AU2012202710A1 - Quinoline derivatives as P13 kinase inhibitors - Google Patents

Abstract

C \NRPortihlDCC\KXG\4 ()d I DOC5-9A 12W 2 Invented is a method of inhibiting the activity/function of P13 kinases using quinoline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases. allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer. sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinoline derivatives.

Description

A ustralian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Quinoline derivatives as l3 kinase inhibitors" The following statement is a full description of this invention, including the best method of performing it known to us:- QUINOLINE DERIVATIVES AS P13 KINASE INHIBITORS This is a divisional of Australian Patent Application No. 2008254915, the entire contents of which are incorporated herein by reference. Field of the invention 5 This invention relates to the use of quinoline derivatives for the modulation, notably the inhibition of the activity or function of the phosphoinositide 3' OH kinase family (hereinafter P13 kinases), suitably, Pl3Ka, P13K6, Pl3Kp, and/or P13Ky, particularly Pl3Ka. Suitably. the present invention relates to the use of 10 quinolines derivatives in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, particularly cancer. 15 Background of the invention Cellular membranes represent a large store of second messengers that can be enlisted in a variety of signal transduction pathways In regards function and 20 regulation of effector enzymes in phospholipids signaling pathways, these enzymes generate second messengers from the membrane phospholipid pools (class 1 P13 kinases (e.g. Pl3Kalpha) are dual-specificity kinase enzymes, meaning they display both: lipid kinase (phosphorylation of phosphoinositides) as well as protein kinase activity, shown to be capable of phosphorylation of protein as substrate, including 25 auto-phosphorylation as intramolecular regulatory mechanism. These enzymes of phospholipids signaling are activated in response to a variety of extra-cellular signals such as growth factors, mitogens, integrins (cell-cell interactions) hormones, cytokines, viruses and neurotransmitters such as described in Scheme I hereinafter and also by intracellular regulation by other signaling molecules (cross-talk, where 30 the original signal can activate some parallel pathways that in a second step transmit signals to Pl3Ks by intra-cellular signaling events), such as small GTPases, kinases or phosphatases for example. Intracellular regulation can also occur as a result of - 1 aberrant expression or lack of expression of cellular oncogenes or tumor suppressors. The inositol phospholipid (phosphoinositides) intracellular signaling pathways begin with activation of signaling molecules (extra cellular ligands, stimuli, receptor dimerization, transactivation by heterologous receptor (e.g. receptor 5 tyrosine kinase) and the recruitment and activation of P13K including the involvement of G-protein linked transmembrane receptor integrated into the plasma membrane. P13K converts the membrane phospholipid Pl(4,5)P 2 into PI(3,4,5)P 3 that functions as a second messenger. Pl and P(4)P are also substrates of l13K and can 10 be phosphorylated and converted into Pl3P" and PI(3,4)P) 2 , respectively. In addition, these phosphoinositides can be converted into other phosphoinositides by 5' specific and 3'-specific phophatases, thus P13K enzymatic activity results either directly or indirectly in the generation of two 3' -phosphoinositide subtypes that function as 2"'n messengers in intra-cellular signal transduction pathways (Trends 15 Biochem. Sci. 22(7) p.

26 7

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72 (1997) by Vanhaesebrocck et al.. Chem. Rev. 10 l(8) p.

23 65

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8 0 (2001) by Leslie et al (2001); Annu. Rev. Cell.Dev. Biol. 17p, 615-75 (2001) by Katso et al. and Cell. Mol. Life Sci. 59(5) p.761- 79 (2002) by Toker et al.). Multiple P13K isoforms categorized by their catalytic subunits. their regulation by corresponding regulatory subunits, expression patterns and signaling-specific 20 functions (p I On, 0, 6 and y) perform this enzymatic reaction (Exp. Cell. Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001, above). The closely related isoforms p1 1On and 0 are ubiquitously expressed, while 6 and y are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (Trends Biochem. Sci. 22(7) p.

2 67

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72 25 (1997) by Vanhaesebroeck et al.). Their expression might also be regulated in an inducible manner depending on the cellular, tissue type and stimuli as well as disease context. Inducibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits. 30 To date. eight mammalian P13Ks have been identified, divided into three main classes (I, 11, and Ill) on the basis of sequence homology, structure, binding partners, mode of activation, and substrate preference. In vitro, class I PI3Ks can -2phosphorylate phosphatidylinositol (1I), phosphatidylinositol-4-phosphate (Pl4P), and phosphatidvlinositol-4,5-bisphosphate (P(4,5)P17) to produce phosphatidylinositol-3-phosphate (Pl3P"), phosphatidylinositol-3,4-bisphosphatc (PI(3,4)P 2 , and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P 3 , respectively. 5 Class 11 Il3Ks phosphorylate P and phosphatidylinositol-4-phosphate. Class Ill PI3Ks can only phosphorylate P (Vanhaesebrokcck et al., 1997, abovc; Vanhaesebroeck et al., 1999, above and Leslie et al, 2001, above) Scheme I: Conversion of PI(4,5)P2 to PIP3 10 P, OH H O 0 2 0 5

O-P

O / H OHH 0 0 Inositol ring 0 Ptdins(4,5)P, 0 0 O O P13K H 1O H S 0 0 2 H 0 O-p-0 04P II O\\ H OHH 0 0 0

CH

2 0 O _O Pid! ns(3.4.5)P, As illustrated in Scheme A above, phosphoinositide 3-kinases (PI3Ks) phosphorylate the hydroxyl of the third carbon of the inositol ring. The -3phosphorylation of phosphoinositides that generate Ptdlins to 3,4,5-trisphosphate (Ptdlns(3,4,5)P3), Ptdlns(3,4)P2 and Ptdins(3)P produce second messengers for a variety of signal transduction pathways, including those essential to cell proliferation, cell differentiation, cell growth. cell size, cell survival, apoptosis, 5 adhesion. cell motility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes, vesicle trafficking and metabolic pathway (Katso ct al., 2001, above and Mol. Med. Today 6(9) p. 347-57 (2000) by Stein). G-protein coupled receptors mediate phosphoinositide 3'O-l-kinase activation via small GTPases such as Gfy and Ras. and consequently Pl3K signaling plays a central role 10 in establishing and coordinating cell polarity and dynamic organization of the cytoskeleton - which together provides the driving force of cells to move. Chemotaxis -- the directed movement of cells toward a concentration gradient of chemical attractants, also called chemokines is involved in many important diseases such as inflammation/auto-immunity, neurodegencration. antiogenesis, 15 invasion/metastasis and wound healing (Immunol. Today 21(6) p. 260-4 (2000) by Wyman et al.; Science 287(5455) p. 1049-53 (2000) by Hirsch et al.; FASEB J. 15(1 ) p. 2019-21 (2001) by Hirsch et al. and Nat. Immunol. 2(2) p. 108-15 (2001) by Gerard et al.). Advances using genetic approaches and pharmacological tools have provided 20 insights into signalling and molecular pathways that mediate chemotaxis in response to chemoattractant activated G-protein coupled receptors. P13-Kinase, responsible for generating these phosphorylated signalling products, was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (Pl) and its phosphorylated 25 derivatives at the 3'-hydroxyl of the inositol ring (Panayotou et al.. Trends Cell Biol. 2 p. 358-60 (1992)). However, more recent biochemical studies revealed that class I P13 kinases (e.g. class IB isoform PI3Ky) are dual-specific kinase enzymes, meaning they display both lipid kinase and protein kinase activity, shown to be capable of phosphorylation of other proteins as substrates, as well as auto-phosphorylation as 30 an intra-molecular regulatory mechanism. P13-kinase activation, is therefore believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis (Parker el al., -4- Current Biology, 5 p. 577-99 (1995); Yao et al., Science, 267 p. 2003-05 (1995)). P13-kinase appears to be involved in a number of aspects of Icukocyte activation. A p85-associated P13-kinase activity has been shown to physically associate with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the 5 activation of T-cells in response to antigen (Pages et -al.. Nature. 369 p. 327-29 (1994); Rudd, Immunity 4 p. 527-34 (1996)). Activation of T cells through CD28 lowers the threshold for activation by antigen and increases the magnitude and duration of the proliferative response. These effects are linked to increases in the transcription of a number of genes including interleukin-2 (IL2), an important T cell 10 growth factor (Fraser et al., Science 25 1 p. 3 l3-16 (1991)). Mutation of CD28 such that it can no longer interact with P13-kinase leads to a failure to initiate IL2 production, suggesting a critical role for Pl3-kinase in T cell activation. PI3Ky has been identified as a mediator of G beta-gamma-dependent regulation of INK activity, and G beta-gamma are subunits of heterotrimeric G proteins (Lopez-llasaca 15 et al., J. Biol. Chem. 273(5) p. 2505-8 (1998)). Cellular processes in which Pl3Ks play an essential role include suppression of apoptosis, reorganization of the actin skeleton, cardiac myocyte growth, glycogen synthase stimulation by insulin. TNFk.

mediated neutrophil priming and superoxide generation, and leukocyte migration and adhesion to endothelial cells. 20 Recently, (Laffargue et al., Immunity 16(3) p. 441-51 (2002)) it has been described that P13Ky relays inflammatory signals through various G(i)-coupled receptors and its central to mast cell function, stimuli in context of leukocytes. immunology includes cytokines, chemokines, adenosines, antibodies. integrins, aggregation factors, growth factors, viruses or hormones for example (J. Cell. Sci. 25 114(Pt 16) p. 2903-10 (2001) by Lawlor et al., Laffargue et al., 2002. above and Curr. Opinion Cell Biol. 14(2) p. 203-13 (2002) by Stephens et al.). Specific inhibitors against individual members of a family of enzymes provide invaluable tools for deciphering functions of each enzyme. Two compounds, LY294002 and wortmannin (cf. hereinafter), have been widely used as 30 P13-kinase inhibitors. These compounds are non-specific PI3K inhibitors, as they do not distinguish among the four members of Class I P13-kinases. For example, the IC50 values of wortmannin against cacti of the various Class I Pl3-kinases are in the -5range of 1-10 nM. Similarly, the IC50 values for LY294002 against each of these P13-kinases is about 15-20 pM (Fruman et al., Ann. Rev. Biochem.. 67, p. 481-507 (1998)), also 5-10 microM on CK2 protein kinase and some inhibitory activity on phospholipases. Wortmannin is a fungal metabolite which irreversibly inhibits P13K 5 activity by binding covalently to the catalytic domain of this enzyme. Inhibition of P13K activity by wortmannin eliminates subsequent cellular response to the extracellular factor. For example, neutrophils respond to the chemokine fMet-Leu Phe (fMILP) by stimulating Pl3K and synthesizing Ptdlns (3, 4, 5)P3. This synthesis correlates with activation of the respirators burst involved in neutrophil destruction 10 of invading microorganisms. Treatment of neutrophils with wortmannin prevents the fMLP-induced respiratory burst response (Thelen et al., Proc. Natl. Acad. Sci. USA, 91, p. 4960-64 (1994)). Indeed, these experiments with wortmannin. as well as other experimental evidence, shows that P13K activity in cells of hematopoictic lineage, particularly neutrophils, monocytes, and other types of leukocytes, is 15 involved in many of the non-memory immune response associated with acute and chronic inflammation. 0 CH40-/ 0

CHGQ

O N 0 0 01 -0 LY294002 Wortmannin 2t) Based oil studies using wortmannin, there is evidence that 11l3-kinasc function is also required for some aspects of Icuikocyie signaling through G-protcin coupled receptors ([helen et al., 1994, above). Moreover, it has been shown that wortmannin and LY294002 block neutrophil migration and superoxide release. Cyclooxygenase inhibiting benzofuran derivatives are disclosed by John M. Janusz 25 et al., in J. Med. Chem. 1998; Vol. 41, No. I8. -6it is now well understood that deregulation of onocogenes and tumour suppressor genes contributes to the formation of malignant tumours, for example by way of increase cell growth and proliferation or increased cell survival. It is also now known that signaling pathways mediated by the ll3K family have a central role 5 in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor a wide spectrum of human cancers and other diseases (Katso et a/., Annual Rev. Cell Dev. Biol., 2001, 17: 615-617 and Foster et a!.. .. Cell Science, 2003, 116: 3037-3040). Class I P13K is a heterodimer consisting of a pI10 catalytic subunit and a 10 regulatory subunit, and the family is further divided into class la and Class lb enzymes on the basis of regulatory partners and mechanism of regulation. Class la enzymes consist of three distinct catalytic subunits (p1 0i, p 1OP, and p11 0 6 ) that dimerise with five distinct regulatory subunits (p85a, p55a, p50a, p85p, and p55y), with all catalytic subunits being able to interact with all regulatory subunits to form 15 -a variety of heterodimers. Class la ll3K are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho-tyrosine residues of the activated receptor or adaptor proteins such as IRS-I. Small GTPases (ras as an example) are also involved in the activation of P1l3K in conjunction with receptor 20 tyrosine kinase activation. Both p l0a and p1 1013 are constitutively expressed in all cell types, whereas ph 106 expression is more restricted to lcukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pi I OY catalytic subunit that interacts with a plI regulatory subunit. Furthermore, the Class lb enzyme is activated in response to G-protein coupled receptor (GPCR) 25 systems and its expression appears to be limited to leukocytes. There is now considerable evidence indicating that Class la Pl3K enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the p II O subunit is amplified in some tumours such as those of the ovary 30 (Shayesteh, et a/., Nature Genetics, 1999. 21: 99-102) and cervix (Ma et a!., Oncogene, 2000, 19: 2739-2744). More recently, activating mutations within p l Ia (PIK3CA gene) have been associated with various other tumors such as those of the -7colon and of the breast and lung (Samucls, et al., Science. 2004, 304, 554). Tumor related mutations in p85rx have also been identified in cancers such as those of the ovary and colon (Philp et a/., Cancer Research, 2001, 61, 7426-7429). In addition to direct effects, it is believed that activation of Class la P13K contributes to 5 tumourigenic events that occur upstream in signaling pathways, for example by way of ligand-depcndent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193 204). Examples of such upstream signaling pathways include over-exprcssion of the receptor tyrosine kinase Erb2 in a variety of tumors leading to activation of P13K 10 mediated pathways (Harari et a!., Oncogene, 2000, 19, 6102-6114) and over expression of the oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544 548). In addition, Class la P13Ks may contribute indirectly to tumourigenesis caused by various downstream signaling events. For example, loss of function of the PTIEN tumor-suppressor phosphatase that catalyses conversion of Pl(3,4,5)P33 back to 15 P(4,5)P2 is associated with a very broad range of tumors via deregulation of PlI3K mediated production of PI(3,4,5))P3 (Simpson and Parsons, Fxp. Cell Res., 2001, 24, 29-41). Furthermore, augmentation of the effects of other 1l3K-mediated signaling events is believed to contribute to a variety of cancers, for example by activation of AKT (Nicholson and Andeson, Cellular Signaling, 2002, 14, 381-395). 20 In addition to a role in mediating proliferative and survival signaling in tumor cells, there is also good evidence that class la Pl3K enzymes also contributes to tumourigenesis via its function in tumor-associated stromal cells. For examples, Pl3K signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (abid et al., 25 Arterioscler, Thromb. Vasc. Biol., 2004, 24, 294-300). As Class I P13K enzymes are also involved in motility and migration (Sawyer, Expert Opinion investing. Drugs, 2004, j3, 1-19), Pl13K inhibitors are anticipated to provide therapeutic benefit via inhibition of tumor cell invasion and metastasis. -8- Summary of the Invention This invention relates to novel compounds of Formula (1): 5 R1 R2 N R4 (R-.)n (I) l() in which R2 is an optionally substituted ring system selected from a group consisting of: formula (11). (111), (IV), (V), (VI), (VII),(VIl), (IX) and (X): X' N X NX N XX x x x (11) (11) (I V) y... X' Y . x .x -rX yX Ix x Y (Vi11) (IX) (X R I is selected from a group consisting of: heterocycloalkyl, substituted 15 heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7hetcrocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted -9hctcroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy; n is 1-2; 5 X isC or N; Y is C, O, N or S; and/or a pharmaceutically acceptable salt thereof; provided that in each of formula (V) to (X) at least one X or Y is not carbon; further provided that R2 is not quinoline or substituted quinoline. R3 can be attached to any one of the four open carbon positions. 10 Suitably, this invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. Suitably, this invention relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I). 15 Suitably, this invention relates to a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises administering to a 20 subject in need thereof an effective amount of a compound of Formula (I). Included in the present invention are methods of co-administering the present P13 kinase inhibiting compounds with further active ingredients. Detailed Description of the Invention 25 Present compounds of Formula (1) inhibit one or more P13 kinases. Suitably, the compounds of formula (1) inhibit Pl3Kx. Also, compounds within the scope of this invention inhibit one or more P13 kinases selected from:P13KS. P3K and P13Ky. Suitably, this invention relates to novel compounds of Formula (])(A): - 10- R1 R2 N R4 (R3)n (l)(A) in which 5 R2 is an optionally substituted ring system selected from a group consisting of: formula (I1), (11l), and (IV) as defined above; Rl is selected from a group consisting of: heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, 10 substituted amino, CI-6alkyl, substituted Cl-6alkyl. C3-7cycloalkyl. substituted C3-7cycloalkyl, C3-7heterocycloalkyl. substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, lieteroaryl., substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted hetcroarylalkyl, cyano, hydroxyl, 15 alkoxy, nitro, acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C, 0, N or S; and/or a pharmaceutically acceptable salt thereof; Suitably, included among the presently invented compounds of formula (1) 20 are those of formula (1)(B), R1 R2 N R4

