1c,-N02, -R1Q-N{RA)2, -RT0-C(O)ORa and -R-c-C(0)N(Ra)2, or any RS and R7, together with the common nitrogen to which they are both attached, fonn an optionally substituted /V-heteroaryl or an optionally substituted W-heterocyclyl; each R* is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, 10 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each RS is independently selected from the group consisting of a direct bond and an 15 optionally substituted straight or branched alkylene chain; and
each R1C is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (Ib1), as set forth above, is a compound of formula (Ib1) wherein:
R1, R4 and Rb are each independently selected from the group consisting of hydrogen 20 and alkyl;
R29 is -R^-NCR^R73 whore RSA and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted W-heterocyclyl, and R10a is an optionally substituted straight or branched alkylene chain; 25 Raa is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R9B-ORSS, -RFT9-C(O)R60, -R90-C(O)ORSS, -RB3-K(RB0)R7G and -RAG-C(0)N{RE9)R79, where each RC9, R7S and RSS is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R®9 Is independently selected from the group consisting of a direct bond and an optionally substituted 30 straight or branched alkylene chain;
R13 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally 35 substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR'5,
-Re-OC{Q)-Rs, -R'-NtR^R7, -Rs-C(0)Rs, -R3-C(0)0Rs, -R9-C(Q)N{R6)R7, -R9-N(RG )C( 0)0RE, -R9-N(RG)C(0)Ra, -R9-N(RG)S(0)tRE (where t is 1 or 2), -Ra-S(0)t0R8 (where t is 1 or 2), -R3-S(C%RG (where p is 0, 1 or 2), and -Rs-S(O)tN(R0)R7 (where t is 1 or 2);
5 each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1u-ORa, 10 -R10-CN, -R10-NO2, -R1C,-N(RV -R10-C(O}OR6 and -R1D-C(0)N{RE)2, or any Ra and
R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl; each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 15 aralkynyl, 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 20 each R10 is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of fonmula (Ib1}, as set forth above, is a compound of formula (Ibi) wherein;
R , R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
25 R^ is -R1i)a-N(RBa)Rr9 where R^ and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl, and R10a is an optionally substituted straight or branched alkylene chain; R2g is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, 30 -R^-OR^, -R09-C(O)RSs, -R^-CfOOR80, -R"-N(R^)R70 and -R"-C(0)N(R^)RTg,
where each R^3, R7e and is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9y is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain: 35 R" is a bicyclic aryl optionally substituted by one or more substituents selected from the
group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR\ -R3-0C(0)-Rb, -Rs-N(Re)R7, -R*-C{0)R*, -R9-C(0)0R3, -R9-C(0)N(Rs)R7, -R9-N(R0)C(O)OR3 -R9-N(R6)C(0)Rsr 5 -R9-N(RB)S(0)iRs (where t is 1 or 2), -R5-S(OXOR* (where t is 1 or 2), -R9-S(0)pRa
(where p is 0, 1 or 2), and -RE-S(0)LN(Ra)R7 (where t is 1 or 2); each R6and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 10 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1B-OR3, -R1u-CN, -R^NOJ, ^R1W-N(RB)2, -R1d-C{0)0Rs and -R1t5-C(Q)N(Rs)2l or any Re and R', together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted W-heterocyclyl; 15 each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; 2D each R9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R1tJ is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (Ib1), as set forth above, is a compound of formula (Ib1) wherein: 25 R1, R4 and R5 are each Independently selected from the group consisting of hydrogen and alkyl;
R2a Is -R^-NKR^JR76 where RGa and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl, and R1Da is an optionally substituted straight 30 or branched alkylene chain;
R2g is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R"-ORRa, -Raa-C(0)R^, -RS9-C(0)0R^, -RSa-N(R0a)R73 and -R0a-C(O)N(Rea)R7a, where each R09, R7a and R^ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RSg is independently 35 selected from the group consisting of a direct bond and an optionally substituted
straight or branched alkylene chain; R3 is a bicyclic heteroaryl optionally substituted by one or more substituents selected
from the group consisting of oxo, halo, haloalkyl, atkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R9-ORB, -RS-0C(0>RE, -RS-N(RS)R7, -R9-C(0)RA. -R0-C(Q)ORFL, -R9-C(0)N(R6)R7, -R5-N{R6)Q(Q)OR0, -R6-N(RB)C(0)R8; -RB-N(RE)S(O),R0 (where t is 1 or 2), -RB-S(0)T0RFL {where I is 1 or 2), -R9-S(O)PR0 (where p is 0, 1 or 2), and -Ra-S(Q)JM(RS}R7 (where t is 1 or 2); each RS and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydraxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORA, -R1D-CN, -RI0-NO2, -R1IJ-N(RA)2, -R10-C(O)ORb and -R1C-C(0)N(Rb)2, or any RA and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl; each R0 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, opLionally 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 art
optionally substituted straight or branched alkylene chain; and each R1U is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (Ib1), as set forth above, is a compound of formula (lb1} wherein;
R\ R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R^is -R1DA-N(REA)R7A where RF,A and RRA, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted ^heterocyclyl, and R10A is an optionally substituted straight or branched alkylene chain; R?3 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -RAA-OR^, -R9G-C(O)R09, -R^-C(0}0R69, -R9S-N{RES>)RR9 and -R"-C(0}N(RG9}R7B, where each R^, R79 and R09 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R3 is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where 5 the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one
or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R^-ORs, -R^OCfQJ-R8, -Rs-N(Re)R7, -RE-C(0)Ra, -R^C(0)0Ra, -R9-C(0}N(RG)R7, 10 -R9-N(R®)C(0)0Ra, -Rs-N(Rs)C(0)Re, -R'-NfR'jStQ^R8 (where t is 1 or 2),
-R9-S(0)t0RB (where t is 1 or 2), -R9-S(0)PR£ (where p is 0, 1 or 2), and -R^-SfOJtNfR^R7 (wherB t is 1 or 2); each Rs and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxysIkyl, optionally substituted aryl, optionally substituted aralkyl, 15 optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -RtQ-ORB, ■*R'c'-CN, -R°-NOa, -R10-N[RV -Rlf,-C(0)0R& and -R1D-C(0)N(Ra)2, or any Ra and R7: together with the common nitrogen to which they are both attached, form an 20 optionally substituted W-heteruaryl or an optionally substituted Nheterocyclyt;
each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 25 optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each Ra is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1D is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ib1), as set forth above, is a 30 compound of formula (lb 1) wherein;
R', R4and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R^is -R1U5-N(Rt9)Rra where R'a and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted Nheteroaryl or an 35 optionally substituted AZ-heterocyclyl, and R103 is an optionally substituted straight
or branched alkylene chain; R2a is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R^-OR36, -R^-C(O)R80, -R"-C
selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R3 is a tricyclic aryl optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, 10 optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally
substituted heterocyclyialkenyl, -Rs-ORe, -R9-OC(0)-Ra, -R9-N(R6}R7, -R9-C(0)R{, -R9-C(0)0Ra, -R*-C(0)N(Rg)R7, -R"-N(RB)C(Q)QRe, -R9-N(RS)C(Q)RE, -R"-N(RB)S(0)iRB (where t is 1 or 2), -RB-S(0):0Rs (where t is 1 or 2), -RB-S(0)pRa (where p is 0, 1 or 2), and -R8-S(0)|N(R*)RT (where t is 1 or 2); 15 each R8 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1O-QR0, 20 -R10-CN, -R,c-NO:, -R10-N(RFI)2, -R'i)-C(0)0Ra and -R1t>-C(0)N(R8)2, or any Rfi and
R', together with the common nitrogen to which they are both attached, form an optionally substituted Nheteroaryl or an optionally substituted N-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 25 aralkynyl, 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 30 each R13 is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ib1), as set forth above, is a compound of formula (Ib1) wherein:
R1, R* and R5 are each independently selected from the group consisting of hydrogen and alkyl;
35 R73 is -R10j-N(R6s)R7a where R6a and R7a, together with the common nitrogen to which
they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl, and RIGA is an optionally substituted straight or branched alkylene chain; R29 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R9S-ORES, -R9S-C(0)RAH, -R^-C(O)OR0U, -R^R^R79 and -RSA-C(0)N(R69}R79, where each R^3, R7A and R1^ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R09 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; RS is a tricyclic heteroaryl optionally substituted by one or more substituents selected
from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R9-ORA, -RS-0C(0)-RA, -R9-N(RA)R7, -R9-C(0)RA, -R^C(0}0RA, -R9-C(0)N(R6)R7, -R9-N(R6)C(0)0RE, -RS-N(RE)C(0)RS, -R9-N(RC)S[0)-R9 (where t is 1 or 2), -R9-S(C)TOR3 (where t is 1 or 2), -RS-S(0)PR3 (where p is 0, 1 or 2), and -R9-S(0)-N(R6)R7 (where t is 1 or 2); each RB and RV is independently selected from the group consisting of hydrogen, alkyf, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1D-ORE, -R*C-CN, -RJ
optionally substituted straight or branched alkylene chain; and each Ria is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (lb), as set forth above, is a compound of formula (lb) which is a compound of formula (lb2):
Rzk
wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl: aralkyl, -C(0)R6 and -C(0)N(R6)R7;
R£b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9fc-OReb,
-R^-C(0)0Rab, -R"b-N(REb)R™ and -Ry6-C(0)N(Ra5)R/b, where each Reb, R"'6 and Rfb is independently selected ffiom the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R0b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R?,: is selected from the group consisting of -C(Q)RA, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
Rik is selected from the group consisting of hydrogen and alkyl;
RJ is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl. -RH-ORFL, -RP-O-R10-OR!!1 -R9-0-R™-G-R1D-0RA, -R9-O-R10-GN, -R9-0-R1C-C(0)0RB, -RE-0-R1TJ-C(0)N(RE)R7, -R9-0-R1D-S{0)^R5 (where p is 0, 1 or 2), -R£-0-R1Cl-N(R6)R7, -R^O-R1D-C(NR11)N(R11)H. -R9-0C(0}-R*, -R"-N(RE)R7, -R9-C(0)R3, -R9-C(0)0RB, -R9-C(0)N(RS)R7, -R9-N(R6)C[Q)QR6, -R9-N(RE)C[0)R#, -RB-N(R0)S(O),R8 (where t is 1 or 2), -RS-S(O)TOR0 (where t is 1 or 2), -R9-S(0)PRA (where p is 0, 1 or £). and -R9-S(OJtN(Rs)R7 (where t is 1 or 2)each R0 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl. haloalkynyl, hydroxyalkyl, optionally
substituted aryl. optionally substituted aralkyt, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally 5 substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally
substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R^-OR®, -R1Cl-CN, -R15-NOs, -R10-N(R*};, -R10-C{O)ORe and -R1D-C(0)N(Rfik. or any Re and R7, together with the common 10 nitrogen to which they are both attached, form an optionally substituted
N-heteroaryl or an optionally substituted W-heterocyclyl; each Re is Independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted 15 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 20 heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl;
each R9 is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; each Rto is an optionally substituted straight or branched alkylene chain; and 25 each R11 is hydrogen, alkyl, cyano, nitro or -ORs.
One embodiment of the compounds of formula (Ib2), as set forth above, is a compound of formula (Ib2) wherein:
R1, R4 and R6 are each independently selected from the group consisting of hydrogen and alkyl;
30 R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-ORat,
-R^-C^OR* -R*b-N(R6b)R7b and -R?b-C(Q}N{Ret)R7s, where each R0t, R7b and RBb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched 35 alkylene chain;
R1* is selected from the group consisting of -C(Q)RK, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
R2k is selected from the group consisting of hydrogen and alkyl;
5 R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by or© or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted 10 heterocyclyialkenyl, -R'-OR*, -R9-0C(0)-R8, -R5-N(RB)R7, -R*-C(0)RA,
-R0-C(O)OR6, -R9-C(0}N(R6)R7, -R9-N(R5)C{0)0R*, -R9-N(RE)C(0)R*, -RA-N(R6)S(Q)|RA (where t is 1 or 2), -RA-S(0),0R* (where t is 1 or 2), -RA-S(Q)PRS (where p is 0,1 or 2), and -R6-S(0),N(R8)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, 15 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-QRE, -R1C-CN, -R1Q-N02, -R10-N(RS)2, -R10-C(O)OR£ and -R1D-C(0)N(R*L or any RS and 20 R7 together with the common nitrogen to which they are both attached, form an
optionally substituted /V-heteroaryl or an optionally substituted /V-heterocyclyl; each RFI is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 25 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R0 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, 30 Another embodiment of the compounds of formula (Ib2), as set forth above, is a
compound of formula (Ib2) wherein:
R1, R4 and R^1 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is solectod from the group consisting of hydrogen, halo, haloalkyl, -R9b-ORab, 35 -Ruc-C(0)0R'itl, -Ryb-N(Rfit5)R/D and -R^-CfOJNfR^JR'5, where each Ret, R'b and
R6b is independently selected from the group consisting of hydrogen, alky], haloalkyl, aryl and aralkyl, and aach RSb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R^is selected from the group consisting of -C[0}Ra, hydrogen and alkyl;
R*11 is selected from the group consisting of hydrogen and alkyl;
R"1 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -Rs-ORa, -R9-QC(0)-Rs, -R9-N(RS)R7, -R5-C(0}RB, -R'-C(0)0Ra, -Ra-C(0)N{Rs)R7, -Rs-N(RB)C(0)0R*, - R9-N(R9)C(0) , -Rs~N(R?)S{0)tRa (where t is 1 or 2), -R"-S(OXOR* (where t is 1 or 2), -R*-S(0)f.Rs (where p is 0, 1 or 2), and -Ra-S(0);N(Ra)Rv (where t is 1 or 2); each Re and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^-OR®, -Rlc-CN, -R10-NO:, -R1D-N(Rs)2l -R1Q-C(0)0R£ and -R10-C(O)N(Rd)2l or any RB and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl; each RS is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, 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 alkylana chain.
AnoLher embodiment of the compounds of formula (Ib2), as set forth above, is a compound of formula (Ib2) wherein:
R1, R4 and R5 are each Independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-QRSb,
-RSb-C(0)0R5b, -R9B-N(R0L)R7b and -R3b-C(0)N(R6b)R7b, where each Rtb, R™ and Rab is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RSb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R2cis an optionally substituted non-bridged cycloalkyl; R211 is selected from the group consisting of hydrogen and alkyl; R3 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R°-ORa, -R0-OC(O)-Ra, -R9-N(R5)R7, -R3-C(0}Rs, -Rs-C(Q)GRa, -Ra-C(Q)N(RG)R7, -R9-N(RG)C(0}0Ra, -R9-N(Rs}C(0)Rs, -R*-N(Ru)S(0):RB (where t is 1 or 2), -Rs-S(0)t0R8 (where t is 1 or 2), -R9-S(Q)PRB (where p is 0, 1 or 2), and -R^StOJ^R^JR7 (where t is 1 or 2}; each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R'°-QRB, -R'c-CN, -R1Q-N02, -R1D-N(Ra)2l -Rl0-C(O)ORfi and -Rin-C(0)N(R®)2: or any R* and R7, together with the common nitrogen to which they are both attached, form an optionally substituted /^heteroaryl or an optionally substituted A/heterocyclyl; each RB is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R0 is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1Q is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (!b2), as set forth above, is a compound of formula (Ib2) wherein:
R , Re and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9h-ORafc,
-R^-CfOJOR®, -R9h-N(R0t>)R7s and -R9h-C(0)N(Ret)R7b, where each R0t, R7t> and 5 R0b is independently selected from the group consisting of hydrogen, alkyl,
haloalkyl, aryl and aralkyl, and each Reh is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R2" is an optionally substituted bridged cycloalkyl; 1D RJt is selected from the group consisting of hydrogen and alkyl;
R0 is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally 15 substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted
heterocyclylalkenyl, -Ry-OR*, -RB-0C(0)-Rs, -Ru-N{Rt)R7J -R9-C(0)Ra, -R9-C(0)0Rfl, -Rs-C(0}N(Re)R7, -R^N(RS)C(0)0R3, -Ra-N(RG}C(0)Ra, -RB-N(R6)5(0},R9 (whore t is 1 or 2), -Rs-S[Q):ORa (where t is 1 or 2), -R9-S(0)FR3 (where p is 0, 1 or 2), and -Ry-S(0)LN{R5)R7 (where t is 1 or 2); 20 each Re and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxysIkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORS, 25 -R1U-CN, -R1J-N02, -Rig-N(R6)2, -R1P-C(0}0R8 and -RltJ-G(0)N(R3)2, or any Re and
R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted Nheterocyclyl; each R0 Is independently selected from the group consisting of hydrogen, alkyl, haloalkyl. optionally substituted aryl, optionally substituted aralkyl, optionally substituted 30 aralkynyl, 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 35 each Ria is an optionally substituted sLraighl or branched alkylene chain.
Another embodiment of the compounds of formula (Ib2), as set forth above, is a compound of formula (Ib2) wherein:
RJ, and R& are each independently selected from the group consisting of hydrogen and alkyl;
5 R2B is selected from the group consisting of hydrogen, halo, haloalkyl, -R9t-0R$|J,
-R9t-C(O)OR0B, -R^-NtR^R76 and -R3B-C(0)N(RET)R7H, where each Ret, R7B and RIB is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R0B is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched 10 alkylene chain;
R2iis selected from the group consisting of -C(0)Rs, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
R2lt is selected from the group consisting of hydrogen and alkyl; 15 RJ is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R0-OR®, 20 -R*-0C(0)-RB, -RY-N(RE)R/, -RY-C(0)RA, -RY-C(0)0RE, -RB-C(0}N(RE)R'F
-RA-N(RC)C(0)0Rs, -R^N(RG)C(0)RA; -R^N(RC)S(0)iRe (where t rs 1 or 2), -R'-S(0),0RE (where t is 1 or 2), -R3-S(0)PRE (where p is 0,1 or 2), and -R"-S(0)TN(RE)R7 (where t is 1 or 2); each R8 and R7 is independently selected from the group consisting of hydrogen, alkyl, 25 haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-GRA, -R'°-CN, -RJ(J-N02, -R10-N(RV -R1D-Q(0)0Rs and -RLC-C(0)N(R:I)£, or any R9 and 30 R7 together with the common nitrogen to which they are both attached, form an
optionally substituted /V-heteroaryl or an optionally substituted Nheterocyclyl; each R6 is Independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 35 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Ra 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.
5 Another embodiment of the compounds of formula (Ib2), as set forth above, is a
compound of formula (Ib2) wherein:
R\ R* and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2" is selected from the group consisting of hydrogen, halo, haloalkyl, ~RSb-ORat, 10 -R9b-qO)ORab, -R9b-N(R6b)R/D and -R0b-C(O}N(Reb)R70, where each R6b, R7* and
R8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain:
15 R2" is selected from the group consisting of -C(0)Ry, hydrogen and alkyl; R2k is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, 20 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R*-ORe, -Rs-0C(0)-R3, -RA-N(Rti)R7, -Rs-C{0)R9, -R9-C(0)0R8, -R^-CTOMR^R7, -R9-N(RG)C(0}0Rs, -Ra-N(Rfi)C(0)R6, -R^R^OJtR4 (where t is 1 or 2), -R9-S(0)t0Ra (where t is 1 or 2), -Rfl-S(0),R{ (where p is 0, 1 or 2), and 25 -R9-S(D)tN(R6)R7 [Where t Is 1 or 2);
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxys Iky I, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 30 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORS,
-R10-CN, -R1c'-NO?r -R10-N(R6K -R1Cl-C(0)0Ra and -R10-C(Q)N(Ra)2, or any Re and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl; each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, 35 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R0 is independently selected from the group consisting of a direct bond and an 5 optionally substituted straight or branched alkylene chain; and
each R1[f is an optionally substituted straight or branched alkylene chain,
Of this embodiment, a preferred embodiment is wherein R3 Is optionally substituted quinazolinyl,
One embodiment of this preferred embodiment is a compound of formula (Ib2), 10 as set forth above, which is 1-(6-chloroquinazolin-4~yl)-//-(4-[4-methylpiperazin-1- yl)phenyl)-1 H-1,2,4-triazole-3,5-d iamine.
Another embodiment of the compounds of formula (IbZ), as set forth above, is a compound of formula (Ib2} wherein:
RJ, R" and R5 are each independently selected from the group consisting of hydrogen 15 and alkyl;
R£b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-ORSb,
-R9b-C(Q)OR0b, -Rstt>-N(Re")RTb and -RHb-C(0)N(R6b)R7b, where each R6b, R7b and Rfib is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9b is independently selected from the group 20 consisting of a direct bond and an optionally substituted straight or branched
alkylene chain; R!tis an optionally substituted non-bridged cycloalkyl; R2li is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where 25 the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one
or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R'-OR6, -Rs-0C(0)-R*, -Rfl-N(RG)R7, -R9-C(0)R3, -Rs-C(O}OR0, -R9-C(0)N(Rb)R7, 30 -R9-N{Re)C(0)0Ra, -R9-N(R6)C(0}RB, -R9-N(R0)S(O)tR3 (where t is 1 or 2),
-R^SfOJtOR® (where t is 1 or 2), -R0-S(O)pRa {where p is 0, 1 or 2), and -Rs-S(OKN(R6)R7 (where t is 1 or 2); each Rft and R' is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, 35 optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORA, -R™-CN, -FT-N02P -R10-N(R4)S, -R1D-C(0)0R6 and -R10-C{O)N(R% or any R6 and R7, together with the common nitrogen to which they are both attached, form an 5 optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl;
each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
10 optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each RD 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.
Of this embodiment, a preferred ambodiment is wherein R3 is optionally
15 substituted quinazolinyl.
One embodiment of this preferred embodiment is a compound of formula (lb£), as set forth above, which is Ns-(4-(4-cyclo hexyl pipe razin-1-yl)p henyl)-1-( 6,7- di met hoxyq u i nazo li n-4-y I)-1 ^M, 2,4-tri azo I e- 3,5-d ia m i ne.
Another embodiment of the compounds of formula (lb2), as set forth above, is a 20 compound of formula (Ib2) wherein:
R1, R+ and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R0b-ORat,
-R6b-C(0)0R^, -RBB-N(R0b)R7a and -RSb-C(O)N(R0T)R75, where each RAB, R^ and 25 REB is independently selected from the group consisting oi hydrogen, alkyl,
haloalkyl, aryl and aralkyl, and each Rst) is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R2c is an optionally substituted bridged cycloalkyl; 30 RSfc is selected from the group consisting of hydrogen and alkyl;
RJ is selected from the group consisting of a bicyclic ary! and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or mora substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
35 substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -Rs-ORB,
-R9-0C(0}-R8, -RS-N(RE)R7, -R--C(0)RA, -R3-C(0)0Rs, -R*-C(0}N(RE)R7, -R9-N(RB)G(Q)ORA, -Rs-N(RB)C(0)RA, -R9-N(Re}S(0)LRfi (where t is 1 or 2), -R^-S(OXOR* (where t is 1 or 2), -R'-S(0)PRc (where p is 0,1 or 2)r and -R9-S(0),N(Rc)R7 (where t is 1 or 2);
5 each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1D-ORFI, 10 -R1C-CN, -R1D-N02, -R1°-IM(RS)2I -R1D-C{O)0R£ and -R10-C(O)N(RA)2, or any R* and
R7, together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted W-heteracyclyl; each R11 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 15 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each RS is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and 20 each R1U is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (Ib2), as set forth above, is a compound of formula (Ib2) wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen and alkyl;
25 R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R5b-OR6b,
-R;b-C(0)0RBB, -RSb-N(R^)R7b and -R9b-C(0)N(R6B)R7B, where each R*b, R"'B and RtCl is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9B is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched 30 alkylene chain;
R;<:is optionally substituted bicyclo>
Rik is selected from the group consisting of hydrogen and alkyl;
RJ is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one 35 or more substituents selected from the group consisting of oxo, halo, haloalkyl,
alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R'-OR5, -R9-0C(0)-R8, -R*-N(Re)R7 -R0-C(O)Ra, -R°-C(0)0Ra, -R3-C(0)N(Rfi)R7, -R9-N(R6)C{0)0Ra, -Ry-N(RB)C(0)R8. -R9-N(R6)5(0)tR9 (where t is 1 or 2), 5 -R9-S(0)i0Ra (Where t is 1 or 2), -Ra-S(0)pRE (where p is 0,1 or 2), and
-R9-S(0),N(Re)R7 (where t is 1 or 2); each RH and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyi, optionally substituted cycloalkyl. optionally substituted cycloalkylalkyl, optionally 10 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-ORa, -R1c'-CN, -R10-NOj, -R10-N(Ra)2l -R10-C(O)OR* and -R1D-C(0)N(Ra)2, or any Re and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted Af-heterocyclyl; 15 each Rs is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; 20 each R" is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each Rll} is an optionally substituted straight or branched alkylone chain,
Of this embodiment, a preferred embodiment is wherein Ra is selected from the group consisting of optionally substituted thienopj^-tflpyrinnicfinyl, optionally substituted 25 benzo[tf]thiazolyl and optionally substituted quinazoiinyl.
One embodiment of this preferred embodiment is a compound of formula (Ib2), as set forth above, selected from the group consisting of:
1-(6-(1,1-dimethylethyl)thieno[3,2^]pyrimidin-4-yl)-Wi-(4-(4-(bicyclo[2,2,1]heptan-2-yl)- piperazi n-1 -y I )ph enyl)-1H-1,2,4-tri azo I e-3,5-diamine; 30 1 -(benzo[cflth ia zol-2-y I)-4-(4-( bicyclo [2.2.1 ] heptan-2-y l)p iperazi n -1 -y l)p heny l)-1 ^ 1,2,4-triazole-3,5-diamine; and W'-(4-(4-( bicyclo[2.2,1 Jheptan-2-yl)piperazin-1 -yl)pheny1)-t -(6r7-dimethoxyquinazolin-4- yl)-1 H-1,2,4-triazole-3,5-diamine.
Another embodiment of the compounds of formula (Ib2), as set forth above, is a 35 compound of formula (Ib2) wherein:
R1, R* and R5are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -RDb-ORSfc.
-RBB-C(O)OR?B, -R9B-N(R6fa}R7b and -R9b-C(O)N(R6fc)R73, where each R6b, R7b and Rab is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each RSb is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
RZc is selected from the group consisting of -C(O)Ra, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
R2K is selected from the group consisting of hydrogen and alkyl;
R3 is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Rq-ORh, -R0-GC(Q)-RA, -RS-N(RC)R7, -Rs-qO)RS, -R0-C(O)ORA, -R9-C(0)N(RC)R7, -Rs-N(Re)C(Q)DRS, -Rs-N(RE)C(Q)R&, -RD-N[R6)S(0},R8 (Where f is T or 2), -RY-S(0)T0RK (where t is 1 or 2), -RS-S(0),,R* (where p is 0, 1 or 2), and -R9-S(0)IN(RG)Rl/ (where t is 1 or 2};
each Reand R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1D-QRa, -R1fJ-CN, -R1(--N02l -R10-N(Rb}2, -R'ID-C(0)0Rfl and -R10-C(O)N(RS)2, or any Re and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted N-heterocyclyl;
each Rs is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each Rs is Independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1D is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ib2), as set forth above, is a compound of formula (Ib2) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and aJkyl;
R2b rs selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-GRflb,
-R^-QOJOR™, -Ryb-N(RUb)R/3 and -Ryb-C(O)N(Ret,}R76, where each Ret, R7b and Ras> is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R5° is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R2" is selected from the group consisting of -C(G)R°, hydrogen and alkyl; R2k is selected from the group consisting of hydrogen and alkyl; R3 is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl. optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R9-QRe, -Rs-0C(0)-Rs, -R9-N(R$)R7, -Rb-C(O)R0, -R3-C(OPRe, -Rd-C(0)N{Rs)R7, rR9-N(RG)C(0)0R'\ -Rfi-N(Rfi)C(0)Rs, -R9-N(Rfi}S(0)tR8 (where I is 1 or2j, -R9-S(Q)tORB (where t is 1 or 2), -R9-S(0)pRs (where p is 0,1 or 2). and -R9-S(0)tN(RB)R7 (where t is 1 or 2); each RK and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryf, optionally substituted aralkyl, optionally substituted cycloalkyl. optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORfl, -R10-CN, -RTC-NG?, -R1Cl-N(Ra)?, -R1Cl-C(0)0Re and -R19-C(0)N(R*)2, oranyRs and R7, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl; each Rs is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, 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 R13 is an optionally substituted straight or branched alkylene chain.