(R

3 )n (l)(B) wherein R2 is selected from a group consisting of: formula (V) ,(VI) and (IX) as defined above; 25 R I is selected from a group consisting of: heterocycloalkyl, substituted - 11 heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl. substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, 5 alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy; n is 1-2; 10 X is C or N; Y is C, O, N or S; and/or a pharmaceutically acceptable salt thereof; provided that in each of formula (V), (VI) and (IX) at least one X or Y is not carbon. Suitably, included among the presently invented compounds of formula (1) 15 are those of formula (1)(C), R1 R2 N R4

(R

3 )n (1)(C) wherein R2 is selected from a group consisting of: formula (VII), (Vill) and (X) as defined above; 20 RI is selected fTom a group consisting of: hetcrocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is independently selected from: hydrogen. halogen. acyl, amino. substituted amino, CI-6alkyl, substituted CI-6alkyl, C3-7cycloalkyl. substituted C3-7cycloalkyl, C3-7hetcrocycloalkyl. substituted C3-7heterocycloalkyl, 25 alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl. substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy; - 12n is 1-2; X is C or N; Y is C, O, N or S; and/or a pharmaceutically acceptable salt thereof, provided that in each of formula (VII), (VIIl) and (X) at least one X or Y is not 5 carbon. Suitably, included among the presently invented compounds of formula (I) are those of formula (l)(D): R1 R2 N R4 10

(R

3 )n (1)(D) in which R2 is an optionally substituted ring system selected from a group consisting of: 15 formula (11), (111), (IV), (V), (VI), and (VIII): x N X X N X x x'x (V) (II) (I ) y x x x0 y) Y Y -X (V)I ( I 1 RI is selected from a group consisting of: heterocycloalkyl, substituted hetcrocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, 20 substituted amino, CI-6alkyl, substituted CI-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7hcterocycloalkyl, - 13alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted hetcroarylalkyl, cyano. hydroxyl, alkoxy, nitro, acyloxy, and aryloxy; 5 n is 1- 2 ; X is C or N'; Y is C, O, N or S, and/or a pharmaceutically acceptable salt thereof; provided that in each of formula (V), (VI) and (VIII) at least one X or Y is not carbon. 10 Suitably, among the present invention are compounds of Formula (l)(D),wherein R I is hetcroaryl or substituted heteroaryl; R2 is selected from agroup consisting of: formula (Il1) and formula (VI). Suitably, among the present invention are compounds of Formulas (1), (1)(A), (1)(B), (1)(C) and (IXD), wherein R2 is pyridinyl or substituted pyridinyl. 15 Suitably, among the present invention are compounds of Formulas (I). (I)(A), (1)(13), (1)(C) and (1)(D), wherein R2 is not pyridinyl or substituted pyridinyl. Suitably, among the present invention are compounds of Formula (I) wherein R2 is an optionally substituted ring system selected from the group consisting of Formulas (V)(A), (VI)(A), (Vl)(13) and (IX)(A): 20 Y N y N Y Y -.- x y--- - x (V)(A) (VI)(A) (IX)(A) / Y Y N (Vl)(B) wherein X is C or N; Y is C, 0, N or S; Suitably, among the present invention are compounds of Formula (I) wherein R2 is an optionally substituted ring system selected from the group consisting of - 14- Formulas (Vil)(A), (Vill)(A) and (X)(A): Y~ .

.

~Y , (VII)(A) (X)(A) 0 N N (VIIl)(A) wherein X is C or N; Y is C. 0. N or S; provided that at least one Y is not carbon. 5 Suitably, this invention relates to novel compounds of Formula (l)(G): N (RON R4 (R3)n N R (1)(G) in which each RI, R3, R4 and R5 is independently selected from: hydrogen, halogen. acyl, amino, substituted amino, arylamino, acylamino, hetcrcycloalkylamino, Cl-6alkyl, substituted Cl-6alkyl, (3-7cycloalkyl. substituted C3-7cycloalkyl. 15 C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy. aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, htceroarylalkyI, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, acyloxy, and aryloxy: or R5 is R6, wherein R6 is -SO2NR80 or -NSO 2 R80, in which R80 is selected - 15from a group consisting of: Cl-C6alkyl. CI-C6cycloalkyl. Cl C6heterocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally fused with a five-mcmbered ring or substituted with one to Five groups selected from a group consisting of: 5 Cl-C6alkyl, CI-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or -(Cl 2 )COOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or 10 (CH),COOH, wherein n is 0-2, n is 0-2, m is 0-3; or a pharmaceutically acceptable salt thereof; Suitably, this invention relates to novel compounds of Formula (l)(H): 15 N (R 11mR1 (R )n N R4 20 in which RI is selected from a group consisting of: heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, arylamino, acylamino, hetercycloalkylamino, alkoxy, Cl-6alkyl and substituted CI-6alkyl; 25 each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano, hydroxyl and alkoxy; - 16each R5 is independently selected from: hydrogen, halogen, acyl. amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl. C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano, hydroxyl and alkoxy; 5 or R5 is R6, wherein R6 is -S02NR8O or -NSO 2 R80 in which R80 is selected from a group consisting of: CI-C6alkyl, CI-C6cycloalkyl, Cl C6heterocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: 10 Cl -C6alkyl, Cl -C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or -(CI-X)nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to fiC groups selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or 15 (Cl-l),COOI, wherein n is 0-2, n is 0-2, i is 0-2: or a pharmaceutically acceptable salt thereof; Suitably, this invention relates to novel compounds of Formula (l)(J): 20 N (RO~MR R6 (R)n N R4 (Il)(J) 25 in which RI is selected from a group consisting of: heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl. amino, substituted amino, arylamino, acylamino, hetercycloalkylamino, alkoxy, C-6alkyl and substituted - 17- Cl -6alkyl; each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano, 5 hydroxyl and alkoxy; each R5 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, C3-7cycloalkyl. substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano, hydroxyl, alkoxy, nitro: 10 R6 is -SO2NR80 or -NSO 2 R8O. in which R8O is selected from a group consisting of: Cl -C6alkyl, Cl -C6cycloalkyl, Cl -C6heterocycloalkyl. substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: (l-C6alkyl, Cl-C6cycloalkyl, 15 halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or -(C1 2 )nCOO-1, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(CI-),COOH, wherein n is 0-2; 20 n is 0-2, in is 0-2; or a pharmaceutically acceptable salt thereof. Suitably, this invention relates to novel compounds of Formula (1)(K): N R1 R6 25 (1)(K) in which -18- RI is selected from a group consisting of: heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, arylanino, acylamino, hetercycloalkylamino, alkoxy, Cl-6alkyl and substituted Cl -6alkyl; 5 each R5 is independently selected from: hydrogen, halogen, acyl. amino, substituted amino, CI -6alkyl, substituted C1-6alkyl, cyano. hydroxyl, alkoxy: n is 0-2, n is 0-1; R6 is -SO2NR80 or -NSO 2 R80. in which R80 is selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, Cl -C6heterocycloalkyl, substituted I) Cl-C6alkyl, substituted Cl -C6cycloalkyl, substituted C I-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or Substituted with one to five groups selected from a group consisting of: CI-C6alkyl, CI-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or -(Clil),COOH, or heteroaryl optionally fused with a five-membered ring 15 or substituted with one to five groups selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(CI-1 2 ),COOI-I, wherein n is 0-2; or a pharmaceutically acceptable salt thereof 20 Suitably, this invention relates to novel compounds of Formula (1)(L): N (ROM R R6 ' N (l)(L) 25 in which RI is selected from a group consisting of: heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, -19arylamino, acylamino, hetercycloalkylarnino, alkoxy, Cl-6alkyl and substituted CI-6alkyl; each R5 is independently selected from: hydrogen, halogen, acyl. amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, cyano, hydroxyl. alkoxy; 5 R6 is -SO2NR80 or -NSOR80, wherein R80 is selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, Cl-C6heterocycloalkyl, substituted Cl C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, I0 halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or -(CH 2 )nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to Five groups selected from a group consisting of: Cl C6alkyl. Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano,. hydroxyl, alkoxy, oxo, or -(ClH 2 ),COO-l: 15 n is 0-2, m is 0-l; or a pharmaceutically acceptable salt thereof. Suitably, this invention relates to novel compounds of Formula (1)(M): 20 N R6 N (1)(M) in which 25 Rl is selected from a group consisting of: heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl., amino, substituted amino, arylarnino, acylamino, hetercycloalkylamino, alkoxy, Cl-6alkyl and substituted CI-6alkyl; - 20 each R5 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted Cl-6alkyl, cyano, hydroxyl, alkoxy; 5 R6 is -NSO 2 R80, wherein R80 is selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, Cl-C6heterocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to Five groups selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, halogen, amino, 10 substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or (CH 2 )rCOOH, or heteroaryl optionally fused with a five-mnimbered ring or substituted with one to Five groups selected from i group consisting of: CI C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethylI. cyano. hydroxyl. alkoxy, oxo, or -(C l),COO-; n is 0-2, mn is 0-1; 15 or a pharmaceutically acceptable salt thereof. Suitably, this invention relates to novel compounds of Formula (l)(N): 20 R1 (R)m R6 N (l)(N) in which 25 R1 is selected from a group consisting of: heteroaryl. substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl. amino, substituted amino, arylanino, acylamino, hetercycloalkylamino, alkoxy, Cl-6alkyl and substituted Cl -6alkyl; - 21 each R5 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, cyano, hydroxyl, alkoxy: 5 R6 is -SO2NR80. wherein R80 is selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, Cl-C6heterocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl. aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, CI-C6cycloalkyl, halogen, amino, 10 substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or (CI-z)nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to Five groups selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(CH:>)nCOOH; 15 n is 0-2, m is 0-1 or a pharmaceutically acceptable salt thereof. Suitably, this invention relates to compounds of Formulas (i)M) and (1)(N), wherein R I is selected from the group consisting of: optionally substituted 2( piperazine, optionally susbstituted pyridazine, optionally substituted morphliine, optionally substituted pyrazole, substituted amino and optionally substituted piperidine. Suitably, this invention relates to compounds of Formulas (I)M) and (l)(N), 25 wherein Rl is selected from the group consisting of: optionally substituted piperazine, optionally susbstituted pyridazine, optionally substituted mnorphline, optionally substituted pyrazole, substituted amino and optionally substituted piperidine; 30 R80 is selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl. Cl C6hetcrocycloalkyl, substituted Cl-C6alkyl., substituted Cl-C6cycloalkyl, substituted CI-C6heterocycloalkyl, aryl and substituted aryl. - 22 - Suitably, this invention relates to compounds of Formulas (I)M) and (l)(N), wherein RI is selected from the group consisting of: optionally substituted piperazine, optionally susbstituted pyridazine, optionally substituted rnorphline, 5 optionally substituted pyrazoic, substituted amino and optionally substituted piperidine; R80 is selected from a group consisting of: aryl optionally substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, Cl C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, 10 hydroxyl, alkoxy, oxo or -(C-2)nCOOH], or heteroaryl optionally substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, Cl C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(C-l 2 ),COO-;: n is 0-2. 15 Suitably, this invention relates to the compound defined in formula (I). (1)(A). (1)(1B), (1)(C), (1)D) 1) ( ()F), (1)(G), (1 () 1()(J), (1)(K), (1)(M) or (l)(N). Suitably, among the present invention are compounds selected from a group consisting of: 20 5-14-(4-pyridinyl)-6-quinolinyl -I H-indazol-3-amine; 4,4'-di-4-pyridinyl-6,6'-biquinoIine; 3-(4-morpholinylsulfonyl)-5-14-(4-pyridinyl)-6-quinolinyl 1-2-pyridinamine; 2-amino-N-methyl-5-14-(4-pyridinyl)-6-quinolinyl -3-pyridinesulfonamide; 2-amino-N,N-dimethyl-5-[4-(4-pyridinyl)-6-quinolinyl I-3-py ridinesulfonamide; 25 2-amino-5-14-(4-pyridinyl)-6-quinolinyll -3-pyridinesulfonamide; 5-[4-(4-pyridinyl)-6-quinolinyl -3-(I H-tetrazol-5-yl)-2-pyridinami ne; 6-(3-methyl-3/I-imidazo[4,5-blpyridin-6-yl)-4-(4-pyridinyl)qui noline: 6-(1 -methyl-I H-imidazol 4,5-blpyridin-6-yl)-4-(4-pyridinyl)quinoline; 3-(1 -piperidinylsullonyl)-5-14-(4-pyridinyl)-6-quinolinyl l-2-pyridinamine; 30 2-amino-N-ethyl-5-14-(4-pyridinyl)-6-quinolinylIl-3-pyridinesulfonamide: 2-amino-N-[ 2-(dirnethylamino)ethyl f-N-methyl-5-14-(4-pyridinyl)-6-quinolinyl l-3 pyridinesulfonamide; - 23 - 2-amino-N-(3-pyr-idinylmethyD)-5-I 4-(4-pyridinyl)-6-quiniolinyl 1-3 pyridlinesullfonamide; 2-ani no-N-3-py rid iny 1-5- [4-(4-pyri dinlyD- 6-quiolhily I j-3-pyi-idinesullionamide; 2.-amino-N-phenyl-5-[4-(4-pyridilyl)-6-qui nolinyt 1-3-pyridinesullIbnamnide; 5 2-amino-N-(3-hvdroxypropyl)-5-4-(4-pyi-dil)-6-quililyI 1-3 pyrid inesulIfonai-ide; 3-( I -piper-azinylsult'onyl)-5- I4-(4-pyridinyl)-6-quinolinyI 1-2-pyridinamine; 3-{ 14-(methylsulfonyl)- I -piperazinyl Isullfonyl }-5-14-(4-py'r-idinvl)-6-quinolinyl-2 pyridinmine; 10( 2-amiino-5-14-(4.pyr-idiniyl)-6-quiinoliniy! I-N-1 3-( 1 -pyrrolidinyl)propyl 1-3 py rid inCSU I tonarnicde; 3-I (-amnino- I /--pyi-azol- I -yl)sulIfonyl 1-5-I 4-(4-pyridi nvl)-6-qniinoli ny 11-2 py rid inmi ne:, 3-I4-mcthyt- I -pipcrazinyl)sult'onyl 1-5-[4-(4-pyridinyl)-6-quinolinyl 1-2 15 pyridinamine: 2-14-(( 2-amino-5-14-(4-pyi-idinyl)-6-quinolinyl J-3-pyridiny)L Jslfonyl)- I p ipcrazinylIj]thanol; 2-ami no-N-(2,4-dilfluoroplienyl)-5 -14-(4-py rid inyvl)-6-qu inol i ny 1-3 pyridinesul fonamide; 2() 2-amnino-N-I 3-(2-oxo- I-pyirrolidinyl)propyl j-5-14-(4-pyridinyl)-6-qlinlOlinyl 1-3 pyridinesultfonaiide; 2-ar-nino-N-2-pyridinyI-5-I 4-(4-pyridinyl)-6-quinolinyI I-3-pyridincsltonarnide: 2-am-ino-N-4-pyridinyl-5-14-(4-pyridinyD-6-quinolinyl I-3-pyridlincsullonanidc; 3- { 14-(2-chlorophenyl)- 1-piperazinyl Isulonyl I -5-14-(4-pyr-idinyl)-6-qlillOlinlV 1-2 25 pyridinamnine: py rid rI nesU i onarnide; N.N-di mcthiy I-3-(4-mior-plol inylIsulltony 1V)-5-I 4