5 Another embodiment of the compounds of formula (Ib2), as set forth above, is a
compound of formula (Ib2) wherein;
R\ R" and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R'b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9T'-OR6B, 10 - R^-C( 0)0RFLB - RSb- N( RGB)RFT and - R8b-CKO) ISK REB)R?B, w here each R®, R7B and
R£b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R0l> is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; 15 R2"is an optionally substituted non-bridged cycloalkyl;
R2k is selected from the group consisting of hydrogen and alkyl; Rs is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, 20 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-ORfi, -R9-DC(0)-Rs, -R9-N(R*)R7, -Rs-C(0)Ra, -Rs-CtOpR?, -R9-C(0)N(Re)R7, -R~-N(RB)C(0)OR5, -R0-N(R0)C(Q)R*, -RS-N(R*)S(Q)tRa (where t is 1 or 2), -R"-S(0)t0Ra (where t is 1 or 2), -Ry-S(0),Ra (where p is 0,1 or 2), and 25 -R*-S(0)tN(R6)R7 (where t is 1 or 2);
each R0 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 30 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORA,
-R10-CN, -R10-NO2, -R1C,-N(R6)2, -R1D-C(0)0RA and -RW-C(0)N(Re>z, or any R6 and R', together with the common nitrogen to which they are both attached, form an optionally substituted /V-heteroaryl or an optionally substituted N-heterocyclyl; each RA is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, 35 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyi, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, arid optionally substituted heteroarylalkyl; each R3 is independently selected from the group consisting of a direct bond and an 5 opiionally substituted straight or branched alkylene chain; and
each R10 is an optionally substituted straight or branched alkylene chain.
Of this embodiment, a preferred embodiment is wherein Rs is optionally substituted phenanthridinyl.
One embodiment of this preferred embodiment is a compound of formula (Ib2), 10 as set forth above, which is 1-(phenanthridin-6-yl>Ar-(3-fluorO"4-(4~cyclopentylpiperazin' 1 -yl)phenyl)-1 H-1, 2,4-triazo I e-3,5-diamine.
Another embodiment of the compounds of formula (Ib2), as set forth above, is a compound of formula (Ib2) wherein:
R', R15 and RG are each independently selected from the group consisting of hydrogen 15 and alkyl;
R?bl is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-ORaiI,
-Refc-C{0)0RSb, -RSb-N(RSb)R/B and -RSb-C(0)N{R*b)R7b, where each Ret, Rrb and Rab is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9b is independently selected from the group 20 consisting of a direct bond and an optionally substituted straight or branched
alkylene chain; R2r- is an optionally substituted bridged cycloalkyl; Ril! is selected from the group consisting of hydrogen and alkyl;
R-1 is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where 25 the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one
or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -R^-ORs, -RD-QC(0)-Ra, -R9-N(R6)R7, -R0-C(O)R8, -R*-C(0)0Ra, -R9-C(0}N(Ra)R7, 30 -R9-N(Rft)C(0)0Rs, -R9-N(R0 )C( 0) R1", -R0-N{R0)S(Q)iRa (where t is 1 or 2),
-Ra-S(0)[0Ra (where t is 1 or 2), -RB-S(0)FRe (where p is 0, 1 or 2), and -RD-S(0)rN(R8)R7 (Where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, 35 optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
.10
.a
,a
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R'm-ORfl, -Ria-CN, -R1D-NOI, -R1C-N(R£)2F -R10-C(O}ORa and -R10-C(O)N(Ra)2, or any Rc and R7, together with the common nitrogen to which they are both attached, form an optionally substituted Af-heteroaryl or an optionally substituted W-heterocyclyl;
each Rs is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
10
optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
each R^ is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1S is an optionally substituted straight or branched alkylene chain,
Another embodiment of the compounds of formula (lb), as set forth above, is a 15 compound of formula (lb) which is a compound of formula (Ib3):
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)R6 and -C(0)N(Ra}R7; 20 R^ is selected from the group consisting of halo, -OR6, -C(0)R3, -QOJOR8,
-Rlte-N(RB)R7, -R1tte-G(0)N(RB)R7, optionally substituted heterocyclyl and optionally substituted heteroaryl, where each R1
R3 Is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each optionally substituted by one or more substituents selected ffom the group consisting of oxo, thioxo, cyano, nitre, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aTyl, optionally substituted 30 aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl,
optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, -R^-OR6, -RG-0-R1
each R9 is independently selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; each R13 is an optionally substituted straight or branched alkylene chain; and each R11 is hydrogen, alkyl, cyano, nrtro or-ORe,
One embodiment of the compounds of formula (Ib3), as set forth above, is a compound of formula (Ib3) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
5 R2e is selected from the group consisting of halo, -OR5, -C
-R10e-N(R6)R7, -R1fe-C(0)N(Re}R7, optionally substituted heterocyclyl and optionally substituted heteroaryl, where each R1I)B is an optionally substituted straight or branched alkylene chain; R2d and R2f are each independently selected from the group consisting of hydrogen, halo, 10 alkyl and-OR*;
RJ is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally 15 substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted
heterocyclylalkenyl, -RB-ORa, -R9-0C(0)-Ra, -Rs-N(Ra)R7, -R6-C(0)Ra, -Rs-Q(0)0Ra, -R9-C(0)N(R*)R7, -R^NfR^CfOJOR6, -R9-N(Rfi)C(0}Re, -R"-N(Rs)S{0)tR5 (where t is 1 or 2), -R9-S(0)t0Rc (where t is 1 or 2), -R9-S(0)pRD (where p is 0, 1 or 2), and -Re-S(0)lN(Ra)Ry (where t is 1 or 2); 20 each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxys Ikyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORa, 25 -R10-CN, -R1K-N02, -R1D-N(Ra)2j -Ria-C(0)0Rs and -Ria-C(0)N[RV or any Re and
R', together with the common nitrogen to which they are both attached, form an opiionally substituted /V-heteroaryl or an optionally substituted Ai-heterocyclyl; each R* is independently selected from tho group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 30 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R& is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and 35 each R10 is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds erf formula (I b3), as set forth above, is a compound of formula (Ib3) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
5 RSE is selected from the group consisting of halo, -ORA, -C(Q)Ra, -C(OJORE,
-RLDB'N(Rs)Ri'p - R13e-C(0 )N( R8) R7, optionally substituted heterocyclyl and optionally substituted heteroaryl, where each R1JS is an optionally substituted straight or branched alkylene chain; R2d and R3f are each independently selected from the group consisting of hydrogen, halo, 10 alkyl and-OR3;
Rs is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally 15 substituted heterocyclyl, optionally substituted heterocyclylalkenyl, -Re-ORs,
-R9-0C(0)-RFIP -RB-N(R6)R7, -R^CtOjR8, -R9-C(Q)QRS, -RG-C(0}N(RB)R7, -R9-N(R0)C(O)ORA, -R&-N{R3)C(0)RS, -R3-N(R6)S(0)TRA (where lis 1 or2), -RB-S(0)t0Re (where t is 1 or 2), -R9-S(0),R4 (where p is 0, 1 or 2), and -R9-S{0)TN(Rf;)R7 (where t is 1 or 2); 20 each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R1°-ORA, 25 -R10-CN, -R10-NO2, -R,0-N(RF}?. -R10-C(O)ORA and -Rlc,-C(0)N(R6)2, or any Re and
RR, together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted Nheterocyclyl; each RB is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 30 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each R0 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and 35 each R1|J is an optionally substituted straight or branched alkylene chain,
Of this embodiment, a preferred embodiment is wherein R3 Is selected from the group consisting of optionally substituted quinoxalinyl, optionally substituted quinazolinyl and optionally substituted isoquinolinyl.
One embodiment of this preferred embodiment is a compound of formula (Ib3), 5 as set forth above, selected from the group consisting of:
Afi-(4'((1-methylpyrrolicfin-2-yl)methoxy)pherty1)"1-(quinoxalin-2-yl)-1H-1,2p4~triazole-3,5- diamine;
1 -(6,7-dimethoxyquinazDfin-4-y|}-Ni!-(4-{1 -methyl pi peridin-3-yloxy)phenyl)-1 H-1,2,4- triazole-3,5-diamine; and 1D 1-(isoquinolin-1-yl)-/V5-(4-morpholinophenyl)-1H-1,2,4-triazole-3,5-diamine,
Another embodiment of the compounds of formula (Ib3), as set forLh above, is a compound of formula (lb3) wherein:
RJ, R- and R5 are each independently selected from the group consisting of hydrogen and alkyl;
15 R^ is selected from the group consisting of halo, -ORB, -C(0)Ra, -C(0)0Ra,
-R10e-N(R3)R7, -R10e-C{O)IM(R0)R7, optionally substituted heterocyclyl and optionally substituted heteroaryl, where each is an optionally substituted straight or branched alkylene chain; R^ and Ra are each independently selected from the group consisting of hydrogen, halo, 20 alkyl and -ORe;
Ra is selected from the group consisting of a tricyclic aryl or a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally 25 substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -RS-OR8,
-R9-QC(OFRS, -RD-N(R6)R7, -RS-C(0)RE, -R0-C(O)OR3, -R3-C(Q)N(RE)R7, -R--N(R*)C(0)0RK, -R"-N(R")C(0)RB, -R^-N^S^R* (where t rs 1 or 2), -R*-S(0)T0RFT (where t is 1 or 2), -R9-S(0)PR6 (where p is 0, 1 or 2), and -RS-S(0),N(RE)R7 (Where t is 1 or 2); 3D each R0 and R7 IS Independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally opLicrially substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORA, 35 -R C'-CN, -R10-NOA, -R^-IMFR8);,, -R10-C{Q)QR6 arid -R^-CfOJNtR®)^ or any R3 and
R7, together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted W-heterocyclyl; each R® is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, 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 10 each R10 is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (lbf, as set forth above, is a compound of formula (lb) which is a compound of formula (Ib4}:
Rz': RZJ
wherein;
15 R , R1 and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0}Ra and -C(Q}N(R®)R7;
RZh is selected from the group consisting of hydrogen, -N(R1Jh)R7hJ optionally substituted heterocyclyl and optionally substituted heteroaryl, where R6h is hydrogen or alkyl and R7* is an optionally substituted bridged cycloalkyl;
2D R2d is independently selected from the group consisting of hydrogen, halo, -OR0 and -R9-N(R^}R7;
R2f, R2' and R2J are each independently selected from the group consisting of hydrogen, halo and -ORa;
R3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the
25 heteroaryl are each optionally substituted by one or more substituents selected
from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryL optionally substituted
aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl.
OPTIONALLY SUBSTITUTED HETEROCYCLYLALKYL, OPTIONALLY SUBSTITUTED HETEROCYCLYLALKENYL, -RS-ORS, -R?-O-R10-OR5, -RS-O-R1D-O-R10-ORE, -RF-OR^-CN, -RD-0-R,C-C(0)0R2, -R9-0-R,C-C(0)N(RE)R7, -RD-O-R10-S{O)PR5 (WHERE P IS 0,1 OR 2], -R0-Q-R1D-N(RE)R7, -R9-0-R1D-C(NR")N(R11)H, -R9-OC(O)-R0, -RST-N(RFC)R7, 5 -R3-C(0 )RS, - R?-C( 0)0RE, - R*-C( 0)N (R6)R7, - R3-N( R®)C( O^R6,
-R9-N(Re)C(0)Re, -R9-N(R6)S(0)[Rs (where t is 1 or 2), -R9-S(0)-OR2 (where 1 is 1 or 2), -R0-S(O),Ra [where p is 0,1 or 2), and -R0-S(Q)tN(R6}R7 (where t is i or 2); each Re and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally 10 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 15 substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R1i:-ORK, -R1U-CN, -Rw-IM02l -Rut-N(Ra)2P -R,0-C(O)ORs and -R10-C(O)N(Ra)2: or any Rc and R7, together with the common nitrogen to which they are both attached, form an optionally substituted 20 /V-heteroaryl or an optionally substituted /V-heterocyclyi;
each R^ is independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, 25 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 30 heteroarylalkynyl;
each Rs is independently selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; each R1C is an optionally substituted straight or branched alkylene chain; and each R1' is hydrogen, alkyl, cyano, nitro or-ORs. 35 One embodiment of the compounds of formula [Ib4), as set forth above, 5s a
compound of formula (Ib4) wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2fl is selected from the group consisting of hydrogen, -N(RBH)R7H, optionally substituted heterocyclyl and optionally substituted heteroaryl, where R0H is hydrogen or alkyl and R7h is an optionally substituted bridged cycloalkyl; R2d is independently selected from the group consisting of hydrogen, halo, -OR8 and -R?-N(R0)R7;
Ra, R2' and R2i are each independently selected from the group consisting of hydrogen, halo and -ORe;
RJ is selected from the group consisting of a monocyclic aryl and a monocyclic
heteroaryl, where the monocyclic aryl and the monocyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Re-ORa, -R^OCfOJ-R11, -R9-N(RE}R\ -Rs-C(0)Re, -R9-C(0)0RS, -R9-C(Q)N(R6)RR, -R9-N(Re)C(0)0Rs, -R0-N(Rd)C(O)R*, -R3-N(RS)S(0)TRB (where t is 1 or 2), -RS-S(0)I0RE (where t is 1 or 2), -R3-S(0}PRB {where p is 0, 1 or 2), and -Rs-S(O)TN(R0)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORE, -R10-CN, -R10-NO2, -R10-N(R0),, -R10-G(Q)ORF and -R10-C(O)N(RA)A, or any R0 and R'P together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted W-heterocyclyl; each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, 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 R1U is an optionally substituted straight or branched alkylene chain.
Another embodiment of the compounds of formula (Ib4), as set forth above, is a compound of formula (Ib4) wherein:
R1, R4 and R^1 are each independently selected from the group consisting of hydrogen and alkyl;
5 R2h is selected from the group consisting of hydrogen, -N(R0h)R7f\ optionally substituted heterocyclyl and optionally substituted heteroaryl, where R5"1 is hydrogen or alkyl and RTh is an optionally substituted bridged cycloalkyl; R2D is independently selected from the group consisting of hydrogen, halo, -OR6 and -Ra-N(Re)R7;
10 R2', R2' and R2J are each independently selected from the group consisting of hydrogen, halo and -OR5;
Rs is selected from the group consisting of a bicyclic aryl and a bicyclic heteroaryl, where the bicyclic aryl and the bicyclic heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, 15 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
SUBSTITUTED HETEROCYCLYL, OPTIONALLY SUBSTITUTED HETEROCYCLYLALKENYL, -R9-0R4, -RFI-0C(0)-R6, -R9-N(R3)R7, -R5-C(Q)R0, -R'-CTOJOR6, -RB-C(Q)N(RE)R7, -R9-N(R6)C(0)0R&, -RS-N(RB)C(0)R*, -R"-N(RH)S(0)LRK (WHERE T IS 1 OR 2), -RS-S(0)T0RH (WHERE T IS 1 OR 2), -RS-S(0}PRA (WHERE P IS 0, 1 OR 2), AND 20 -RB-S(O)LN(R0}R7 (WHERE T IS 1 OR 2);
each Rs and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, 25 optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-ORB,
-R10-CN, -R1°-N02I -R^N(RE)ZL -R10-C(O)ORA and -R'C-C(0)N(Re}a or any RE and R7, together with the common nitrogen to which they are bath attached, form an optionally subslituled Nheteroaryl or an optionally substituted W-heterocyclyl; each Rb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, 30 optionally substituted aryl, optionally substituted aralkyl, optionally substituted
aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each Ry is independently selected from the group consisting of a direct bond and an 35 optionally substituted straight or branched alkylene chain; and
each R1D is an optionally substituted straight or branched alkylene chain.
Another embodiment of tho compounds of formula (Ib4), as set forth abovo, is a compound of formula (IB4) wherein:
R1, R4 and R5 are each independently selected from the group consisting of hydrogen 5 and alkyl;
R2H is selected from the group consisting of hydrogen, -N(R6H)R7H, optionally substituted heterocyclyl and optionally substituted heteroaryl, where Rfih is hydrogen or alkyl and R7h is an optionally substituted bridged cycloalkyl; Rad is independently selected from the group consisting of hydrogen, halo, -OR3 and 10 -R*-N(RFI)R7;
Ra, R2' and R2i are each independently selected from the group consisting of hydrogen, halo and -ORs;
R° is selected from the group consisting of a tricyclic aryl and a tricyclic heteroaryl, where the tricyclic aryl and the tricyclic heteroaryl are each optionally substituted by one 15 or more substituents selected from the group consisting of oxo, halo, haloalkyl,
alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR3, -RS-OC(OJ-RS, -R6-N(RG)R7, -R9-C(0)RE, -R9-C(0)0Rs, -R6-C(0)N(R6)R'. - RS- N{ Rs )C( O )0 R8. -R^-NtR^CfQJR6, -R9-N(Rfl)S(0)LRe (where t is 1 or 2), 20 -R^-SfOJjGR^ (where t is 1 or 2), -R^O^R® (where p Is 0r 1 or 2), and
-R9-S(0)|N{RG}R7 (where t is 1 or 2); each Rs and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally 25 optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR3, -R10-CN, -R1U-NQ:, -R °-N(R0)I, -R10-C(O)OR° and -R13-C(0)N[RV or any R0 and R', together with the common nitrogen to which they are both attached, form an optionally substituted W-heteroaryl or an optionally substituted /V-heterocyclyl; 30 each R3 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; 35 each R9 is independently selected from the group consisting of a direct bond and an
optionally substituted straight or branched alkylene chain; and each R1[l is an optionally substituted straight or branched alkylene chain.
In particular embodiments, in compounds of formula (la) and (lb), R2 is optionally substituted phenyl or optionally substituted 6,7,8,9-tetrahydro-5tf-benzo[7]annulenyl and 5 RJ is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted quinoxalinyl, optionally substituted benzothiophenyl, optionally substituted benzimidazoyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, 10 optionally substituted cyclopenta[d]pyrimidinyl, optionally substituted isoquinolinyl, optionally substituted thienopyrimidinyl, optionally substituted 5,6,7,6- tetrahydrobonzo[4,5]thienopyriinidinyl, optionally substituted thienopyhdinyl, optionally substituted 6,7-dihydro-5H-cyclopentaI4,5]thienopyrimidinyl, optionally substituted furopyridinyi, optionally substituted benzothienopyrimidinyl, optionally substituted 15 dihydrobenzo[ft]quinazolinyl, optionally substituted octa hydro be nzo [/^quinazolinyl, optionally substituted dihydrobenzo[h]clnnolhnyl, optionally substituted tetrahydroquinazolinyl, optionally substituted naphthyridin-2(1H)-one-yl, optionally substituted pyrido[4,3-c]pyridazinyl, optionally substituted tetrahydro-5/-/- cyclohepta[4,5]thienopyrimidinyl, optionally substituted 5,6Hjlhydrobenzo[ft]quinazolinyl, 20 optionally substituted pyridopyrimido[4r5-d]thiophenyl, optionally substituted
phenanthridinyl, optionally substituted thienopyridazinyl and optionally substituted chrom en o[4,3-c] pyridazinyl; where the optional substitutents on each R2 and R3 group are independently selected from Lhe group consisting of 2-(piperidin-1-yl)ethoxy, 2- (pyrrolidin-l-yl)ethoxy, alkyl, halo, haloalkyl, sulfonamido, morpholino, alkoxy, 25 alkylamino, dralkylamino, hydroxy, phenyl, carboxybenzyl, benzyloxy, piperazinyl (optionally substituted with alkyl), cycloalkyl, acyl, bicycloalkyl, thiophenyl, benzodioxanyl, aminosulfonylalkyl, (pyrralidin-1-yl)prap-1-enyl, (alkylpiperazin-1-ylJpnop- 1-enyl, (moipholin-4-yi)prop-1-enyl, carboxyalkyl, (pyrrolidin-l-ylmethyl)pyrrolidrnyl, (pyrrolidin-1-yl)propan-1-one^yl, 1 -alkyl pipe rid in-3-yloxy, (4-alkylpiperazin-1-yl)methyl, 3- 30 (dialkylamirio)pyrrolidin-1 -y1, 1-alky!piperidin-4-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl, 4-
(cycloalkyl)piperazin-l -ylcarbonyl, (2-(pyrrolidin-1 -yl)ethyl)aminocarbonyl, 4-piperidin-1 - ylplperidin-1-yl, 3-alkylaminopyrrolidin-1-yl, (4-alkylpiperazin-1-yl)piperidln-1-ylJ 4- isoindclin-2-yl, alkylaminocarbonyl, 4-{2-azabicyclo[2.2.1 Jheptan-2-yl)piperidin-1-yi, (1- (bicyclo[2.2.1]heptan-2-yl)piperidirw1--yl, 4-(1-alkylpyrrolidin-2-yl)methoxy. 1- alkyIpiperidin-3-yIoxy, pyrrolidinyl, N-alkyl-N-bicyclo[2.2.1]heptan-2-ylamino, N- bl cyclo[2,2.1 jhepta n-2-yla m ino an d 2-a I kylami noethyI.
Of the various aspects of the pharmaceutical compositions of the invention comprising a pharmaceuticaily acceptable excipient and a therapeutically effective 5 amount of a compound of formula (I), as set forth above in the Summary of the Invention, certain embodiments aie preferred.
One embodiment of these pharmaceutical compositions is wherein the compound of formula (I) therein is selected from any one embodiment of the compound of formula (la), as set forth above, or from any combination of embodiments of the compound of 10 formula (la), as set forth above; or the compound of formula (I) therein is selected from any one embodiment of the compound of formula (lb), as set forth above, or from any combination of embodiments of the compound of formula (lb), as set forth above,
Of the various aspects of methods of treating a disease or condition associated with Axl activity in a mammal, wherein the method comprises administering to a mammal 15 in need thereof a therapeutically effective amount of a compound of formula (I), as set forth above in the Summary of the Invention, certain embodiments are preferred, One embodiment of these methods is the method wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease, vascular injury, psoriasis, visual impairment due to macular degeneration, diabetic 20 retinopathy, retinopathy of prematurity, kidney disease, osteoporosis, osteoarthritis and cataracts,
One embodiment of these methods is the method wherein a manifestation of the disease or condition is solid tumor formation in said mammal,
One embodiment of these methods is the method wherein the disease or 25 condition is selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, and uveal melanoma,
One embodiment of these methods is the method wherein a manifestation of the disease or condition is liquid tumor formation in said mammal. 30 One embodiment of these methods is the method wherein the disease or
condition is myeloid leukemia or lymphoma.
One embodiment of these methods is the method wherein the disease or condition Is endometriosis.
One embodiment of these methods is the method wherein the compounds of 35 formula (1) utilized therein is selected from any one embodiment of the compound of
formula (la), as set forth above, or from any combination of embodiments of the compound of formula (la), as set forth above, or the compound of formula (I) therein is selected from any one embodiment of the compound of formula (lb), as set forth above, or from any combination of embodiments of the compound of formula (lb), as set forth 5 above.
Another embodiment of the invention are those methods of treating a disease or condition associated with Axl activity by administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention, as set forth above in the Summary of the Invention, wherein the disease or condition is selected from the 10 group consisting of rheumatoid arthritis, vascular disease! 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), osteoporosis, osteoarthritis and cataracts. 15 Another embodiment of the invention are those methods of treating a disease or
condition associated with Axl activity by administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention, as set forth above in the Summary of the Invention, wherein the disease or condition is selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian 20 carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate
carcinoma, sarcoma, gastric cancer, uveal melanoma, myeloid leukemia and lymphoma.
Another embodiment of the invention are those methods of treating a disease or condition associated with Axl activity by administering to the mammal of therapeutically effective amount of a pharmaceutical composition of the invention, as set forth above in 25 the Summary of the Invention, wherein the disease or condition is endometriosis.
It is understood that any embodiment of the compounds of formula (I), as set forth above, and any specific substituent set forth herein for a R1, R2, R\ R4 and R5 group in the compounds of formula (I), as set forth above, may be independently combined with other embodiments and/or substituents of compounds of formula (I) to form 3D embodiments of the inventions not specifically set forth above, In addition, in the event that a list of substitutonts is listed for any particular R group in a particular embodiment andfor claim, it is understood that each individual substituent may be deleted from the particular embedment and/or claim and that the remaining list of substituents will be considered to be within the scope of the invention. 35 Specific embodiments of the invention are described in more detail bslow in the following sections.
UTILITY AMD TESTING DF THE COMPOUNDS OF THE INVENTION
The oncogenic RTK, Axl, was recently identified, using a retro viral-based functional genetic screening protocol, as a regulator of haptotactic migration, which is a 5 key event in angiogenesis. Axl inhibition by RNAi-mediated silencing blocked endothelial cell migration, proliferation and in vitro tube formation. These observations, which were disclosed at the American Association Cancer Research General Meeting, April 10-20, 2005, Anaheim, California, and The 7th Annual Symposium on Anti-Angiogenic Agents, February 10-13, 2005, San Diego, California; [Requirement for The Receptor Tyrosine 10 Kinase Axl in Angiogenesis and Tumor Growth, Holland, S.J, Powell, M.J., Franci, C„ Chan, E., Friera, A.M., Afchison, R., Xu, W., McLaughlin, J., Swift,S.E., Pali, E., Yam, G.f Wong, S., Xu, X., Hu, Y., Lasaga, J., Shen, M., Yu, S„ Daniel, R„ Hitoshi, Y., Bogenberger, J,, Nor, J.E., Payan, D.G and Lorens, J.B), were substantiated by an in vivo study which demonstrated that stable, shRNAi-mediated Axl knockdown impaired 15 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, Paii 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 20 Res. (2005) Vol 65 pp 9294-303. These observations are also disclosed in U.S.
Published Patent Application 2005/0118604 and European Patent Application 1 563 094, the disclosures of which are incorporated in full by reference. Axl signaling, therefore, impacts multiple functions required for neovascularization in vitro, and regulates angiogenesis in vivo. Regulation of these pro-angiogenic processes required the 25 catalytic activity of Axl, Thus, Axl-mediated angiogenic stimulation would be amenable to modulation by a small molecule Inhibitor of Axl catalytic activity.
Accordingly, the compounds of the invention are small molecule inhibitors of Axl catalytic activity, and are therefore useful in treating diseases and conditions which are associated with Axl catalytic activity Including those diseases and conditions which are 30 characterized by angiogenesis and/or cell proliferation. In particular, the compounds of the invention and pharmaceutical compositions of the invention are useful in treating diseases and conditions which are alleviated by the modulation of Axl activity. For purposes of this invention, diseases and condtions which are alleviated by the "modulation of Axl activity" includes diseases and conditions which are alleviated by a
decrease in Axt activity arid diseases and conditions which are alleviated by an increase in Axl activity. Preferably such diseases and conditions are alleviated by a decrease in Axl activity. Diseases and conditions which are alleviated by the modulation of Axl activity include, but are not limited to, solid tumors, including, but not limited to, breast, 5 renal, endometrial, ovarian, thyroid, and non-small cell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma; liquid tumors, including but not limited to, leukemias (particularly myeloid leukemias) and lymphomas; endometriosis, vascular disease (injury (including but not limited to restenosis, atherosclerosis and thrombosis), psoriasis; visual impairment due to macular 10 degeneration; diabetic retinopathy and retinopathy of prematurity; kidney disease
(including but not limited to glomerulonephritis, diabetic nephropathy and renal transplant rejection), rheumatoid arthritis; osteoarthritis, osteoporosis and cataracts,
In addition to the foregoing, the compounds of the Invention are useful in treating diseases and conditions which are affected by the following biological processes: 15 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 homeostatasis as manifested in osteoporosis or osteoarthritis; viral infection as manifested, for example, in ebola virus 20 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 potentiating the immune response in immuno-compromised patients
The following animal models provide guidance to one of ordinary skill in the art in 25 testing the compounds of the invention for their use in treating the disease or condition indicated,
The compounds of the invention may be tested for their use in treating feukemias and lymphomas by testing the compounds in the xenograft in SCID mouse model using human Axl-expresing cancer cell lines including, but not limited to, HeLa, MDA-MB-231, 30 SK-OV-3, QVCAR-8, DU145, H1299, ACHN, A498 and Caki-1.
The compounds of the invention may be tested for their use in treating leukemias in the xenograft in SCID or nu/nu mouse model using human Axl-expressing AML and CML leukemia cell fines,
The compounds of the invention may be tested for their use in treating 35 endometriosis by using the syngenic mouse mode! of endometriosis (see Somlgliana, E,
eta/., "Endomelrial 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, pp. 2844-50). The compounds may also be tested for their use in treating endometriosis by using the rat model of endometriosis (see Lebovlc, Dr|. ef at., "Peroxisome proliferator-activated 5 receptor-gamma induces regression of endometrial explants in a rat model of endometriosis", Fertil. Stent. (2004), 02 Suppl 3, pp, 1Q0B-13).
The compounds of the invention may be tested for their use in treating restenosis by using the balloon-injured rate carotid artery model (see Kim, D.W, et ai, "Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury 10 model", Circulation (2004), Vol. 109, No. 12, pp. 1553-63, Epub 2004 Mar fl).
The compounds of the invention may also be tested for their use in treating restenosis by using the percutaneous transluminal coronary angioplasty in apoE deficient mouse model (see von derThusen, J.H. eta/,, "Adenoviral transfer of endothelial nitric oxide synthase attenuates lesion formation in a novel murine model of 15 postangioplasty restenosis", Arterioscler. Thnjmb. Vase. Biol. (2004), Vol, 24, No, 2, pp, 357-62).