-(

4 -py i i ny )I)-6-qu i nolinv 1 pyridinarninc; 30 N-mcth\'I-3-(4-morpholinyisulfonvl)-5-14-(4-pyridinyl)-6-quinolinyl 1-2 pyridinariine: N-cthyl-3-(4-morpholinylsulfonyl)-5-14-(4-pyridinyl)-6-quinolinyI I-2-pyridinaminc; - 24 - N,N-diethy I 3-(4-morpholinylsulfony1)-5-14-(4-pyidilyl)-6-qui no I iy 1-2 pyrid inri ne; 6-6(eh lol) -4mrhliyI uIfn )3prd y1-4-(4- pyrid Inyl)qu I nolIi nc: 6-I 6-(m-ethy lox y)-5-(4-morpholinylsu l'onyl)-3-py rid il 1-4-(4- pyridinyl)qui no line; 5 3-mcthyl-7-[4-(4-pyr-idinyD)-6-quinolinyl j-2 I- I ,21,4-bcnzothiadiazinc 1.1 -dioxide:, 6-14.(4-pyridinyl)-6-quinolinyll-3,4-dihiydro- I(2Hl-)-isoquinolinonc: 4-(4-pyridinyl)-6-( 1 l-pyrrolol 2,3-h 1pyridin-5 -y Iqu inol ie; 6-( 11II-indaizoI-5-yl)-4-(4-pyr-idiniiv)quinoline, 6-14-(4-pyridinyl)-6-qulinolinyvl -1/U-lindazol-3-aiiine; 10C 4-(4-pyridi nyl)-6-( I H- pyrrolol 2,3-h jpyri di n-4-y I)qunlJ 1101e; 6-( 1 H-indazol-6-yIl)-4-(4-pyr-idinyl)quiinolinc:; f3-oxo-6414-(4-pyr-idinyl)-6-quinolinyl -2-,3-dihydr-o- I lI-isoindol-1I-yl )acetic acid: 4-(4-pyridinyl)-6-(7H-pyi-rolol2.3-dlpyimidil-4-y)quililC: 6-14-(4-pyridinyl)-6-quinolinyll-1I,3-dihydro-211-imidazoI 4,5-h jpyridin-2-onc; 15 6-14-(4-pyridinyI)-6-quinolinvylI 1,3joxazolol4,5-bjpyridin-2(31I)-onc; 6-(1I H-pyrazolol3,4-bjpyridin5-yI)-4-(4-pyridinyl)quilolile; 4-(4-pyr-id infl)-6 -(11-11,2,3 Itiiaiolol 4,5-h Ipyridi n-6-y I)qu inoli ne: 6-( 1 H-i mida,.ol4,5 -bj pyridi n-6-yI)-4-(4-pyridi nyl)qui no line; 6-( 1-oxido-3-pyr-idinyl)-4-(4-pyr-idinyl)quinolinc:, 20) 4-C4-pyridinyl)-6-( 1 1-pyr-rolol 3,2-h jpyr-idin-6-yl)quinlolinic; 5-14-(4-pyridinyl)-6-quinolinyvl -I Il-pyr-aizoloI3,4-hlpyridin-3-amine: (,-(3-r-nethvl- IH1-pyrazolol 3,4-hlpyraizin-5-yi)-4-(4-pyridin>Iv)qulinl(Iinc:, 2-mcithyl-N- f5-14-(4-pyr-idinyl)-6-quinolinyl -I I/J-pyrazolol 3,4-h IpyridIn-3 yI }propunamide; 2.5 N-f 5-1 4-(4-pyri di nyl)-6-qui noli nyl I-I HI-pyrazo lol 3,4-bhIpyrid in-3-y I }acclainide: N-f 5-[4-(4-pyridinyl)-6-quinolinyl i-I H-pyrazolol 3,4-b)lpvyridin-3 yI }mcihanesulfonarnidc; 2-(methyloxy)-N-{ 5-I 4-(4-pyridinyl)-6-qulinolinyl I-I I--pyrazolol3,4-blpyridin-3 yI }acetamide; 30) 6-pyrazolol. I ,5-cajpyrimidin-6-yl-4-(4-pyridinyl)quinoline; 5-14-(4-pyridinyl)-6-quinolinvll- I ,2-dillydro-3/1-pyrazolo[ 3,4-blpyilidin-3-onc: 6-( 1-methyl- I 1J-pyrrolol 3,2-bjpyridin-6-yl)-4-(4-pyridinyl)quinolince; - 25 - 6-(3-methyl- I H-pyrazololI 3,4-bfIpyridii-5-v)-4-(4-pyiidiyl)quiioiiiC, 3-I16-( M I-py razolo[3 ,4-b I pyriin-5 -yI)-4-qu Inol inyl I I hctzcnlcsul I fonamil de, 7-f 4-(4-pyridinyvl)-6-qujinolinyl f-21If-pyr-idof 3,2-1)11 4 xail (4)uc 4-I 4-(4-pyrid iny I)-6-qul inol i ny lI 3-dihyvdro- 2/1-pyrrol of 2?,3-i) I py rid i ln-2 -one; 5 2-airnino-N,N-dir-nethyl-5-I 2-rnicthl1-4-(4-pyr-idinyl)-6-quinolinvi -3 pyrid inesul fonarnide; 2-amino-5-18-tluoro-4-(4-pyridiny)-6-quilil -N,N-dirnethlyl-3 pyrid inesulfonami de; 2-amino-N,N-dimethyI-5-18-methyl-4-(4-pyridiny)-6-quioliny 1-3 10) pyridinesulfonarnide; 2-amino.5-17-tluloro-4-(4-pyr-idinyl)-6-qujinoliflyl f-N,N-diirnetIl'I-3 pyridinesulf'Onamide; 5-I 5-tluoro-4-(4-pyridinyl)-6-cjuinolinyl j-3-pyridinesultonamide; 5-I 7-methyl-4-(4-pyr-idinyl)-6-quinolinyl 1-3-pyiridi nesulf'onar-nide: 15 5-1I5-methyl-4-(4-pyiridinyl)-6-quinolinyl 1-3-pyr-idinesulf'onamlidc; 4-(4-pyridi nyf )-6-I 5-(tri fluororneihy I)-3- pyridi nyI lquinol nce; (4,6- di-4- pyridi ny k~iluilnl c; 6-(3-pyridinvl)-4-(4-pyridinyl)quinoline; 6-(2-pyridinyl)-4-(4-pyridinyl)quinoline; 20 6-(2, I ,3-benzoxadiazol-5-yI)-4-(4-pyridinyl)quinoline; 6-(2,1I,3-bcnzothiadiazoI-5-yI)-4-(4-pyridinyl)quinolinc:. 5-f 4-(4-pyridinyl)-6-quinolinyl I-I ,2-dihydro-31-I-pyrazol-3-onc;, 2-ethyl-6-14-(4-pyr-idinyl)-6-quinolinyI 1-4(l I H)-pyrimidinonc; 7-14-(4-pyridinyl)-6-quinolinyl 1-2-quinoxalinol; 25 2-(4-morpholinyl)-7-14-(4-pyr-idinyl)-6-quinolinylIquinoxaline; 4-(4-morpholinyl)-6-[f4-(4-pyridiinyl)-6-quiniolinyIl quinazoline; I -plienyl-5-[4-(4-pyridinvl)-6-qujinoliniyI f-I '-dilivdr-o-31-I-pyiazol-3-onic: I -(3-mcthiylphenyI)-5-f4-(4-pyridini'I)-6-quiniolinyI f-I ,2-dihi'dr-o-3H-p~vi-azoI-3-onc; I -(3-chilorophcnyl)-5-f 4-(4-pyridinyl)-6-quinolinyl I- I .2-dihy dro-31-I-pyr-azol1-3-onc: 30 I -menthlyl-5-f4-(4-pyr-idinyl)-6-quilnolliyl I-I ,2-dlihydro-3-I-pyr-azol-3-one: N-(2.4-difluorophcnyl)-5-f 4-(4-pyvridinyl)-6-quinolinylI f-3-pyriidineSullon(iamiide: 6-( 1 H-indol-5-yI)-4-(4-pyr-idinyl)quinoline; - 26 - 6-( 1I--indol-6-y I) -4-(4-pyridinyl)qui nolIi nc; 5-I 4-(4-pyiridinyl)-6-qu Ino Iiny vI ,3-dihydro-21-l- Indol-2-one: 6-14-(4-pyridinyl)-6-quinolinyl I ,3-dihydro-2H-indo I-2-one; 7-14-(4-pyridinyl)-6-quinolinylJ-4( I H)-quinazolinone; 5 6-1i4-(4-pyridinyl)-6-quinolinyI J-4( 1 J)-qui nazolIi none; 6-14-(4-pyridinyI)-6-quinolinyI i-I,2-bcnzisothiazol-3(2U P)-one 1.1 -dioxidc: 6-14-(4-pyridinyD)-6-quinolinvl -1,8-naphthyi-idin-2(11 I)-onc-, 6-(1I,3-benzoxazol-5-yI)-4-(4-pyridinyl)quinoliflc; 7-14-(4-pyridinyD)-6-quinolinvyl -I,4-dihydropyr-idol 2,3-bjpyrazinc-2.3-dionc:; 10 3-arnino-5-14-(4-pyr-idinyl)-6-quinoliniyl j-2-pyr-idincecarboxamidc; 5-I 4-(4-pyrid Inv I)-6-qu m il nyIV 1-3-pyrid I na n [ie; 4-14-(4-pyrid in),l)-6-qui[nol iny I thleno 2.3-c ipyrid 1n-2 -Larbox,1ut1 ie', methyl 4-I 4-(4-pyr-idinyil)-6-cquinolinyI I-I /1-pyrroh)I 2.3-c-Ipyridinc-2-cariboxvlzatc; 4-14-(4-pyr-idiny'D)-6-quinolinyI I- I I/-pyrrolol ,-~viic2cvoaic 15 6-(l I -- bcnzimidazol-2-yl)-4-(4-pyr-idinyl)quinoline; 6-(lI 1-1-imidazol 4,5-c jpyr-idin-2-yl)-4-(4-pyridinyl)quifloliflc; 6-( 1 H-imidazol 4,5-blpyridin-2--yI)-4-(4-pyr-idinyl)quiinoline; 6-(l II-pu ri n-8-y I)-4-(4-pyridi ny )qui nolIie; 6-imidaizoI I,2-alpyridin-6-yl-4-(4-pyiridinyl)quinoline; 2() 6-imidazol I,2-ajpyi-imidin-6-yl-4-(4-pyr-idinyl)quinolinc; I -{6-14-(4-pyridinyl)-6-quinolinyllimidazo 1,2-a jpyridin-3-yi 1-1I-propanone; 6-(4-pyridazinyl)-4-(4-pyr-idinyl)quinoline; I -{6-14-(4-pyr-idinyl)-6-quinolinyl limidazoIl1,2--a jpyridin-3-yI 1- -pr-opanol; 4-(l -pipcridi ny 1)-6-(] 1- l-pyrazolol 3,4-b jpyridin-5-y l)qUi nol inc; 25 4-(4-rnorpholinyl)-6-( I 1-1-pyrazolol 3,4-bjpyridin-5-yI)quinolinc; 4-(4-methyl- I-pipcrazinyl)-6-( I I--pyrazolol3,4-b Ipyridin-5-yl)q~ujnolinc; 4-(4-pyrtidazinyl)-6-( 1 l--pyr-rolol 2,3-bjp~yridini-5-yl)quinl inlc. 6-( IFII-iiniidazol4,5-1blpyridi n-6-yl)-4-( I-piperiidi iiyl)qtiiinoli nc; 6-(1I -I-imidazoJ 4,5-blIpyi-idi n-6-yI)-4-(4-irnorplhol i ny )qu mnu~ll nc; 30) 2-amino-5- (4-13-(atmi nosultfonyl)phcenyl 1-6-qui nolInyv I) -N,N-di methyl -3 pyridinesul fonam-ide; 2-amino-N,N-dimethyl-5-I 4-(2.-mcthyl-4-pyridinyl)-6-quinolinyl 1-3 - 27 pyridinesulIfo namide; 2-amino-5-(4- ( 3-1(d Imetlhylarnino)su I onyl I penyI) )-6-quinol Invl)-N,N-d I methyl1-3 pyrid1nsuli'onarnide; 2-amino-N,N-dimethyl-5-14-(4-pyidzil-6-quillinylI-3-pyi-idincsultlonarniide, 5 2-arnino- N.N-dI methyl1-5-[.4-(1 I -l-pyr-azol-4-yi)-6-qui1no] llyl 1-3 pyridincsufftonamidc; 2-am-ino-N,N-dimcthiyl-5-(4-phenlyl-6-quinoliflyl)-3-pyridi ncsultbonamlidc; 2-ai-ino-N,N-diimcthlyl-5-I 4-( I I]-pyr-azol-3-vI)-6-quinolinyvl -3 pyridincsullonarnide; 10) 2-amino-5-14-(2,6-dinmethyI-4-pyridiniyl)-6-quiilOilyI j-N,N-dirncthyl-3 pyridinesul fonaniide; 2-amino-5-(4-{ 3-I (amninosuffonyl)rnethyl Iphienyl )-6-quinolinyl)-N,N-diinthyI-3 pyrid inesu it'onam-ide; 2-amino-5-[4-(3-cyanophcnyl)-6-quinolinyI I- N,N-dir-ncthyl-3-pyridincsullonamiidc: 15 2-amino-5- 14-1I5-(aminosultonyl)-3-pyi-idinyI 1-6-quinoliny! }-N,N-dir-ncthiyl-3 pyrid inesulIfonami de; 5,5'-(4,6-quinolincdiyl)di(3-pyr-idinesultbniai-nidc); -arino-N,N-dimethyl-5-1-3 11-ntychlaiosloy I phenyh-6 quinolinyl I-3-pyiridincsulb'namnidc; 2() 2 -amino- N,N-d imethyl-514 (3-1 (methylamino)sulfonlyl Iphienvi }-6-quinolinyl)-3 pyridincsultonlarnide; 2-am-ino-N,N-dirncthyl-5- (4-16-(4-i-ncthyl- I -pipet-azinyi)-3-pyridinyl 1-6 quinolinyl) -3-pyridincsulf'onarnide; 5-14-(3-cyanophcnyl)-6-quilnoli nyI 1-3-pyridincsuffoIonmidc; 25 5-14-(-rncithlyI-4-pyr-idinyI)-6-quinolinyI l-3-pyiridinesulf'onamlidc, 5-14-(4-pyridaiinyl)-6-quinlolinyl 1-3-pyridinesulfonamidc; 5-{4-I6-(4-iincthyl- I-piper-azlinyl)-3-pyr-idinyl -6-qujinolinyl }-3-pyr-idincsulifoniaidc; 5-14-(2,6-dimcithyl-4-pyr-idi nyl)-6-qui noli nyl J-3-pyr-idincsult'onamiide; 5-14-0 1 -- pyraizo-4-vl)-6-quinolinyll-3-pyridincsuillonamidc;, 30 5-(4- {3-I(dimethylai-ino)sulfonyllphienyl )-6-quinolinyI)-3-pyridiniesult'onarinide, 5-14-( I-methyl- IH-pyrazol-4-yI)-6-quinolinyl j-3-pyridinesulf'onarnide; 5-f{4-I2-(4-rnorpholinylmcthyl)phecnyl j-6-quinoliny I)-3-pyridinCSLIIIrnainidc; - 28 - 5-112(-o-pilnlabiypleyI -- unI in I)-3-pyridinlesulIfonami111de; 5-(4-I 1''-(4-rnorpholi nyl)phcny I I-6-qu inol I nyl I}-3- pyr I d I fle I I fnarIin de; 4'-(4-pyridinyl)-3,4-dihyvdru-0,6'-biquinolin-2( I l1)-one; 6-14-(4-pyridinyI)-6-quinolinyi 1-3,4-dihydro- 1 ,8-naphthyridin-2(l I )-one; 5 2-amino-5-I14-(4-pyr-idinyI)-6-quinolinyI J-3-pyridinecarbaldehyde; I 2-amino-5-14-(4-pyr-idinyl)-6-quinolinyl -3-pyridinyil imetlv acetate; 5-14-(4-pyridinyI)-6-quinolinyI I-2,3-pyridincdiamine; 2-amino-5.i4-(4-pyr-idinvl)-6-quinolinyI 1-3-pyridinccarboxarnide; 6-[4-(4-pyridinyl)-6-quinolinflpyidol.2,3-dI pyr-imidin-4(I 11-)-one, 10 5-t 5-14-(4-pyridinyl)-6-quinolinyl 1-3-pyridinyl }- I ,2-dhydro-31I-pyrazol-3-one; 7-14-(4-pyr-idinyl)-6-qlinlOlinylJpyridol 3,2-djpyrirnidin-4( I111)-one; 6-15-( 1 II-pyrazol-5-vI)-3-pyridilyI 1-4-(4-pyridiyl)quililC N-'14dturpey)514(-yiiy)6qio y 1-3-pyridinccarboxamide-; 6-J 2-(inethyloxy)-4-pyridinyl J-4-(4-pyridinyl)quinoine, 15 6-16-(inethyloxy)-3-pyridinyl 1-4-(4-pyridinyl)quinolinc: 4-14-(4-pyr-idinyl)-6-quinolinyl J-2-pyridinol; 6-I 2'-( mcithyloxy)-5- pyimiidiny I J-414- pyridiny I)qU i l i nC; J6-[4-(4-pyridinyl)-6-quinolinvl 1-2-pyridinyl methanolo; 6-(2--chloro-4-pyr-idinyl)-4-(4-pyr-idinyl)qui noline, 2 0 4- (4 -p yri d iny1)- 6 -(5- p yri m id iny1)q u inoIi n e; 5 -14-(4-py rid iny ])-6-quinol inyl 1 -2( I 1-1)- pyri mi dinone; 6-12,6-bis(metliyloxy)-3-pyridinyl 1-4-(4-pyridinyl)quinoline; 6-I6-(4-methyl- I -piperazinyl)-3-pyridinyl J-4-(4-pyridinyl)quinolinc; 6-l6-(4-mor-pholinyl)-3-pyridinyl j-4-(4-pyr-idinyl)quinoline; 25 6-(6-chloro-3-pyridinyl)-4-(4-pyridinyl)quinoline; 6-I 6-(cthyloxy)-3-pyridinyl j-4-(4-pyridinyl)quinoline; N,N-dirnetliyl-3-( I5-14-(4-pyidliyl)-6-qu llnlyl 1-2-pyridi nyl I oxy)- I propanamine; 5-I 4-(4-pyi-idiny l)-6-quinoliiyl i-3-pyridiniecarboxamide; 30 methyl 5 -I4-(4-py ridi nylI)-6-qui noli ny I -2-pyridi11necarhux yl ate; N- I5-14-(4-pyridinvl)-6-quinolinyl -2-pyr-idinyl }acetamidc; N-I 2-(4-morpholinyl)ethyl j-5-14-(4-pyridinyl)-6-quinolinyll-2-pyr-idinamiine: - 29 - 6-I16-(lI -pipcrazinyl)-3-pyridinyl I -4-(4-pyridinyl)quinolinc; 6-1j5-(methiylox y)-3-pyridi ny I J-4-(4-pyrId in yl)qui nol ine; 6-(6-tfluoro- 3-pyridinylI)-4-(4-py ridi ny l)qL i nol Inc; 5-[4-(4-pyrid inylI)-6-qu inolIinylI J-2-pyrimidinecarboni tri le; 5 6-[2-(methyloxy)-3-pyridinyl 1-4-(4-pyridinyl)quinolinc; 5-14-(4-pyridinyl)-6-quinoliny I 1-3-pyridinecarbonitrile; 6-16-(rncthy lox y)-2-pyridinyl 1-4-(4-pyridinyl)quinolinc:, 6-I 5-(4-mor-pholinylcarbonvl)-3-pyridinylI J-4-(4-pyidinvl)qui nolIinc; 6-14-(i-ncthyloxy)-3-pyrid In y I -4-(4-pyrid Inyl)quinoline: 10( 6-I5-(4-mor-phol inylsulItonyl)-3-pyridinyl Ij-4-(4-pyridinyl)quino Ilie-, 7-14-(4-pyridinyi)-6-quinolinyvl -2,3-diiydr-olI ],4 dioxinol 2,3-hipyridine:, 5-14-(4-pyridinyl)-6-quinolinyl j-3-pyridinesulItonarnide: 2-(irnethyloxv)-5-I 4-(4-pyr-idinylI)-6-quinol inyl j-3-pyr-idincarbatldchvdc; 6-(4-chlor~o-3-pyridi nvl)-4-(4-pyiridinyl)quinolince: 15 4-(4-pyridinyl)-6-I 5-(11 -- tctr-a/AJ-5-yi)-3-pyridinyl iquinoline; N-methyl-5-14-(4-pyridinyl)-6-quinolinyl I-3-pyr-idincsulf'onar-nide; N,N-dimcthyl-5-14-(4-pyridinyl)-6-quinotinyl I-3-pyr-idincsult~oinamiidc; 6-14-methyl-6-(r-nethyloxy)-3-pyridinyl j-4-(4-pyridinyl)quinoline; N- {4-mcthyl-5-14-(4-pyr-idinyl)-6-quinolinyl j.2-pyridinyl lacetar-nide; 20 6-(4-methyl-3-pyridinyl)-4-(4-pyr-idinyl)quinolinc; 6-15-( 1,3,4-oxadiazol-2-yI)-3-pyridinyvl -4-(4-pyi-idinyl)quinolinc:, 2-ar-nino-N-(4-pyridinvlmcthyl)-5-14-(4-pyr-idinyl)-6-quinoiil1-3 py rid ncsu itfonar-nide; 2-amino-N,N-diethiyl-5-I 4-(4-pyr idinyl)-6-quinol inyl J-3-pyr-idincsu ifonarnide: 25 5-14-(4-pyridinyl)-6-quinolinyl j-3-( I-pyr-rolidinylsult'onyI)-2--pyimidinarninc: 2-ai-niio-.5-14-(4-pyr-idinlyl)-6-quinoliinyl j-N-12-( I -pyrrol1idinyl)lhvl1-3 py rid inesu I onainide; 6-I 6-( met hy Isul f onyl)-3-pyridi nyl 1-4-(4-pyridi ny I)qui no! lie 2-aino- N-( phcnylr-ncthyl)-5-1I4-( 4-pyr-idiny I)- 6 -qu mno! inyIIv-3-py'rid ineSu I t'Onaiild' 30 2-amino-N-(2)-hydroxyethyl)-5-14-(4-pyridinvl)-6-quinolinvl1-3 pyrid incsu I fonam nidc; I-({2-amino-5-14-(4-pyridinyl)-6-quinolinyl -3-pyridinyl }SuLtbInyl)-4-pipcridinlol; - 30 - 2-a inoN-(-amnoehyl-5-4-(-pyidiiyl-6-ui o IinyI -3-pyridinesull'onamnide; 6-I5-(mecthyllhio)-3-pyrid Inyl 1-4-(4-py rid inyl)qu Inolinc; 6-j*5-(rnethyIs u Il tnyl)-3-pyridinyl I -4-(4-py rid InvI)qu Ino Iine; 2-mn- ( hdoytll--ehl51-4prdnl--un inl v 1-3 5 py rid incsuIlfo narnide; 2-amino-N-cyclopropyl-5-I 4-(4-pyr-id Inyl)-6-quinol Inyl 1-3-pyridincstil fonamride, 2-amino-N-I ,3-benzodioxol-5-yi-5-I 4-(4-pyi-idinyl)-6-quinolinyl 1-3 py rid incsulIfonai de; N,N-dicthyl-5-l 4-(4-pyridi nvl)-6-qiiioli nylI 1-3-pyriidiincsulliioinamide: 10 ()I-((5-I 4-(4-pyi-idinyl)-6-quinol iiyl 1-3-pyr-idiinyl }suiltonl)-4-pi peridinlol; 4-(4-pyridinyl)-6-I 5-( I -pyr-rolidinylsuiloniyl)-3-pyr-idinyl quinloline; N-(2-hydr-oxyethyI)-5-14-(4-pyr-idinvi)-6-quinoiinyI 1-3-pyridinesul tornmide: N-(phenylmethyl)-5-I 4-(4-pyr-idinyl)-6-quinolinyl j-3-pyridinesu Itoniimide; 5-[4-(4-pyridinyl)-6-quinolinyl I-N-I2-( 1 -pyrrolidinyl)ethyl I-3-pyridinesulf'onam-ide; 15 6- {5-I (4-methyl- I -piperazinyl)suItonyl j-3-pyr-idinyl }-4-(4-pyr-idinvl)quinolinc;I N-cyclopropyI-5-1I4-(4-pyr-idiny)-6-quinoiny]-3-pyridislIt'onar-nide; N-I 2-(methyloxy)ethyl J-5-1I4-(4-pyr-idiinyl)-6-qulinolinyI 1-3-pyridinesulf'onan-Iidc; N-plienyl-5-1L4-(4-pyr-idinyl)-6-qui nolinyl i-3-pyridincsultfonar-nide; N-I .3-bcnzodioxol-5-yl-5-I 4-(4-pyridinyl)-6-quinolinyI 1-3-pyridinesulf'onamide; 20) N-(3-pyr-idinylmcnthlyl)-5-14-(4-pyridinyl)-6-quinoliflyl j-3-pyridincsult'onarnidc; N -2-pyridi nyl-5-I 4-(4-pyi-idi nylI)-6-qui nol inyl Ij-3-pyridincsulf'onaimide: N -(2-chlloroplheny 1)-5-I 4-(4- pyiridi nyl)-6-qui not I nylI 1-3-pyridi ncsu Ilfonai de:, N-cyclohcxvl-5-I 4- (4-pyridi nyl)-6-qui nol inyl 1- 3- pyridi nesu Itonia ilide; N-I 2-(m-ethyloxv)plhenyl j-5-14-(4-pyridinyl)-6-quinolinyl I-3-pyridi ncSul tonarnide; 25 2,4- d i tILoro-N- ( 5 -14-(4 -pyri d inylI)- 6-q u in olIiny 11-3 -p yri d inyl I )be n zcne S LIto n arnide; I -mreth ylI-N- 15-I14- (4- pyri d invyl)-6- qu inoIi n ylI 1- 3 -pyri d iny } I I H- im idazolIC- 4 SulItonamide; N- {5 -14- (4- pyrid iny 1) -6-q u inoIi ny11-3 -py ri d iny I)-2-t h i cph en1CS Ll o namni de; 3,5 -d imet hylI-N- {5 -14- (4- pyr idin ylI)- 6-q u inoI In y 11-3 -pyr Id in y I}-4 30 isoxa zo les ulIfo nami de; 3,4-bi s(meth yl oxy)-N-{ (5-14-(4- pyri d iny1) -6-qu inoIi nyl I-3 py ri diny ) be nzencs ulIfon am ide; - 31 - 2-mcthyl-N-t 5-14-(4-pyr-idinyl)-6-quiioliny I 1-3-pyridinyI )- I -propaflesu Ifoflarnide; N- I 5-I 4-(4-pyidi nyl-6-qu I nol I ny I 1-3-pyr di ny I} cvc Iopi-opanC.SL '. ln amide; N-{I 5-14-(4-pyr-idinyI)-6-qui no[ iny I J-3-pyridinyl I Ihenzene.SLII()[ l ide: N- 2-chilor-o-5-I 4-( 4-pyrid i ny )-6-qu iniol i ny I-3-pyridi my I] b)c n ,,CIICsu Itunam dc1((: 111d 5 I -phcnyl-N- {5-14-(4-pyridinyl)-6-quinolinyl I-3-pvidinyl i ncthiancSLItunamiiidc 5-14-I 3-chloro-4-(mcthyvloxy)phlenyl -6-quinolinyl )-3-pyridinceSLIt'onamlidc, 5-{4-13-(aminosulfonyl)phenyl -6-quinolinyil-}3-pyr-idincsult'onar-nidc; 5-f{4-I.1-(2-hydroxycthyl)- I I--pyrazoI-4-ylJ-6-quinolinyl I -3-pyridinesultonamide: N-(cyclopropylsultonyl)-N-{ 5-[4-(4-pyridinyl)-6-quinolinyl 1-3 10 pyridinyvl cyclopropanesulf'onamide; N-(2,4-ditluor-oplhenyl)-5-[14-( 1-ethiyl- I l-1-pyr-azol-4-vl)-6-quiniollilyl -3 pyridinesu Ifonai-nide; N-methyl-N-phenyl-5-14-(4-pyr-idinyl)-6-quinolinyI 1-3-pyridinesull'onarnide-, N-(2,4-difluorophcnyl)-5-(4-j 1-I2-(dirncthylamino)etilyl I- I I--pyrazol-4-vi 1-6 15 quinolinyl)-3-pyr-idinesultonar-nide, N.(2,4-ditluorophcnyl)-5-14-(4-isoquinolinyl)-6-quinol inyl J-3-pyridinesulftknamide; N-plienyl-N'-1 5-14-(4-pyr-idiniyl)-6-qulinolinyI 1-3-pyridinyl I urea; 2-(4-16-(5- I I(2,4-difluoropllenvl)arnino IsulltonN' 11-3-pyridinvl)-4-quinoliivl I- 11-1 pyrazol- I -yI ) acetarnide; 2 0 N -15 -14- (1 -mct hyI--1-pyrav.o I- 4-yI ) -6-q uin olIin y I -3 pyridinyl I benzenes ulItonamidc 4'-(4-pyridinyl)-3,6'-biquinolinc; N- (5-I4-(4-pyridinyl)-6-quinolinyilj-3-pyridinyl )benzinidc; 5-14-( 1-benzotfuran-2-yi)-6-quinolinyl -N -(2,4-difluoroplienyl)-3 25 pyridinesulfonar-nide; 6-I5-( 1H-pyrazol-4-yi)-3-pyridinyll-4-(4-pyridi nyl)quinoliine; N,N-diethyl-2-oxo-5-[4-(4-pyiridinyl)-6-quinolinyl -I ,2-dihydro-3 py rid inesu I tonarnide; 4-cyano-N-{ 5-I 4-(4-pyi-idinyl)-6-quinoilinyl 1-3-pyr-idinyvl bcnZI)CnSulfonar[inidc;, 30 N--ncthlyl-N-phenyl-5-[4-(4-pyi-idinyl)-6-quinolinylI I-3-pyridinecarboxamide; N- J5-I 4-(4-pyr-idinyl)-6-quinolinyl 1-3-pyi-idinyl lethaneSUltbnarni~ide: 4-(methyloxy)-N-1 5-I4-(4-pyiridinyl)-6-quinolinyl 1-3 - 32 pyrid inyl I)benzenes ul fon ami dc; 4-( 1-methylethyl)-N- {5-14-(4-pyr-idinyl)-6-quiniolinyl 1-3 py rid inyl I)benzenes ul fbnamnide; 2-chloro-5 [-(4-pyr-idinyl)-6-quinolinylI]-3-pyiidilamile; 5 4-tluoro-N-{ 5-14-(4-pyrid Inyl)-6-quinoliny I -3-pyridiny I) ben zenesu Itoniam Ide-, N-f 5-14-( 1-ethyl- I ll-pyrazol-4-yl)-6-qui no linyl Ij-3-pyrid Inv I -2,4 d iflu orobcnzenesu lfonami de; 1-methyl-N-f 5-[4-(4-pyridinyl)-6-quinolinyl I -3-pyridiny I I- I l-l-pyrazolc-3 Sul1fonamride:, I10 2-tluoro-N-f 5-14-(4-pyr-idinyl)-6-quiinolIiny I -3-pyridiny I) bellzencsulIfonlamidc; N-fI 2-aininlo-5-14-(4-pyi-idiinyl)-6-quinio Iin y I -3-pyidinylI I be nzencsu1fl Itillide; N-f )-i-nethyvl-5-I 4-(4-pyr-idinyl)-6-q.I Iino I In -3-pyrid Inv I )benin/lcSt flrnide, N-f J 2-cyano-5-l4-(4-pyr-idinyI)-6-qui no Iiny] 1-3-pyridiny I) benizcneSU I narnidc;, 2-mcnthlyl-5-nitro-N- I5-14-(4-pyridinyl)-6-qulI noliny 11-3 15 pyrid iny v )benzenes uIfonaiIdc, N-{ 5-[4-(4-pyridinyl)-6-quinolinylI 1-3-pyridinyl I)-I I--pyrazolc-4-su Itoniamide; N- f 2-chloro-5-14-(4-pyr-idinyl)-6-quinoliiylI 1-3-pyi-idinyl I-2-methyl-5 n itrobe nze nes u Ifon ami de; N-f 2-chloro-5-l4-( 1-ethyl- I H-pyrazol-4-yl)-6-quinolinyl 1-3 2(0 py rid inyI) benzenesul fonami de; N-fI 2-chloro-5-[4-(4-pyridazinyl)-6-quinol I nvl-3-pyiidilyl I ben zenesulIfonarnidc:, 3-nitro-N- I 5-14-(4-pyr-idinyl)-6-quinolIin yl 1-2-pyridi ny I) benzenesu I onam-ide: 2-m-ethyl-N-f 5-14-(4-pyi-idinyl)-6-quinol In yl-3-pyridinyl) be bczcnesu KO namli Ide, 2,4-dilluoro-N-f 5-I 4-(4-pyridazInyl)-6-quinol Inv 1-3 25 py rid inyl I)benzenes ulIfon ari dc 5-tluor-o-2-methlyl-N-{ 5-14-(4-pyridinyl)-6-quiniolIinl v1-3 pyrid inyvl I benz.cnCS1.lfonariIde; N-fI 2-chloro-5-14-(4-pyr-idinyl)-6-quiniol inyl Ij-3-pyridinyl 1 -3 nit robenienCS UlIloia m ide; 30 N-f (2-chloro-5-14-(2-methyl-4-pyrid Inv )-6-quinolinyl 1-3 pyrid iny v} IbenzenesulIfornamide; N-f I 2-chloro-5-14-(4-pyridinyl)-6-quinolinyl Ij-3-pyridinyl 1)-2 - 33 methy Iben ze nesulIfonam ide; N- I 2-chilor-o-5-14-(4-pyi-idinyvl)-6-quiiol inyl Ij-3-pyrid Inyl I1-3 fluorobenzenesu I fonamide; N- {2-chloro-5-14-(4-pyridinyl)-6-quinolinyl -3-pyridinyl I-2-thiophcniesil(tiIbnanidc: 5 N- {2-clhloro-5-14-(4-pyridinyl)-6-quilnolinyl -3-pyridinvl )cyclopropunCSuilfonai-nide, N-( 2-chloro-5-14-(4-pyridinyl)-6-quilnotinyl -3-pyr-idinyl I-5-f'luoro-2.