The compounds of the invention may be tested for their use in treating atherosclerosis/thrombosis in the ApoE deficient mouse model (see Nakashima, Y. etal., "ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the 20 arterial tree1', Arterioscler. Thromb. (1994), Vol. 14, No, 1, pp. 133-40).
The compounds of the invention may also be tested for their use in treating thrombosis using the collagen-epinophrin-induced pulmonary thromboembolism model and the stasis induced venous thrombosis model (see Angelillo-Scherrer A. e( al.: "Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for 25 antithrombotic therapy", J Clin Invest. (2005) Vol 115 pp237-46).
The compounds of the invention may be tested for their use in treating psoriasis by using the SCID mouse model or the human skin model of psoriasis (see Nickoloff, B.J. ctai., ' Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model", Am. J. Pathol. (1995), Vol, 146, No, 3, pp. 30 580-8).
The compounds of the invention may be tested for their use in treating age- related macular degeneration or diabetic retinopathy by using the rat corneal angiogenesis model (see Sarayba MA, Li L, TungsiripatT, Liu NH, Sweet PM, Patel AJ, Osann KE, Chittiboyina A, Benson SO, Pershadslngh HA, Chuck RS, Inhibition of 35 corneal neovascularization by a peroxisome proliferator-activated receptor-gamma
ligand. Exp Eye Res, 2005 Mar;80(3):435-42) or the laser-induced mouse choroidal neovasculation mods! (see Bora, P.S., ef a(., "Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration", Proc. Natl, Acad. Set. U. S, A. (2003), Vol, 100, No, 5, pp. 2679-84, Epub 5 2003 Feb 14}
The compounds of (he invention may be tested tor their use in treating retinopathy of prematurity in the mouse retinopathy of prematurity model (see Smith, L.E. etat., "Oxygen-induced retinopathy in the mouse", Invest. Ophthalmol. Vis. Sci. (1994), Vol. 35, No, 1, pp 1QT-11). 10 The compounds of the invention may be tested for their use in treating
glomerulonephritis or diabetic nephropathy in the rat anti-Thy 1.1 -induced experimental mesengial proiiterative glomerulonephritis model (see Smith, L.E etat. cited above). The compounds of the invention may be tested for their use in treating renal tranplant rejection by using a rat model of chronic renal transplant rejection (see Yin, J.L 15 e£ at., "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).
The compounds of the invention may be tested for their use in treating rheumatoid arthritis by using the CAIAmcuse model (see Phadke, K, eta!., "Evaluation of the effects of various anti-arthritic drugs on type II collagen-Induced mouse arthritis 20 model", !mmunophermacobgy (1985),'Vol. 10, No. 1, pp, 51-60).
The compounds of the invention may be tested for their use in treating osteoarthritis by using the STR/ORT mouse mode! (see Brewster, M, et a!., "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. 25 1639-44).
The compounds of the invention may be tested for their use in treating osteoporosis by using the ovariectomized rat model (see Wronski, T.J. eist., "Endocrine and pharmacological suppressors of bore turnover protect against osteopenia in ovariectomized rats", Endocrinology (1989), Vol. 125, no. 2, pp 810-6) or the 30 ovariectomized mouse model (see Alexander, J.M. eta!., "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. ef sl,: "Equol, a metabolite of daidzern, inhibits bone loss in Gvarisctoniized mice", J Nutr (2004), Vol. 134, no. 10, pp 2623-7).
The compounds of the invention may be tested for their use in treating cataracts 35 by using the HsO;-induced model (see KacJoya, K. et a/., "Role of calpain in hydrogen
peroxide induced cataract", Curr. Eye Res. (1993), Vol, 12, No, 4, pp. 341-6} or the Emory mouse model (see Sheets, N.L. et al., "Cataract- and lens-specific upnegulation of ARK receptor tyrosine kinase in Emory mouse cataract", invest. Ophthalmol. Vis. Sci. (2002), Vol. 43, No. 6, pp. 1670-5).
5
PHARMACEUTICAL COMPOSITIONS OF THE INVENTION AND ADMINISTRATION
Administration of the compounds of the invention, or their pharmaceuticaily acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar 10 utilities. The pharmaceutical compositions of the invention can be prepared by
combining a compound of the invention with an appropriate pharmaceuticaily acceptable earner, diluentorexciplent, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical 15 routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal, Tha term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques, Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients 20 contained therein to bo bioavailable upon administration of the composition to a patient, Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units, Actual methods of preparing such dosage forms are known, or will be apparent, to 25 those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000}. The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceuticaily acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this 30 invention,
A pharmaceutical composition of the invention may be in the form of a solid or liquid, In one aspect, the carriers) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral oil, injectable liquid or an aerosol, which is useful in, for
example, inhalatory administration.
When intended tor oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
5 As a solid composition for oral administration, the pharmaceutical composition
may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like 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 carboxyrnethylcellulose, ethyl cellulose, microcrystailine cellulose, gum 10 tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primage I, corn starch and the like; lubricants such as magnesium stearate or Sterotex, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent- 15 When the pharmaceutical composition is in the form of a capsule, for example, a
gelatin capsule, it may contain, in addition to materials of tha above type, a liquid carrier such as polyethylene glycol or oil.
The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration 2D or for delivery by injection, as two examples, When Intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer, In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent 25 maybe included.
The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's soluLion, isotonic sodium chloride, fixed oils such as 30 synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents 3uch as ethylenediaminetetraaoetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as 35 sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic, Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.
A liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the 5 invention such that a suitable dosage will be obtained, Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0,1 and about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 75% of the compound of the invention. Preferred pharmaceutical 1D compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of the compound prior to dilution of the invention,
The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, 15 ointment or gel base. The base, for example, may comprise one or more of the
following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration, If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. 20 Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w/v (weight per unit volume).
The pharmaceutical composition of the invention may bo intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an 25 oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
The pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active 3Q ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.
The pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the 35 delivery of the compound. Suitable agents that may act in this capacity include a
monoclonal or polyclonal antibody, a protein or a liposome.
The pharmaceutical composition of the invention may consist of dosage units that can he administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized 5 packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredients). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One of ordinary skill 10 in the art, without undue experimentation may determine preferred aerosols.
The pharmaceutical compositions of the invention may be prepared by methodology well known in the pharmaceutical art, For example, a pharmaceutical composition intended to be administered by Injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A 15 surfactant may be added to facilitate the formation of a homogeneous solution or
suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
The compounds of the invention, or their pharmaceutical^ acceptable salts, are 20 administered in a therapeutically effective amount, whigh will vary depending upon a
variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject 25 undergoing therapy, Generally, a therapeutically effective daily dose is (for a 70 kg mammal) from about 0,001 mg/kg (j.e., 0,07 mg)to about 100 mg/kg [i.e., 7.0 gm); preferaby a therapeutically effective dose is (for a 70 kg mammal) from about 0-01 mg/kg (/.e.. 0.7 mg) to about 50 mg/kg {Lo., 3.5 gm); more preferably a therapeutically effective dose is (for a 70 kg mammal) from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg 30 1.75 gm).
Compounds of the invention, or pharmaceutical^ acceptable salts thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents, Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one 35 or more additional active agents, as well as administration of the compound of the
invention and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where 5 separate dosage formulations are used, the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
PREPARATION OF THE COMPOUNDS OF THE INVENTION
10 The following Reaction Scheme illustrates methods to make compounds of this
invention, i.e., compounds of formula (I):
N-l-N
(I)
where R', R2, R3, and R5 are described above in the Summary of the Invention for compounds of formula (I), as isolated stereoisomers or mixtures thereof, or as 15 pharmaceutical^ acceptable salts thereof. In particular, the following Reaction Scheme illustrates methods to make compounds of formula (la):
/
N-—N
where R1, Rz, R3, R4 and R5 are as described above in the Summary of the Invention for compounds of formula (I), as isolated stereoisomers or mixtures thereof, or as 20 pharmaceutical^ acceptable salts thereof, and methods to make compounds of formula
(lb);
rV'S (ib)
where R1, R2, R3, R* and Rs are as described above in the Summary of the Invention for compounds of formula (I), as isolated stereoisomers or mixtures thereof, or as pharmaceutical^ acceptable salts thereof. It is understood that in the following Reaction 5 Schemes, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions resull in stable compounds.
It will also be appreciated by those skilled in the art that in the processes described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, 10 mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, f-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include benzyl, f-butoxycarbcnyl, benzyloxycarbonyl, and the lika. Suitable protecting groups for mercapto include -C{0)-R,r (where R" is alkyl, aryl or 15 aryfalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acids include alkyl, aryl or arylalkyl esters.
Protecting groups may be added or removed in accordance with standard techniques, which are known to one of ordinary skill in the art and as described herein.
The use of protecting groups is described in detail in Greene. T.W, and P.G.M. 20 Wuts, Greece's Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
It will also be appreciated by those skilled in the art, although such protected derivatives oF compounds of this invenLicn may noL possess pharmacological activity as 25 such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs oi compounds oT this invention are included within the scope of the invention.
It is understood that one of ordinary skill in the art would be able to make the 30 compounds oT ihe invention by methods simliar to the methods described herein or by methods known to one of ordinary skill in the art, It is also understood that one of
ordinary skill in the art would be able to make in a similar manner as described below other compounds of formula (I) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, 5 Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TGI, 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 this invention, 1H NMR spectra were recorded in CDC la, DMSOh^, CD^OD, Acetone-ck with trimethylsilane (TMS) as internal 10 reference using Gemini 300 MHz instrument, Reagents and solvents were purchased from commercial sources and used without further purification. Flash column chromatography was conducted using silica gel (230-400 mesh) under a positive pressure of nitrogen, LCMS spectra for purity and mass were recorded using Waters LCMS instruments, Deionlzed water was used to dilute the reactions and wash the 15 products, Brine used was prepared by dissolving sodium chloride into deionized water to saturation point.
Compounds of formula (la), as set forth 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, are generally prepared as 20 illustrated below in Reaction Scheme 1 where R1, R2 and R* are as defined above in the Summary of the Invention for compounds of formula (I):
WCN n-N'R
X R'-HHNH£' Rl 1 X
R'"N OPh D M N NH2
Pa,
REACTION SCHEME 1
Jj R^N(R1)H
PhO QPh (B)
(A)
Compounds of formula (A), formula (B) and formula (D) are commercially 25 available or can be prepared by methods known to one skilled in the art or by methods disclosed herein.
in general, compounds of formula (la) are prepared, as set forth by Reaction Scheme 1, by first IreaLing a compound of formula (A) (1.1 equiv) with an equivalent amount of an aniline of formula (B) in an polar solvent, including, but not limited to, 30 isopropyl alcohol, at ambient temperatures overnight. The diarylisourea product of formula (C) generally precipitates and isolation can be accomplished via filtration,
washing with an appropriate solvent, and drying. Hydrazine hydrate of formula (D) (2 equivalents) is added to a slurry of the compound of formula (C) in an alcohol or other appropriate solvent. Generally, the ring formation reaction occurs at ambient temperature and the product triazole of formula (la) can be isolated by standard Isolation techniques. Compounds of formula (la) can be subsequently treated with an appropriately substituted alkylating or acylating agent under standard conditions to form compounds of formula (la) where R4 and R5 are as described above in the Summary of the Invention for compounds of formula (I),
10
Compounds of formula (lb) can be prepared using the synthetic route outlined in Reaction Scheme 1 in varying amounts depending on the steric and electronic nature of R1, R' and Rs as well as the particular reaction conditions employed. In some instances, compounds of formula (lb) are isolated as minor isomers along with compounds of formula (la) as major isomers, e.g.. during column chromatography as described herein.
Compounds of formula (C-1) are compounds of formula (C), as set forth above in Reaction Scheme 1, where R1 is hydrogen and Rz is 7-(pyrrolidin-1-yl)-t>r7r8r9- tetrahydro-5H-benzo[7]annulene-2-yl, that is, where R2 has the following structure:
Compounds of formula (C-1) can be prepared according to the method described below in relation to Reaction Scheme 2:
REACTION SCHEME 2
O2N,
(Ca)
0
arcc
GH3N03 Yield: 40% from
SJ'J IN
ketone
(Cb2)
o
MH
r^ Ha, '0% Pd/C H^v'^vX"^,
N
NaBH{OAcfe, AcOH ^ Me0H
CH2C1CH3CI
(Cc) (Ba)
PhcAoph
(A) PhON..N, ^
'PrOH, it NC'N '
(C-1)
Compounds of formula (Ca) and formula (A) are commercially available or can be prepared according to methods described herein or known to one skilled in the art.
5 Compounds of formula (Ba) are compounds of formula (B), as set forth above in Reaction Scheme 1,
In general, compounds of formula (C-1) are prepared, for example, as seL forth above in Reaction Scheme 2, by nitration of the ben£o[7]annulene of formula (Ca), followed by isolation of the ketone of formula (Cb1), for example, by crystallization. 10 Reductive amination of the keto group in the ketone of formula (Cb1) yields the
pyrrolidine-substituted compound of formula (Cc), Reduction of the nitro group of the pyrrolidine-substituted compound of formula (Cc), for example, by catalytic hydrogenation, gives the aniline of formula (Ba). Reaction of the aniline of formula (Ba) with, for example, diphenyl cyanocarbonimidate of formula (A), yields the compound of 15 formula (C-1).
One aspect of the invention is a process for preparing an aryl-fused cycloheptanone or a heteroaryl-fused cycloheptanone of formula (i):
R1£
(i)
where is an aryl ring or a hetenoaryi ring fused to the ring with the R
substituents and each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl. and optionally 5 substituted heteroarylalkyl. These compounds are useful as intermediates in the
preparation of the compounds of the invention, and can be prepared as described below
■rri
in REACTION SCHEME 2 A wherein ' - - -' i s a n a ryI ri ng or a heteroa ryl ri ng fused to the ring with the R12 substituents, each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, grid 10 optionally substituted heteroarylalkyl, each R13 is independently selected from the group consisting of optionally substituted alkyi, optionally substituted arylalkyl. and optionally substituted heteroarylalkyl, and each LG is independently a suitable leaving group;
REACTION SCHEME 2A
embodiments, the intermediate, for example, &,9-dihydro-5H-benzo[7]annulen-7(6H)- one, is subjected to an acid media prior to exposure to the basic hydrolytic media, in some embodiments the intermediate, for example, 8,9-dihydro-5H-benzo[7]annulen- 7(6H)-one, is subjected to an acid media and isolated prior to exposure to the basic 5 hydrolytic media.
in some embodiments, is a phenyl ring, R1S is lower alkyl and R12 is
hydrogen. Exemplary protic solvents include, but are limited to, alcohols, preferably alkanols, o.g., methanol, ethanol and the like, Exemplary aprotic solvents include, but are not limited to, ethers, e.g. THF, crown ethers and the like. In some embodiments, 1D the aprotic and protic solvents are in about a 1:1 ratio by volume. 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 media include inorganic and organic acids, typically diluted with water. Such inorganic and organic acids are described above in the Definitions 15 section, under "pharmaceuticaily acceptable acid addition salt" and "pharmaceulically acceptable base addition salt", Exemplary basic hydrolytic media include, but are not limited to, alcoholic solutions of metal hydroxides or metal alkoxides, In some embodiments, the basic hydrolytic media includes an alcoholic solution of a metal hydroxide.
20 Preferably the combination of a reactant of formula (iij with a reactsnt of formula
(iii) in the presence of a protic solvent, an aprotic solvent, and a base process described above is performed within a temperature range of between about -10 aC and about 100 °C, more preferably within a temperature range of between about 0 "C and about 50 "C, even more preferably, within a temperature range of between about 0 °C and about 25 30 °C.
Preferably, exposure of the intermediate of the first step of the process to basic hydrolytic media followed by an acid to form compounds of formula (i) is performed within a Lemperature range of between about 40 aC and about 150 °C, more preferably within a temperature range of between about 60 °C and about 100 °C, even more 30 preferably within a temperature range of between about 60 °C and about 100 °C,
Accordingly, an exemplary process for making the compound of formula (Ca), i.e., 9,9-dihydro-5H-benzo[7]annulem7(6H)-one, as described above in Reaction Scheme 2. is described below in relation to REACTION SCHEME 2B.
REACTION SCHEME 2B
Br MeOH-THF
(■:1)
MeONa
o 0 o
U O O
2 M KOH
EtOH
53%
Dimethyl 3-oxopentanedioate and 1 r2-bis(2-bromomethyf)benzene are commercially available, or can be prepared according to methods disclosed herein or 5 methods known to one skilled in the art. The ester groups need not be methyl esters and the bromo groups need not be bromo groups in that any suitable leaving group will suffice, Also, as described above, the 3-oxopentanedioate may be substituted at the 2- and 4-positions as long as as one proton on each of the 2- and 4-positions exists given that at least one proton is needed for the deprotonation and subsequent C-C bond 10 formation with the carbon bearing the leaving group.
Accordingly, compounds of formula (Ca)are prepared, as set forth above in REACTION SCHEME 2B, by first combining a pentane-3-dioate, e.g. dimethyl 3- oxopentanedioate shown, with a 1,2-bismethyl aromatic having a suitable leaving group on each methyl group, e.g.. 1.2-bis(bnomomethyl)benzene, in a mixed protic/aprotic 15 solvent medium, e.g., THF-MeOH, and a metal alkoxide, e.g., sodium methoxide. The metal alkoxide can be added as such or made in situ via careful addition (e.3., at low temperature) of the appropriate metal to at least the protrc solvent, preferably prior lo combination with the remaining reactants, The intermediate benzo[7]annulene product so formed can be optionally isolated and may contain one or two oarboxy ester groups 20 depending on the reaction conditions, e.g., methyl 7-oxo-e,7,8,9-tetrahydro-5H-
benzo[7]annulene-6,8-dicarboxylate, as shown above. The intermediate, dimethyl 7- oxo-6,7J8lg-tstrahydro-5H-benzo[7]annulene-6,8-dicarbDxylatel is subjected to basic hydrolysis (saponfication) conditions followed by acidification to give compounds of formula (Ca).
25 All compounds of the invention which exist in free base or acid form can be
converted to their pharmaceutical^ acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one of ordinary skill in the art.
Salts of the compounds of the invention can be converted to their free base or acid form by standard techniques known to one skilled in the art.
The following specific Synthetic Examples are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention. The number following each compound below refers to its number in Tables 1- 7, as discussed in more detail below.
SYNTHETIC EXAMPLE 1 Synthesis of 1-{5,6-Dihydrobenzo[/r]quiinazolin-£'yl)-A^-[4-(4-methylpiperazin-1 - yl)phenyl)-1 H-1,2,-4-triazole-3,5-d iamine
V)
N-N
A, Synthesis of 5.6-Dihvdrobonzo[/Tlauinazofin-2-amine
10
a-Tetralone (5.00 g, 34.2 mmol) was heated with t-butoxy b i s(d i m ethy lam ino)m ethane (5.96 g, 34.2 mMol) at 90 °C overnight. The solvent was 15 removed under vacuum to give a brown oil. The oil was dissolved in anhydrous ethanol (30 mL) and treated with guanidine hydrochloride (6.53 g, 68.4 mmol) and sodium metal (1.64 g, 71.3 mmol). After the sodium dissolved, the mixture was heated under reflux for 46 h. The mixture was cooled to ambient temperature and guanidine hydrochloride (1,00 g) and sodium metal (0.4 g) were added. Heating was then continued for 24 h. The 20 solvent was removed under vacuum. The residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was crystallized from ethanol to give 5,6- dihydrobenzo[/i]quinazolin-2-amine as brown needles, 3.07 g; 1H NMR (DMSO-cfe, 300 MHz) 8.08 (m, 2H), 7.2^7.40 (m, 3H), 6,40 (s, 1H), 2.81 (m, 2H), 2.68 (m, 2H) ppm; 13C- 25 NMR (DMSO-cfe, 75 MHz ) 163.60, 159.09, 157.54, 140.14, 133.22, 131.02, 128.30,
0
1
N NH
127.37, 125.16, 117.15,28.46,23.30; MS (ES) 193 (M+H). B. Synthesis of 5.6-Dihydrobenzio|ft1quinazolin-2{3tf)-one
5,6-Dihydrobenzo[h]quinazolin-2-amine (3,07 g) was heated under reflux with 5 120 ml_ of 50% aqueous hydrochloric acid. The solvent was removed under vacuum to give 5,6-dihydrobenzo[ft]quinazolin-2(3H)one as a tan solid, 2.97 g; 1H NMR (DMSO-cfo, 300 MHz} 8.16 (d, 1H), 8,08 (s, 1H), 7.50 {t, 1H), 7.35 (m, 2H), 2.8S (m, 2H), 2.70 (m, 2H) ppm; ':"C NMR (DMSO-d0, 75 MHz } 164.86, 155.14, 143,28, 142.07, 133.49, 130.30, 129.23, 127.73, 127.01, 112,91, 28.26, 23.37; MS (ES) 199 (M+H),
10 C. Synthesis of 2-Chloro-5,6-dihydmbenza[/ilquinazpline
CI
5,6-Dihydrobenzo[/i]quinazolin-2(3tf)-one [2.97 g) was heated at 100 °C in phosphorus (III) oxychloride (70 mL)for2 h. The solvent was removed under vacuum and the residue was treated with ice, followed by 1 M aqueous potassium carbonate T5 solution. The aqueous solution was extracted with a mixture of ether and ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-chloro- 5,6-dihydrobenzo[fc]quinazoline as a yellow solid: ^H NMR (CDCI^MeOD4, 300 MHz) 8.86 (s, 1H), 8.16 (m. 1H), 7.25-7.35 (m, 2H), 7.15 (m, 1H), 2.85 (m, 4H) ppm; 13C NMR (CDCfe/MeCD*, 75 MHz ) 162.83, 159.45, 157,40, 139.60, 132.35, 130,99, 128.38, 20 1 27.61, 127,20, 126.14,27,39, 24,11; MS (ES) 217/219 (M+H).
D. Synthesis of 2-Hvdnazinvl-5.6-dihvdrobenzortt1quinazoline
Crude 2-chloro-5,6-dihydrobenzo[fr]quinazoline was heated at 120 PC in a mixture of anhydrous pyridine (20 mL) and anhydrous hydrazine (7 mL) for 4 h. The solvent was 5 removed under vacuum and the residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-hydraziny 1-5,6- dihydrobenzo[fr]quinazoIine as a white solid, 2,16 g. 1H NMR (CDCIS, 300 MHz) 8,27 (d, 1H)r 8.20 (s, 1H), 7.35 (m, 2H), 7.21 (d, 1H), 6.42 (sr 1H), 4.00 (br s, 2H), 2.91 (m, 2H), 10 2.80 (m, 2H) ppm; 1JC NMR (CDCU, 75 MHz ) 164.29, 160.00, 156.72, 139.87, 132.83, 131.02, 128,25, 127.25, 125,47, 119.03, 28.54, 24.24; MS (ES) 213 (M+H).
E. Synthesis of 1"f5,6-Dihvdrob&nzol^1quinai:olin-2-v1VJV3"(4-f4-mettivlpiperazin-1- y I )p he nyl V1H-1.2,4-f riazole-3,5-dia m ine
2"Hydrazinyl-5,6-dihydrobenz:o[/j]quinazoline (40 mg, 0.19 mmol) and (Z)-phenyl 15 JV-cya no-N(4-(4-m ethyl pi perazin -1 -yl)phenyl) carbarn i mid ate (67 mg. 0.20 mMol) were suspended in isopropanol and subjected to microwave irradiation (150 °C, 20 min). A precipitate formed in the microwave vial. After further cooling at -20 °C, the solid was filtered off, washed with cold isopropanol and dried under vacuum to give 1-(5,6- dihydrobenzo [fr]q uinazolin-2-yl)-A/3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazDle- 20 3,5-d iamine, compound #92, 32 mg; 'H NMR (DMSO-ck 300 MHz) 8.76 (s, 1H), 8.65 (s, 1H), 8.16 (d, 1H), 7.65 (s, 2H), 7.46-7.53 (m. 4H), 7.37 (m, 1H), 6.84 (d, ZH). 2.90-3.05 (m, 8H), 2,48 (m, 4H), 2.22 (s. 3H) ppm; MS (ES) 454.17 (M+H).
SYNTHETIC EXAMPLE 2 Synthesis of 1 -(5,6-Dihydrobenzo[fr]cinnolin-3-yl)-N3-^3-fluoro-4'(4-{pyrroliclin'1 yi)piperidin-i -yi)phenyi)-1 H-1,2,4-triazole-3,5-diamine
ON
5 A. Synthesis of 5.6-Pihvdrobenzol/iltinnolin-3(2H)-one
O
a-Tetralone (6.00 g, 40 mmol) and glyoxyiic acid monohydrate (4.00 g, 44 mmol) were cooled on en ice-water bath. A solution of sodium hydroxide [4.92 g, 123 mmol) in water [100 mL) was added. The Ice bath was then removed and the reaction mixture 10 stirred for 0.5 h. The mixture was extracted with diethyl elher (discarded). The aqueous layer was then cooled on ice and acidified with concentrated hydrochloric acid. The white solid which precipitated was filtered off, washed well with water and air dried. The solid was then heated under reflux with hydrazine m on oh yd rate (20 mL) for 0.5 h. After cooling, the precipitated solid was filtered off, washed with ethanol and dried under 15 vacuum to give 5,6-dihydrobenzo[ftIcinnolin-3(2H>one as a pale yellow solid, 4.5 g; 1H NMR (DMSO-d6, 300 MHz) 12,93 (s, 1H), 7.86 (m, 1H), 7.29 [m, 3H), 6.75 (s, 1H), 2.62 (m, 4H) ppm;1JC NMR (DMSO-cfe, 75 MHz) 161.30, 144.74, 141.64, 136,24, 131,00, 129,83, 128,96, 127,77, 126,01, 124,01, 28,48, 27.48; MS (ES) 199 (M+H). This procedure is similar to the procedure described in S, Villa ef. a/,, J. Heterocyclic Chem., 20 36, 485 (1999).
B, Synthesis of 3-Chloro-5,6"dihydrobenzD[^lc|nn_olin_e
5,6-Dihydrobenzo[fr]cinnolin-3(2H)-one (4.5 g) was heated at 100 5C with phosphorus (III) Oxychloride (SO mL) for 6.5 h. The solvent was removed under vacuum and the residue was treated with ice water. The resulting solid was filtered off, washed well with water and air dried to give 3-chloro-5,6-dihydrobenzo//?]cinnoline; 'H NMR 5 (DMSO-tfa 300 MHz) 8.32 (m, 1H), 7,36 (s, 1H), 7,32 (m, 2H), 7.19 (dr 1 H)r 2.91 (s, 4H) ppm; MS (ES) 217/219 [M+H).
C. Synthesis of 3-Hydrazinyl-5,6-dihydrobenzo[ft]cjnnoline
3-Chloro-5,6-dihydTobenzo[fr]cinnoline was heated at 100 DC in a mixture of 10 anhydrous pyridine (30 ML) and anhydrous hydrazine (5 mL) For 3.25 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with diethyl ether and filtered to give 3-hydrazinyl-5,&-dihydrobenzo[ft]cinnoline as a beige solid; 15 NMR (DMSO-cfe, 300 MHz) B.17 (d, 1 H)r 7,91 (br s, 1H), 7.2S (m, 3H). 6.37 (a, 1H), 4.34 (brs, 2H), 2,92 (m, 4H)ppm;l3C NMR (DMSO-cfe, 75 MHz) 162.49, 147.92, 137.95, 137.39, 132.97, 123.87, 128.75, 127.56, 123.59, 110.55, 28.01,27.66; MS(ES)213 (M+H),
P. Synthesis of 1-f5.6-DihvdrQbenzo[^lcinnolin-3-yl)-A/3-(3-fluoro-4-(4-(pyrro1idin-1- 20 vhpiperid i n-1 -y I )ph en vf V1 ^ 1.2,4-triazo I s-3,5-d ia mi no
3-Hydraziny|-5,6-dihydrobenzo[/j]cinnoline (51 mg, 0.24 mMol) and (Z)-phenyl W- cyano-W-(3-fluoro^l-(4^(pyrrolidin-1-yl)piperidin-1-yf)phenyl)carbamimidate(93mg,0,24 mMol) were suspended in isopropanol (3 mL) and subjected LO microwave irradiation (150°C, 20 min). The crude product was purified by radial chromatography on silica gel, 25 eluting with 95% dichloromethane and 5% 2M ammonia in methanol to give 1 -(5,6-
di hydro be n^o[/i]cinnolin-3-yl)-/VJ-(3-ruoro-4-(4-(pyirolidin-1 -yl)piperidin-1 -yl)phenyl)-1 H- 1,2p4-tnazole-3,5-diamine, compound #170, 1H NMR (CDCl3/MeOD^, 300 MHz) 10.84 (6,1H), 8.43 (d, 1H), 7.75 (s, 1H), 7.61 (d, 1H), 7.41 (m, 2H), 7.26 (m, 2H), 6.93 (t, 1H), 3.42 (m,2H), 3.00 (m, 3H), 2,00-2.75 (m, 6H), 2.15 (m, 1H), 1.98 (m, 2H), 1,74-1.95 (m, 30 7H) ppm; MS (ES) 526,43 (M+H).
SYNTHETIC EXAMPLE 3 Synthesis of AfJ-(4-(^(( 15,2S,4R)-bicyclo[2.2.1 jheptan-2-yl)piperazin-1 -yl) phenyl ch loro-7-m et hylth ie no [3,2-dJpyrimidi n-4-yl)-1H-1,2, ■4-tri azo I e-3,5-diamine
k" ^n^w™ , u ^XX J
" ^ w A^ r Y
H Oh ^ ^ NaBH(OAc)3 zTj^-N^
then Hj, PA'C H
CH3
NXN "AM CI SCXM
X (IT XI
PH0 0PH JFY NHNH,
fjH rp'
5 A- Synthesis of (+H1S, 4 f?VNo ream phor
To a stirred solution of (+)-enafo-Norborneol (3.4 g; 30.30 mmol; 1,0 equiv) and 3 g of Molucular Sieves (4 A) in 100 mL of anhydrous methylene chloride was added pyridinium chlorochromate (9.6 g; 45.47 mmol; 1.5 equiv) in small portions. The reaction was stirred at 0 cC for 2 hours. Thon other was added and the solution was filtered 10 through a celite pad. The celite was washed with ether (3X). The organic solutions were combined, dried over MgSQ*, filtered and evaporated to give (+H1S, 4R)-norcamphor in quantitative yiold; 1H-NMR (CDCI*, 300 MHz) 2.64 (d, J= 19 6 Hz, 2H), 2.1D-2.05 (m, 2H), 1,88-1.72 (m, 3H), 1.57-1.41 (m, 3H) ppm,
B- 3vnthesisof1-Bicvclor2.2.11hept-2"Vl-4-f4-nitrophenyl)pip9razine
15 1-(4-Nitrophenyl)piperazine (6.28g; 30.3 mmol; 1.0 equiv) was dissolved in 60 mL
of anhydrous dichloroethane, followed by the addition of (-i-)-(l S, 4fl)-norcamphor, glacial acetic acid (3.47 mL; 60.6 mmol; 2.0 equiv) and NaBH{OAc)3(S.C g; 42.42 mmol; 1.4 equiv), The flask was flushed with N£ and allowed to stir at ambient temperature overnight. The reaction mixture was diluted with methylene chloride and washed with 20 saturated NaHCOa. The organic layer was dried over MgSCti and evaporated to give 1-bicyclo[2.2.1]hept-2-yl-4-(4-nitrophenyl)piperazine as a yellow solid (9,0 g; 98% yield);
'H-IMMR (DMSO-tfs, 300 MHz) 8-02 (d, J = 9.3 Hz, 2H), 6.99
C. Synthesis of 1-Brcvclor2.2.1lheat-2"Vl"4"(4-3minophenvl)Diperazlne
5 To a suspension of (3.0 g; 9.95 mmol) in MeOH (100 ml) was added 10% Pd/C.
The reaction was shaken under (40-50 psi) at ambient temperature for 2 hours and then filtered through a celite pad. The celite was washed with MeOH, The filtrate was concentrated in vacuo to give 1-bicyclo[2.2.1]hept-2-yl-4-(4-aminophenyl)plperazine as a tan solid (quantitative yield); 1H-NMR (DMSO-efe, 300 MHz) 6.64 (d, J = 8,7 Hz, 2H), 10 6,45 (d, J - 8.7 Hz, 2H),4.53(br. s, 2HJ, 2.88 (t, J = 4.2 Hz, 4H), 2,39 (t. J = 4.2 Hz, 4H), 2,27-2.13 (m, 3H), 1,75-1,61 (m, 2H), 1,50-1.47 (m, 1H), 1.35-1.12 (m, 4H], 0-87-0.83 (m, 1H) ppm; MS (E5) 272.18 (M+H),
D. Synthesis of AlCyano-W-{4-[4-f bi cyclo 12,2,1 ihept-2-vl M-pi psrazinvll Phenyl }-Q- phenylisourea
15 A mixture of Vbicyclo[2.2l1]h9pt-2-yl-4-(4-aminophenyl)piperazine (2.0 g; 7.4
mmol; 1,0 equiv) and diphenyl cyanocarboirmidate (1.76 g; 7.4 mmol; 1.0 equiv) in 20 mL of isopropanol was stirred at ambient temperature overnight. The solid was filtered, washed with /sopropanol and dried to give /V-cyano-A^4-[4^1-bicyclo[2.2.1]hept-2-yl)-1- piperazinyi]phenyl}-0-phenylisourea as a pale-pink solid (2.84 g, 92% yield), 'H-NMR 20 (DMSO-c^ 300 MHz) 10.56 (br, s, 1H), 7.41 (t, J = 6.0 Hz, 2H), 7.26-7.21 (m, 5H), 6.90 (d, J = 6.9 Hi, 2H), 3.15-3.05 (m, 4H), 2,45-2.34 (m, 4H), 2.29-2.14 (m, 3H), 1.73-1.62 (m, 2H), 1,50-1.40 (m, 1H), 1.36-1.17 (m, 4H), 0.89-0.86 (m, 1H) ppm; MS (ES) 416.55 (M+H), 414,24 (M-H).
E. Synthesis of 2-Chloro-4-hvdrazino-7-methvlthieno[3,2'd1pyrimidine
25 Hydrazine monohydrate (2.21 mL; 45.6 mmol; 2.0 equiv) was added to a
suspentlon of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (5 g; 22.8 mmol; 1.0 equiv) in 40 mL of EtOH. The reaction was stirred at ambient temperature for 2 days. The solid was filtered, washed with H20 and dried to give 2-chloro-4-hydrazino-7- methylthleno[3,2-d]pyrimidine as an off-white solid (4.4 g; 90% yield); MS (ES) 214.97 30 (M+H), 212.99 (M-H).
F. Synthesis of AP-f4-f4-ff1 S.2S,4f?)-bicvclor2.2.1 lheptan^-yllpiperazin-l-
vhphenyn-l-fE-chloro-T-rnethylthienoyS.a-cflpvTirnidin^-vh-IH-l^^triaaole-gs- diamine
A mixture of Ncyano-/V-{4-[4-(bicyclo[2.2.1]hept-2-yl)-1-piperazinyl]phenyl}-0- 5 phenylisourea (50 mg; 0.12 mmol; 1,0 equiv) and 2-chloro-4-hydrazino-7-
methylthierio[3,2-d]pyrimidine (26 mg; 0.12 mmol; 1 equiv) in 0.5 ML of NMR was heated in the microwave apparatus at 180 ^C for & min. Purification by HPLC gave iV;i-(4-(4- ((IS^S^R^-bicydo^^.llheptan^ylJpiperazrn-l-ylJphenylJ-l^-chloro-T- methylthieno[3r2-^pyrimidin-4-yl)-1/-M ,2,4-triazole-3,5-
H)
15 SYNTHETIC EXAMPLE 4
In a similar manner as described above utilizing the appropriately substituted starting materials, the following compounds of the invention were prepared: 1 -phe ny i-N*-{>4—(2-{ pi perid in-1 -y I )ethoxy)phenyl)-1 tf-1,2,4-triazo le-3,5-diamine, compound #1, pale-yellow solid; MS (ES) 379.67 (M+H). 377.&4 (M-H); 20 1 -phenyl-/V';-(4-(2-(piperidin-1 -yl)ethoxy)pheriyl)-1 H-1,2,4-triazo le-3,5-diamine, compound #2, yeffow solid; MS (ES) 379.26 (M+H), 377.25 (M-H); i-(4-isopropylpheny^/V3-[4-(2-(piperidin-1-yl)ethoxy)phenyl)-1W-1,2,4-triazole-3,5-
diamine, compound #3, MS (ES) 421.47 (M+H), 419 46 (M-H); JV3-( 3-ch loro-4-( 2-( py rro I id i n-1 -yl )ethoxy )phenyl)-1 -(pyri d i n-2 -y I)-1H-1,2,4-triazo le-3 r5- 25 diamine, compound #4, white solid; 'H NMR (DMSO-ck, 300 MHz) 9.10 (s, 1H),
6.40 (d, 1H), 8,19 (s, 1 H)r 7,99 (t, 1H), 7.80-7,60 (m, 3H), 7.42 (d, 1H)r 7.20 (t, 1H), 7.03 (d, 1H), 4.00 (t, 2H), 2.02 (t, 2H), 2.61 (broad s, 4H), 1.75 (broad s, 4H) ppm; MS (ES) 402.4S (M+H), 397.92 (M-H); 1-(pyridin-2-yl)-A^-(4"(2-(pyrrDlidin-1-yl)ethoxy}phenyl)-1H-1,2,4-triazole-3,5-diaminer 30 compound #5, white solid; 1H NMR (DMSO-cfe, 300 MHz) 8.80 (s, 1H), 8.40 (d,
1H), 8.20
A^-(4-(2-(pyrrplidin-1-yl)ethoxy)phenyl)-1-(4-[trifluoromethy1)pyrimidin-2'yl)-1H"1,2l4- triazole-3,5-d iamine, compound #7, MS (ES] 435-00 (M+H), 433.15 (M-H);
4-(5-arnino-3-{4-(2-(pyrnolidin-1-yl)ethoxy)phenylamino)-1H-1l2l4-trrazol-1- 5 yl)benzenosulfonamide, compound #S, MS (ES) 443.97 (M+H), 442.13 (M-H);
W3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(qulno!
1-(2-chloropyridin-+-yl)-/Va-(4-(2-(piperidin-1-yl)ethoxy)pheny1)-1H-1f2l4-triazole-3,5-
diamine, compound #10, pale-yellow solid; MS (ES) 414.46 (M+H), 412,44 (M-H); 10 1 -(benzo[c/J1hiazol-2-yf)-W'i-(4-(2-(pyrrolidin-1-yl}etboxy)phenyl)-1 H-l ,2,4-triazole-3,5- diaminer compound #11 r MS (ES) 421.98 (M+H), 420.03 (M-H);
1-(6"Chloropyridazin-3-yl)-r^-(4-(2-(pyrnolidin-1-yl)ethoxy)phenyl)-1H-1,2l4-triazole-3,5- diamine, compound #12, MS (ES) 400.99 (M+H), 399.01 (M-H);
1 -(pyrazin-2-yl)-/V3-(4-(2'{pyrrolidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5-d iamine, 15 compound #13, MS (ES) 367.05 (M+H), 365.17 (M-H);
1-(1-methyl-1 H-be nzo[c(]im id azol-2-yl )-A/3-(4-(2-(pyrTolidi n-1 -yl Jet hoxy) phenyl)-1 H-1,2,4- triazole-3,5-diamine, compound #14, MS (ES) 419-09 (M+H), 417.24 (M-H);
1-(2-morpholiriopyridin-4-yl)-Ws-(4-(2-(piperidin-1 -y I )ethoxy) phenyl)-1 tf-1,2,4-triazole-3,5- diamine, compound #15, pale-yellow solid; MS (ES) 465,29 (M+H)r 463.23 (M-H); 20 1 -[6-c hlo ro py ridin-2-yl)-WJ-( 4-( 2-(pyrro I i d i n-1 -y I )ethoxy) p he ny I )-1 H-1,2,4-triazole-3,5- diamine, compound fi16, MS (ES) 400,02 (M+H), 396.19 (M-H);
1 -(5-chloropyrid in-2-y IJ-A^-f 4-(2-(py rro I i d i n-1 -y I )ethox y) p he ny I)-1 tf-1,2,4-t riazole-3,5- diamine, compound #17, MS (ES) 399.99 (M+H), 397.94 (M-H);
1 -(3-chloropy rid in-2-y l)-WJ-(4- (2-(pyrro I id i n-1 -y I )ot hoxy )p he ny I)-1 tf-1,2,4-triazole-3,5- 25 diamine, compound #18, MS (ES) 400.02 (M+H);
1-(6-chloropyridin-2-yl)-W3-(4-(2-(piperidin-1-yl)ethoxy)phenyi)-1H-1l2l4-triazole-3.5- diamine, compound #19, off-white solid; MS (ES) 414,15 (M+H), 412.00 (M-H);
1-(6-morpholinopyridin-2-yl)-WJ-(4-{2-(pipendin-1-yl)ethoxy}phenyl)-1H-1,2,4-triazole-3,5™ diamine, compound #20, pale-brown solid; MS (ES) 465.50 (M+H); 30 Wi-(4-(2-(2-methylpyrrolidin-1-y|)ethoxy}phenyl)-1-(quinoxalin-2-yl)-1H-1,2,4-triazole-3,5- diamine, compound #21, yeilow solid; MS [ES) 431.25 (M+H), 429.20 (M-H);
1 -(be nzo [tflth i azo I -2-y I 2- methyl pyrrolid i n-1 -yl)ethoxy)pheny I)-1■1,2,4-
triazole-3,5-diamine, compound #22, off-white solid; MS (ES) 436,16 (M+H), 434.13 (M-H);
35 1-(1-methyl-1H-benzo[d]i mid azol-2-y I)-f\fs-(4-(2-(2-m ethyl pyrrol id in-1-y l)ethoxy )ph en y I )-
1H-1,2,4-triazole-3,5-diamine, compound #23, purple solid; MS (ES) 433,56 (M+H), 431.16 (M-H);
H1H-benzo[^imidazol-2-yl)-/V3-[4-(2-(2-methylpyrrolidin-l-yl)ethoxy)phenyl)-lH-l,2,4- triazole-3,5-diamine, compound #24, purple solid; MS (ES) 419.50 (M+H), 417.21 5 (M-H);
1-{phthalazin-1-yl)-A/3-(4-(2-( pyirolid i n-1 -y l)eth oxy )ph en y I)-1H-1,2,4-triazo le-3,5-diam i ne, compound #25, yellow foam; MS (ES) 417.09 (M+H), 414.97 (M-H);
Wa-(4~(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(4-(trifluoromethyl)pyridin-2-yl)-1H-1,2,4-
triazole-3,5-diamine, compound #26, white solid; 'H NMR (DMSO-c/6, 300 MHz) 10 0.63 (d, 1H), 7.76 (d, 2H), 7.50 (rn, 2H), 6.09 (dr 2H), 4.00 (L, 2H), 2.62 (t, 2H),
2.61 (m, 4H), 1.73 (broad sf 4H) ppm; MS (ES) 434.05 (M+H), 431.95 (M-H);
1 -
1 -(2-flu oro ph eny I)-W5^ 4-(2-( pi perid in -1 -y I )ethoxy) p he n y I)-1 ft-1,2,4-triazo le-3,5-diamine, 15 compound #28, off-white solid; MS (ES) 397,38 (M+H), 395,11 (M-H);
^-(4-(2-( p y rro I id i n-1 -y I )ethoxy) p he ny I)-1 -(3-(trif I uo romethyl )py rid in-2-y I)-1H-1,2,4- triazole-3,5-diamine, compound #29, MS (ES)434.04(M+H), 432.05 (M-H);
1 -(6-methoKypyridin-2-yl)-/V;'-(4-(2-(pyrroNdin-1 -yl)othoxy)phenyl)-1 H-1,2,4^triazolo-3,5- diamine, compound #30, MS (ES) 396,09 (M+H), 394.21 (M-H); 20 1 -(1 H-benzo[d]imidazol-2-yl)-/V3-(4-(2-(pyrTiolidin-1 -yljethoxy )phenyl)-1 H-1,2,4-triazo le- 3,5-diamine, compound #31, MS (ES) 405.10 (M+H), 403.05 (M-H);
1-(5-bromopyridin-2-yl)-Af3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1l2l4-triazole-3,5- diamine, compound #32, MS (ES) 445.97 (M+H);
methyl T-(2-(4-(5-amino-1-(qui noxa I in -2-y I 1W-1,2,4-triazo I-3- 25 ylamino)phenoxy)ethyl)pyrrolidine-2-carboxylata, compound #33, off white solid;
]H NMR (CDjOD, 300 MHz) 9.41 (s, 1H), 8.08 (m, 2H), 7.39 (m, 3H), 7.58 (d, 2H), 6.90 (d, 2H), 4.12 (m, 2H), 3,60 (s, 3H), 3,40 (m, 1H), 3.01 (m, 2H), 2,79 (m, 2H), 2.20 (m, 2H), 1.84 (m, 3H) ppm; MS (ES) 475.43 (M+H), 473,16 (M-H);
1 -(2-fluorop he nyl)-//'-(4-(2-( pyrrolid in-1 -y1)ethoxy)phenyl)-1 H-1,2r4-triazole-3,5"diamine, 30 compound #34, pale-brown solid; MS (ES) 383.40 (M+H), 381.12 (M-H);
1 -(6-(methylamino)pyhdin-2-yl)-Af3-(4-(2-(plperldin-1 -yl)ethoxy)phenyl)-l H-\,2,4-triazole- 3,5-diamine, compound #35, pale-yellow solid; MS (ES) 409.48 (M+H), 407,32 (M-H);
1 -(6-(dimethylamino)pyr!dln-2-yl)-yv3-(4-(2-(plperidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4- 35 triazole-3,5-diamine, compound #36, pale-brown solid; MS (ES) 423.41 (M+H);
1 -(2-chloroquinazolin-4-yl)-W'f-(4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5- diamine, compound #37, yellow solid; MS (ES) 451.50 (M+H), 449,38 [M-H);
1- (2-nnorpholinoquiriazoljn-4-yi)-W5-(4-(2-(pyrrolidjn-1-yS)etho?
5 1 -(benzo[^thiazol-2-y1)-W5-(3-chloro-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4- triazole-3,5-diamine, compound #39, MS (ES) 456.06 (M+H), 454.20 (M-H);
w^[3-chloro-4-(2-(pyrrofidiri-i -yi)ethoxy)phenyi)-i-[1 -methyl-1 H-benzo[d]imidazoi-2-yi)- 1 H-1,2.4-triazole-3,5-d iamine, compound #40, MS (ES) 453.14 (M+H), 451.22 (M-H);
10 /V3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1-(quinolin-2-yl)-1H-1,2,4-triazcl0-3l 5-diami ne, compound #41, MS (ES) 410.46 (M+H), 414.41 (M-H);
2- (5-amino-3-(4-(2-[pyiTolidin-1-yl)ethoxy)phenylamino)~1H'1p2r4-triazol-1-yl)-6- methyIpyrimidin-4-01, compound #42, MS (ES) 397.15 [M+H), 395.25 [M-H);
methyl 1-(2-(4-(5-amino-1 -(benzo[rt]thiazol-2-yl)-1H-1,2,4-triazol-3-
15 ylamino)phenoxy)ethyl)pyrrolidine-2-carboxylate, compound #43, off white solid;
MS (ES) 4S0.21 (M+H), 478.21 (M-H);
1 -(2-ch loro-6,7-d i methoxyq u i n aza I in- 4-yl)-WJ-(4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl J-1H- 1r2,4-triazole-3,5-diamine, compound #44. yellow solid; MS (ES) 511.17 (M+H), 509.13 (M-H);
20 1 -(6,7-d im eth oxy q ui nazoli n-4-yl 4-( 2-( py rrolidin-1 -yl )ethoxy )pheny I)-1H-1,2,4-
triazole-3,5-diaminer compound #45, yeilow solid; MS (ES) 477.19 (M+H), 475.26 (M-H);
/V-3-(4-(2-(2,5-dimelhyipyrrolidin-1-yl)ethoxy)phenyl)-1-(qulnoxalin-2-yl)'1H-1,2,4-triazole- 3,5-diamine, compound #46, orange solid; MS (ES) 445.51 [M+H), 443.43 (M-
25 H);
1 -(pyrimidin-2-yl)-WJ-(4-(2-(pyrrolidin-1 -yl)ethoxy) phenyl)-1W-1,2,4-triazole-3,5-d iamine, compound #47, MS (ES) 367.14 (M+H);
1 -(6-chloroquinazolin-4-yl)-W3-(4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl}-1 H-1,2,4-triazole-3,5- diamine, compound #43, yellow solid; MS (ES) 451.14 (M+H), 449,19 (M-H);
3D 1-(2-chlorQ-6r7-dihydno-5H-cyclopenta[{flpyrimidin'4-yl)-/V3-(4'(2-(pyrrolidin-1-
yl)ethoxy)phenyl)-lH-l,2,4-triazole-3,5-diamine, compound #49, yellow solid; MS (ES) 441.11 (M+H), 439.24 (M-H);
1 -(isoquinolin-1 -yl)-W3-(4-(2-( pyrrol id in-1 -yl)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5-d iamine, compound #60, yellow solid; MS (ES) 416.41 (M+H), 414,48 (M-H);
35 W3-(4-(2-(pyrTolidin-1-yl)ethoxy)phenyl)-1-(thieno[2,3-c(]pyrimidin-4-yl)-1H-1r2l4-triazole-
3,5-diamine, compound #51, pale-brown solid; MS (ES) 423,36 (M+H), 421.15 (M-H);
1-(6-phenylthieno[3,2-of]pyrimidin-4-vl)-W;?-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-lH-l,2,4^ triazole-3,5-diamine, compound #52, yellow solid; MS (ES) 499.25 (M+H), 497,14 (M-H);
yvJ-(4-(Z^pyrrolidin-1-yl)ethDxy)phenyl)-1-(2-(trifluoromethyl)c;uinazolin-4-yl)-1H-1,2.4- triazole-3,5-diamine, compound #53, orange solid; MS (ES) 465,32 (M+H), 463.22 (M-H);
W7-(4-(2-(pyrrolidir!-1-y1)ethoxy)phenyl)-1-(thienor3,2-£f]pyrimidin-4-yl)-1H-1,2,4-triazole- 3,5-diamine, compound #54, pale-yellow solid; MS (ES) 423.21 (M+H), 421.20 (M-H);
/V3^ 3-fluoro-4-(2-( pyrrol id in-1 -yl)ethoxy)phenyl)-1-(quinoxalin-2-yl)-1H-1,2,4-triazo le-3,5- diamine, compound #55, yellow solid; MS (ES) 435.60 (M+H), 433-20 (M-H);
1 -(be nzo [cflth iazol-2-y I)- /V^-{3-tl uo ro-4-
iV3-(3-fluoro-4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)-1 -(pyridin-2-yl)-1 N-1,2,
r/,-(3-fluoro-4-(2-{pyrrolidin-1-yl)ethoxy)phenyl)-1-{isoquino![n-1-yl)-1 H-1,2,4-triazo le-3,5- diamine, compound #58, pale-yellow solid: MS (ES) 434,43 (M+H), 432,34 (M-H);
/V3-(3-chloro-4-(2-(pyrroiidin-1-yl)ethoxy)phenyl)-1-(E,7-dimetho>iyquinazolin-4-yl)-1H- 1,2,4-triazole-3,5-diamine, compound #59, pale-yellow solid; MS (ES) 511,17 (M+H), 509.25 (M-H);
1-(2-chloro-7-methylthieno[3i2-rf]pyrimidin-4-yl)"/V;!-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl }- 1W-1,2,4-triazo le-3,5-diamine, compound #60, pale-yellow solid; MS (ES) 471,11 (M+H), 469.19 {M-H);
1-(5,6 J, 8-tetra hyd rabenzo [4r5]th i a no [2,3-^pyrim id in-4-y!)-W3^ 4-(2-( py rrolid in -1-
yl )et hoxy )p he ny I )-1H-1,2,4-triazo le-3,5-diamine, compound #61, pale-yellow solid; MS (ES) 477 46 (M+H), 475,15 (M-H);
A/s-(3-chloro-4-(2-(pyrrolidin-1-yl)athoxy)phenyl)-1-(isoqijinolin-1-yl)-1/-/-1.2r4-triazole-3,5- diamine, compound #62, yellow solid; MS (ES) 450.21 (M+H), 443.02 (M-H);
1-(6-fluoroquinazolin-4'yl)-W3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1l2l4-triazole-3,5- diamine, compound #63, yellow solid; MS (ES) 435.62 (M+H), 433.21 (M-H);
W:-(4-(2-(pymolidin-1-yl )ethoxy)ph en y I)-1 -(thic no [2,3-e]py ri d in-7-y l)-1 H-1,2,4-tri azol e^3,5- diamine, compound #64, pale-brown solid; MS (ES) 422.4B (M+H), 420.01 (M-H);
1 -(2-m ethyIq ui nazo I i n-4-yl )-Af-( 4-( 2-^pynol^
diamine, compound #05, yellow solid; MS (ES) 431,41 (M+H);
1 -(6,7-d ihydro-5H-cyclopenta [4,5]th i e no [2 h3-d]pyri m Id in-4-y l)-^ 4-(2-( py rro I i d in -1 -
yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #66, off-white solid;
5 MS (ES) 463.29 (M+H), 461,20 (M-H);
3-ch loro-4-( 2-( py rrolid i n-1 -yl )ethoxy )phenyl)-1 -(5,6,7,8-
tetra hyd ro be nzo [4,5]th ie no [2,3-d] pyrimidi n-4-yl)-1H-1,2,4-triazo I e-3,5-d ia m i ne, compound #67, pale-yellow solid; MS (ES) 511.20 (M+H), 509.20 (M-H);
Af3-(3-fluoro-4-(2-(pyrriolidin-1 -yl)ethoxy )pheny1)-1 -(5,6f 7,8- 10 tetrahydTObGnzo[4,5]thieno[2,3-^pyrimidin-4-yl)-1H-1,2,4-triazDle-3,5-diamine,
compound #68, yellow solid; MS (ES) 495.26 (M+H), 493.29 (M-H);
1 -(f u no [3,2-c]p yridi n-4-yl )-/Vs-(4-(2-
1-(2-methyl-5!6,7f8-tetrahydrobenzo[4,5]thieno[2r3-(flpyrimidin-4-yl)-A^-(4-(2-(pyrrolidiii- 15 1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #70r yellow solid;
MS (ES) 491.24 (M+H). 469-67 (M-H);
1 -(benzothieno[3,2-cf]pyrimidin-4-yl)-/VJ-(4-(2-(pyrrolidin-1 -yl)ethoxy) phenyl )-1 H-1,2,4- triazole-3,5-diamine, compound #71, orange solid; MS (ES) 473.07 (M+H), 471,44 (M-H);
2D 1-(5,6H3ihydiX)benzo[/]]quinazolin-2-yl)-Ws-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1l2l4- triazole-3,5-d iamine, compound #72, 'H NMR (DMSQ-cfe. 300 MHz) 8.65 (s, 1H), 8.66 (s, 1H), 8.16 (d, 1H), 7.66 (s, 1h), 7,55 (d, 2H), 7.48 (m, 2H), 7.38 (d, 1H), 6,84 (d, 2H), 4.00 (t 2H), 2.95 (m, 4H), 2.80 (t, 2H), 2.50 (m, 6H), 1.69 (m, 2H) ppm; MS (ES) 469.29 (M+H); 25 1 -(7-tert-b utyl-5l6l7,8-tetrahydrobenzo[4,5]thieno[2,3-rf3pyrimidin-4-yl)-A/3-(4-(2-
(py rrolid in-1-y l)eth oxy )ph enyl)-1 H-1,2,4-triaza le-3,5-d iamine, compound #73, off- white solid; MS (ES) 533.42 (M+H), 531.39 (M-H);
1-(5,6,6a,7,8,9,10,1 Oa-octahydrobenzo[/i]qui nazoli n-2-yl)-/Vs-(4-(2-( pyrrol idin-1- yl)ethcxy)phenyl)-1 W-1.2.4-triazoJe-3,5-diamine, compound #74, 'H NMR 30 (DMSO-C/3, 300 MHz) 8,55 (s, 1H), 8.45 (s, 1H), 7.52 (d, 2H), 6.81 (d, 2H), 4.00 (t,
2H), 3.13 (m, 4H), 2.76 (t, 2H), 2,49 (m, 4H), 2.39 (m, 1H), 1.88-1.60 (m, 7H), 1.55-1,50 (m, 6H) ppm; MS (ES) 475 (M+H);
1 -(5,6-dihydrobenzo[fr]cinnolin-3-yl)-/V;,-(4-(2-[pyrTolidiri-1 -yl)ethoxy)phenyl)-1 H-1,2,4- triazole-3,5-d iamine, compound #75, 'H NMR (DMSO-c/6l 300 MHz) 8.98 (s, 1H), 35 8.32 (m, 1H), 7.85 (s, 1H), 7.78 (s, 1H) 7.54 (d, 2H), 7.34-7.40 (m, 3H), 6.87 (d,
2H), 4.07 (t, 2H), 3.08 (m; 2H), 2.95 (m, 2H), 2.75 (m, 2H), 2.49 (m,2H), 1.76 (m, 6H) ppm; MS (ES) 469.30 (M+H);
2-(5-amino-3-(^(2-( pyrrol idiri-i-yi)ethoxy)p he nylami no )-iH-i ,2,4-triazoM -yi)-5,6,7,8- tetrahydroquinazolin-4-ol, compound #76, yellow solid; MS (ES) 437.23 (M+H), 5 435,27 (M-H);
1 -(6,7-dimethoxyisoquinolin-1 -yl)-W3-(4-(2-(pyrnolidin"1 -yl)ethoxy)phenyl)-1 H-1,2,4- triazole-35-diamrne, compound £77, off-white solid; MS (ES) 476.40 (M+H);