methylbenzencsult'onai-nide; N-(2-chlioro-5-{ 4-I 3-(methylsultonvl)phcnyll-6-quinolinyl }-3 pyridinvl)benizeniesulf~onamiidec: 10 N-{ 2-chlor-o-5-14-(4-pyiridinyl)-6-qlinlOlilnyll-3-pyridinlyl }-3,5-diimcthlly-4 isoxazolesil f'onarnidc; 2,4-ditluoro-N-(5- {4-13-(methiylsullonyl)phenyl -6-quinolinyl )-3 pyridinvl)benzenesulf'onamide; 2,4-ditluoro-N-1{5-14-(2-methyl-4-pyridinyl)-6-quinolinyl 1-3 15 pyridinvl~benzcnesuit'onarnidc; 3-(trnethyloxy)-N-{ 5-14-(4-pyr-idinyl)-6-quinolinyl 1-3 pyridinyil benzenesulfoiiamide; N-I 4-(cyanorncthyl)phenyl I-5-14-(4-pyridinyl)-6-quinoiinyllI-3-pyr-idinesul Ionaide; 3-tluoro-N-{ 5-I 4-(4-pyr-idinyl)-6-quinolinyl j-3-pyr-idinyi }bcnzenesult'onarnlidc; 2() N-{ 2-(r-ncthyloxy)-5-14-(4-pyridinyl)-6-quinolinyll-3 pyridinyvl benzcneSuiltonamide; N- { 2-chlor-o-5-14-(4-pyridinyl)-6-quinolinyl I-3-pyi-idinyi }-2,4 ditluorobenzencsull'onami de; 3-niti-o-N- (5-14-(4-pyi-idinyl)-6-quinolinyl I-3-pyiridinyl }bcnzcncesuilionamiidc; 25 N-{5-I4-( 1-bcnzoturan-21-yI)-6-qulinolinyl -3-pyr-idinyl }-2,4I ditluorobcnzenesultfonamide; 3-cyano-N-{ 5-I 4-(4-pyr-idinyl)-6-quinollinyl -3-pyr-idinyl }bcnzcnesuiltoniamiide; N-f 5-14-(4-pyridinyl)-6-quiniolinyl -3-pyi-idinyl }-4 (tilluoror-nethyl)bentcenesult'onamidc; 30 N-f 2-hydroxy-5-14-(4-pyridinyl)-6-quinolinyl 1-3-pyridinyl IbenzeneSLultonarinide; N- {5-14-(4-pyridinyl)-6-quinolinyi -3-pyr-idinyl )-3 (tiluorornethyl)benzcncsull'ona-n idc; -34 - N- [5-1 4-(l1 -benzof'uran-21-yl)-6-qlinlinyl I -2-ch Ioro-3 pyrid Iny } Ibenzenesu Ifo(namidc; N-methylI-N- I 5-I 4-(4-pyrid Inyl)-6-quIn olinyl 1-3-pyridiny I benzarnide, 2,4-d i 11Luoro-N - I 5-I 4-(4-fluorophleny I)-6-qL i nol i ny 11-3 5 pyridinyl I)benzeneSuL onamnI de; N-methlylI-N-[{ 5-I 4-(4-pyr-idinyl)-6-qu in olIinl v 1-3-pyridinyl I benzenes u Itonarn Ide; 2,4-ditluoro-N-15-(4-pyrazolol I ,5-ajpyridin-3-yl-6-quinolinyD-3 pyridinyl Ibenzenesulfonamide; 2,4-ditluoro-N- I 5-I 4-(2-tiuorophecnyl)-6-quiniolinyl 1-3 10 pyridinyl) benzencsult'onamidc; 2,4-difluoro-N-(5- {4-14-(tiiluoroi-nethyl)phenyI 1-6-qui noli nyl 1-3 pyridinylbenzenesulfonamide; 2,4-difluoro-N-(5-{4-14-(i-ethylsulfbonyl)phenyl 1-6-quinolinyl) -3 pyridinvl)benzcnesulfonai-ide, 15 methyl 1-i-cthyl-5-1({ 5-14-(4-pyridinyl)-6-quinolinyll-3-pyridinyl Iam-ino)sult'onil I I--pyiolc-2-carboxylIate; 5-brorno-2-(metllyloxy)-N- f 5-I 4-(4-pyriidinyvl)-6-quiniolinyl 1-3 pyr-idinyl }benzenesult'onamnidc:, 5-(5-isoxazolyl)-N- I 5-14-(4-pyr-idinyi)-6-quinoliNylI 1-3-pyridinyl 1-2 20) thiophicnesultonamidc; 2,4-difluoro-N- J 5-I 4-(3-tluorophicnyl)-6-quinolinyI 1-3 pyridinyl Ibenzecsul tbnamide; 2,4-difluoro-N-(5- { 4-I 3-(ti-itluoromcthyl)phcnyl 1-6-quinolinyl) -3 pyridinyl)bcnzenesull'onamide; 25 2-chloro-4-cvano-N- I 5-14-(4-pyrid inyl)-6-quinolinyI 1-3 pyridinyl )benzenesuitfonamide; N-15-(4-1 3-I (dimethylarnino)sulf'onyl Iphenyl )-6-quiinolinyl)-3-pyridinyI I-2,4 di fluorobenzenesult'onamide; N-15-(4-1 4-1 (dimethvlai-nino)sullonyl Iphenyl 1-6-qulinolinvl)-3-pyridinlyl I-2,4 30 difluorobenzenesull'onamide:. I ,2-dirncthyl-N- I 5-14-(4-pyridinyl)-6-quinolinyl 1-3-pyridinyl I}- I 1-l-irnidazole-4 su ltonan-idc; - 35 - 3-16-(5-{ I(2,4-ditluoroplienyl)su Itonyl Ilarnino 1-3-pyrid Inyl)-4 qui not inyl I ben zamide; 4-16-(5-f I(2,4-difluoropheny~lt onylI jarni no 1-3-pyi-idinyl)-4 qu inol iny1J]ben zami de; 5 N- ( 4-[6-(5-f [(2,4-dililuorophenvi)sulf'onyl I am ino)} -3-pyrid Inyl)-4 quinolinyl phenyl lacetamide; N-1{ 3-I 6-(5-f (2,4-difluorophenvl)sultfonyI jamnino } -3-pyridinyl)-4 quinolinyl lphenyl acetamide; 6-(4-morpliolinyl)-N- (5-14-(4-pyridinyl)-6-quinolinyl 1-3-pyridiinyl }-3 10) py'ridlinesulfonarnile; 2-tluoro-4-inethyl-N- I 5-I 4-(4-pyid~inyl)-6-quinoliniyl 1-3 pyr-idinyl )benzenesul tbinar-nidc N-fI 5-14-(4-pyridinyl)-6-quinolinyl 1-3-pyr-idinyl )-2-tfuransulf'onamilidc; I ,3-diimcthyl-N- I 5-I 4-(4-pyridinyl)-6-quinoiinyI j-3-pyridinyl I-1 I -- pyraiolc-4 15 sulfonamide; N-fI 5-14-(4-pyridinyl)-6-quinolinyi 1-3-pyridinyl }-2 (titluoromethyl)benzencsultonam-idc; N- { 2-(mcthyloxy)-5-I 4-(4-pyr-idinyl)-6-quinolinyI 1-3 pyridinyl }cyclohcxancsultonar-nide; 20 N-[5-(4-cyclopentyl-6-quinolinyi)-2-(methyloxy)-3-pyridiny jbenzenes u Ifonai de; 2,5-dichloro-N-1 5-14-(4-pyr-idinyl)-6-quinolinyll-3-pyridinyI }bcnzcncsultfonam-idc;, 3-cyano-4-tluoro-N- {5-14-(4-pyridinyl)-6-qui nolinyl 1-3 pyridinyl lbenzcnesuit'onamidc; N-f 5-I4-(4-pyridinyl)-6-quinolinyl 1-3-pyiridinyl }- I -pyrrolidlincsulfonarnidc; 25 (5Z)-5-( I 5-14-(4-pyridinyl)-6-quinolinyl 1-3-pyridinyl) }mcthvlidcnc)- 1,3 th iazol idine- 2,4 -di one; N-fi 2-(miethyloxy)-5-14-(4-pyr-idiinyl)-6-quiniolliyl 1-3 pyridlinyl }cyclopropanesult'onairidc; N-f 5-I4-(4-pyridinyl)-6-quiniolinyl 1-3-pyr-idinyl )-2-pyridILinesuLl forinidC; 30 1 ,2-dimethyl-N- f5-I 4-(4-pyridinyl)-6-quinoiinyl 1-3-pyiridinyl- -I [l-imlicazole-5 SUlf'onamidle; 1-methyl-N-f 5-14-(4-pyr-idinyl)-6-quinolinyll-3-pyridinyI }-3-(tritluoromnethiyl)- 11 - 36 pyrazole-4-sulfonamide; I,3,5-trinethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyIJ-3-pyridinyl }-1 -- pyrazole-4 sulfonamide; N-{2-(ethyIoxy)-5-[4-(4-pyridinyl)-6-quinolinyl -3-pyridinyl }benzenesulfonamide; 5 N,N-dimethyl-N'-{5-[4-(4-pyridinyl)-6-quinolinyl 1-3-pyridinyl Isulfamide; N- { 2-chloro-5-14-(4-pyridazinyl)-6-quinolinyl j-3-pyridinyl 1-2,4 difluorobenzenesulfonamide; N-{ 2-chloro- l-oxido-5-14-(4-pyridinyl)-6-quinolinyl -3 pyridinyl }benzcnesul fonarnide; 10 N-{6-methyl-5-14-(4-pyridinyl)-6-quinolinyl -3-pyridinyl bencznesulfonamide; N- { 2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl 1-3 pyridinyl I methanesulfonamide; N-{ 2-chloro-5-14-(4-pyridinvl)-6-quinolinyl 1-3-pyridinyl }methanesulfonamide; 2,4-ditluoro-N- i2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl -3 15 pyridinylbenzenesulfonamide; and/or a pharmaceutically acceptable salt thereof. This invention also relates to a method of treating cancer, which comprises co-administering to a subject in need thereof an effective amount of a compound of Formula (1), and/or a pharmaceutically acceptable salt thereof; and at least one anti 20 neoplastic agent such as one selected from the group consisting of: anti-microtubule agents, plantinun coordination complexes, alkylating agents. antibiotic agents, topoisomerase 11 inhibitors, antimetabolites, topoisomerase I hinibitors, hormones and hormonal anlogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic 25 agents, and cell cycle signaling inhibitors. This invention also relates to a method of treating cancer, which comprises co-administering to a subject in need thereof an effective amount of a compound of Formula (1), and/or a pharmaceutically acceptable salt thereof; and at least one signal transduction pathway inhibitor such as one selected from the group consisting 30 of: receptor tyrosine kinase inhibitor, non-receptor tyrosine kinase inhibitor. S-12/SH3 domain blocker, serine/threonine kinase inhibitor, phosphotidyl inositol-3 kinase inhibitor, rnyo-inositol singaling inhibitor, and Ras oncogene inhibitor. - 37 - As used herein, the term "effective amount" means that amount ofa drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any 5 amount which, as compared to a corresponding subject who has not received suCh amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. 10 Compounds of Formula (1) are included in the pharmaceutical compositions of the invention. Definitions By the term "substituted amino" as used herein, is meant -NR30R40 wherein each R30 and R40 is independently selected from a group including hydrogen, CI 15 6alkyl, acyl, C3-C7cycloalkyl, wherein at least one of R30 and R40 is not hydrogen. By the term "acyl" as used herein, unless otherwise defined, is meant -C(O)(alkyl), -C(O)(cycloalkyl), -C(O)(aryl) or -C(O)(heteroaryl), wherein heteroaryl and aryl are optionally substituted. By the term "aryl" as used herein, unless otherwise defined, is meant 20 aromatic, hydrocarbon, ring system. The ring system may be monocyclic or fused polycyclic (e.g. bicyclic, tricyclic, etc.). In various embodiments, the monocyclic aryl ring is C5-CIO, or C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the ring system. A C6 ring system, i.e. a phenyl ring is a suitable aryl group. In various embodiments, the polycyclic ring is a 25 bicyclic aryl group, where suitable bicyclic aryl groups are C8-C 12, or C9-C 10. A naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group. By the term "heteroaryl" as used herein, unless otherwise defined, is meant an aromatic ring system containing carbon(s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic. A inonocyclic heteroaryl group may 30 have I to 4 hctcroatoms in the ring, while a polycyclic heteroaryl may contain I to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is, a polycyclic heteroaryl. Bicyclic - 38 heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms). Exemplary heteroaryl groups include but are not limited to: bcnzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, 5 pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole, and thiophene. By the term "monocyclic heteroaryl" as used herein, unless otherwise defined, is meant a monocyclic heteroaryl ring containing 1-5 carbon atoms and 1-4 hetero atoms. By the term "alkylcarboxy" as used herein, unless otherwise defined. is 10 meant -(C-l 2 ),COOReo, wherein R80 is hydrogen or CI-C6alkyl, n is 0-6. By the term "alkoxy" as used herein is meant -O(alkyl) including -OCI-3, OCI-1 2 C-1 3 and -OC(CH 3