5-( 5-a mi no-3-( 4-(2-( py rro I i d i n -1 -y I )ethoxy )p he ny I am ino)-1H-1,2,4-triazo I-1 -yl)-1,6 -
raphthyridin-2( 1 H)-one, compound #78, yellow solid; MS (ES) 433,56 (M+H), 10 431.24 (M-H);
benzyl 3-(5-amino-3-(4-(2-(pyrrolidin-1-y1)ethoxy)phenylamino)-1H-1,2,4-triazol-1-yl)-7,8- dihydropyrido[4,3-c]pyridazine-6(5tf)-carboxylate, compound #79, 'H NMR (CDCIj, 300 MHz) 7,62 (s, 1H), 7,32 (m, 6H), 7.07 (m, 1H)r 6.83 (d, 2H), 5.17 (s, 2H), 4.66 (m, 2H), 4.07 (m, 2H), 3.01 (m. 2H), 3.13 (m, 2H), 2.89 (m, 2H), 2.66 15 (m, 4H), 1.79 (m, 4H) ppm; MS (ES) 556.42 (M+H);
A/3-(4-[2-(pyrrolidin-1-yl)ethDxy)phenyf)-1-(5l6,7,8-tetrahydropyrido[4,3-c]pyridazin-3-yl)- 1 H~ 1,2,4-triazoI e-3 r 5-d ia mi ne. compound #80, 1H NMR (CDCI^/MeOD4, 300 MHz) S.30 (s, 1H), 7.42 (d, 2H)r 6.39 (d, 2H), 4,25 (m, 2H), 3.11-3.16 (mr 12H)r 2.01 (m, 4H) ppm; MS (ES) 422.16 (M+H); 20 A/3-(4-(4-cydohexylpiperazin-1 -y!)phenyl)-1-(isoquinolin-1-yl)-1 tf-1,2,4-triazo le-3,5- diamine, compound #31, yellow solid: MS (ES) 469.56 (M+H);
4-(5-amino-3-(4-(4-cyclohexylpiperazin-1-yl)phenylamino> 1 tf-1,2,4-triazo 1-1 -yl)-6-
methoxyquinazolin-7-ol, compound #82, yellow solid; MS (ES) 516,52 (M+H), 514.33 (M-H);
25 //-(4-(4-cyclohexylpiperazin-1 -yl)phenyl)-1 -(6,7-dimethoxyquinazolin-4-y| y\H-1,2,4-
triazole-3,5-diamine, compound #33, yellow solid; MS (ES) 530.53 (M+H), 520.31 (M-H);
1-(isoquinolin-1-yl)-/V3-(4-(4-methylpiperazin-1-yl)phenyl)-1W-1,2,4-triazole-3,5-diamine, compound #34, yellow solid; MS (ES) 401.38 (M+H); 30 1-(6-chloroquinazolin-4-yl)-WJ-(4-{4-methylpiperazin-1-yl)phenyl)-1H-1 f2,4-triazole-3,5- diamine, compound #85r yellow solid; MS (ES) 436.04 (M+H), 434.20 (M-H);
1-(6-chloroquinazolin-4-yl)-/V;'-(4-(4-methylpiperazin"1-yl)phenyl)-1H-1f2.4-triazole-3,5- diamine, compound #36, yeilow solid; MS (ES) 436.08 (M+H);
A^'-(4-( 4-cy clohoxy I p i po razi n-1 -yl )-3-fl uorop h e n y I)- H i soq u inol i n-1 -yi)-1H-'1,2, ■4-triazo le- 35 3,5-diamine, compound #87, pale-yellow solid; MS (ES) 487.53 (M+H), 485.15
(M-H);
1-(4-(4-(5-amino-1 -(isoquinolin-1 -yl>1 W-1,2,4-triazol-3-ylamino)phenyl)piperazin-1 -
yl)ethanone, compound #88, brown solid; MS (ES) 429.10 (M+H), 426.93 (M-H):
/Vff-(4-(4-(bicyclo[2.2.1 ]heptan-2-yl)piperazin-1 -yl)phenyl)-1 -(isoquinolin-1 -yl)-1 H-1,2,4- 5 triazole-3,5-diamine, compound #89, yellow solid; MS (ES) 481.34 (M+H), 479,06
(M-H);
3-1luoro-4-(4-m ethy Ipiperazin-1 -y I) phe nyl)-1 -(isoq u i nol in-1 -y!)-1H-1,2,4-triazo le-3,5- diamine, compound #90, yellow solid; MS (ES) 419.37 (M+H), 417.20 (M-H);
Af3-( 3-ch lo no-4-(4-cyclohexy I pi pera zin -1 -y I )ph en y I)-1 -(isoq uin olin-1 -y I)-1H-1,2,4-triazole- 10 3,5-diamine, compound #91, pale-brown solid; MS (ES) 503.26 (M+H), 501,58
(M-H);
/VI-(4-(4-cyclohexy1piperazin-1 -yl) phenyl )-1 -(5,6-dihydrobenzo[/i]quinazolin-2-yt)-1 H-
1,2,4-triazole-3,&-diamine, compound #93,1H NMR (DMSO-efc, 300 MHz) 3.76 (s, 1H), 8.65 (s, 1H), 8.16 (d, 1H), 7,65 (s, 2H), 7.48 (M, 4H), 7.38 (d, 1H), 6,84 (d, 15 2H), 2.95 (m, 8H), 2.61 (m, 4H), 1.72 (M, 4H), 1.57 (m, 1H), 1.20-1,01 (m, 6H)
ppm; MS (ES) 522.36 (M+H);
/V;i-(4-(4-(bicyclo[2.2.1 ]heptan-2-yl)piperazin-1 -yl)phenyl)-1 -(pyridin-2-yl)-1 H-1,2,4-
triazole-3,5-diamine, compound #94, pale-brown solid; MS (ES) 431.20 (M+H);
1(benzo[tf]thiazol-2-yl)-/V5-(4-(4-(bicycio[2.2.1]heptan-2-yi)piperazin-i-yt)phenyi)-iH- 2U 1,2,4-triazole-3,5-diamine, compound #95, off-white solid; MS (ES) 487.27
(M+H), 485.25 (M-H);
1-(benzoJtf]thiazol-2-yl)-W2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)pheny1)-1H- 1,2,4-triazole-3,5-diamine, compound #96, off-white solid; MS (ES) 487.24 (M+H), 485.20 (M-H);
25 /VJ-(4-(4-(bicyclo[2,2,1]heptan-2-yl )piperazin-1 -yl)phenyl)-1 -(quinoxalin-2-yl)-1 ft-1,2,4- triazole-3,5-diamine, compound #97, orange solid; MS (ES) 482.52 (M+H), 460.1S (M-H);
/V5-(4-(4-(blcyclo[2,2,1 ]heptan-2-yf)piperazin-1 -yl)phenyl)-1 -(S,7-dimethoxyquinazolin-4- yI)-1H-1,2,4-triazole-3,5-diamine, compound #98, pale-yellow solid; MS (ES) 3D 542.30 (M+H), 540-59 (M-H),
/V3-(4-(4-(brcyclo[2,2,1 ]heptan-2-yl)plperazin-1 -yl)phenyl)-1 -(2-chloro-7-methylthieno[3,2- cflpyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamrne, compound yellow solid; MS (ES) 536.13 (M+H), 535.51 (M-H);
W*-{4-(4-(bicyclo[2.2.1 ]heptan-2-yl)plperazin-1 -yl)phenyl)-1 -(6,7-dimethoxyquinazolin-4- 35 yl)-1 ff 1,2,4-triazole-3,5-diamine, compound #100, yellow solid; MS (ES) 542.47
(M+H), 540.22 (M-H);
W3- (4-{4-( ta i cyclo [2.2.1] hepta n-2-y I )pi perazi n-1 -yl )pheny I)-1 2-ch!oro-6,7-
di methoxyq u i nazolin-4-yl)-l H-1,2,4-triazo]e-3,5-d iamine, compound #101, yellow solid; MS (ES) 570.19 (M+H), 574.22 (M-H);
4-(5-amino-3-(4-(4-(bicyclo[2J2,1 jheptan-2-yl)piperazin-1 -yl)phenylamino)-1 H-1,2,4-
triazci-1-yl)-2-chloro-6-methQxyquinazolin-7-al, compound #102, yehow solid; MS (ES) 502.21 (M+H), 560 33 (M-H);
yv3-(4-(4-(bicyclo(2,2,1 ]heptan-2-yl)pipsrazin-1 -yl)phenyl)-1 -(&-chloroquinazoliri-4-yl)-1 H- 1,2,4-triazole-3,5-d iamine, compound #103, yellow solid; MS (ES) 516,21 (M+H), 514.26 (M-H);
1-(7-(benzyloxy}-6-methoxyquinazofin-4-yl)-W;)-(4-(2-(pyrnolidin-1-yl)ethoxy)phenyl)-1H- 1,2,4-triazole-3,5-diamine, compound #104, yellow solid; MS (ES) 553,45 (M+H), 551.33 (M-H);
1 -(6,7 -d i methoxyq u i n a zoli n-4-yl )-A^-(3-f I u oro-4-( 4-methy I p i p erazi n -1 -y I )p he ny I)-1 rt-1,2,4- triazole-S.S-diamine, compound #105, yoiiow solid; MS (ES) 480.34 (M+H);
4-(5-arnino-3-(4-(4-(blcyclo[2.2,1]heptan-2-yl)piperazin-1 -yl)-3-fluorophenylamino)-1 H- 1,2,4-triazol-1-yl)-6-methoxyquinazolin-7-ol, compound #106, yellow solid; MS (ES) 546.22 (M+H), 544.33 (M-H);
1 -(4-(4-(5-amino-1 -(6,7-d i methoxyq uinazolin-4-yl)-1 H-1,2,4-tnazol-3-
ylamino)phenyl)pipenazin-1-yl)ethanone, compound #107, yellow solid; MS (ES) 490.32 (M+H);
1 -(5,6-dihydrobenzo[/i]cinnolin-3-yl)- WJ-(4-(4-m ethyl piperazin-1 -yl)phenyl)-1 H-1,2,4-
triazole-3,5-d iamine, compound #108, 'H NMR (CDCIj/MeODj, 300 MHz) 7.65 (s, 1H), 7.33 (d, 1H), 7.27 (d, 2H), 7.15-7.25 (m, 2H), 7,03 (m, 1H), 6.77 (d, 2H), 2.81-2,93 (m, BH), 2,45 (M, 4H), 2,17 (s, 3H) ppm; MS (ES) 454.30 (M+H);
4-(5-amino-3-(4-(4-cycioheptylpipenazin-1-yl)phenylamino)-1W-1,2,4-triazo!-1-yl)-6-
methoxyquinazolin-7-of, compound #109, yellow solid; MS (ES) 530.22 (M+H), 528.01 (M-H);
A^i-(4-(4-cydolieptylpiperazin-1-yl)phenyf)-1-(6,7-dimelhoxyquinazolin-4-yl)-1H-1,2,4- triazole-3,5-diamine, compound #110, yellow solid; MS (ES) 544.30 (M+H);
W^-^-adamantan^-ylJpiperazin-l -y])phenyl)-1 -(6,7-dimethoxyquinazolin-4-yl)-1 H-
l^^triazole-S^-diamine, compound #111, yellow solid; MS (ES) 582.45 (M+H);
W;-(4-( 4-oy cloocty I pi perazi n -1 -y I )p h e n y I)-1 -(6,7-d i met hoxyq u i nazo I i n -4-y I)-1H-1,2,4- triazole-3,5-dlamlne, compound #112, yellow solid; MS (ES) 558,25 (M+H), 556.39 (M-H);
5-(5-am i no-3-(3-fluoro-4-(4-methyl pi pe razi n-1 -yl)phenylam i no )-■1H-1,2,4-tri azol-1 -yl)-1,6- naphthyridin-2(1/4)-one, compound #113, dark-yellow solid; MS (ES) 436,20 (M+H), 434.20 (M-H);
A/J-(3-chlono-4-(4-cyclohexyl pipe razi n-1 -yl)phenyl>1 -(6,7-dimethoxyquinazolin-4-yl)-1 H- 5 1,2,4-triazole-3,5-diamine, compound #114, yellow solid; MS (ES) 564,21 (M+H);
/V3-(4-(4-cydoliexylpiperazin-1 -yl)phenyl)-1-(5,6-dihydnobenzo[/?]cinnolin'3-yl)-1 H-\,2,4- triazole-3,5-diamine, compound #115, 'H NMR (CDQ3/MeGD4l 300 MHz) 3.22 (s, 1H)f 7.66 (s, 1H), 7.52 (d, 2H)r 7.34 (m, 2H), 7.28 (m, 2H), 6.89
4-(5-amino-3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)-1W-1,2,4-tri azol-1-
yl)quinazoline-6,7-diol, compound #116, off-white solid; MS (ES) 452.23 (M+H), 450,16 (M-H);
4- (5-amino-3-(3-fiuoro-4-(4-methylpiperazin-1-yl)phenylamino)"1H-1,2,4-triazol-1-yl)-0- 15 methoxyquinazolin-7-ol, compound #117, pale-yellow solid; MS (ES) 466,41
(M+H), 464.25 (M-H);
A/3-(4-(4-(bicyclo[3.3.1]nonan-9-yi)piperazin-1-yl)phenyl)-1-(5,7-dimethoxyquinazolin-4- yl)-1H-1,2,4-triazole-3,5-diamine, compound #118, yellow solid; MS (ES) 570.27 (M+H), 568.38 (M-H);
20 AfT-(4-chloro-3-(4-ethyl pipe razi n-1 -yl) phenyl )-1 -(0,7-d imethoxyq uinazoli n-4-y I)-1tf-1,2,4- triazole-3,5-diamine, compound #119, yellow solid; MS (ES) 511.75 (M+H), 508.25 (M-H);
1-(4-(5-(5-amrno-1 -(6,7-dimethoxyquinazolin-4-yi)-1tf-1,2,4-trlazol-3-ylarninc)-2-
ehloro phenyl )pipenazin-1-y1)ethanone, compound #120, yellow solid; MS (ES) 25 524.16 (M+H), 522.24 (M-H);
5- (5-amino-1 -(6,7-dimethcxyquinazolin-4-yl)-1 H-1,2,4-triazol-3-ylamino)-2-(4- methylpiperazin-1-yl)benzamide, compound #121, yellow solid; MS (ES) 505.27 (M+H), 503,23 (M-H);
/^-(4-(4-cy d oh exyip i pe raz i n-1 -yl )-3-fl uorop h e n y I)-1 -(6, 7-dimethoxyq u i nazo lin-4-y I)-1H- 30 1,2,4-triazole-3,5-diamine, compound #122, yellow solid; MS (ES) 540,53 (M+H),
546,33 (M-H);
Ar3-(4-(4-(bicyclo[2,2,1]heptan-2-yl)piperazin-1-yl)-3-fluorophenyl)-1-(6,7-
dimethoxyquinazolin-4-yl)-1 H-1,2,4-triazole-3,5-diamine, compound #123, yellow solid; MS {ES) 560.35 (M+H), 558,34 (M-H); 35 W5-(4-{4-(bicyclo[3.2.0]heptan-6-yl)piperazin-1-yl)phenyl)-1 -(6,7-dimethoxyquinazoiin-4-
yl)-1H-1,2,4-triazole-3,5Hjiamine, compound #124, yellow solid; MS {ES) 542.54 (M+H), 540.32 (M-H);
/V3-(4-{4-(bicyclo[2.2.1 ]heptan-2-yl)piperazln-1 -yl)phenyl)-1 -(6,7-dimethoKyisoquinolin-1 - yi)-i/+i,2,4-triazoie-3,5-diamine, compound #125, pale-yellow solid; MS (ES) 541.38 (M+H);
W3-(4-{4-cycloheptylpiperazin-1-yl)phenyl)-1-(6,7-dimethoxyisoquino]in-1-yl)-1H-1l2l4- triazole-3,5-d iamine, compound ff126. pale-yellow solid; MS (ES) &43.63 (M+H);
Af"?-{4-{4-( b i cyclo [2.2.1 ]heptan-2-yl)piperazin-1 -yl)phenyl)-1 -(Lhieno[2,3-cflpyrirriidin-4-yl)- 1W-1,2,4-triazole-3,5-diannine, compound #127, yellow solid; MS (ES) 488.77 (M+H), 486-27 (M-H);
Af-(4-(4-(bi cyclop. 2.1 ]heptan-2-yl)piperazin-1 -yl)phenyl)-1 -(ihieno[3,2-cf]pyrimidin-4-yl)- 1/-M,2.4-triazole-3,5-d iamine, compound #128, pale-yellow solid; MS (ES)
-(4-( 4-( b icyclo[2.2.1 ]heptan-2-yl)piperazin-1 -yl)pheriyl)-1 -(0-phenyHhieno[3,2-
tfjpy rimid i n-4-yl)-1H-1,2,4-triazole-3,5-d iamine, compound #129, yellow solid; MS (ES) 564.71 (M+H), 562,37 (M-H);
A^-(4-(4-(bicyclo[2.2.1 Jhepta n-2-yl)piperazin-1 -yl)phenyl)-2-(6-phenylthieno[2,3-
djpyrim idi n-4-yl )-2H-1,2,4-triazole~3,5-d iamine, compound #130, yellow solid; MS (ES) 564.69 (M+H), 562,37 (M-H);
W7-(4-(4-(bicyclo[2.2.1]heptan-2-y|)plperazin-1-yl)phenyl)-1-(furo[3l2-c]pyridin-4-y])-1H- 1,2,4-triazole-3,5-diamine, compound #131, off-white solid; MS (ES) 471.62 (M+H), 469.39 (M-H);
4-( 4-(bicy clo[2.2.1 ]h epta n-2-y I) p i pe razi n-1 -yl )pheny I)-1 -(6,7-d i hyd ro-5H- cyclopenta[4,5]thienD[2,3-d]pyrimidin-4-yl)-1H-1,2,4-tnazole-3,5-diaminep compound #132, yellow solid; MS (ES) 528.82 (M+H), 526 35 (M-H);
A/J-(4-[4-(bicyclo[2,2,1]heptan-2-yl)piperazin-1 -yl)pheny1)-1 -(6-fluoroquinazolin-4-yl)-1 H- 1,2,4-triazole-3,5-diamine, compound #133, orange solid; MS (ES) 500,71 (M+H), 490.34 (M-H);
^-(4~(1-(bicycloE2.2.1]heptan-2-yl)pipejid!n-4-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2- cdpynmldin^-ylJ-IH-l^^triazole-S^-diamine, compound #134, pale-yellow solid; MS (ES) 535.27 (M+H), 533.31 (M-H);
A/i-(4-(4-(bicyclo[2.2.1]heptan-2"yl)piperazin-1-yl)phenyl)-1-(2-methy1quinazolin-^yl)-1H- I.S^triazole-S.S-diamine, compound #135, red solid; MS (ES) 496,04 (M+H), 494.38 (M-H);
/V!-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperaziri-1-yl)phQnyl]-1-(2-(trifluoromethyl)quinazolin-
4-y I )-1H-1,2,4-triazo le-3,5-diamine, compound #136, orange solid; MS (ES) 550,75 (M+H), 548.39 (M-H);
W5-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperaz]n-1 -yl)pheny])-1-(2,5,6-trimethylthieno[2,3-
tf]pyrimidin-4-yI)-1H-1,2,4-triazole-3,5-diamine, compound #137. yellow solid; MS 5 (ES) 530.59 (M+H), 528.40 (M-H);
/V5-(4-(4-(bicyclo[2.2.1]heptan"2-yl)piperazin-1-yl)phenyl)-1-(5,6-dimethylthieno[2,3-
d]py nmidi n-4-y I)-1 tt-1,2,4-tria zole-3,5-d i a m i ne, compound #138, yellow solid; MS (ES) 516.74 (M+H), 514.30 (M-H);
A/s-(4-(4-(bicyclo[2,2,1]heptan"2-yl)piperazin-1-yl)-3-fluorophenyl)-1-(2-chloro-7- 10 methylthieno[3,2-d]pyrim]din-4-y1)-1H-1,2,4-triazale-3,5-diamine, compound #140,
pale-yellow solid; MS (ES) 554.20 (M+H), 552.30 (M-H);
ArJ-(4-(4-((lR,£ff,4S)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-y!)phenyl)-1-(2-ch!ono-7-
methylthieno[3,2-rf]pyrim]d]n-4-yl)-1W-1,2,4-triazole-3,5-diamrne,compound#141, yellow solid; MS (ES) 538.19 (M+H), 534.16 (M-H); 15 yv^-methoxyphenylJ-l-tpyridin-S-ylJ-lff-l^^-lriazole-SjS-diamine, compound #142, tan solid; MS (ES) 283,46 (M+H);
ethyl 4-(5-amino-1-(2-chionopyridin-4-y!)-1 HA,2,4-triazol-3-ylamino)benzoate, compound #143, pale-yellow solid; MS (ES) 359,02 (M+H), 357.02 (M-H);
1-(4-(5-annino-1-(quinoxalrn-2-yl)-1 W-1,2,4-triazo I-3-yia mi no) phenyl )etha none, compound 20 #144, tan solid; MS (ES) 346.00 (M+H), 344.19 (M-H);
(SiJ-ethyl4-(5-amino-1-(2-(2-(pyrrolidin-1-ylmothyl)pyrro1idin-1-yl)pyndin-4-yl)-1f-f-1l2,4- triazol-3-ylamino)banzoatef compound #145, pale-brown solid; MS (ES) 477.19 (M+H), 475.27 (M-H);
(SJ-4-( 5-a m i n o-1 -(2-( 2-(py rrol i d i n-1 -yl m eth y I )pyrTolidin-1 -y I )pyrid i n-4-y I)-1H-1,2,4-triazol- 25 3-ylamino)benzoic acid, compound #146, brown solid; MS (ES) 440.17 (M+H)f
447.23 (M-H);
1 -{4-(5-arnino-1 -(2-fluorophenyl)-1 HA ,2,4-triazol-3-ylamino)phenyl Jethanone, compound #147, pale-yellow solid; MS (ES) 312.33 (M+H), 310.11 (M-H);
1-(pyridin-2-yl)-/V1-(3,4,5-trimathoxyphanyl)-1H-1l2l4-triazole-3l5-tJiaminel com pound 30 #148, off-white solid; MS (ES) 343.60 (M+H), 341.14 (M-H):
l-fpyridin-S-yl)-/^ (3,4,5-trifiuorophenyl) 1 HA,2,4-trlazole-3,5-dlamine, compound #149, off-white solid; MS (ES) 307.14 (M+H), 305,03 (M-H);
3-(5-amino-1-(pyridin-2-yl}-1H-1.2,4-triazol-3-ylamino)phenol, compound #150, off-white solid; MS (ES) 269.54 (M+H), 267.08 (M-H): 35 Af-(4-((1-methylpyrrolidin-2-yl)methoKy)phenyl)-1-(quinoxaiin-2-yl)-1H-1,2,4-triazole-3,5- diamine, compound #151, yellow solid; MS (ES) 417.62 (M+H), 415.23 (M-H);
3-( 4~{5-am ino-1 -{q ul noxa I i n-2-y I)-1H-1,2,4-triaEo!-3-y1ami no) phenyl)-1 -(py rrol id i n-1 - yl)propan-1-one, compound #152, MS (ES) 429.57 (M+H), 427.50 (M-H);
1 -(ej-dirnethoxyquinazolin^-ylJ-ZV3-^-^ -methyl pi peridin-3-y1oxy)pheryl)-1 H-1,2,4- 5 triazole-3,5-diamine, compound #153, yellow solid; MS (ES) 477.60 (M+H),
475.15 (M-H);
1 -(ej-dimethoxyquinazolin^-ylj-rtf-^fl -methylpiperidin-3-yloxy)phenyl)-1 H-1,2,4- triazole-3,5-diamine, compound #154, yeflow solid; MS (ES) 477.43 (M+H), 475.25 (M-H);
10 1-(isoquinolin-1-yl)-/V3-(4-(1-methylpiperidin-3-yloxy)phenyl)-1H-1l2r4-triazole-3l5-
diamine, compound #155, off-white solid; MS (ES) 416,44 (M+H), 414,16 (M-H);
1 -(isoquinolin-1 -yl)-/^ 4- mo rpholi no phenyl )-1 H-1,2,4-triazole-3.5-diamine, compound #156, yellow solid; MS (ES) 388.39 (M+H);
1-(isoquinolin-1 -ylJ-A^-f^mo rpholi no phenyl )-1 / M ,2,4-triazole-3,5-diamine, compound 15 #157, yellow solid; MS (ES) 388.60 (M+H), 366.16 (M-H);
1 -(6 r7-di met hoxyq u i nazo lrn-4-yl )- ^-(4- morpholi no phenyl)-1 fM, 2,4-tri azole-3,5-d i a m i n e, compound #158, yeflow solid; MS (ES) 449.30 (M+H)r 447.02 (M-H);
A^-(3-chloro-4-morpholinophenyl)-l-(6,7-dimethoxyquinazolin-4-y| )-l W-1,2,4-triazoie-3,5- diamine, compound #159, yellow solid; MS (ES)433.03 (M+H), 431,00 (M-H); 20 ^-(S-chloro^morpholinophenyh-l^-chloraquinazolin^ylJ-l H-1 ,2,4-triazole-3,5- diamine, compound #160, off-white solid; MS (ES) 458,08 (M+H);
Af^3-fluora-4-morphol in ophenyl)-1-{ isoquinolin-1 -yl)-1 H-1,2,4-triazo le-3,5-diamine, compound #161, yellow solid; MS (ES) 406.49 (M+H), 404.16 (M-H);
1 -[6,7-d imethoxyq u i nazo I i n-4-yl uo ro-4-morpholi no p he ny I)-1 ft-1,2 ,■4-triazo le-3,5-
25 diamine, compound #162, yellow solid; MS (ES) 467,13 (M+H);
1-(isoq uinol in-1-yl)-/V3-(4-((4-meLhyl pipe razi n-1-yl) methyl )p he nyl)-1H-1,2,4-triazole-3,5- diamine, compound #163, yellow solid; MS (ES) 415.14 (M+H);
WJ-(4-((ff)-3-[dimethylamino)pyrrolidin-1 -yl)pheny!)-1 -(isoquinolin-1 -yl)-1 H-1,2,4-triazole- 3,5-diamine, compound #164, yellow solid; MS (ES) 415.23 (M+H); 30 W3-{4-((S)-3-(dimethylamrno)pyrroiidin-1-yl)phenyl)-1-(isoquinolin-1-yl)-1H-1,2r4-triazole- 3,5-diamine, compound #165, yellow solid; MS (ES) 415.12 (M+H);
1-(isoquinolin-1-yl)-JV3-{4-(oxazul-5-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #166, yellow solid; MS (ES) 370.49 (M+H), 368.15 (M-H);
1-(i soq ui no I in-1-yiJ-iV3^^ 1 - met hylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, 35 compound #167, pale-yellow solid; MS (ES) 400.38 (M+H);
1 -(6 J-dimethoxyquinazolin^-ylJ-W^-tl - methyl pipe rid in-4-yl) phenyl)-1 H-1,2,4-triazole- 3,5-d iamine, compound #168, yellow solid; MS (ES) 461.61 (M+H), 459.28 (M-H);
4-(5-amino3-(4-( 1 -methylpiperidin-4-yi)phenylamino)-l H-1,2,4-triazoM -yl)-6-
methaxyquinazolin-7-ol, compound #169, pale-yellow solid; MS (ES) 446.92 5 (M+H)p 445,25 (M-H);
1-(6,7-dimethaxyquinazolin-4-yl)-AP-(4-((S)-3-(dimethylamino)pyrTolidin-1-y!)phenyl)-1H- 1,2,4-triazole-3,5-d famine, compound #171, yellow solid; MS (ES) 476,35 (M+H);
4-(5-amino-3-(4-(1 -methylpiperidin-4-yl)phenylamino)-1 H-1,2,4-triazoM -y1)q uinazoline- 6,7-diol, compound #172, pale-yellow solid; MS (ES) 433-07 (M+H), 431.54 (M- 10 H);
1 -(6,7-d i methoxyq uinazolin-4-yl )-Af-(4-((4-m ©thy I pipe razin-1-yl )methy1) phenyl )-1 H-1,2,4- tri3zole-3,5-diaminer compound #173, yellow solid; MS (ES) 476.09 (M+H)p 474,26 (M-H);
1-(6,7-d imeth oxyi soq uinol in-1-yl)-/\l'J-(4-(1-methyl piperidin-4-yl)p he nyl)-1 H-1,2,4-triazole- 15 3,5-dlamine, compound #174, pale-yellow solid; MS (ES) 460.44 (M+H);
1 -(2,6-dichlorothieno[3,2-cf] pyrimidin^l-y^ IV3-(4-( 2-pyrrolidFn-1-ylethoxy)phenyl)-1rt-
l^^-triazole^S-diamfne, compound #175, 'H NMR (DMSO-dg, 300 MHz) 9,36 (s, 1H), 6.63 (s, 1H), 8.17 (s, 1H), 7.96 (brs, 2H), 7.58 (d, 2H), 6.93 (d, 2H), 6.55 (s, 1H), 4.04 (1, 2H), 2.79 (m, 2H). 1.70 (m, 4H), 1.04 (m, 4H) ppm; MS (ES) 20 491.03 (M+);
1 -(2-chlorothieno[2,3-of]pyrimidin-4-yl)-/Vs-(4-(2-pyrrolidin-1 -ylethoxy)phenyl)-1 H-1,2,4- triazole-3,5-d iamine, compound #176,1H NMR (DMSO-dg, 300 MHz) 9,21 (s, 1H), 8.32 (d, 1H), 7.99 (br s, 2H}, 7.91 (d, 1H), 7.49 (d, 2H), 6.93 (d, 2H), 4.06 (t, 2H), 2.89 (m, 2H), 2.65 (m, 4H), 1.73 (m, 4H) ppm; MS (ES) 457.07 (M+); 25 1 -(2-chlorothieno[3,2-o(]pyrimidin-4-yl)-r/(-(4-(2-pyrroiidin-1 -ylethoxy)phenyl)-1 H-1,2,4- 1riazole-3,5-diamine, compound #177,1H NMR (DMSO-d3, 300 MHz) 9.28 (s, 1H), 8.55 (d, 1H), 8.17 (s, 1H), 7.92 (br s, 2H), 7.53 (m, 3H), 6.92 (d, 2H), 4.02 (t, 2H), 2.76 (m, 2H), 2.40 (m, 4H), 1.67 (m, 4H) ppm; MS (ES) 457.01 (M+);
Af3-(4-(2-(pyrTolidin-1-yl)ethoxy)phenyl)-1-(6!7,B,9-tetrahydro-5H- 30 cyc1ohepta[4,5]thieno[2,3-tf]pyrimidin'4-yl)-1 H-1 ^^-triazole-SjS-diamine,
compound #178, pale-yellow solid MS (ES) 491.24 (M+H), 439 61 (M-H);
1-(2-chlorothieno[3,2-d]pyrimidin-4"yl)-/Vs-(4-(4-((1Sl2S,4R)-bicyclo[2.2.1]heptan-2-yl)- piperazin-1 -yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #179, nH NMR (DMSO-ds, 3DO MHz) 9.21 (s, 1H), 8.55 (d, 1H), 7.91 (brs, 2H), 7.58 (m, 3H), 35 6.92 (d, 2H), 3.05 (m, 5H), 2.72 (s, 1H), 2.43 (m, 4H), 2.30 (m, 2H), 2.18 (t, 1H),
1.40 (m, ZH), 122 (m, 4H) ppm; MS (ES) 522.04 (M+);
1 -(6,7>-d imeth oxyq uinazo Ii n-2-yl)-Af-(4-(4- methyl pi pe razin-1 -yl)phen yl)-1H-1,2,4-triazole- 3,5-diamine, compound #130, 1H-NMR £CDCIS> 300 MHz) 9,36 (s, 1H), 7,50 (d, 2H), 7.40 (s, 1H), 7.10 (s, 1 H)r 6.95 (d, ZH), 0.80 (s, 2H), 6.62 {s, 1H), 4.02 (s, 6H), 3.19 (m, 4H), 2,60 (m, 4H), 2.35 (s, 3H) ppm; MS (ES)462 (M+H);
1 -(6,7-d i meth □xyquinazolin-2-yl)-Wi"(3-fluoro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1H- 1,2,4-triazole-3,5-diamine, compound #181, 1H-NMR (CDCI3, 300 MHz) 9.31 (s, 1H), 7,47 (m, 1H), 7,40 (s, 1H), 7.16 (s, 1H), 7.13 (m, 1H)f6.96(t, 1H), 6.77 (s, 2H), 6.70 (s, 1H), 4.07 (s, 6H), 3.06 (m, 2H), 2.79 (m, 2H)P 2.35 (m, 1H), 1,96 (m, 2H), 1.63 (m, 2H), 1.67 (m, 4H), 1.26 (m, 2H) ppm; MS (ES) 548 (M+H);
1-(6,7-dimethoxyquinazoliri-Z-yl)-W5-(4-(4-((lS,2S,4R)"bicyclo[2.2.1]hepfan-2-yf)-
piperazin-1-yl)phenyl)-lH-1,2,4triazole-3f5-diamine (racemic), compound #132, 1H-NMR (CDCIj, 300 MHz) 9.10 (s, 1H), 7.36 (d, 2H), 7.22
bfcyclo[2.2.1]hGptan-2-yl)-piporazin-1-yl)phenyf)-1H-1,2,4-triazo le-3 r5-diarnine (racemic), compound #133, 'H-NMR (DMSO-dfi, 300 MHz) 9.17 (s, 1H), 8,18 (s, 1H), 7 89 (broad s, 2H), 7.55 (d, 2H), 6,91 (d, 2H), 3.28 (m, 2H), 3,05 (m, 3H), 2.48 (m. 3H), 2.36 (s, 3H), 2.10-2.29 (m, 3H), 1.90 (m, 1H), 1.71 (m, 2H), 1,46 (m, 1H), 1.20-1.40 (m, 3H), 0.87 (m, 1H) ppm; MS (ES) 536.10 (M+H);
1-(pyrido[2,3-b]pyrimido[4r5-d]thiophene-4-yl)-/V3-(4"(4-(bicyclo[2,2.1]heptan-2-yl)-
pi pe razi n-1-y I) pheny I)-1H-1,2,4-triazole-3,5-diamine, compound #184,1H NMR (DMSO-dfil 300 MHz) 9.15 (br s, 1H), 9.02 (s, 1H), 8 92 (d, 1H), 8.77 (d, 1H), 8.10 (brs, 2H), 7.70 (dd, 1H), 7.59 (d, 2H), 6.93 (d, 2H), 3.08 (m, 4H), 2.48 (m, 4H), 2.30-2,14 (m, 3H), 1.80-1,62 (m, 2H)P 1.46-1.15 (m, 5H)f 0.90-0.36 (m, 1H) ppm; MS (ES) 539.67 (M+H);
1 - (5-(th ioph ®n-2-y I )th ie no [2,3-d]py rii TI idin-4-y I)-4-(4-(bicyc!o[2 2,1 ]h epta n-2-yl)-
p i pe razi n-1 -yl )phen yl)-1H-1,2,4-tri azole-3,5-diamine, compound #185, 'H NMR {□USO-dB. 300 MHz) 8,93 (br s. 1H), 8.32 (s. 1H), 8.03 (s, 1H), 7,30 (d, 1 H)r 7,02 (br s, 2H), 6.97 (m, 1H), 6.93 (d, 2H), 6.78-6.76 (m, 1H), 6,67 (d, 2H), 2.96 (m, 4H), 2.42 (m, 4H), 2.23-2.13 (m, 3H), 1.70-1.60 (m, 2H), 1.45-1.14 (m, 5H), 0.90- 0.60 (m, 1H) ppm; MS (ES) 570,38 (M+H);
1 -(6 -{4-cbto ro phenyl )thieno[3,2-d] py ri rn id in-4-y I)-A^-f 4-(4-( bicyclo[2.2.1 ]h epta n-2-y I)-
piperazin-1-yl)phenyl)-1W-1J2J4-Eriazole-3,5-diamine, compound #186. 1H NMR (DMSO-d$r 300 MHz) 9.10 (br s, 1H), B.81 (s, 1H), 8.05 (br s, 2H), 7.95 (dr 2H), 7.64 (d, 2H), 7.57 (d, 2H): 6.93 (d, 2H), 3.08 (m, 4H), 2.43 (m, 4H), 3.31-2,15 (m, 3H), 1.70-1.63 (m, 2H), 1.46-1.15 (m, 5H), 0.91-0-87 £m, 1H) ppm; MS (ES) 5 598,16 (M+H);
1-(6-(1l1-dimethylethyl)thieno[3r2-d]pyrimSdin-4-y1)-/V;?-(4-(4-(bicyclo[2.2.1]heptan-2-yl> pEper azf n -1 -yl )phe n yl 1W-1,2,4-triazo Ie- 3,5-d ia mi ne, compound #187, 1H NMR (DMSO-ds, 300 MHz) 9.06 (br s, 1H), B.70 (sr 1H), 7.99 (br s, 2H), 7.58 (d, 2H): 7.38 (5, 1H), 6,86 (dr 2H), 3.03 (m, 4H), 2.43 (m, 4H), 2.29-2.14 (m, 3H), 1.80- 10 1.64 (m:2H), 1.49 (S, 6H), 1-48 [S, 3H)r 1.32-1.15 (m, 5H), 0.90-0.80 (m, 1H)
ppm; MS (ES) 544 81 (M+H);
1-(7-methy]thieno[3p2-d]pyrimidin-4-yi)-M;?-(4-(4-{( 1 S,2S,4R>bicyclo[2.2. 1]heptan-2-yl)- piperazin-1-yl)phenyl)-1 H-1,2,4-triazo le-3 r 5-diamine, compound #138,1H NMR (DMSO-d5, 300 MHz) 9.08 (br s, 1H), 8.85 (s, 1H), 8.12 (s, 1 H); 8.06 (br s, 2H), 15 7.58 (d, 2H), 6.91 (d, 2H), 3.05 (m, 4H), 2.46-2.44 (m, 4H), 2.42 (sr 3H), 2 30-
2.14 (m, 3H), 1.80-1.62 (m, 2H), 1.46-1.14 (m, 5H), 0.39-0.86 (m, 1H)ppm; MS (ES) 502.71 (M+H);
1 -(th ie no [3,2-d]pyrim id i n -4-yl )-/V3-( 4-(4-( (1 S,2 S, 4R)-bi eye lo [2.2.1 ] he ptan-2-y l)-p i pe razi n- 1-yl)phenyl)-1 H-1,2,4-triazo1e-3,5-diamine, compound #189, 1H NMR (DMSO-de, 20 300 MHz) 9,10 (br s, 1H), 8.82 (s, 1 H)r 8.47 (d, 1H), 8,06 (br s, 2H), 7.59 (s, 1H),
7.57 (d, 2H): 6.91 (d, 2H), 3.05 (m, 4H), 2-47 (m, 4H)r 2.30-2.14 (m, 3H), 1,80- 1.62 (m, 2H), 1.46-1.14 (m, 5H), 0.90-0.86 (m, 1H) ppm; MS (ES) 488.55 (M+H);
1-(Lhieno[2,3-^pyrimidin-4-yl)-A/5-(4-(4-((1Sr2S,4R)-bicyclo[2.2.1]heptan-2-yl)-piperazin- 1-yl)phenyl)-1H-1,2:4^triazole-3,5-diamine, compound #190, 1H NMR (DMSO-de, 25 300 MHz) 9.02 (br s, 1H), 8.77 (s, 1H), 8.37 (d, 1H), 8,15 (br 5, 2H), 7,91 (d, 1H),
7,45 (d, 2H), 6,91 (d, 2H), 3,04 (m, 4H), 2.47 (m, 4H), 2,30-2,14 (m, 3H), 1.80- 1.62 (m, 2H)r 1.45-1.14 (m, 5H), 0.89-0.86 (m, 1H) ppm; MS (ES) 488.53 (M+H);
1-(5-mothylthieno[2,3-d]pyrimrdin-4-ylVW5-(4-(4-((1S,2S,4/?)-bicyclo[2.2.1]heptan-2-yl)- p i pe razi n-1-yi) pheny I )-1H-1r2:4-triazole-3,5^3 iamine, compound #191,1H NMR 30 (DMSO-d6, 300 MHz) 8,89 (s, 1H), 8.72 (br s, 1H), 7.63 ($, 1H), 7.36 (d, 2H), 7.01
(brs, 2H), 6.79 (d, 2H), 2,98 (mr 4H)r 2.42 (m, 4H), 2.30-2.14 (m, 3H), 1.30-1.62 (m, 2H), 1.46-1.14 (m, 5H), 1.24 (s, 3H), 0.90-0,86 (m, 1H)ppm; MS (ES) 502.36 (M+H);
1 -(p h e n a nth rid i n-6-y I)- N3-^-fl uo ro-4-(4-cyclope nty I p i pe razi n-1 -y I) p he ny I)-1H-1,2,4- 35 trfazole-3,5-diamine, compound #192, 'H NMR (DMSO-d6, 300 MHz) 9,26 (dr
1H), 9.16 (br s, 1H), 0.91 (d, 1H), B.78 (d, 1H), 8.09 (d, 1H), 7.99 (t, 1H), 7.62- 7.69 (m, 3H), 7.50 (d, 1H), 7.44 (brs, 2H), 7.13 (dr 1H}P 6.92 {t, 1H), 2.39 (m, 4H), 2.46 (m, 4H), 2.26 (m, 1H), 1,73 (m,2H), 1.61-1.51 (m, 4H), 1.36 (n, 2H) ppm; MS (ES) 523.40 (M+H);
5 1-(7-niethy(-2-chlorothieno[3l2-tf]pyrimidirr-4-yl)-W'-(4-(4-((1SJ2S,4/?)-
bicyc[o[2.2.1]heptan-2-yl)-piperazin-1-yl)phenyl)-1H-1l2,4-triazole-3f5-diamiriaI compound #193. 1H NMR (DMSQ-d&, 300 MHz) 9.30 (br s, 1H), 8.20 (d, 1H), 7.92 {br s, 2H), 7,02 (d, 2H), 7,55 (dd, 2H), 7.30-7.26 (in, 3H), 7.01 (d, 2H), 3.70-3.66 (m, 2H), 3,54-3.46 (m, 2H), 3.26-3.00 (m, 4H), 2.60 (m, 1H), 2.38 {s, 3H), 2.30 10 (m, 1H), 2.02-1.98 (m, 1H), 1.58 [m, 4H), 1.41 (m, 2H), 1.38 (m, 1H), 1.21-1.16
(m, 1H) ppm; MS (ES) 53B.40 (M+H); 1 -(7-methylthieno[3,2-c/]pyrimidrn-4-yl)-/V3-(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-y()- piperazin-l-yl)phenyl)-1H-1,2,4-triazo!e-3,5-diamine, compound #194, 'H NMR (DMSO-d,;, 300 MHz) 9.38 (br s. 1H), 8-67 (sr 1H), 8.16 (s, 1H), 8.11 (br s, 2H), 15 7,63 (d, 1H), 7.32 (d, 1H):6.99(t, 1H), 2.95 (m, 4H), 2.56 (m, 4H), 2,42 (5, 3H),
2,85-2.14 (m, 3H)P 1.80-1,62 (m, 2H), 1,46-1.14 (m, 5H)r 0.83-0.64 (m, 1H)ppm; MS {ES) 520.21 (M+H); 1 -(thieno[3,2-a(]pyrimidin-4-yl)-W3-(3-fluoro-4-(4-(bicyclo[2.2.1 ]heptan-2-yt)-piperazin-1 - yl)phenyl)-lH-1,2,4-triazole-3,5-diamine, compound #195; ^-NMR (DMSO-de, 20 300 MHz) 9.40 (br. s, 1H), 8,84 (s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.11 (br. s, 2H),
7.60 (dr J = 5.7 Hz, 1H), 7.33 (d, J = 9-0 Hz, 1 H)r 7.00 (t, J = 9.9 Hz, 1H), 2.95 (m. 4H), 2.45 (m, 4H), 2.2B-226 (m, 2H), 2.16-2.14 (m, 1H), 1.73-1.69 (m, 2H)r 1.45-1,17 (m, 5H), 0.88-0.85 (mr 1H) ppm; MS (ES) 506.21 (M+H) 1-(thieno[2,3-^pyrimidin-4-yl)-A/3-(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1- 25 yi)phenyi)-1 tf-1,2,4-triazo le-3,5-diamine, compound #196; fH-NMR (DMSQ-ds,
300 MHz) 9.34 (br. sr 1H), 8.79 (s, 1H), 8.33 {d, J = 0.0 Hz, 1H), 8.19 (br. S. 2H), 7.94 (d, J - 6,0 Hz, 1H), 7,46 (dd, J - 15.0, 2.4 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 7.00 (t, J = 10.2 Hz, 1H), 2.95 (m, 4H), 2.45 (m, 4H), 2.28-2.25 (m, 2H), 2.16-2.14 (m, 1H), 1.72-1.64 (m, 2H), 1.45-1.17 (m, 5H), 0.88-0,84 (m, 1H) ppm; MS (ES) 30 506.20 (M+H);
1-{6-tluoroquinazofin-4-yl )-W5-(3-fluoro-4-(4-(bicyclo[2.2.1]heptan-2-yl)-piperazin-1-
yl)phenyl)-1 tt-1 ,2,4-41^32016-3,5-diamine, compound #197; 1H-NMR (DMSO-de, 300 MHz) 9,50 (dd, J = 11,1, 3.0 Hz, 1H), 9,42 (br. s, 1H), 8.93 (s, 1H}, 8.35 (br, s, 2H), B.07-8.02 (m, 1H), 7.98-7.91 (m. 1H), 7.54 (dd, J = 15.3, 2.4 Hz, 1H), 7.18 35 (d, J = 3.1 Hz, 1H), 6.97 (t J = 6.0 Hz, 1H), 2.94 (m, 4H), 2.42 (m, 4H), 2,28-2.25
(m, 2H), 2.16-2.14 (m, 1H), 1.72-1.60 (m, 2H), 1.45-1.16 (m, 5H), 0,68-0.84 {m, 1H) ppm; MS (ES) 51S.24 (M+H);
1-{4-methylthieno[3,2-d|pyridazin-7-yl)-W5-(4-(4-(bicycto[2.2.1]heptan-2-yl)-piperazin-1- yl)phenyl>*1H-1,2,4-triazole-3,5-diamine, compound #198;
5 1-f7-methylthienoI3,2-cflpynmidin-4-yl>^
p i pe razi n-1-yl )phenyl)-1 H-1,2,4-triazole-3,5-d iamine, compound #199;
1-{7-methy^2-chlorothie^o[3,2-c/]py^imidi^-4-yl)-A/3-^2-methyl-4-(4-{bicyclo[2,2.1]heptan- 2-y1)-piperazin-1-yl)ph&nyl)-1H-1J2,4-triazole-3,5-diamine. compound #200;
1-{7^nnethy[thieno[3,2-£flpyrimidin-4-yl>W'l-(3-fluoro-4-(4-((1Sl2S,4R)- 10 tiicyclo[2.2.l]heptan-2-yl)-piparazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine
(TFA salt), compound #201;
1-{7-m ethy fth ieno[3,py ri m i d in-4-y I > N3^^^
piperazin-l-yl)phenyl)-1H-1,2,4-triazofe-3.5-diamine (TFA salt), compound #202;
1-(4-methylthieno[3,2-cf|pyridazin-7-yl)-W3-(3-1iuono-4-(4-(Eiicyclo[2.2.1]heptan-2-yl)- 15 p i pe razi n-1-yl )ph en yl)-1 H-1,2,4-triazo le-3,5-d iamine (TFA salt), compound #203;
1-{6-(1,1-dimethylethyl)thieno[3,2-d]pyrimidin-4-yl)-A/5-(4-(4-{tiicyclo[2,2,1]heptan-2-yl)- pipefazm-l-yl)phenyl)-lH-l,2,4-triazole-3,5-diamine, compound #204,1H NMR (DMSO-ds, 300 MHz) 10.89 (brs, 1H), 8.85
1 -(ph en a nth rid i n-6-y I)-AF-(3-fl uo ro-4-(4-cyclo pe nty I p i pe razi n-1 -y I) p he ny I)-1W-1,2,4-
triazole-3,5-diamine, compound #205,1H NMR (DMSO-dfl, 300 MHz) 10.49 (brs, 1H), 9.27-9.25 (m, 1H), 9.17 (m, 1H), 8.91-8,69 (m, 1H), 8-79 (d, 1H), 8.10-8,05 25 (m, 1H), 7.99 (t, 1H), 7.79-7.68 (m, 2H), 7.44 (m, 1H), 7.20 (d, 1H), 6.94-6.90 (m,
1H), 5.81 (br s, 2H), 3.00-2.90 (m, 4H), 2.46 (m, 4H), 2.26 (m, 1H), 1.79 (m, 2H), 1.00-1.51 (m. 4H), 1,34 (m, 2H) ppm; MS (ES) 523.45 (M+H);
1-(6,7-d imethoxyqu in azolin-4-yl )-WJ-(4-(4-(cyclo pentyl) pipe razin-1-ylcarbo nyl) phenyl )- 1 H-1,2,4-triazoie-3,5-d iamine, compound #206, 'H NMR (DMSO-dB, 300 MHz) 30 9.25 (s, 1H), 9,07 (s, 1H), 8.79 (s, 1H), 8.10 (brs, 2H), 7.69 (m, 2H), 7.41 (m,
3H), 3.97 (s, 3H), 3.92 (s, 3H), 3-35 (m, 6H); 2.42 (m, 4H), 1.70-1,33 (m, 7H) ppm; MS (ES) 544.5 (M+H);
1-(7-rnethylthieno[3;2-t/]pyrimidin-4-yl)-WJ-(4-(4-(cyclopentyl)piperazin-1-
ylcarbonyl)phenyi)-1H-1,2,4-triazole-3,5-diamine, compound #207, 'H NMR 35 (DMSO-dg, 300 MHz) 9.75 (s, 1H), 8,22 (s, 1H), 7,97 (br s, 2H), 7.73 (d, 2H), 7.39
(d, 2H>, 3.43 (m, 6H), 2,41 (m, 4H), 2.37 (s, 3H), 1.74-1.31 (m, 7H) ppm; MS (ES) 538.0 (M+H);
1-(7-methyl-2-chlorothierio[3I2-tf]pyrimidm^-yl)-/V3-(4-((2-(pvrrolidin-1-
yl)ethyl)aminocarbonyl)phenyl}-1 W-1,2,4-triazo le-3,5-diamine. compound #208, 5 1H NMR (DMSO-de, 300 MHz) 9.80 (s, 1H), 9.56 (s, 1H), 7.99 (s, 1H), 7,88 (brs,
2H)r 7.75 (m, 2H)r 7.45 (m, 2H), 3.35 (m, 2H)r 2.59 (mr 2H)r 2.35 (s, 3H), 2,28 (m, 4H), 170 (m, 4H) ppm; MS (ES) 499,0 (M+H);
1-(6,7-d i meth oxyq ui nazo I i n-4-yl)-
1,2,4-trf a zole-3,5-diamine, compound #209, 'H NMR (DMSO-d5r 300 MHz) 9,32 ID (S, 1H), 9.00 (S, 1H), 8.79 (s, 1H), 8.14 (br s, 2H), 7.48 (dr1H), 7.36 (s, 1H), 7.26
(d, 1H), 6.95 (t, 1H), 3.99 {&, 3H), 3 94 (s, 3H), 3-25 (m, 5H), 2-57 (t, 2H), 2 35 (t, 2H), 1.78 (d, 2H), 1.60 (m, 2H), 1,49 (s, 4H), 1.38 (d, 2H) ppm; MS (ES) 548.17 (M+H);
1-(7-m ethy l-2-ch loroth i eno [3,py ri m id i n-4^ 15 1-yl)phenyl)-1H-1,2,4-triazole-3s5-diamine, compound #210,1H NMR (DMSO-de,
300 MHz) 9.47 (s, 1H), 8.26 (s, 2H), 7,94 (3, 2H), 7.56 (d, 1H), 7.32 (d, 1H), 7.00 (I, 1H), 3.31 (d, 4H), 2.58 (m; 3H), 2.37 (s, 3H), 2.30 (m, 2H), 1.80 (d,2H), 1,60 (m, 2H), 1,48(s, 4H), 1.33 (d, 2H), ppm; MS (ES) 542.00 (M+);
1-(7-methy l-2-ch lo roth i e no [3,2-d]pyri m id ^ 20 l-yl)phenyl)-TH-l,2,4-trlazote-3?5-diamine, compound #211,1H NMR(DMSO-d6l
300 MHz) 9.30 (sr 1H)r 3.25 (s, 1H), 7.91 (s, 2H), 7.54 (d, 1H), 7,27 (dr 1H), 6.75 (s, 1H), 3.12 (s, 2H), 2.36 (m, 3H), 2.04 (s, 2H), 1.73 (s, 2H), 1.50 (d, 2H), 1,22 (S, 1H), 0.96 (m, 8H) ppm; MS (ES) 516,38 (M+);
1 -(8-met hoxy-5,5-d im ethyl-5H-ch ro me no [4,3-cjpyridazi n-3-yf)-//-( 3-fIuoro-4-( 25 methy1piperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazo le-3,5-diamine,
compound #212, 'H-NMR (DMSO-dGl 300 MHz) 9.21 (s, 1H), 7.63 (broad 6, 2H), 7.75 (s, 1H), 7.44 (d, 1H), 7.24 (d, 2H), 6.93 (m, 3H), 3.76 (m, 1H), 2.50-2.60 (m, 9H), 2.29 (m,2H), 2.13 (s, 3H), 1.79 (m, 1H), 1.50-1,70 (m; 4H)r 1.04 (s, 3H), 1.02 (s, 3H) ppm; MS (ES) 515,29 (M+H); 30 1-(phenanthridin-6-yf)-/^-(4-(1-methytpiperidin-4-yi)phenyl)-lH-1l2,4-triazole-3!5-
diamine, compound #213, 1H NMR (DMSCHjfj, 300 MHz) 9.31 (d, 1H), 9,04 (brs, 1H), 8.91 (d, 1H), 8,73 (d, 1 H)r 8,03 (d, 1H), 7.99 (t, 1H), 7.85-7,64 (m, 3H), 7,50 (d, 2H), 7.42 (brs, 2H), 7.08 (d, 2H), 2,92-2.39 (m, 2H), 2.24 (s, 3H), 2.06 (I, 3H), 1.69-1.00 (m, 4H) ppm; MS (ES) 450 58 (M+H); 35 1-(phenanthridin-6-yl)-W3-(3-methyl-4-(4-pyrrolidin-1 -yipiporidin-1-y|)phenyl)-1H-1,2,4-
triazole-3,5-diaminer compound #214,1H NMR (DMSO-dE, 300 MHz) 9,46 (d, 1H), 8.92 (d, 1H), B 39 (br S, 1H), 8.77 (d, 1H}, S OB (d, 1H), 7 99 (t, 1H), 7.81 (tr 1H), 7.74 ft, 1H), 7.6B (t, 1H), 7.51 (br sr 2H), 7.47 (s, 1H), 7.31 (d, 1H), 6.91 (d, 1H), 2.97-2.94 (m, 2H), 2,59 (m, 4H), 2.57 (m, 2H), 2,24-2,18 (mr 1H), 2.22 (s, 5 3H), 1.95-1.91 (m, 2H), 1.70 {m, 2H), 1.60-1.50 (m, 2H) ppm; MS (ES) 519-45
(M+H);
1-(7-methyl-2-chlorothieno[3.2-tfJpyri m id i n-4-y I)-W^fS-f f uoro-4-( iso i ndo I i n -2-yl )p henyl )-
1/-J-1,2,4-tria zole-3,5-diamine, compound #215, 'H NMR (CD30D, 300 MHz) 8,65 (S, 1H), B.23-3.04 (m, 2H), 7.98-7.65 (m, 4H), 7.46 (m, 1H), 4.53 (m, 4H), 2.44 (S, 10 3H); MS (ES) 493.01 (M+H);
1 -(ej-dinnethoxyquinazolin^-ylJ-W^-fS-fluoro^isoindolin-S-ylJphenylJ-l H-1,2,4-triazole- 3,5-diamine, compound #216. 'H NMR (CD3QD, 300 MHz) 6.70 (s, 1H), 8.74 (s, 1H), 8,50 (m, TH>, 8.12-7,38 (m, 5H), 7,38 (S, 1H), 4,53 (m. 4H), 4.08 (6, 3H), 3,99 (5, 3H); MS (ES) 499.06 (M+H); 15 1-(4-rnethylthieno[3,2-a(]pyridazin-7-yl)-A/3-(3-methyl-4-(4-(bicyclo[2,2.1]heptan-2-yl)-
piperazin-1-yi)pheny|)-1^-1,2,4-triazo le-3,5-diamine (TEA salt), compound #217, 'H NMR (DMSO-dc, 300 MHz) 3.38 (br s, 1H), 8.43 (m, 1H), 7.90 (s, 1H), 7.B1 (m, 1H), 7.62 (m, 1H), 7.44 (m, 1H), 7.07 (brs, 1H), 7,04 (m, 1H), 3.51 (m, 3H), 3.00-3.30 (m, 6H), 2.60 (m, 1H), 2.49 (5, 3H), 2.32 (s, 3H), 2.00 (m, 1H), 1.59 {m, 20 3H), 1.41 (m, 3H), 1.73 (m, 2H) ppm; MS (ES) 516.14 (M+H);
1-(4HSDpropylphenyl)-W3-(4-morpholinopheny1)-1 tf-1,2,4-tria zole-3,5-diamine, compound #218, MS (ES) 379.73 (M+H), 377.02 (M-H);
1-(7-metbyl-2-chlorothieno[3,2-(^pyrimidin-4-yl)-r^-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro- 5H-benzo[7]annulene-2-yl)-1H-1 r2,4-triazole-3,5-diamine, compound #219, 1H 25 NMR (DMSO-d6, 300 MHz) 9,31 (s, 1H), 8.26 (s, 1H), 7.91 (brs, 2H), 7.47 (m,
1H), 7.38 (m, 1H), 7.05 (m, 1H), 2,82 (m, 7H), 2,36 (s, 3H), 1,80 (m, 4H)r 1.71 (m, 3H) ppm; MS (ES) 496.1 (M+H);
1 - [6,7-d imeth oxyq u inazo I i n-4-yl )-A^-(7-pyrro I i d in -1 -y f-6,7,8,9-tetra hyd ro-5H-
be nzo [7]a n n u le ne-2-yl)-1H-1,2,4-triazol e*3,5-d i a m i n e, com pou nd #2 20,1H N MR 30 (DMSO-d6. 300 MHz) 9 21 (5, 1H), 9,06 (s, 1H), 8.80 (s, 1 H)r 8.11 (br s, 2H), 7.55
(m, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 6.98 (m, 1H), 3.93 (s, 3H), 3.93 (s, 3H), 2.71 (m, 7H), 2.17 (m, 3H), 1.80 (m, 4H), 1.44 (m, 3H) ppm; MS (ES) 501.2 (M+H);
1 -(7-methy l-2-ch lorothieno[3,2-d]pyrimidin-4-yl)-W3-(7"(N-methyl-N-bicyclo[2,2,1]heptan- 2-yl)amino-6,7,8p9-tetraiiydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4triazDle-3,5- 35 diamine, compound #221, 1H NMR (DMSO-d6, 300 MHz) 9.33 (sr 1H), 3.23 (s,
1H), 7,93 (br s, 2H), 7.52 (m, 1H), 7.42 (m, 1H). 7.11 (m, 1H). 3.86 (m, 1H), 3.55 (mr 1H), 3.27 (m, 1H), 2.73 (m, 5H), 2.04 (m; 2H), 2.36 (s, 3H), 2.27 (m, 3H), 2,06 (mf 4H). 1,80-1.13 (m, 10H)ppm; MS (ES) 549.1 (M+H);
H7-memy l-2-chloroth ieno[3,2-c(] py ri m i d in-4-y I )-N?~(T-i N-bicy cl o[2.2.1 ]h epta n-2- 5 y I )a m i n o-6,7, 8r 9-tetrahy d ro-GH-benzo[7] a n n u I en e*2-y I)-1H-1 r2,4-triazole-3,5-
diamine, compound #222,1H NMR [DMSO-d«, 300 MHz) 9.40 [s, 1H), 8.24 (s, 1H), 7.93 (brs, 2H),7.47(m, 2H). 7.11 (m, 1H), 3.42 (m, 1H): 3.24 (m, 1H), 2.80 (m, 4H): 2.64 (rn, 2H), 2.37 (s, 3H), 2.31 (mf 4H), 1.69 (m, 2H),. 1.51-1.11 (m, 9H) ppm; MS (ES) 535.1 [M+H); 10 1-(6,7-dimethoxyquinazolin-4-yl)-A/!-(7"(N-bicyclo[2.2.l]heptan-2-yl)amino-e,7l3,9-
tetrahydro-5H-benzo[7]annulene-2-yl)-1 H-1 ^-triazole-S.S-diamine, compound #223,1H NMR (DMSO-d6r 300 MHz) 9-25 (s, 1H)r9.06 (s, 1H), 8.32 (s, 1H), 6.14 (br s, 2H), 7,56 (m, 1H), 7.37 {s, 1H), 7.21 (s, 1H), 7.01 (m, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3,40 (m, 1H), 3,23 (m, 1H)f 2.73 {m, 4H), 2.43 (m, 1H), 2.30 [m, 3H), 15 173-1.11 [IT, 11H) ppm; MS (ES) 541.1 (M+H);
1-(6,7-dimethoxyqufnazolin-4-yl)-A^-(7-(N-methyl-N-bicyclo[2.2,1]heptan-2-yl)amino- 6,7,8,9-tetra hyd ro-5W- be nzo [7]a n nu Ie ne-2-y I)-1H-1,2,4-triazo te-3,5-dia m i ne, compound #224, 1H NMR (DMSO-ds, 300 MHz) 9.25 (s, 1H), 9.06 {s, 1H), 8.31 (s, 1H), B.14 (br s, 2H), 7.57 [m, 1H). 7.37 (s, 1H), 7.23 (m, 1H), 7.01 (m, 1H), 20 3,99 (s, 3H), 3.94 (s, 3H), 3.52 (m, 1H), 3.21 (m, 1H), 2.76 (S, 3H), 2.64 (m, 3H)r
2.25 (m, 4H), 1.73-1.12 (m, 11H)ppm; MS (ES) 555.3 (M+H);
1 -(7-methyl-2-chlorothieno[3,2-c/]pyrim idin-4-yl)-W}-(3- methy l-4-(4-( b i cyclo [2.2.1 ] he ptan- 2-yl)piperazin-1-yf)phenyl)-1H-1,2,4-triazole-3r5-diamine (TFA salt), compound #225; 1H-NMR (DMSO-ds, 300 MHz) 9.14 (s,1 H), 8.20 (s, 1H), 7.80 (s, 2H), 7.64 25 (m, 1H), 7.46 (m, 1H), 7,05 (m, 1H), 3.55 (m, 2H), 3.12 (m, 1H), 2.63 (m, 1H),
2.41 (m, 1H), 2.39 (s, 3H), 2-35 [m ,2H), 2.33 (s, 3H), 2,03 (m, 2H), 1.61 (m, 4H), 1.44 (m, 4H), 1.22 (m, 2H); MS (ES) 550.14 (M+H);
1-{4-methylthieno[3,2-d]pyr!dazin-7-y1)-W;i-(3-fluoro-4-(4-({1Sr2S,4R)-
bicyclor2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1s2,4-triazole-3l5-diamine 30 (TFA salt), compound #226; 'H-NMR (DMSO-dQp 300 MHz) 9.29 (s, 1H), 8.42 (dr