)

3 where alkyl is as described herein. By the term "alkylthio" as used herein is meant -S(alkyl) including -SCH 3 , SCHI- 2 CHi1 where where alkyl is as described herein. 15 The term "cycloalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C 3 -C 1. Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, aininocyclohexyl, cyclobutyl, aminocyclobutyl, 4 hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl4-methoxycyclohexyl, 4 20 methoxycyclohexyl, 4-carboxycyclohexyl, cyclopropyl, aminocyclopentyl, and cyclopentyl. By the term "heterocycloalkyf" as used herein is meant a non-aromatic, unsaturated or saturated, monocyclic or polycyclic, heterocyclic ring containing at least one carbon and at least one heteroatom. Exemplary monocyclic heterocyclic 25 rings include: piperidine. piperazine, pyrrolidine, and morpholine. Exemplary polycyclic heterocyclic rings include quinuclidine. By the term "substituted" as used herein, unless otherwise defined. is meant that the subject chemical moiety has one to Five substituents, suitably from one to three substituents selected from the group consisting of: hydrogen, halogen, Cl 30 C6alkyl, amino, urea, trifluoromethyl, -(CH 2 )nCOO-, C3-C7cycloalkyl, substituted amino, aryl, heteroaryl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heterocycloalkyl, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, aminoacyl, - 39 arylamino, nitro, oxo, -C0 2

R

5 0 , -S0 2

R

70 , -NR 50 S0 2

R

70 , NR 5 oC(O)R 7 y and CONR 55

R

60 , wherein R50 and R55 are each independently selected from: hydrogen. alkyl, and C3-C7cycloalkyl; R55 and R60 can optionally form a heterocycloalkyl ring; n is 0 to 6; R75 is selected from the group consisting of: Cl-C6alkyl, C3 5 7cylcoalkyl, substituted C3-7cycloalkyl. aryl, substituted aryl. hcteroaryl, substituted hetcraryl, amino, substituted amino, arylamino, Cl-C6hctcrocycloalkyl, alkoxy, aryloxy and substituted CI-C6heterocycloalkyl; each R60 and R70 is independently selected from the group consisting of: Cl -C6alkyl, C3-C7cycloalkyl, substituted CI C6heterocycloalkyl, Cl-C6heterocycloalkyl, halogen, amino, substituted amino, 10 arylamino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, -(C-l 2 ),COOH, aryl optionally fused with a five-memlbered ring or substituted with one to five groups selected from the group consisting of: Cl-C6alkyl, C3-C7cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo. or (CHz),COOH, or heteroaryl optionally fused with a five-membered ring or 15 substituted with one to five groups selected from the group consisting of: Cl C6alkyl, C3-C7cycloalkyl, halogen, amino, trilluoromethyl, cyano. hydroxyl, alkoxy, oxo, or -(CH 2 ),COOH. By the term "substituted", when referred in the definition of R60, 170, R75, "arylamino", and "aryloxy", is meant that the subject chemical moicty has one to 2 five substituents, suitably from one to three, selected from the group consisting of: hydrogen, Cl-C6alkyl, halogen, trilluoromethyl, -(Cl-l,),COOl. amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy. acyloxy, acyl, acylamino, and nitro, n is 0-6. By the term "acyloxy" as used herein is meant -OC(O)alkyl where alkyl is as 25 described herein. Examples of acyloxy substituents as used herein include: OC(O)CH 3 , -OC(O)CH(CH 3

)

2 and -OC(O)(CI 2

)

3

CH

3 By the term "acylamino" as used herein is meant -N(H)C(O)alkyl, N(I-I)C(O)(cycloalkyl) where alkyl is as described herein. Examples of N-acylamino substituents as used herein include: -N(-l)C(O)CI-13, -N(-I)C(O)CH(CH 3

)

2 and 30 -N(H)C(O)(CH 2

)

3

CH

3 . By the term "aminoacyl" as used herein is meant -C(O)N(alkyl),, C(O)N(cycloalkyl), where alkyl is as described herein, n is 1-2. - 40 - By the term "aryloxy" as used herein is meant -O(aryl), -O(substituted aryl), -O(heteroaryl) or -O(substituted heteroaryl). By the term "arylarnino" as used herein is meant -NRao(aryl), NRo(substituted aryl), -NR 8 (hcteroaryl) or -INRs(substituted hetcroaryl). wherein 5 R80 is H, CI-6alkyl or C3-C7cycloalkyl. By the term "hetcroatom" as used herein is meant oxygen, nitrogen or sulfur. By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride. By the term "alkyl" and derivatives thereof and in all carbon chains as used 10 herein, including alkyl chains defined by the term "-(CHl2)n", "-(Cl- 2 )m-" and the like, is meant a linear or branched. saturated or unsaturated hydrocarbon chain, and unless otherwise defined, the carbon chain will contain from I to 12 carbon atoms. By the term "substituted alkyl" as used herein is meant an alkyl group substituted with one to six substituents selected from the group consisting of: 15 halogen, trifluoromethyl, alkylcarboxy, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, carbamate, urea, sulfonamate, C3-7cyclohcteralkyl, C3-7cycloalkyl and nitro. Examples of alkyl and substituted alkyl substituents as used herein include:

-CH

3 , -CI-1 2

-CH

3 , -C-1 2

-CH

2

-CH]

3 , -CI-(CIH 3

)

2 , -C-12-C-1 2 -C(C-1 3 )3, -CH2-CF 3 , 20 -CEC-C(CH3)3, -C C-C-1 2 -0-1, cyclopropylmethyl, -CH 2 -C(CH 3)2-C-l2-N 2,

-C=C-C

6

H-

5 , -C-C-C(C-13)2-OHi, -CH 2 -CI-(0-)-CI-(0-)-CI-(0-)-C-(0)

CH

2 -OH, piperidinylmethyl, methoxyphenylethyl, -C(CH 3

)

3 , -(C1 2

)

3 -C-1 3 , -Cl-I CH(C1 3

)

2 , -CH(CH 3 )-CI-12-C-13, -CH=C1 2 , and -CzC-CI- 3 . By the term "treating" and derivatives thereof as used herein, is meant 25 prophylatic and therapeutic therapy. Prophylatic therapy is meant the institution of measures to protect a person from a disease to which lie or she has been, or may be, exposed. Also called preventive i-eatmnent. By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential 30 administration of a ll3 kinase inhibiting compound, as described herein, and a -41 further active ingredient or ingredients. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of' treatment. Suitably, if the administration is not simultaneous, the compounds are 5 administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally. The term "compound" as used herein includes all isomers of the compound. 10 Examples of such isomers include: enantiomers, tautomers, rotamers. In formula (V) to (X), when a "dot" bond is drawn between two atoms, it is meant that such bond can be either single or double bond. A ring system containing such bonds can be aromatic or non-aromatic. Certain compounds described herein may contain one or more chiral atoms, 15 or may otherwise be capable of existing as two enantiomers, or two or more diastereoisomers. Accordingly, the compounds of this invention include mixtures of enantiomers/diastercoisomers as well as purified enantiomers/diastercoisomers or enantiomerically/diastereoisomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by 20 formula I or II above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Further, an example of a possible tautomer is an oxo substituent in place of a hydroxy substituent. Also, as stated above, it is 25 understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of Formula I or II. Compounds of Formula (1) are included in the pharmaceutical compositions of the invention. Where a -COOH or -01- group is present. pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, 30 and the like for -COOH, and acetate malcate and the like for -011, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations. - 42 - It has now been found that compounds of the present invention are inhibitors of the Phosphatoinositides 3-kinases (PI3Ks), particularly lI3Kw. When the phosphatoinositides 3-kinase (Pl3K) enzyme is inhibited by a compound of the present invention, PI3K is unable to exert its enzymatic, biological and/or 5 pharmacological effects. The compounds of the present invention arc therefore useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodcgcncrative diseases, allcrgy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, particularly cancer. 10 Compounds according to Formula (1) are suitable for the modulation, notably the inhibition of the activity of phosphatoinositide 3-kinases (l3K), suitably phosphatoinositides 3-kinase (PI3KQ). Therefore the compounds of the present invention are also useful for the treatment of disorders which are mediated by P1l3Ks. Said treatment involves the modulation - notably the inhibition or the down 15 regulation - of the phosphatoinositides 3-kinases. Suitably, the compounds of the present invention arc used for the preparation of a medicament for the treatment of a disorder selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus crythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation, such as 20 meningitis or encephalitis, Alzheimer's disease. Huntington's disease, CNS trauma, stroke or ischemic conditions, cardiovascular diseases such as athero-sclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction. Suitably, the compounds of Formula (1) are useful for the treatment of 25 autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis. rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation such as meningitis or encephalitis. Suitably, the compounds of Formula (1) are useful for the treatment of 30 neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions. -43 - Suitably, the compounds of Formula (i) are useful for the treatment of cardiovascular diseases such as atherosclerosis, heart hypertrophy, cardiac rnyocytc dysfunction, elevated blood pressure or vasoconstriction. Suitably, the compounds of Formula (1) are useful for the treatment of 5 chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke, ischcrnic conditions, ischcmia-repcrlusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastasis, in particular melanoma, Karposi's sarcoma, acute and chronic bacterial and virual infections, 10 sepsis, transplantation rejection, graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung, and lung airway inflammation. Because the pharmaceutically active compounds of the present invention are active as P13 kinase inhibitors, particularly the compounds that inhibit PI3KrL, either 15 selectively or in conjunction with one or more of Pl13K6, PI3Kp, and/or P13K7, they exhibit therapeutic utility in treating cancer. Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhcrmittc 20 Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid. Suitably, the invention relates to a method of treating cancer in a mammal. 25 including a human, wherein the cancer is selected from: Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Irmmunoblastic large cell Ieukemia, Mantle cell leukemia, Multiple myeloma 30 Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocytic leukemia, promyclocytic leukemia and Erythroleukemia. - 44 - Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicular lymphoma. 5 Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer 10 of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. When a compound of Formula (1) is administered for the treatment of cancer. the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a P13 kinase inhibiting compound., as described herein, and a further active 15 ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the 20 compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally. Typically, any anti-neoplastic agent that has activity versus a susceptible 25 tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 *' cdfition (February t15, 2001), L.ippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on 30 the particular characteristics of the drugs and the cancer involved. Typical anti neoplastic agents useful in the present invention include, but are not limited to, anti microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination - 45 complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase 11 inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and 5 anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-reccptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. Examples of a further active ingredient or ingredients (anti-neoplastic agent) 10 for use in combination or co-administered with the presently invented AKT inhibiting compounds are chemotherapeutic agents. Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, 15 diterpenoids and vinca alkaloids. Diterpenoids, which are derived from natural sources, are phase specific anti -cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the p-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis 20 being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Paclitaxel, 5 ,20-epoxy-l,2a,4,7fi,I0 , I 3a-hexa-hydroxytax-lI -en-9-one 4.10-diacetate 2-benzoate 13-ester with (2R,3S)-N-bcnzoyl-3-phenylisoserinc; is a natural diterpene product isolated from the Pacific yew tree Taxuis hrevifolia and is 25 commercially available as an injectable solution TAXOL@. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. .1. Am. Chem, Soc., 93:2325. 1971), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. 30 NatI, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis - 46 and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston el al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235. 5 Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intem, Med., 111:273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. 10 Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Scm. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages. Ignoff, R.J. et. al. Cancer Chemotherapy Pocket Guide, 15 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, C.M. et. al., Seminars in Oncology, 3(6) p.

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2 3 , 1995). Docctaxcl, (2R.3S)- N-carboxy-3-phenylisoscrineN-tert-butyl ester, 13-ester with 501-20-epoxy-I,2ct,4,7fi ,00,13c-hexahydroxytax-I I-cn-9-onc 4-acetate 2 benzoate. trihydrate, is commercially available as an injectable solution as 20 TAXOTER.E@. Docetaxel is indicated for the treatment of breast cancer. Docctaxel is a scmisynthctic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin Ill, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia. Vinca alkaloids are phase specific anti-ncoplastic agents derived from the 25 periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. 30 Vinblastine, vincalcukoblastine sulfate, is commercially available as VEl.,3AN@ as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors. it is primarily indicated in the treatment - 47 of testicular cancer and various lymphomas including Hodgkin's Disease, and lymphocytic and histiocytic lymphomas. Myclosuppression is the dose limiting side effect of vinblastine. Vincristine, vincalcukoblastine, 22-oxo-, sulfate, is commercially available 5 as ONCOVIN@ as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myclosupression and gastrointestinal mucositis effects occur. I Vinorelbine, 3',4'-didchydro -4'-dcoxy-C'-norvincalcukoblastinc [R (R*,R*)-2,3-dihydroxybutancdioate (1:2)(salt)l, commercially available as an injectable solution of vinorelbine tartrate (NAV EL3IN E@), is a sernisynthctic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, 15 particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myclosuppression is the most common dose limiting side effect of vinorcibine. Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, 20 undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin. Cisplatin. cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the 25 treatment of' metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of'cisplatin are nephrotoxicity. which may be controlled by hydration and diuresis, arid ototoxicity. Carboplatin, platinum, diammine [1,1 -cyclobutane-dicarboxylatc(2-)-0,O' , is commercially available as PARAPLATIN® as an injectable solution. Carboplatin 30 is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin. - 48 - Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts 5 nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine. Cyclophosphamide, 2-[bis(2-chlorocthyl)aminojtetrahydro-2H- 1,3,2 10 oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN@. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents. in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of 15 cyclophosphamide. Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN@. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common 20 dose limiting side effect of melphalan. Chlorambucil, 4-[bis(2-chloroethyl)aminolbenzenebutanoic acid, is commercially available as LEUK FRAN@ tablets. Chlorambucil is indicated ftr IIe palliative treatment of chronic lymphatic leukemia, and malignant lymphoma such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone 25 marrow suppression is the most common dose limiting side effect of chlorambucil. Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN@ TABLETS. Busulfan is indicated for the palliative treatment of chronic myclogenous leukemia. Bone marrow suppression is the most common dose limiting side effects ofbusulfan. 30 Carmustine, 1,3-[bis(2-chloroethyl)-I-nitrosourca, is commercially available as single vials of lyophilized material as BiCNU@. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain - 49 tumors. multiple myeloma. Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine. Dacarbazine. 5-(3,3-dimethyl- I -triazeno)-imidazolc-4-carboxamide, is 5 commercially available as single vials of material as DTIC-Dome@. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine. 10 Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and 15 doxorubicin; and bleomycins. Dactinomycin, also know as Actinomycin ), is commercially available in injectable form as COSMEGEN@. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea. vomiting, and anorexia are the most common dose limiting side effects of dactinomycin. 20 Daunorubicin. (8S-cis-)-8-acetyl- I0-[(3-amino-2,3,6-trideoxy-a-L-lyxo hexopyranosyl)oxy]-7,8,9, I 0-tetrahydro-6,8,1 I -trihydroxy- I -methoxy-5,12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia 25 and advanced HIV associated Kaposi's sarcoma. MyClosuppression is the most common dose limiting side effect of daunorubicin. Doxorubicin, (8S, 1 OS)- I 0-[(3-amino-2,3,6-trideoxy-caL-l.-yxo hexopyranosyl)oxy]-8-glycoloyl, 7,8,9,1 0-tetrahydro-6,8, 1 -trihydroxy- I -methoxy 5,12 naphthacenedione hydrochloride, is commercially available as an injectable 30 form as RUBEX@ or ADRIAMYCIN RDF@. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute mycloblastic leukemia, but is also a useful component in the treatment of sonic solid tumors and - 50lymphomas. Myclosuppression is the most common dose limiting side effect of doxorubicin. Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces vertici/lus, is commercially available as BLENOXANE@. 5 Blcomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin. Topoisomerase 11 inhibitors include, but are not limited to. 10 epipodophyllotoxins. Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase Il and DNA causing DNA strand breaks. The strand breaks accumulate and cell death 15 follows. Examples of epipodophyllotoxins include, but are not limited to, ctoposide and teniposide. Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene-fi-D glucopyranoside], is commercially available as an injectable solution or capsules as VePESID@ and is commonly known as VP-16. Etoposide is indicated as a single 20 agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myclosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia. Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene-fi-D 25 glucopyranoside], is commercially available as an injectable solution as VUMON@ and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. MyClosupprcssion is the most common close limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia. 30 Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA -51 synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. 5 5-fluorouracil, 5-fluoro-2,4- (111,31) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast. colon, 10 rectum, stomach and pancreas. Myclosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-Iluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinc monophosphate. Cytarabine, 4-amino-I -p-D-arabinofuranosyl-2 (I 1-1)-pyrimidinone, is commercially available as CYTOSAR-U@ and is commonly known as Ara-C. It is 15 believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-diluorodeoxycytidine (gemcitabine). Cytarabine 20 induces leucopenia, thrombocytopenia, and mucositis. Mercaptopurine. I.7-dihydro-61--purine-6-thione monohydrate, is commercially available as PURINEVITHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with 25 other chemotherapy agents in the treatment of acute leukemia. Myclosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine. Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID@. Thioguanine exhibits cell phase specificity at S-phasc by 30 inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myclosuppression, including leucopenia. -52thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine. 5 Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ([ isomer), is commercially available as GEMZAR@. Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the Gl/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally 10 advanced pancreatic cancer. Myclosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration. Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methylImethylamino I benzoyl]-L-glutamic acid, is commercially available as methotrexate sodium. 15 Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non 20 Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myclosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration. Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins 25 cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10, 1| ethylenedioxy-20-camplothecin described below. Irinotecan H Cl, (4S)-4, 1 1-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) 30 carbonyloxy]- I lH-pyrano[3',4',6,7 Iindolizinol 1,2-b Iquinoline-3,14(41-,1 21-1)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR@. - 53 lrinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with 5 replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myclosuppression, including neutropenia., and GI effects, including diarrhea. Topotecan HICI, (S)-10-[(dimethylamino)methyll-4-ethyl-4,9-dihydroxy-li-I pyrano[3',4',6,7]indolizino[ 1,2-b]quinoline-3,14-(41-,12H)-dione 10 monohydrochloride, is commercially available as the injectable solution HYCAMTIN@. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the 15 ovary and small cell lung cancer. The dose limiting side effect of topolecan HICI is myclosuppression, primarily neutropenia. Also of interest, is the camptothecin derivative of formula A following, currently tinder development, including the racemic mixture (R,S) form as well as the R and S enantiomers: r NMe N N A 0 N 0 20 M 0 0 known by the chemical name "7-(4-methylpiperazino-methylene)-10,1I1 cthylencdioxy-20(R,S)-camptothccin (racemic mixture) or "7-(4-methylpipcrazino methylene)-10,l 1-ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4 25 methylpiperazino-methylene)- 10,11 -ethylcncdioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including - 54 methods of making, in U.S. Patent Nos. 6,063.923; 5,342,947; 5,559.235; 5,491,237 and pending U.S. patent Application No. 08/977,2 17 filed November 24, 1997. Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or 5 lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimidc and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestanC useful in the 10 treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as Ilutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and 15 dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxi fene, droloxifene, iodoxyfcne, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and 20 gonadotropin-releasing hormone (GnR-l) and analogues thereof which stimulate the release of leutinizing hormone (L-I) and/or follicle stimulating hormone (F-SH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide. Signal transduction pathway inhibitors are those inhibitors. which block or 25 inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SlH2/Si-3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes. 30 Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such - 55 protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases. Receptor tyrosine kinases are transmcmbrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase 5 domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has 10 been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGIr), platelet derived growth factor receptor (PDGFr), erbB2, erb34, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor 15 homology domains (TIE-2), insulin growth factor -l (IGI) receptor, macrophage colony stimulating factor (cfms), BTK. ekit, cmet. fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB3, and TrkC). cphrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists. antibodies, tyrosine kinase inhibitors and anti-sense 20 oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Other. Patents (2000) 10(6):803-818; Shawver ct al DDT Vol 2, No. 2 February 1997: and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, 25 London. Tyrosine kinases, which are not growth factor receptor kinases are termed non-receptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak. cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase. 30 and Ber-Abl. Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of -lematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, JiB.. Brugge. -56- J.S.. (1997) Annual review of Immunology. 15: 371-404. SH2/SH3 domain blockers are agents that disrupt S-12 or S-13 domain binding in a variety of enzymes or adaptor proteins including, P13-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. 5 SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32. Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and 10 Protein kinase C family member blockers including blockers of PKCs (alpha. beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb). PK3 family kinases, aki kinase family members, and TGF beta receptor kinases. Such Serinefhrconine kinases and inhibitors thereof are described in Yamamoto. T., Taya, S.. Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803;- Brodt, P, 15 Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6.268,391; and Martinez-lacaci, L., et al. Int. J. Cancer (2000). 88(l). 44-52. 20 Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of P13-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998). Oncogene 17 (25) 3301 3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 25 29 (7):935-8: and Zhong, -1. et al, Cancer res, (2000) 60(6), 1541-1545. Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994. 30 London. Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl - 57 transferase, and CAAX proteases as well as anti-sense oligonucleotides., ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, 5 S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30. As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction 10 pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M.C. ct al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin @ erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor 15 Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2C13 VEGFR2 specific antibody (see Brekken, R.A. et al. Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124). Non-receptor kinase angiogenesis inhibitors may also be useful in the present 20 invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2!EGFR signaling since inhibitors of crbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be 25 used in combination with the compounds of the present invention. For example. anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin alphay beta.) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), 30 Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen I et al. (2000), Oncogene 19: 3460-3469). -58- Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic 5 approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against crbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971. 10 Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-I). Therefore, 15 strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase li/Ill trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonuclcotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71 20 79. Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of 25 different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and C)K6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. - 59