1H)f 7.98 (broads, 2H), 7.78 (d, 1H), 7.57[mr 1H), 7.31 (m, 1H), 7 00 (t, 1H), 2,95 (m, 4H), 2,84 (s, 3H), 2,49 (rn, 5H), 2.30 (m, 2H), 2,14(m, 1H), 1.71 (m, 2H), 1.10-1.50 (m,4H), 0.87 (m, 1H); MS (ES) 520.17 (M+H);
1 -(2-ch I oro-6- methoxy-qui noxa I i n- 3-y I)-A/3-^ luora-4-(4-( [ 1S, 25,4 fl}- 35 bicyclo[2.2.1]heptan-2-yl)piperazin-1 -yl) phenyl )-1 H-1 ^^-triazole-S.S-diamfne
(TFA salt), compound #227; qH-NMR (DMSO-dfj, 300 MHz) 9.19 (sr 1H), 7.96 (d, 1H), 7.50-7.61 (m, 2H): 7.25 (d, 1H), 7.15 (m, TH), 7.00 (t, 1H)r 3.96 (s, 3H), 3.00- 3.60 (m, 1UH), 2.53 (in, 1H), 2.48 (m , 2H), 2.28 (m. 1H), 1.96 [m, 1H), 1,55 (m: 1H), 1-37 (mr2H), 1.13 (m, 1H); MS (ES) 565.14 (M+H);
1 -(6,7-dimethoxy-1 -m eth y Iphth alazin-4-yl3-f lu oro4-
b i cy clo [2.2:1 ] he ptan-2-y I Jpiperazin-1 -y I )p h e ny I)-1 tf-1,2,'4-triazo le-3 , 5-diami ne (TFA salt), compound #228; 'H-NMR (DMSO-d6, 300 MHz) 9.00 (broad S, 1 H)r 8.60 (s, 1H), 7.83 (d, 1 H)r 7.52 (s, 1H), 7.28 (d, 1H), 7.06 (t, 1H), 4.05 (s, 3H), 3.96 (s. 3H), 3.37-3.52 (m, 4H), 3.07-3.17 (m, 4H), 2.S3 (s, 3H), 2.59 (m, 1H), 2.49 (s, 3H), 2.29 (m, 1H), 1.98 (m, 1H), 1.57 (m, 2H), 1.38 (m, 2H), 1.21 (m, 1H); MS (ES) 574.34 (M+H);
1 -(6-ph any Ipyrid a zi n-3-y f J-A/3^ 3-fIuoro-4-( 4-((1S,2S,4R)-bicyc!o[2.2.1]heptan-2-
ylJpiperazin-l-ylJphenyO-lH-l^^triazole-J,5-diamine, compound #229; ^-IMMR (DMSO-ds, 300 MHz) 9.23 (s, 1H), 8.40 (d, 1H), 8.11 (dr 1H), 7.99 (d, 1H), 7.B4 (broad s, 2H), 7,54 (m, 5H), 7,28 (m, 1H)r 6.96 (m, 1H), 3.29 (s, 3H), 2.97 (mr 4H). 2.46 (m, 4H), 2,28 (m, 2H), 2.13 (m,1H), 1.70 (m, 1H), 1.46 (m, 1H), 1.34(m, 1H), 1.13-1,25 (m, 3H), 0.85 (m, 1H); MS (ES) 526.31 (M+H);
1-(4-phenylpyridin-2-yl)-/V3-(3-fluoro-4-(4-((25)-bicyclo[2.2. IJheptan^-ylJpiperazin-l- ylJphenylJ-l /-M,2,4-triazole-3,5-diamine (TFA salt), compound # 230; 'H-NMR (CDCyMeOD-4. 300 MHz) 3.26 (d, 1H), 7.B6 (s, 1H)r 7.56 (m, 2H), 7,35-7.43 (m, 3H), 7.26 (m, 2H), 7,10 (ra, 1H), 6.37 (t, 1H), 3.25 (m, 1H), 3.12 (m, 1H), 2.50 (m, 1H), 2.27 (m, 1H), 1.77-1.94 (m, 4H), 1.38-1,65 (m, 11H); MS (ES) 525.13 (M+H);
1-(4-methylthi0no[3,2-d]pyridazin-7-yl)-AP-(3-chloro-4-(4-((2S)-bicyclo[2.2.1]heptan-2- y^piperazfn-l-ylJphenylJ-lH-l^^-triazole^S-diamine (TFA salt), compound #231; 1H-NMR (CDCI3/MeOD-4, 300 MHz) 9,35 (s, 1H), 6.34 (d, 1H), 7.90 (m, 1H), 7.72 (d, 1H), 7.43 (m, 1H), 7.10 (d, 1H), 3,36-3.46 (m, 2H), 2.97-3.21 (m, 9H), 2.50 {mr 1H), 2.39 (s, 3H), 2.20 (m, 1H), 1.90 (m, 1H), 1,50 (m, 2H), 1.31 (m, 2H), 1.10 {mr 1H); MS (ES) 537.16 (M+H);
1-(4-methylthienol3,2-d]pyridazin-7-yl)-WJ-(3-methyl-4-(4-((1Sl2S,4ft)-
bicyclo[2.2.1 ]heptan-2-yl )piperazin-1 -yl)phenyi)-1 H-1, 2,4-triazole-3,5-diamine, compound # 231; 1H-NMR (CDCI3/MeOD-4, 300 MHz) 7.89 (d, 1H), 7,41 (m, 1H), 7.26 (m, 2H), 6,94 (d, 1H), 3.94 (mr 4H), 2,84 (m, 4H), 2.75 (s, 3H), 2,49 (m, 2H), 2.23 (s, 3H), 2.10 (m, 1H), 1.67 (m, 2H), 1,42 (m, 1 H)p 1.25 (m, 4H), 0.8B (m, 1H); MS (ES) 516.22 (M+H);
1 -(7-methy I -2-m-tolylth ie no [3,2-d]pyri mid i n-4-yl )-A/5-(4-( 4-( b i cy clo [2.2.1 ]hepta n-2- yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound # 233; 1H NMR (DMSO-ds, 300 MHz) 9.11 (s, 1H, NH), 8.16-8.02 (m, 5H), 7.62 (d, 1H), 7.51-7.32 (m. 2H),6.91 (m, 2H), 3.32 (s, 3H), 3.04 (m,4H), 2.87-2.31 (m, 11H), 1.69 (m, 2H}, 1,51-1.10 (rn, 4H), 0.85 (d, 1H)ppm; MS (ES) 592.13 (M+H);
1-(7-methyl-2-(3-cyanophenyl)thieno[3,2-d]pyrimidin^^
2-yi)piperazin-i-yi)phanyi|-iH-i,z,+-triazole-3,5-diamine, compound # 234; 1H NMR (DMSO-dg, 300 MHz) 9.05 (s, 1Hr NH), 3.62 (s, 1H), 8.11 (s, 1H), 7.97 (a, 3H), 7.59 (m, 2H), 7.56 (d, 2H), 6.90 (d, 2H), 3,32 (s, 3H), 3,02 (s br, 4H), 2.43- 2.11 (m, BH), 1.6B (m, 2H), 1.40-1.07 (m, 4H). 0.84 (d, 1H) ppm; MS (ES) 603.07 (M+H);
1 -(7-methy l-2-( 2-ch lorophe nyl )th i e n o [3,2 -d] py ri m id i n-4-y I)-A/3-(4-(4-( (2S )-
bicyclo[2.2.1]hsptan-2-y1)piperazin-1 -yl)phenyl)-1 H-1,2,4-triazole-3,5-diamine, compound #235; 1H NMR (DMSO-d0[ 300 MHz) 9.25 (s, 1H, NH), 8.19 (s, 1H), 8.09 (s, 2H, NHZ), 7.89 (rn, 1H), 7.64 (m, 3H), 7,54 (5, 2H), 7.01 (d, 2H), 3,70- 2.96 (m, 11H), 2.59 (s, 1H), 2.58 (s, 4H), 2.28 (s, 1H}, 1.97 (m, 1 H); 1.59 (m, 2H), 1,39 (m, 1H), 1.18 (M, 1H) ppm; MS (ES) 612.21 (M+H), 610-41 (M-H);
1 -(7-methyl-2-benzo [d] [ 1,3]dioxo Ie -5-y It hie no [3 ,2-cf]py rim id i n-4-y I )-ftf-(4-( 4-((2 S)-
bicyclo[2.2.1]heptan-2-yl)piperazin-1 -yl)phenyf }-1 H-1,2,4-triazole-3,5-diamine (formic acid salt), compound #236; 1H NMR (DMSQ-dt, 300 MHz) 9,39 (s br, 2H, NH2), 9.21 (s, 1H, NH), B.08 (m, 2H), 7.B8 (d, 1H), 7,77 (s, 1H), 7.65 (d, 2H), 7.08-6.95 (m, 2H), 6.1 (s, 2H), 3.65 (m, 2H), 3,59-3.39 (m, 3H)r 2.58 (s, 1H), 2.27 (s, 1H), 2.02-1.91 (m, 1H)r 1.63-1,42 (m. 2H), 1.41-1.18 (m, 2H)ppm; MS (ES) 622,27 (M+H);
1-(7methy|-2-pyridin-4-ylthienoi;3l2-c0pyTimidin-4-yl)-IV3-(4-(4-((2S)-bicyclo[2.2.1]heptan- 2-yl)piporazin-1-yi)phenyi)-1H-1,2,4-triazole-3,5-dFamine (formic acid salt), compound # 237; 'H NMR (DMSO-d0, 300 MHz) 9 25 (s, 1H, NH), 8 90 (S, 1H), 8.45 (s, 1H), G.22 (s, TH), 8.15-8.02 (m, 2H), 7.65 (dr 2H), 7.37 (m, 1H), 7.02 (d, 2H), 3.81-3.42 (m, 4H), 3.29-2.91 (mr 5H), 2.66-2.19 (m, 6H), 1.98 (m, £H), 1.71- 1.32 (m, 4H), 1.21 (d, 1H)ppm; MS (ES) 579,25 (M+H), 577.37 (M-H);
1-(7-methyf-2-(3-(methy1sulfonyl)aminophenyl)thienD[3,2-c(]pyrimidin-4-yl)-W3-(4-(4-((2S> bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl) phenyl )-1 H-1,2,4-triazo le-3 r 5-d iamine (formic acid salt), compound # 238; 'H NMR (DMSO-d6, 300 MHz) 9.12 (s, 1H, NH), 8.26 (s, 1H), 8.10 (s, 1H), 8.12-8.02 (m, 3H), 7,60 (d, 2H), 7.53 (t, 1H), 7.37 (d, 1H), 6,93 (d, 2H), 3.04 (s br, BH)r 2.56-2.34 (m, 6H), 2.29-2.13 (m, 4H)r 1.69
(m, 2H), 1.51-1.06 (m, 4H), 0,86 (d, 1H) ppm; MS (ES) 671.24 (M+H), 669-39 (M-
H);
H7-methy1-2-(3--1 H-1,2,4-tr iazol e-3,5-dia mine 5 (formic acid salt), compound #239;
l-(7-methyl-2-(3-(4-methylpiperazin-l-yl)prop-l-ariyl)thieno[3,2-d]pyrimidin-4-yl)-W;i-(4- (4-(( 2 S)-bicyclo[2.2,11 hepta n-2-y! )pipera zi n-1 -y I )ph any I )■ ■1H-1,2, ■4-triazole-3,5- diamine (formic acid salt), compound #240; 1H NMR (DMSQ-de, 300 MHz) 9,04 (S, 1H, NH), 3.15-0,02 (m, 4H), 7.58 (d, 2H), 7.05-5.76 (m, 3H), 3.22 (d, 2H), 3.05 10 (sr 4H), 2.55-2.10 (m, 12H), 1.71 (m, 2H), 1.48-1.05 (m, 6H), 0.82 (d, 2H); MS
(ES) 64D.36 (M+H), 638.53 (M-H);
T-(7-methyt-2-(3-(morpholin-4-yf)prop-1-enyl)thieno[3,2-d]pyrimidin"4-yl)-A/3-(4-(4-((2S)- bi c^clo [2.2.1 ] he ptan-2-y l)pipera zin-1 -y I )phe ny I )-1 H-1,2,4-triazo le-3,5-diamine (formic acid salt), compound #241; 'H MMR (OMSO-de, 300 MHz) 9.05 (s, 1H, 15 NH), S. 12-8.01 (M, 3H), 7.59 (d, 2H), 7.02-6.78 (M, 4H), 3.59 (m, 4H), 3.21 (d,
2H), 3.04 (s, 4H), 2.56-2,09 (m, 14H), 1.78-1.59 (m, 2H), 1.41 (m, 1H), 1.39-1 -OB (m, 4H), 0.65 (d, 1H) ppm; MS (ES) 627.31 (M+H), 625.60 (M-H);
1 -(7-methylthieno[3,2-d]pyrimidin-4-yl )-W3-(3-chloro-4-(4-(( 1 5,2S,4f?)-
bi cy cl o [2.2,1 ]heptan-2-y !)piperazi n-1 -y I )p he ny I)-1 tf-1,2,4-triazo le-3,5-diam ino 20 (TFA salt), compound #242; 'H-NMR (DMSO-de, 300 MHz) 9.52 (br. s, 1H), 6.63
(s, 1H). 8.15-8.12 (n, 3H), 8.04 (m, 1H), 7.53-7.51 (m, 1H), 7.21-7.19 (m, 1H), 3.35 (m, 4H), 3.16 (rti, 4H), 2.50 (m, 3H), 2.43 (S, 3H), 2.29 (m, 2H), 1,98 (m, 1H), 1,58 (m, 2H), 1.40 (m, 2H), 1.20-1.13 (m, 1H) ppm; MS (ES) 536.64 (M+H);
1 -thieno[3,2-cflpyrim rdi n-4-y I 3-ch loro-4-(4-( (1 S,2S,4R)-bicyclo[2 2 1 ]heptan-2- 25 yl)piperazin-1 -yl)pheny1)-1 tf-1,2,4-triazole-3,5-diamine (TFA salt), compound
#243; ^-NMR (DMSO-de, 300 MHz 9.55 (br. s, 1H), 8-86 (d, 1H), 3,53 (dd, 1H), 6.14 (br. s, 2H), 8,04 (s, 1H), 7,62 (dd, 1H), 7.51
1 -th ieno[2,3-d] py ri m id i n-4-y HV:-( 3-ch I oro-4-(4-(( 1 £,2S,4R)-bicyclo[2.2.1 ]heptan-2- yl)piparazin-1-yl)phany1)-1/-M,2,4-triazole-3,5»dfamine (TFA salt), compound #244; 'H-NMR (DMSO-dG, 300 MHz 9.50 (br. s, 1H), 8.81 (s, 1H), 3.34 (d, 1H), 8.22 (br. s, 2H), 7.92 (d, 1H), 7.89 (s, 1H), 7.44 (d, 1H), 7.20 (d, 1H), 3.55-3.49 35 (m, 4H), 3.32 (m, 2H), 3.18-3.14 (m, 2H), 3-09-3.05 (m, 1H), 2.60 (m, 1H), 2.29
(m, 1H), 2.01-1.98 (m, 1H), 1.58 [m, 4H), 1.40 (m, 3H), 1.21-1.10 (m, 1H]ppm; MS (ES) 523.12 (M+H);
1-[7-rnethyl1hieno[3l2-£/|pyrirnidin-4-yl)-/V3-(3-fluora-4-(4-((1S,2Sl4ff)-
bicycloI2.2.l]heptan-2-yl)pipera7iri-1-yl)pheny|)-lH-l,2I4-trlazole-3,5-diamineI 5 compound #245; 1H-NMR (DMSO-d& 300 MHz) 9.38 (br. s, 1H), 8.87 (s, 1H),
8.16 (S, 1H), 0.10 (br. 3, 2H), 7.54 (ds J= 15.3 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H). 6.99 (t, J = 9.6 Hz, 1H), 2,95 (m, 4H), 2.42 (m, 4H), 2.43 (sr 3H), 2.28 (m, 2H), 2.14 (m, 1H), 1.71-1.66 (m, 2H}, 1.45-1.16 (rn, 5H), 0.88-0.84 (mr 1H)ppm; MS (ES) 520.01 (M+H);
10 1-phenyl-N's-(4-(me1hylaminocart)ony1)phenyl)-N;;-meth^-1 H-1, 2,4-triazole-3,5-d iamine, compound # 246; 'H NMR (CDjOD, 300 MHz) 7.87 (m, 2H), 7.54 (m, 7H), 7.38 (m, 1H), 3.85 (s, 3H), 2.96 (s, 3H); MS (ES) 323.17 (M+H);
1-phenyl-N5-(4-(ethyloxocarbonyl)phenyl)-N5-methyf-1H-1l2l4-triazole-3,5-diamine, compound #247; 'H NMR (CDjOD, 300 MHz) 7.90 (rn, 2H), 7,74 (m, 2H), 7.51 15 (m, 5H), 7.35 (m, 1H), 4.31 (m, 2H), 2.95 (s, 3H)r 1.37 (m, 3H); MS (ES) 338.10
(M+H);
1 -(7-methy Ith reno[3,2-d] py ri m id i n-4-y I)-A^-(3-fluoro-4-(3-( R)-m ethy I -4-
(bicyclo[2.2.1]heptan-2-y1)piperazin-1-y[)phenyl)-1H-1,2,4-trigzole-3,5-diamine (TFA salt), compound #248; ^-NMR (GDCI,
3.30-3.39 (m, 6H); 2.96 (m, 1H), 2,49 (s, 3H), 2.39 (m, 1H), 2,02 (m, 1H)r 1.60- 1.80 (m,2H), 1.65 (dr 3H), 1.51 (m, 6H); MS (ES) 534,20 (M+H);
1-(7-methylthieno[3;2-d]pyrimidin-4-y!)-/V:'"(3-fl uoro4-( 3-( S )-m ethy I -4-
(bi cyclo [2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1 tf-1,2.4-triazole-3,5-diamine 25 (TFA salt), compound #249; 1H-NMR (CDCI3fMeOD-4, 300 MHz) S.S1 (a, 1H),
7.78 (m, 1H) , 7.62 (m, 1H), 7.44 (s, 1H), 7.22 (m, 1H), 6,95 (t, 1H), 3.68 fm, 1H), 3.20-3,45 (m, 8H), 2,59 (m, 1H), 2.47 (s, 3H), 2.39 (m, 1H), 2.00 (m, 1H), 1.65 (d, 2H), 1,40-1.80 (m, 6H); MS (ES) 534,20 (M+H);
1-(7-methylthieno[3.2-c^pyrimidin^^ 30 bicyclo[2.2.1 ]heptan-2-yl )pfperazrn-1 -yl)phenyl)-1 H-1, 2.4-triazole-3,5-d iamine
(TFA salt), compound #250; 1H-NMR (CDCIj/MeOD-4, 300 MHz) B.65 (s, 1H), 8.25 (s, 1H), 7.62 (s, 1H), 7,40 (d, 1H), 7.05 (d, 1H), 6.80 (t, 1H), 3,55 (m, 1H), 3.00-3.25 (m, 7H), 2.36 (mr 1H)2.34(s, 3H), 2.19 (m, 1H), 1.70 (m, 2H), 1,36 (d, 3H),1.20-1.40 (m, 6H); MS (ES) 534.20 (M+H); 35 1-(7-methy I thiano[3,2-cf]py rim id in-4-yl)-Af3-( 3-fluoro-4-(3-(S)-m et hy |-4-(( 1 S,2S,4f!)-
bicyclc[2.2.1]heptan-2-yl)piperazin-1 -yi)phanyl)-1 H-1,2,4-triazole-3,5-diamine (TFA salt), compound #251; fH-NMR(CDCI3MeOD-4, 300 MHz) 8-46 (s, 1H), 8,21 (5, 1H), 7,45 (s, 1H), 7.29 (d, 1H), 6,90 (d, 1H), 6,64 (t, 1H), 3.35 (m, 1H), 2,96-3.10 (m, 7H). 2.31 (m, 1H), 2.16 (s, 3H), 2,10 (m, 1H), 1.73 (m, 1H)r 1,53 (m, 1H), 1.33 (d, 3H), 1.20-1.40 (m, 6H); MS (ES) 534,24 (M+H);
1-(7-methylthieno[3J2-tf|pvTimidin-4-yl)-Ws-(3-m8thyl'4~(4-((1Sl2SI4R)-
bicyclo[2.2.1 ]h epta n-2-yl) pipe razi n-1 -yl)phenyl)-1 H-1,2,4-triazole-3,5-diamine (TFA salt), compound #252; 1H-NMR (DMSO-dGl 300 MHz) 9.22 (s, 1H, exchanges with D20)f 8,67 (s, 1H), 8,15 (s, 1H), 8,07 (broad s, 2H, exchanges with D20), 7.66 (m, 1H), 7.45 (m, 1H), 7.03 (d, 1H), 3.51 (m, 6H), 3.00-3.25 (m, 4H), 2.61 (s, 1H), 2.49 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 1,99 (m, 1H), 1.59 (m, 1H), 1.38 (m, 1H), 1.22 (m, 1H); MS (ES) 516.32 (M+H);
1 -(7-methy Ith ien o[3,2-cf| py ri m i d i n-4-y I)-A^-^-meth y t-4-( 3-{ S)- methyl-4-(( 1S, 2S, 4ff )- bicycloI2,2,1 ]heptan-2-yl )piperazin-1 -yl) phenyl )-1 H-1,2,4-triazole-3,5-diamine (TFA salt), compound #253; 1H-NMR (DMSO-de, 300 MHz) 8.91 (s, 1H), 8.85 (s, 1H), 8.10(5, 1H), 7.92 (sf 2H), 7.59 (m, 1H), 7,42 (m, 1H), 7,00 (m, 1H), 2.98 (m, 1H), 2.80 (m, 4H)r 2.65 (m , 2H), 2.55 (m, 1H), 2.49 [m, 1H), 2.45 (s, 3H), 2.32 (s, 3H), 2.25 (m, 1H),2.14(m, 1H), 1.70 (m, 2H), 1.20-1,50 (m, 4H), 1,15 (d, 3H), 0.82 (m, 1H); MS (ES) 530.70 (M+H);
1-(7-methylthieno[3l2-d]pyrimidin-4-yl)-W5-(3-methyl-4-{3-(R)-methyl -4-(( 1S ,2 S, 4R)- bicyclo[2.2.1]heptan-2-yl)piperazin-1 -yl)pheny!)-1 H-1 ^-triazole-S.S-diamine (TFA salt), compound #254; 'H-NMR (DMSO-dc, 300 MHz) 9,14 (broad s, 1H), 8.83 {s, 1H), 8.16 9s, 1H), 8,12 (s, 1H), 8.0S (broad s, 2H)r 7.60 (m, 1H), 7.43 (m, 1H), 7,01 (m, 1H), 2.85 (m,2H)r 2.52 (m, 1H), 2.43 (s, 3H), 2,32 (s, 3H), 2.15 (m, 1H), 1.60-1.80 (m,2H), 1 30-1 50 (m, 2H), 1.10-1.30 (m, 9H), 1.03 9d, 3H), 0.95 (m, 1H); MS (ES) 530 (M+H);
1-thieno[3.2-c/]pyrimidin-4-yl-W:i-(3-fluoro-4-(3-(S)-methyl-4-((1S,2Sl 4R>
bicyclo[2.2.1] h epta n-2-yl) pipe razin-1 -yl)phenyl)-1 H-1,2,4-triazole-3,5-diamine (TFA salt), compound #255; ""H-NMR (DMSO-dBl 300 MHz) 9,50 (s, 1H), 9,10 (broad sp 1H), 6.85 (s, 1H), B.54(d, 1H), 8.13 (s, 1H), 7.71 (d, 1H), 7.61 (d, 1H)r 7.33 (m; 1H), 7.06 (t, 1H), 3.66 (m, 1H), 3.00-3-50 (mr 5H)r 2.56 (m, 1H), 2.48 (s, 3H), 2,30 (m, 1H), 1.94 {m, 1 H), 1.22-1,63 (m, 9H); MS (ES) 520.28 (M+H);
1-(2-chloro-6-methoxy-quinoxalin-3-yl)-W'f-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1- y I )phe nyl )-1 H-1,2,4-tri azol e-3,5-d i a m i n e, compound # 256; 1H-NMR (CDCI;i/McOD-4, 300 MHz) 9.21 {s, 1H), 7,B4(d, 1H), 7,28-7.41 (m, 2H), 7,24 (m,
1H), 7.12 (m, 1H), 6.89 (t, 1H), 3,90 (s, 3H), 3.78 (mr 4H), 3.30 (in, 2H), 2.63 (m, 4H), 2.18 (m, 1H), 1.93 (m, 2H), 1.78 (m, 4H); MS (ES) 538.14 (M+H);
1-(2-chlQro-7-m©thy1thieno[3,2-d]pyrimidin-4~yl)-/V3-(3-methyl-4-(3-(S)-iTiethyl-4-
((1S, 2 S, 4R)-b icydo[2.2.1 ] he pta n-2-yi Jpiperaz in-1 -y f )ph en y I )-l H-1,2,4-lrlazo le- 5 3,5-d iamine (TFA salL), compound #257, 1 H-NMR (DMSO-dc, 300 MHz) 9.59 (s,
1H), 0.02 (broad s, 1H), 8.26 (a, 1H), 7.96 (s, 1H), 7.66 (m, 1H), 7.32 (m, 1H), 7.07 (t, 1H), 3.68 (m, 1H), 3.50 (m, 1H>, 3.23-3.33 (m, 5H), 2,56 (m. 1H), 2.38 (s, 3H)r 2.30 (rn, 1H), 1.97 (m, 1H), 1.51 (d, 3H), 1-35-1.60 (m, 6H), 1.24 (m, 1H); MS (ES) 568.21 (M+H); 10 1-(6-phenylpyridaziri"3"yf)-A/5-(3-fluoro-4~(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-
1,2,4-tri azole-3,5-d la m Ine (TFA salt), compound #258; 1H-NMR (QDCl^/MeOD-4, 300 MHz) 7.92-8.06 (m, 4H), 7.47-7.57 (m, 4H), 7.11 (m, 1H), 6.93 9t, 1H), 3.42 (m, 4H), 3,17 (m, 2H), 2.78 (m, 2H)r 1.94-2.16 (m, 6H); MS (ES) 500.22 (M+H);
1 -(4-phenylpyridin-2-yl)-/^3-(3-fluoro-4-(4-(pymolidin-1 -yl)piperidin-1 -yl)phenyl)-1 H-1,2,4- 15 triazole-3,5-d iamine (TFA salt), compound #259;1 H-NMR (CDCI3,'MeOD-4, 300
MHz) 8.29 (d, 1H), 7.89 (S, 1H), 7.60 (d, 2H), 7.36-7.45 (m, 3H), 7.29 (d, 2H), 7,06 (m, 1H), 6,85 (t, 1H), 3.40 (m, 2H), 3.25 (m, 1H), 3,07 (m, 6H), 2,66 (t 2H), 1.90-2,00 (m, 6H); MS (ES) 499,14 (M+H);
1 -(7-rmethylthieno[3,2-cdpyrimidin-4-yl j- w3-(3-fluono-4-(4-(2-azabicyclo[2.2.1 ]heptan-2- 20 yl)piperidiri-1-yl)pheriyl)-1HL1l2l4-triazole-3j5-diamine (TFA salt), compound
#260; 1 H-NMR (DMSO-de, 300 MHz) 9,43 (br s, 1H), 8,87 (s, 1H), 8.15 (s, 1H), 8.12 (br. S, 2H), 7,65 (d, J= 15.3 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.03 (t, J = 9,3 Hz, 1H), 3.55 (m, 4H), 3.35-3.20 (m, 3H), 2.71-2.65 (m, 1H), 2.43 (s, 3H), 2.28-2.26 (m, 3H), 2.05-1.92 (m, 4H), 1.74-1,69 (m, 4H) ppm; MS (ES) 520,24 25 (M+H);
1 -(7-methylthieno[3,2-cGpyrimidin-4-yl)-W3-(4-(1 -(bi cyclo [2.2.1 ]heptan-2-yl)piperidin-4- yl)phenyl)-1H-1f2,4-triazols-3,5-diamine (TFA salt), compound #261; 'H-NMR (DMSO-d3, 300 MHz) 9,38 (br. s, 1H), 8.87 (s, 1H), 8,12 (s, 1H), 8.12 (s, 1H), 8.10 (br. s, 2H), 7,68 (d, J = 8.4 Hz. 2H), 7.19 (d, J = 8.4 Hz, 2H), 3.50-3.40 (m, 3D 4H)r 3.02 (m, 1H), 2.43 (s, 3H), 2.23-2.20 [m, 1H), 1.98(m, 6H), 1.58 (in, 4H),
1.41 (m, 4H) ppm; MS (ES) 501.24 (M+H), 439.36 (M-H);
1 -(7-methylthleno[3,2-c/]pyrimidin-4-yl)-/V?-(3-fluoro4-(1-((1 S,2S,4R)-bicycloI2,2.1]heptan- 2-yl)piperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-dlamlne (TFA salt), compound #262,1H-NMR (DMSO-dGl 300 MHz 9.64 (br. s, 1H), 8.89 (s, 1H), 8.15 (br. s, 3H), 35 7.68 (d, 1H), 7.39 (d,2H), 7.20 (t, 1H), 3.06 (m, 4H), 2.60 (m, 1H), 2.43 (s, 3H>,
2.29 (m, 1H), 2,02-1.96 (m, 4H), 1.57 (m. 4H), 1.40-1.36 (m. 4H), 1.16-1-14 1H) ppm; MS (ES) 519.68 (M+H); 1 -(7-m ethy l-2-oh loroth i e no [3,2-dJpyrim id i n-4-yl J-W^-f 8-(2-diethy la m i n oeth y I }-9- hydroxy- 6,7,8,9-1etra hyd ro- 5H- benzo [7]an nule ne-2-y I)-1 H-1, 2,4-tri azol e-3,5-diamine, 5 compound #263; 1H NMR (DMSO-dg, 300 MHz) 9.43 (s, 1H), 9.24 (s br, 1H), 8.25
(s, 1H), 7.94 (s, 2H), 7.57 (d, 1H), 7.47 (s, 1H), 7.09 (d, 1H), 4.50 {d, 1H), 3.75- 3.43 (m, 2H), 3.34-3.07 (m, 5H)r 2.89 (m, 1H), 2,61 (m, 1H), 2.47 (s, 3H), 2.36 (m, 2H), 2,10-1.39 (m, 4H)r 1.17 (m, 6H) ppm; MS (ES) 541.20 (M+H); and 1-(7-methyl-2-chlorothieno[372-^pyrimidin-4"yl)-W3"(8-(2'diethylaminosthy{)-9-hydroxy-
10 6,7,8,9-tetrahyd ra- 5H- benzo [7]an nu le ne-2-yl)-1H-1, 2,4-tri azol e-3,5-diamine
trifleuroacetic acid salt (TFA salt of compound #263); 1H NMR (DMSQ-d^, 300 MHz) 9.43 (s, 1H), 9.24 (s br, 1H), 6.25 (s, 1H), 7.94 (s, 2H), 7.57 (d, 1H), 7.47 (s, 1H), 7,09 (d, 1H), 4,50 (d, 1H), 3.75-3.43 (m, 2H), 3,34-3,07 (m, 5H), 2.89 (m, 1H), 2.61 (m, 1H), 2.47(5, 3H), 2,36 (mr 2H), 2.10-1.39 (m, 4H), 1.17 (m,6H)
15 ppm; MS (ES) 541.15 (M+H)r 539.35 (M-H).
TESTING OF THE COMPOUNDS OF THE INVENTION
The compounds of the invention were tested in the following assay for their ability to inhibit Axl activity.
20 PHOSPHO-AKT JN-CELL WESTERN ASSAY
REAGENTS AND BUFFERS:
Cell culture plate; 96 well assay plate (Coming 3610), white, clear bottom, tissue-
culture treated. Cells: Hela cells.
25 Starvation medium; For Axl stimulation; 0.5% FCS (fetal calf serum) in DMEM, plus Axl/Fc (extracellular domain of AXL fused to imunoglobulin Fc region) (R&D, 154-AL) 500ng/mL.
For EGF (epidermal growth factor) stimulation: 0.5% FCS in DMEM (Dulbecco's modified Eagles medium).
30 Poly-L-Lysine 0,01% solution (the working solution): 1Gpg/ml, dilute In PBS (phosphate buffered saline). Axl antibody cross-linking:
1sl: Mouse anti-Axl (R&D, MAB154).
2na: Biotin-SP-conjugated AffiniPure goat anti-mouse IgG (H+L) (Jackson ImmunoResearch #115-065-003). Fixing buffer: 4% formaldehyde in PBS. 5 Wash buffer: 0.1 % Trito nX-100 in PBS.
Quenching buffer: 3% H1O2, 0.1% AEide in wash buffer, Azide and hydrogen peroxide
(H202) are added fresh. Blocking buffer: 5% BSA in TBST (iris buffered saline pi us 0.1% Tween 20). Frimary antibody: Rabbit anti-human PhosphoAkt antibody (Cell Signaling 9271): 10 1x250 diluted in blocking buffer.