-

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of formula I and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination 5 complexes, alkylating agents, antibiotic agents, topoisomerase 11 inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors. I0 Because the pharmaceutically active compounds of the present invention are active as P13 kinase inhibitors. particularly the compounds that modulate/inhibit Pl3K(., it is useful in treating cancer. Because the pharmaceutically active compounds of the present invention are also active against one or more of P13K6, Pl3K, and/or PI3Ky, they exhibit therapeutic utility in treating a disease state 15 selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries. When a compound of' Formula (I) is administered for the treatment of a 20 disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, cancer, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection. graft rejection or lung injuries, the term "co administering" and derivatives thereof as used herein is meant either simultaneous 25 administration or any manner of separate sequential administration of a P13 kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of such autoimmune disorder. cancer, inflammatory diseases, cardiovascular disease, neurodeCenerative disease. allergy, asthma, pancreatitis. multiorgan failure, kidney diseases, platelet 30 aggregation, sperm motility, transplantation rejection, graft rejection and/or lung injuries. -60 - Biological assays P13K alpha Leadseeker SPA Assay Compounds of the present invention were tested according to the following assays and found as inhibitors of P13 kinases, particularly Pl3K. The exemplified 5 compounds were tested and found active against Pl3Ka. The 1Cs s ranged from about I nM to 10 pM. The majority of the compounds were under 500 nM; the most active compounds were under 10 nM. The compound of Example 249 was tested generally according to the assays 10 described herein and in at least one experimental run exhibited a IC50 value: equal to 1.6 nM against PI3KrL. The compound of Example 252 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 0.8 nM against P13KL. 15 The compound of Example 263 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 7.9 nM against PI3Ku. The compound of Example 289 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal 20 to 2.5 nM against P13Kx. The compound of Example 154 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 316 nM against P1l3K. The compound of Example 156 was tested generally according to the assays 25 described herein and in at least one experimental run exhibited a IC50 value: equal to 79 nM against PI3KL. The compound of Example 224 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 1000 nM against PI3KQ. -61 - Assay principle SPA imaging beads are microspheres containing scitillant which em it light in the red region of the visible spectrum. As a result, these beads are ideally suited to use 5 with a CCD imager such as the Viewlux. The Lcudseekcr beads used in this system are polystyrene beads that have been coupled with polyethylenciine. When added to the assay mixture, the beads absorb both the substrate (P111P2) and product (PllP3). Adsorbed P 33 -P]P3 will cause an increase in signal, measured as ADUs (analog to digital units). This protocol details the use of the PEl-PS Leadseeker beads for 10 assays using His-pI 10/p85 P13K alpha. Assay protocol Solid compounds are typically plated with 0.1 tl of 100% DMSO in all wells (except column 6 and 18) of a 384-well, flat bottom, low volume plate (Greiner 15 784075). The compounds are serially diluted (3-fold in 100% DMSO) across the plate from column I to column 12 and column 13 to column 24 and leave column 6 and 18 containing only DMSO to yield I I concentrations for each test compound. The assay buffer contains MOPS (p1 6.5), CHAPS, and DTT. Pl3K alpha and PIP2 20 (L-alpha-D-myo-Phosphatidylinositol 4,5-bisphosphate [Pl(4,5)P2j3-0-phospho linked, D(-i-)-sn-1,2-di-O-octanoylglyceryl, CellSignals ft 901) are mixed and incubated in the plate with compound for 30min prior to starting the reaction with the addition of pl 33 -ATP and MgCl 2 (reagents added using Zoom). Enzyme-free wells (column 18) are typically done to determine the low control. PEl-PS 25 Leadsceker beads in PBS/EDTA/CHAPS are added (by Multidrop) to quench the reaction, and the plates are allowed to incubate for at least one hour (typically overnight) before centrifugation. The signal is determined using a Viewlux detector and is then imported into curve fitting software (Activity Base) for construction of concentration response curves. The percent inhibition of activity is calculated 30) relative to high controls (Cl, 0.1g l DMSO in column 6, rows A-P)) and low controls (C2, 5 l of 40 uM lP'2 in buffer in column 18, rows A-P) using, 100*(,I-(lt C2)/(C l-C2)). The concentration of test compound yielding 50% inhibition is -62determined using the equation, y = ((Vmax*x) / (K+x)) + Y2, where "K" is equal to the IC50. The IC50 values are converted to pIC50 values, i.e., -log IC50 in Molar concentration. 5 Celluar assays: DAY I " Plate cells before noon o 10K cells/well in clear flat-bottomed 96-well plates (fv. 105ul) o Last four wells in last column receive media only 10 o Place in 37degC incubator overnight * Compound plate o Prepare in polypropylene round-bottomed 96-well plates; 8 compounds pcr plate, I l-pt titrations of each (3x serial dilution), DMSO in last column 15 (0.15% f.c. on cells) o 15ul in first well, 1Oul DMSO in the rest; take 5ul from first well and mix in next, continue across plate (excluding last column); scal with foil lid and place at 4degC DAY 2 20 * Take out Lysis buffer inhibitors (4degC/-20degC) and compound plates (4degC), thaw on bench top; make Ix Tris wash buffer (V/B) to Fill reservoir on plate washer and top off bench supply (use MiliQ), turn on centrifuge to allow it to cool B lock MSD plates 25 o Make 20ml 3% blocking solution/plate (600 mg blocker A in 20ml W13), add 150ul/well and incubate at RT for at least I hr * Add compound (while blocking) o Add 3 0 0 ul growth media (RPMI w/ Q, 10% FiS) per well ( 6 82x dil of compound) to each compound plate 30 o Add Sul compound dilution into each well (fv. //Oul) on duplicate plates o Place in 37degC incubator for 30min - 63 - * Make lysates o Prepare MSD Lysis buffer; for 10m] add 200ul protease inhibitor solution, and 100ul each of Phosphatase inhibitors I & 11 (Keep on ice until readyfor use) 5 o Remove plates post-incubation, aspirate media with plate washer, wash lx with cold PBS, and add 8Oul MSD Lysis buffer per well: incubate on shaker at 4dcgC for 230min o Spin cold at 2500rpm for 10min; leave plates in 4dcgC centrifuge until ready for use 10 * AKI' duplex assay o Wash plates (4x with 200ul/well WB in plate washer); tap plates on paper towel to blot o Add 60ul of lysates/well, incubate on shaker at RT for I hr o During incubation prepare detection Ab (3 ml/plate; 2 ml W13 and I 15 ml blocking solution w/ Ab at lOnM); repeat wash step as above o Add 25ul of Ab/well, incubate on shaker at RT for I hr; repeat wash step as above o Add 150ul/well lx Read Buffer (dilute 4x stock in ddl-20, 20ml/plate), read immediately 20 0 Analysis o Observe all the data points at each compound concentration. o The data point from highest inhibitor concentration must be equal or greater than 70% of DMSO control. o IC50 for duplicate runs must be within 2-fold of each other (not 25 flagged in summary template). o Y min must be greater than zero; if both mins arc red flagged (>35) then compound is listed as inactive (IC50= > highest dose). If only one min is red flagged, but still <50 then call 1C50 as listed. o Any data points equal or greater than 30% off the curve will not be 30 considered. - 64 - Cell Growth/Death Assay: BT474, -CC1954 and T-471) (human breast) were cultured in RPMI-1640 containing 10% fetal bovine scrum at 37'"C in 5% CO 2 incubator. Cells were split 5 into T75 flask (Falcon #353136) two to three days prior to assay set up at density which yields approximately 70-80% confluence at time of harvest for assay. Cells were harvested using 0.25% trypsin-EDTA (Sigma #4049). Cell counts were performed on cell suspension using Trypan Blue exclusion staining. Cells were then plated in 384 well black flat bottom polystyrene (Greiner #781086) in 48 .il of 10 culture media per well at 1,000 cells/well. All plates were placed at 5% CO 2 ,. 37 0 C overnight and test compounds were added the following day. One plate was treated with CellTiter-Glo (Promega #G7573) for a day 0 (1=0) measurement and read as described below. The test compounds were prepared in clear bottom polypropylene 384 well plates (Greincr#781280) with consecutive two fold dilutions. 4 ptl of these 15 dilutions were added to 105 ltl culture media, after mixing the solution, 2 fd of these dilutions were added into each well of' the cell plates. The final concentration of' DMSO in all wells was 0.15%. Cells were incubated at 37"C, 5% CO> for 72 hours. Following 72 hours of' incubation with compounds each plate was developed and read. CellTiter-Glo reagent was added to assay plates using a volume equivalent to 20 the cell culture volume in the wells. Plates were shaken for approximately two minutes and incubated at room temperature for approximately 30 minutes and chemiluminescent signal was read on the Analyst GT (Molecular Devices) reader. Results were expressed as a percent of the t=0 and plotted against the compound concentration. Cell growth inhibition was determined for each compound by fitting 25 the dose response with a 4 or 6 parameter curve fit using XLfit software and determining the concentration that inhibited 50% of the cell growth (glC50) with the Y min as the t=0 and Y max as the DMSO control. Value from wells with no cells was subtracted from all samples for background correction. Additional references: 30 The compounds of the present invention can also be tested to determine their inhibitory activity at Pl3Ka, P13K6. PI3K3 and PI3Ky according to the assays in the following references: - 65 - For all ll3K isoforms: I. Cloning, expression, purification, and characterization of the human Class la phosphoinositide 3-kinase isoforms: Meier, T.I.; Cook, J.A.; Thomas, J1.; Radding, J.A.; Horn, C.; Lingaraj, T.; Smith, M.C. Protein Expr. Purif.. 5 2004, 35(2), 218. 2. Competitive fluorescence polarization assays for the detection of phosphoinositide kinase and phosphatase activity: Drees, B.E.; Wcipert, A.: -udson, I-I.; Ferguson, C.G.; Chakravarty, L.; Prestwich, G.D. Comb. Chem. High Throughput.Screen., 2003, 6(4), 321. 10 For ll3Ky: WO 2005/011686AI The pharmaceutically active compounds within the scope of this invention are useful as P13 Kinase inhibitors in mammals, particularly humans, in need thereof. The present invention therefore provides a method of treating diseases 15 associated with P13 kinase inhibition, particularly: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries and other conditions requiring P13 kinase modulation/inhibition, which comprises 20 administering an effective compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (1) also provide for a method of treating the above indicated disease states because of their ability to act as P1l3 inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, 25 intramuscular, oral, subcutaneous, intradermal, and parenteral. The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include. starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin. 30 agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostcarate or glyceryl -66 distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about I g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, ernulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or 5 nonaqucous liquid suspension. The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolvingi. the ingredients, as appropriate, to give the desired oral or parenteral products. It Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a P13K inhibitor, the selected dose is administered preferably from 1-6 times daily, 15 orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and 20 convenient for the patient. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular ll3 kinase inhibitor in use, the strength of' the preparation, the mode of administration, and the advancement of the disease condition. Additional Factors depending on the particular patient being 25 treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration. The method of this invention of inducing P13 kinase inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective P13 kinase modulating/inhibiting amount of a pharmaceutically 30 active compound of the present invention. The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use as a P13 kinase inhibitor. -67- The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in therapy. The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in treating autoimmune disorders. 5 inflammatory diseases. cardiovascular diseases. neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation. cancer, sperm motility, transplantation rejection, graft rejection and lung injuries. The invention also provides for a pharmaceutical composition for use as a P13 inhibitor which comprises a compound of Formula (I) or a pharmaceutically 10 acceptable carrier. The invention also provides for a pharmaceutical composition for use in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft 15 rejection and lung injuries, which comprises a compound of Formula (I) or a pharmaceutically acceptable carrier. In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, including compounds known to have utility when used in combination with a P13 kinase inhibitor. 20 Without further elaboration, it is believed that one skilled in the art can., using the preceding description, utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. 25 Experimental Details The compounds of the following examples are readily made according to Schemes I or by analogous methods. 30 - 68 - Scheme 1: R1 Br '. a Br b Br NC N - N'

~L

0 Ri R1 c d R2 Conditions: a) 2 M HCI in diethylether. THF. i: then sodiuim iodide, propionitilei rc.lux; h) aryl 5 (1RI) bromide. palladium ncatalyst, 2 M K 2 CO . dioxane. heat: e) his(pinacolato)dihoroni. potassiim i acetate. palladiumi catalyst. dioxanc. heat: d) heleroa-yl (R2) hiomide. pall adh unii catalyst. satirated aqueous NaHlICO,. diOXaIe. heat. Example I 5-|4-(4-pyridinyl)-6-quinolinyl I-3-pyridinesulOnamide N N N 15 a) 6-hromo-4-iodoquinoline Following the general procedure of Wolf, Christian ct. al. (SynLetn 2003 12, 1801-1804). to a solution of 6-bromo-4-chl oroqu inol inc (30 g, 0.124 mol) in anhydrous TIHF (500 mL) was added 2 M HCI in diethylether (74 mL, 0. 14 mol). A 20 while precipitate formed immediately. After stirring for 30 iin, the suspension was concentrated in vacuo and dried under vacuum to provide 6-bromo-4 chloroquinoline hydrochloride as an ofl-white solid (34.6 g,. quantitative yield). A 3-neck roundbottom flask equipped with a reflux condenser and mechanical stirrer was charged with 6-bromo-4-chloroquinoline hydrochloride (34.6 - 69 g, 0.124 mol), anhydrous sodium iodide (92.93 g, 0.62 mol) and propionitrile (1 l). The resulting slurry was stirred vigorously at reflux for 96 hrs. The solution was cooled to room temperature and 500 mL of 10% K 2 C0 3 solution was added, followed by a 200 mL of a 5% sodium sulfite solution. The reaction mixture was 5 extracted with CHCl, (600 mL x 4). The combined organic extracts were dried (Na 2

SO

1 ), filtered and conc. in vacuo to provide the title compound as an off-white solid (41.8 g, >quantitative yield), which was used without further purification. LCMS [MlV = 333.8, 334.8, 336.0 and 337.0: IT NMR (400 MlIz, (-)MSO) 6 (ppm) = 7.98-7.96 (2 H, m), 8.14-8.16 (1 H, in), 8.23 (1 I1-, d), 8.53 (1 IH. LI). 10 b) 6-bromo-4-(4-pyridinyl)quinoline A I L sealed tube charged with 6-bromo-4-iodoquinoline (11.58 g, 0.0347 mol), 4-pyridineboronic acid (5.97 g, 0.0486 nolI), tetrakis(triphenyphosphine)palladium[l01 (2.0 g, 0.00173 mol), 2 M aqueous 15 potassium carbonate (152 mL) and 1,4-dioxane (152 mL.) was stirred at 100 "C for 28 hrs. After cooling to rt, the organic layer was separated and the aqueous portion extracted with EtOAc (200 mL x 3). The combined organic extracts were dried (Na 2

SO

1 ), filtered and pautially concentrated in vacuo. The resultant mixture was filtered to give the title compound (9.13 g) as a tan solid. The residual supernatant 20 was concentrated to dryness and purified by silica gel chromatography (I W% ethyl acetate to 2% methanol in ethyl acetate) to provide an additional 0.036 g of the title compound as a tan solid (combined 9.166 g, 92% yield). LCMS IM] =285.9; 287.8. H' NMR (400 MIIz, d-DMSO) 6 (ppm)= 7.53 7.71 (3 1-, m). 7.85 (1 -, s), 8.05 (1 1-, d.). 8.17 (1 1-, d). 8.8 1 (2 -1, d), 9.05 (1 H, d) 25 c) 4-(4-pyri d inyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxa borolan-2-yl)quinoline A mixture of (6-bromo-4-(4-pyridinyl)quinoline (5.0 g, 17.5 mmol), bis(pinacolato)diboron (4.9 g, 19.3 mmole), potassium acetate (5.2 g, 52.6 mmol), 30 and dichloro-[ 1, l'bis(diphenylphosphino)ferrocenelpalladitum (11) dichloromethane adduct (430 mg, 0.53 mmol) in dioxane (30 mL) was heated at 130 "C for 4 h and cooled to room temperature. The reaction was cooled and filtered through Na 2 SO. -70 and Celite onto silica. The mixture was purified by silica gel chromatography eluting with :tOAc/ ethanol (0-20% methanol gradieni) to give the title compound as a semi-puLe solid. (2.14 u, 64 % ) mix of' horonic acid and ester used without further purification. 5 d) 5-14-(4-pyridinyl)-6-quinolinyll-3-pyridinesulfonamide A mixture of 4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)quinoline (250 mg, 0.75 mmol), 5-bromopyridine-3-sulfonamide (213 mg, 0.9 10 mmol), tetrakistriphenylphosphine palladium (0) (95 mg, 0.08 mmol), and saturated aqueous NaHCO 3 (2.5 mL), and dioxane (5 mL) ) was heated at 120 "C for I h and cooled to room temperature. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude product was purified by Gilson reverse phase HlPLC (8-25% 6 min gradient 0.1% TFA in H 2 0 / Cl-3CN) 15 followed by neutralization with saturated aqueous Nal-C03 and extracted into EtOAc. Evaporation provided the title compound as an ofT white solid. (85 mg, 31%). ESMS IM+HlI+= 363.1 The following compounds were or can he prepared following the general procedures 20 used to prepare the compound of Example 1: MS(ES) Example Structure IM+H|* N N 2 N 338 N N N - 71 - N NN 3 .- ~ . N411 N~ NN NN N N N ,N N- N 50 392 %NN 0:;N NN N N N N ~ ,N N N N N N N N 7N ... N78 0 N 0N N N N NN 36 N N N N NN N - 72 - N N // 10 N 1 338 NN N N IN O N 525 CN N N N 15 444 N N N 07 NN NN N N N NN 0 N NN N5 NN 0 8' 14 ~ '~ 7 0 00 73- N N N 16 - 'N461 NNI o N NN N N N 170 N N,49 0 0 N N N N 18 490 N -, F N N 0 N N 19~' NN, ,50 0 0 N N N N 20 N , ' -N 454 N N N N 21 N 454 N N N 22 111 557 0 0I N - 74 - N N N 23 436 0I 0 N N N 24 N476Z 0 'N NN 25 4 0 NN N N N N 26 476 NN N N N 0 IN NN N 2750 N N I50 N0 N I/No N 0 N 28 ~ii 477 N - 75 - C N N 29 -463 C) N N 0 30 N N~396 0 N 0 N N ~N 31 o=< N'340 N N N N N N 32I= 341 323 N N2 N N NN N 2 NN N NN N -76- N NN N N N N N NN1 N N N N 38 N\ N N N33 N N N NN N N NN 39 \~ N N N40 41N N- 41 N INN 42 3 2. N N N N N 0 N N. NN N. -7 -2 N 45 ON N 355 0 N N 46 N339 N N 0N N 47 352 F3C N N NN N NN N N) 7-- 53(,;N 420 F F FN 5945 N N 60~ ~ N-2 N N N N== N 2 60 N 140 N NN N NN NN N 63 395N NN 62 ~A -395 0 11 0 S-N 0 ll / O=S-N 64 N 498 NN N IS 0= =0 N'-\ N0 65 -485 N N N I N,. 0=S=0 66 364 N N 0= =0 N-N 67 11 352 -~;- -N (18 36 N N 69S= 300 0/ -80 0O NN oN 71 433 o IN? 72 N341 N O= =0 i. 73 3- 363 N 0. -0 74 341 N=N N 4N N 75 3 52 76 377/ 7 ,N 77 -391 N - 81 - N 78 9 ~ 328 N N 79I 355 NN N NN N NN N -N N - 82 - N' 84 QzN. = 408 N- o N -- r 85 N0--s 0 422" N 6NN 86 C~0462 - N 88 1 436 NN 89 N 418 N - 83 - 0 90 cJNN498 ~ / N 91 4 19 NN 92 447 93 417 94 I407 95 i1453 r- I - 84 - 0 O/ N 96 460 N - - N o I 99 44 NN 102 439 -85- N N NN -~ N. 104- 473. N N- _ 0 N. 1046 463.2 N N _NN 0 NN N, N 86 N C ' 251 N 537. T D N N Cil N NN I l N 254 N N0. N N 255 N 49. NN NN 5C6 N 7 1 . 0N N -87 N 257 0 c42 NN N 0 N 258 441 N N 0 N$ 259 396 NN N 260 N \N 4 92 0 0F N- N N NN~ 262 .14 N 525 NIN - 88 - 00 N--NO 2 63 N \ 0/ N 0