Secondary antibody: HRP (horse radish peroxidasey-conjugated Goat anti-Rabbit secondary, stock solution: Jackson I mmu no Re search (Goat anti-Rabbit HRP, #111-035-144 ) 1:1 diluted in glycerol, store at-20° C. The working solution: 1x 2000 dilution of stock in blocking buffer, 15 ChemHuminescent working solution (Pierce, 37030): SuperSignal ELISA (enzyme linked immunosorbant assay) Pico Chemiluminescent substrate, Crystal Violet solution: Stock: 2.5% Crystal violet in methanol, filtered and kept at ambient temperature. The working solution: dilute the stock 1:20 with PBS immediately before use. 20 10% SDS: working solution: 5% SDS (sodium dodecy I sulfate), diluted in PBS
METHODS: Day 1:
A 96 well TC (tissue culture treated) plate was coated with 10^g/mL poly-L- Lysine at 373C for 30 min, washed twice with PBS, and air-dried for 5 minutes before 25 cells were added. Hela cells were seeded at 10,000 cells/well and the cells were starved in 100 |JL starvation medium containing Axl/Fcfor24 hrs.
Pay.2:
The cells were pre-treated with test compounds by adding 10Q pL of 2X test compound to the starvation medium on the cells, The cells were incubated at 37°C for 1 30 hr before stimulation.
The cells were stimulated by Axl-antibody cross-linking as follows: A 5X iEV2nd Axl antibody mixture was made (37.5pg/mL 157 100|jgfrnL 2nd) in starvation medium and nutated at 4'C with thorough mixing for 1-2 hours for clustering. The resulting mix was
warmed to 37°C. 50pL of 5X Axl 1Et /2nd of antibody cluster was added to the cells and the cells were incubated at 37C,C for 5 min.
After 5 minutes stimulation, the plate was flicked to remove medium and the plate was tapped onto paper towels. Formaldehyde (4.0% in PBS, 1D0 pL) was added to fix 5 the cells and the cells were incubated at ambient temperature for 20 min without shaking.
The cells were washed with a plate washor buffer to remove the formaldehyde solution, The plate was flicked to removed excess wash buffer and tapped onto paper towels. Quenching buffer (100 pL) was added to each well and the cells were incubaled 10 at ambient temperature for 20 minutes without shaking.
The cells were washed with a plate washer buffer to remove the quenching buffer. Blocking buffer (100 pL) was added and the cells were incubated at ambierrt temperature for at least an hour with gentle shaking.
The cells were washed with a plate washer buffer and diluted primary antibody 15 (50 pL) was added to each well (blocking buffer was added to the negative control wells instead). The plates were incubated overnight at 4° C with gentle shaking. Day 3:
The wash buffer was removed, diluted secondary antibody (100 pL) was added, and the cells were incubated at ambient temperature for 1 hour with gentle shaking. 20 During the incubation, the chemiluminescent reagent was brought to ambient temperature.
The secondary antibody was removed by washing the cells 1X with wash buffer, 1X with PBS by plate washer, The PBS was removed from the plate and the chemiluminescent reagent (SO pL; 40 pl_ A and 40 pL B) was added to each well at 25 ambient temperature.
The resulting chemiluminescence was read with a Luminomitor within 10 minutes to minimize changes in signal inLensity. After reading the chemiluminescence, the cells were washed 1X with wash buffer and 1X with PBS by plate washer. The plate was tapped onto paper towels to remove excess liquid from wells and air-dried at ambient 30 temperature for 5 minutes.
Crystal Violet working solution (00 pL) 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 rinsed wiLh PBS, then washed 3X with PBS (200 pL) for 5 minutes each.
35 5% SDS solution (70 pL) was added to each well and the cells were incubated on
a shaker for 30 min at ambienL temperature.
The absorbance was read at 590 nM on a Wallac photospec. The 590nM readings indicated the relative cell number in each well. This relative call number was then used to normalize each luminescence reading.
5 The results of the ability of the compounds of the invention to inhibit Axl activity,
when tested in the above assay, are shown in the following Tables wherein the level of activity f/.e., the IC5D) for each compound is indicated in each Table. The compound numbers in the Tables referred to the compounds disclosed herein as being prepared by the methods disclosed herein:
a shaker for 30 min at ambienL temperature.
The absorbance was read at 590 nM on a Wallac photospec. The 590nM readings indicated the relative cell number in each well. This relative call number was then used to normalize each luminescence reading.
5 The results of the ability of the compounds of the invention to inhibit Axl activity,
when tested in the above assay, are shown in the following Tables wherein the level of activity f/.e., the IC5D) for each compound is indicated in each Table. The compound numbers in the Tables referred to the compounds disclosed herein as being prepared by the methods disclosed herein:
All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are 5 incorporated herein by reference, in their entireties.
Although the foregoing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of th© appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is
10 not to be limited to the details given herein, but may be modified wilhin the scope and equivalents of the appended claims.
CO
CLAIM
1. A compound according to formula (la):
R3
N—N
(la)
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)R8 and -C(0)N(R6)R7;
R2 is aryl optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -R°-OR8, -R9-O-R10-OR8, -R*-O-R10-O-R10-OR8, -R9-O-R10-CN, -R9-O-R10-C(O)ORS, -R9-O-R10-C(O)N(RS)R7, -R*-O-R10-S(O)PR8 (where p is 0, 1 or 2), -RG-O-R10-N (R6)R7, -F?-O-R10-C(NR11)N(R11)H, -R^-OQCO-R8 -RG-N(R6)R7, -RG-C(0)R8, -RG-C(0)0R8, -R^CFOJNFR^R7, -R^-NFR^CFOJOR8 -RG-N(R6)C(0)R8, -R^NFR^SFO)^!8 (where t is 1 or 2), -RG-S(0)T0R8 (where t is 1 or 2), -RG-S(0)PR8 (where p is 0, 1 or 2), and -R^SFOJTNFR^R7 (where t is 1 or 2);
R3 is aryl optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -Rg-OR8, -Rg-O-R10-OR8, -R^-O-R^-O-R^-OR8, -RG-O-R10-CN, -Rg-O-R10-C(O)OR8, -RG-O-R10-C(O)N(Rs)R7, -R^-O-R^-SfOjpR8 (where p is 0, 1 or 2), -Rg-O-R10-N (Re)R7, -R^O-R^qNR^NfR^H, -R^-OqOj-R8 -Rg-N(Re)R7, -RG-C(0)Rs, -R9-C(0)0Rs, -R^C(0)N(R6)R7, -R^-NfR^CfOJOR8,
-R9-N(R6)C(0)RS, -R^-NFR^SFO)^5 (WHERE T IS 1 OR 2), -RA-S(0)T0R8 (WHERE T IS 1 OR 2), -RG-S(0)PR8 (WHERE P IS 0, 1 OR 2), AND -R^-SPMR^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 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 heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,-R10-OR8, -R10-CN, -R10-NO2l -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 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 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted hete roaryl alkynyl;
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 hydrogen, alkyl, cyano, nitro or -OR8;
as an isolated stereoisomer or mixture thereof, or a pharmaceutical^ acceptable salt there of.
2. The compound of Claim 1 having the following formula (Ia1):
(la1)
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)Rs and -C(0)N(Re)R7;
R2a is -R10a-N(R6a)R7a where R6a and R7a, together with the common nitrogen to which they are both attached, form an optionally substituted Nheteroaryl or an optionally substituted Nheterocyclyl, and R10disan optionally substituted straight or branched alkylene chain;
R29 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R"-OR89, -R^-CfOjR89, -R"-C(0)0R89, -R"-N(R69)R79 and -R"-C(0)N(R69)R79, where each R69, R79 and R89 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R99 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R3 is aryl optionally substituted by one or more substituents selected from the group
consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -Rg-OR8, -R9-O-R10-OR8, -R^O-R^-O-R^-OR8 -R9-O-R10-CN, -R9-O-R10-C(O)OR8, -R°-O-R10-C(O)N(R6)R7, -R^-O-R^-SfOJpR8 (where p is 0, 1 or 2), -R9-O-R10-N(R6)R7, -F?-O-R10-C(NR11)N(R11)H, -R^OqCO-R8 -R9-N(R6)R7, -R9-C(0)R8, -R9-C(0)0R8, -R^-QOMR^R7, -R^-NfR^CfOJOR8, -R9-N(R6)C(0)R8, -R^-NfR^SfO)^!8 (where t is 1 or 2), -R9-S(0)t0R8 (where t is 1
□r 2), -R9-S(0)pR8 (where p is 0, 1 or 2), and -R^-SfOJtNfR^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 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 heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,-R10-OR8, -R10-CN, -R10-NO2l -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 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 heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted hete roaryl alkynyl;
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 hydrogen, alkyl, cyano, nitro or -OR8.
3. The compound of Claim 1 wherein: R1, R4and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2a is -R10a-N(R6a)R7a where R6aand R7a, together with the common nitrogen to which they are both attached, form an optionally substituted Nheteroaryl or an optionally substituted W-heterocyclyl, and R10aisan optionally substituted straight or branched alkylene chain; R29 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, aryl, aralkyl, -R"-OR89, -R^-CfOjR89, -R"-C(0)0R89, -R"-N(R69)R79 and -R"-C(0)N(R69)R79, where each R69, R79 and R89 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R99 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R3 is a bicyclic aryl optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR8, -R^-OCfOJ-R8, -R9-N(R6)R7, -R^-CfOJR8 -R9-C(0)0R8, -R9-C(0)N(R6)R7, -R9-N(R6)C(0)0R8, -R9-N(Rs)C(0)R8, -R9-N(R6)S(0)tR8 (where t is 1 or 2), -R^-S^OR8 (where t is 1 or 2), -R9-S(0)pR8 (where p is 0, 1 or 2), and -R9-S(0)tN(R6)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR8 -R10-CN, -R10-NO2, -R10-N(R8)2i -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 Nheteroaryl or an optionally substituted Nheterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl,
haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted hete roarylalkyl;
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.
4. The compound of Claim 1 having the following formula (Ia2):
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)R8 and -C(0)N(R6)R7;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -Rgb-ORSb,
-R9b-C(0)0R8b, -R^b-N(R6b)R7b and -R9b-C(0)N(R6b)R7b, where each R6b, R7b and RSb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R0b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
R2c is selected from the group consisting of-C(0)R8, hydrogen, alkyl, an optionally substituted non-bridged cycloalkyl and an optionally substituted bridged cycloalkyl;
R3* is selected from the group consisting of hydrogen and alkyl;
R3 is aryl optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -Rg-OR8,
-R9-O-R10-OR8, -R^O-R^-O-R^-OR8 -R9-O-R10-CN, -RA-O-R10-C(O)OR8, -R9-O-R10-C(O)N(RS)R7, -R^-O-R^-STOJPR8 (WHERE P IS 0, 1 OR 2), -R9-O-R10-N(R6)R7, -F?-O-R10-C(NR11)N(R11)H, -^-0C{0)-RS, -R9-N(R6)R'
,8
-Ra-C(0)Rs, -R9-C(0)0Rs, -R^-CfOJNfR^R7, -R^-NfR^CfOjOR8 -R°-N(R6)C(0)R8, -F^-NtR^StOJiR8 (where t is 1 or 2), -R°-S(0)t0R8 (where t is 1 or 2), -Rg-S(0)pR8 (where p is 0, 1 or 2), and -R®-S(0)tN(R6)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxy alky I, 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 heteroarylalkynyl, -R10-OR8, -R10-CN, -R10-NO2l -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 Nheteroaryl or an optionally substituted N-heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, 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 hete roaryl alkynyl;
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 hydrogen, alkyl, cyano, nitro or -OR8.
5. The compound of Claim 4 wherein: R1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl;
R2b is selected from the group consisting of hydrogen, halo, haloalkyl, -R9b-OR8b,
-Rgb-C(0)0RSb, -F3eb-N(Reb)R7b and -R0b-C(O)N(R6b)R7b, where each R6b, R7b and R8b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and aralkyl, and each R9b is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; R2cis an optionally substituted non-bridged cycloalkyl; R21* is selected from the group consisting of hydrogen and alkyl;
R3 is a bicyclic aryl optionally substituted by one or more substituents selected from the group consisting of oxo, halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -R9-OR8, -R*-0C(0)-R8 -R9-N(R6)R7, -R*-C(0)R8 -Rg-C(0)0R8, -R9-C(0)N(R6)R7, -R9-N(R6)C(0)0R8, -R9-N(Rs)C(0)R8, -R9-N(R6)S(0)tR8 (where t is 1 or 2), -R^-S^OR8 (where t is 1 or 2), -Rg-S(0)pR8 (where p is 0, 1 or 2), and -R9-S(0)tN(R6)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR8 -R10-CN, -R10-NO2, -R10-N(R8)2i -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 Nheteroaryl 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 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted hete roarylalkyl;
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.
6. The compound of Claim 5 wherein:
R20is selected from the group consisting of optionally substituted bicyclo[2.2.1]heptanyl, optionally substituted bicyclo[3.2.0]heptan-6-yl, optionally substituted bicyclo[3.3.1]nonanyl and optionally substituted adamantanyl.
7. The compound of Claim 1 having the following formula (Ia3)
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, -C(0)R8 and -C(0)N(R6)R7;
R2e is selected from the group consisting of halo, -OR8, -C(0)R8, -C(0)0R8,
-R10e-N(R6)R7, -R10e-C(O)N(R6)R7, optionally substituted heterocyclyl and optionally substituted heteroaryl, where each R10eisan optionally substituted straight or branched alkylene chain;
R2d and R2* are each independently selected from the group consisting of hydrogen, halo, alkyl and -OR8;
R3 is aryl optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, -Rg-OR8, -Rg-O-R10-OR8, -R^-O-R^-O-R^-OR8, -Rg-O-R10-CN, -Rg-O-R10-C(O)OR8, -Rg-O-R10-C(O)N(Rs)R7, -Rs-O-R10-S(O)pR8 (where p is 0, 1 or 2), -R9-O-R10-N(R6)R7, -F?-O-R10-C(NR11)N(R11)H, -F?-0C(0)-R®, -R9-N(R6)R7, -R°-C(0)Rs, -R°-C(0)0Rs, -R^-qOMR^R7, -R^-N^qOjOR8 -R9-N(R6)C(0)R8, -R^-NfR^SfO)^8 (where t is 1 or 2), -Rg-
S(0)t0R8 (where t is 1 or 2), -R9-S(0)pR8 (where p is 0, 1 or 2), and -R^SfOJtNfR^R7 (where t is 1 or 2);
each R6 and R7 are each independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, 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 heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,-R10-ORS, -R10-CN, -R10-NO2l -R10-N(RS)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 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 aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyialkenyl, optionally substituted heterocydyialkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted hete roaryl alkynyl;
each R9 is independently selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; each R10 is an optionally substituted straight or branched alkylene chain; and each R11 is hydrogen, alkyl, cyano, nitro or -OR8.
8. The compound of Claim 1 having the following formula (Ia4):
(la4)
R2f R^
wherein:
R1, R4and R5 are each independently selected from the group consisting of hydrogen,
alkyl, aryl, aralkyl, -C(0)R8 and -C(0)N(R6)R7; R2h is selected from the group consisting of hydrogen, -N(R6h)R7h, optionally substituted heterocyclyl and optionally substituted heteroaryl, where RSh is hydrogen or alkyl and R7h is an optionally substituted bridged cycloalkyl; R2d is independently selected from the group consisting of hydrogen, halo, -OR8 and -Rg-N(R6)R7;
Ra, R2land R2j are each independently selected from the group consisting of hydrogen, halo and -OR8;
R3 is aryl optionally substituted by one or more substituents selected from the group consisting of halo, haloalkyl, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclyialkenyl, -Rg-OR8, -R^-OqOj-R8 -Rg-N(Re)R7, -Rg-C(0)R8, -Rg-C(0)0R8, -Rg-C(0)N(R6)R7, -Rg-N(R6)C(0)0R8, -Rg-N(Rs)C(0)R8, -Rg-N(R6)S(0)tR8 (where t is 1 or 2), -R0-S(O)tOR8 (where t is 1 or 2), -Rg-S(0)pR8 (where p is 0, 1 or 2), and -Rg-S(0),N(Re)R7 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R10-OR8 -R10-CN, -R10-NO2, -R10-N(R8)2i -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 Nheteroaryl or an optionally substituted Nheterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl,
haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted hete roarylalkyl;
each Rg 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.
9. The compound of any one of claims 1,2,4,7 or B wherein R3 is monocyclic, bicyclic or tricyclic.
10. The compound of Claim 1 selected from the group consisting of: 1-phenyl-A/3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5-diamine; 1-(4-isopropylphenyl)-W3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1 H-1,2,4-triazo le-3,5-
diamine;
4-(5-amino-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-1 H-1,2,4-triazo 1-1 -
yl)benzenesu If on amide; 1-(2-fluorophenyl)-W3-(4-(2-(2-methylpyrrolidin-1 -yl)ethoxy)phenyl)-1 H-1,2,4-tria zo le-3,5- diamine;
1-(2-fluorophenyl)-/V3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1 H-1,2,4-triazole-3,5-diamine; and
1-(2-fluorophenyl)-A/3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine; 1-(4-isopropylphenyl)-A/3-(4-morpholinophenyl)-1 H-1,2,4-triazo le-3,5-diamine; W3-(4-methoxyphenyl)-1-(pyridin-2-yl)-1 H-1,2,4-triazole-3,5-diamine; 1-(4-(5-amino-1-(2-fluorophenyl)-1 H-1,2,4-triazo I-3-ylamino)p he nyl)eth an one; 1-(pyridin-2-yl)-A/3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazo le-3,5-diamine; 1-(pyridin-2-yl)-A/3-(3,4,5-trifluorophenyl)-1 H-1,2,4-triazole-3,5-diamine; 1-phenyl-A/3-(4-(methylaminocarbonyl)phenyl)-N5-methyl-1 H-1,2,4-triazo le-3,5-diamine; and
1-phenyl-A/3-(4-(ethyloxocarbonyl)phenyl)-N5-methyl-1 H-1,2,4-triazole-3,5-diamine.
11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to any one of Claims 1, 2,4, 7 or 8.
12. A method of treating a disease or condition associated with Axl activity in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound according to any one of Claims 1,2,4,7 or 8.
13. The method of Claim 1 2 wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease, vascular injury, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, kidney disease, osteoporosis, osteoarthritis and cataracts.
14. The method of Claim 1 3, wherein a manifestation of the disease or condition is solid tumor formation in said mammal.
15. The method of Claim 14, wherein the disease or condition is selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma.
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