O-S=

26 5 ci N N N N 9 N N> N N 266 c N- 492 N N 5N N 4\/o0 A ) 0 s\ N 267 0 4507 NN N -89- 'NN N-N N 270 N 464 N 0 N . N. // 0 NN -0- 273 0N 481 N NN NN N N NN 274 6 0,1 N 418 N N N I91 278 ( 437 N N Scheme 2: Ri R1 Br R2 N N 5 Conditions: a) hetmcraryl (R2) boronic acid or hetcroarvl (R2) horoINItC. pialLdiumi caLyvst. 2 M potassiuin carbonate, beit; or heteroa-yl (R2) stannanc. palladiuim catalyst, dioxane. heat. Example 107 6-[5-(methylsulfonyl)-3-pyridinyll-4-(4-pyridinyl)quinoline 0 o- / N - N 10) N A mixture of (6-bromo-4-(4-pyridinyl)quinoline (250 mg, 0.88 mmol), 5 methylsulfonyl pyridine-3-boronic acid (201 mg, 1.0 mmol), tetrakistriphenylphosphine palladium (0) (104 mg, 0.09 mmol), and sat. aqueous NaHCO 3 (1.75 mL), in dioxane (5 mL) was heated at 1l10 0 C for I h then cooled to 15 room temperature. The rxn was filtered through Cclite and Na 2 SO, onto silica and the crude product was purified by column chromatography (5% EtOAc/-lex -- 10% Ethanol/EtOAc ; 30 min gradient). Evaporation and precipitation firom NMeOH/watcr (2/98) provided the title compound as a yellow solid. (160 ing, 50%). ESMS [ M+-I j4= 362. 1 20 The following compoInds were or can be prepared following the general procedures used to prepare the compoInd of Example 107: - 92 - MS(ICIS) Example Structure I+I N NN 108 3 323 N NN NN N N N 1102' N N2 N N N N

N

112 3132 -- 93 115 N, 313 116 A314 117 NI317 118 A285 N N 123 NN 344 -94N 124 UN328 125 385 12741 126 N 31 N KN N f-c N N 12830'N ' 310 N 131 31 129 A -302 132 309 133 N313 0 134 39*7 135 KI3130 N 136 317 N N 138 2918 N - 96 - 0 139 13 62 N>~ N ,4 N 279 334.1 Scheme 3: R I BrR2N N N Conditions: it) aryl (RI) horoniLu auid or aryl (111) horonatc. palklidiumi cLat;LysL. 2 N/I potassiumn 5 carhonaic. d ioxane. I1Cil ; dill heLeroa ry I ( R2) horoi ii acid or- heteroary (142) hurotile. p I aLJLl iii caua yst. 2 MA polassiumi carhuiatc. heat. Example 139 10 2-urn 110-5-({4-I 3-( ainoul fLIIoniyl)pheniyl I-6-qu l i l } I- 3-pyt-i di jieSoII Ibomd 0,N~j, SONH, N N A i-ixture' of 4-iodo-6-bromnoq~in1oliIC (1. 18 g 3.53 mmi-ol), 3-(4,4,5 ,5 15 tetramnethyl- I ,3,2-dioxatbor-olan-2-yI)bcnizcnesulf'onamiide ( I g, 3. 5 3 mmcin)o dichloro- 11,1 'bis(dipheniylphosphino) 1'i-i-occne I palladiumn (11) dichioromethanc adduct (177 mg, 0. 176 mmol), 2 M potassium carbonate (5 rml.), in dioxane (I15 ml-) was heated at IMX TC for 1.5 h and cooled to roomn tcrnlpfitur11C. LCMS indicated the reaction wits finished. TO the finished reaction w~as added 2-arnino-5 20) (4,4,5,5-tetrami-ethyl-1I,3,2-dioxatbor-olani-2-yD)-3-pyvridincSuIIlfairide (1.2 g, 4 rnrnol), Dich loro- I lj I'bis(diphenyl phosphi no) fercee l I d Iadi urn (11) - 97 dichloromethane adduct (177 mg, 0.176 mmol), and 2 M potassium carbonate (5 rnL). The reaction was heated at 100"C for 3 h and cooled to room temperature. The dioxane and water were separated and the dioxane evaporated to get the crude product which was purified on silica gel Cluting with ethyl acetate/methanol, 0-3 % 5 methanol. The product which crystall ized from ethyl acetate contained ethyl acetate. The ethyl acetate was removed by dissolving the product in a excess of acetone and evaporation. Residual actone was then removed by triturating with distilled water at 60 deg followed by filtration and drying Under vacuum. A yield of the title compound (540 mg, 31 %) was obtained. MS(ES)+ m/e 484 1 M+- I. 10 The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 139 MS(ES) Example Structure IM+I 0 N \ IN I S 0=S=0 N 1o 1 0 140 442 N N N N 141 N 527 N N N\I 0 N 1 42 N 9 N8 - 98 - N 0 143 05N ~ N504 N N N 144 \N 387 N 'N 0 145 s 377 N' N NN (N N N 146 0= =0 "N 461 N N \ 0 147 - \s 391 N N NN N N 148 11 401 N N--) N N 0=s=0 0 149 NI N 475 N -99 - N O lz~ N 150 N N ) 442 N 151 0-341 152 341 Scheme 4: Rl Ri Br a~ Br b R2 N.- aN.

Cond itions: a) aryl (RI) hoioi ac id or aryl (WII) horimaic. palIladiu caIiitalysi. 2 Mi polassiti lII 5 carbonate. d jOX.ali. hical; b) hi s(pinaco Iato)d I Nwon. polass win acct lai. pai lahd il in l llysl. dioxane. hecat; thlen IiCeteoayl ( R2) biomiide, palladiumi catalyst. 2 M poiaSSAuili Ufihoil tc. licat. Example 153 10( 2 -inio-5-14-( I U-pyr-azol-4-yl)-6-qlinlOlinyl j-3-pyiridineSuitlfnamidc SONH, N a) 6-br-omo-4-( 1H-pyirazol-4-yl)quinoline 15 A mixture of' 6-hmorno-4-iodloquitnolinc (1.37 ~,4 rnol) and 4-(4.4,5,5 tetrami-ethyl- 1,3 ,2-d ioxaibor-olani-2-yl)- 11-1-pyiaizole (852 in u. 4 inm-ol), d ich loro - 100 - [1,1'bis(diphenylphosphino) ferroceneI palladium (11) dichlorornethane adduct (162 mg, 0.2 mmol), 2 M potassium carbonate (6 mL), in dioxane (25 inLI) was heated at 100 "C for 1.5 h and cooled to room ternperature.I The dioxane and water were separated and the dioxane evaporated to get the crude product which was purified on 5 silica gel eluting with ethyl acetate/methanol, 0-3% methanol. A yield of the title compound (340 mg, 34 %) was obtained. MS(ES)+ n/e 275 IM+H|I. b) 2-amino-5-[4-(l H-pyrazol-4-yl)-6-quinolinyll-3-pyridinesulfonamide 10 6-bromo-4-(lI H-pyrazol-4-yl)quinoline(330 mg,1.2 rnmol), 4,4,4',4',5,5,5',5' octamethyl-2,2'-bi- 1,3,2-dioxaborolane (304 mg, 1.2 mmol), dichloro [1,1 'bis(diphenylphosphino)ferrocenelpalladium (11) dichloromethane adduct (48 ing, 0.06 mmol), potassium acetate (352 mg, 3.6 mmol), in dioxane (5 ml) was heated at 1X) "C for 1.5 h and cooled to room temperature. LCMS indicated the 15 reaction was complete (formation of' 4-( l--pyrazol-4-yl)-6-(4,4,5,5-tetramethyl 1.3.2-dioxaborolan-2-yl)quinoline). To this same reaction mixture was added dichloro I 1,1'bis(diphenylphosphino)ferrocenelpalladium (11) dichloromethane addLIct (48 ing, 0.06 mmol), 2-ami no-5-bromo-3-pyridinesulfonamide (280 mg, I mmol) and 2 20 M potassium carbonate (1.5 mL). The reaction mixture was heated a second time to 1 15 C for 18 h. The dioxane and water were separated and the dioxane evaporated. The crude product was trituated with methylene chloride (insoluble), then dissolved in DMF and filtered through a glass fiber filter. The DMF was evaporated and the product triturated with methanol, filtered and dried. A yield of the title compound 25 (108 mg, 22 %, two steps) was obtained. MS(ES)+i- m/e 395 IM+H I'. The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 153 - 101 - M S(fES) Example Structure IM+ilI N 154 N,. 401 0 0 N N oN N35 155 N 3 2) N N NN 57 \N N 338 NN

N

N NN 157 N, j 33 NN N N 160 N IN N 3238 N /102

N

161 0402 N, ~N \/ =O NN N HN NN 16 3 2) NN 162 3 322 N~ No H' N H NN N N 165 0 338 NN HN N N 0 IIN 166 N'351 LZ N N N 167 HN I351 N -103- N 0 168 HN~ \ 388 N N HO0 N N 169 35N N - N N NN H 0 NI N N N HO 0 N 172 2~ 342 N N N NN

H

2 N N N2 174~~ A 8 N 0N NH2 N 14 N N 175 H 381 N 1756 N 3X o N NH2_ N I77 N 0 N 1768 362 I 7 NN NHN NN 8 N - 0 N0 . N N . N N N N~ N O- N05N N N NA N -91 357 o "N N N N N 182 NN 314 N N NA 193 N ', A 341 NN N N N 0 NA 185 N N A N 3521 o N' N N N 186 KN N 350 N'N N 18 F N 439 -10A 6N35 CI N, 01 N,,1 473

-NI

N N 0 N o N 280 \/ S .I411 SN . N N N cl N NN CI N S N. NN 2X2 '349. NN N N NN N N 0 ,N N, 'N N,, 10 - N 286 N417.3 N 287 0453.0 NN N 287 N0 45.0 NN 289N N N N N N N 2890 432.2 N N NN ON N 0 1 0 291 435.2 O \\ - 108- N CI N 292 S51 0. F aF N 0, S 0 293 C; 0 513 N . N Scheme 5: R1 Br N N. a N. N. N' N Conditlions: a) his(pinnicolato)d ihoron. p pillad im calalysi. potnssi ,1 CCI..alC. d IoXflic. licat: 111C11 5 hc liS).IyI (R2) hmrn uk, pal ladiu rn cud yst, 2 M POtaULSiL11 II roIaIC, I1:1 i I ay (111 I) anlic acid or aryl (1H 1) corona Ic. pal ladiur IT atalyst. 2 MI fx)tas sini carhonaic. licat. Example 189 10( -artnino-5- 14-I 3-(arininosuLIIOnyl)phenyl -6-quilnolinvl l-3-pyridinesult'onamnidc S02 SNH 2 H N aN N 1 N TIhis comnpound was prepared in onlC pot (three steps) with no workups between steps. A mixture of' 6-bromro-4-chloroquinoline, (484 In , 2 mmi-ol), bis(pinacolato)dibor-on, (506 nrg, 2 mm-ol), dichloro- 11.1 'bis(diphenylphosphino) 15 tel-rocenej palladium (11) dichlorornethane adduct. (81.5 MO, 0.1 mm11ol). and potassium acetate (588m-g, 6 mmnol) in dioxane (6 rnL) was heated at. 100T "Ctr 4 h. To this reaction was added 2-amiino-5-br-olno-3-pyr-id ineSu II onaide, (560) mn- 2 inmol) an equal amount of the palladiuIm catalyst used above (0.1 inmol) and 2 M - 109 potassium carbonate (3 rnL). The reaction was heated at 95 de, centigrade for one hour. To this reaction was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)bcnzenCsul fonamide, (566 mc 2 mmol), dichloro- |1.1 'bis(d iphenylphosphino) ferrocenel palladium (11) dichloromethane adduct (81.5 mg, 0.1 mmol) and 2 M 5 potassium carbonate (3 rnL). The reaction was heated at 95 "C for three hours. The solvent was evaporated and the crude material purified by silica gel chromatography, eluting with ethyl acetate. The product was purified further by crystallizing from hot ethyl acetate. Obtained 181 mg (18.7%) for three steps. MS(ES)+ n/e 484 |M+Hi*. The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 189: MS(ES) Example Structure MSiII N> HN N 190 420 o's 0 N N\ o=s=0 191 N 484 N N N N 192 N 1 420 N N -110- .1 0 1 N N 13N 5 7 2 N =0 NN N N =S=O 1945. 405) N 00 N 1956 4620 NK N 0 I T r N 6"N

N

296 F 514 N F 0) N OSO N 0F 0 N O O N N 299 F 492 N O F N-O N 299 F 54 F I= rr

N

N/ / N 299 F 542 F - 1 N N F12 301 I552 'N

I

N 'NN N0 492'N ' NN N 6 303 r 5 4 2 NN, N. N. 304 581 N N NN 113- 306 517 N F N N N N N 3087 N3N N NI 307 F 531 N 0IN N N' r N) ' N0 N N'N N 310 N

N

311 0 O \\ N 0 o F N N Scheme 6: R1 RI R1 Br a MeSn b R2 N- N'N 5 Conditions: a) hexameithylditin, et rakis(thriphenyIphosphmC)pai]lldimI (0). lithliumn chloride. ietrahydrofurau. hc~at; b) hetcroaryl (R2) broiuidc. pal bidiumu catalyst. dioxauc. icat. Example 197 10 4-(4-pyridinyl)-6-(l H-1 1,2,3 Itriazolol 4,5-bjpyridin-6-yl)quinoline N N N N N a) 4-(4-pyridiiiyl)-6-(trinethylstan nanyl)qu inoline 15 A mixture of 4-(4-pyridinyl)-6-bromoquinolinc (15 g, 53 nmmol), hexamethylditin (19 g, 59 mnol), lithium chloride (16 g, 370 rnmol), tctrakis(triphenyphosphine)-palladium (0) (3 g, 2.7 mmol), in tetrahydrofuran (4(X) mL) was heated at reflux for 16 hours, at which time the reaction was allowed to 20 cool to room temperature and concentrated under reduced pressure. Methylene chloride (500 mL) was added to the residue and the mixture was stirred for 2 hours to help break up the solids. The mixture was then filtered and concentrated under -115reduced pressure. The resulting residue was purified by silica gel chromatography (gradient: CH 2 Cl 2 to 2% MeOH]/C-1 2 Clz) to give the title compound (I I 56 %) as a beige solid. MS(IES)+ m/e 370 1 M+H 1'. 5 b) 4-(4-pyridinyl)-6-(111-1 1,2,3 tiazolol 4,5-b pyridin-6-yl)q uinol ine A mixture of 6-bromo-lH-11,2,31triazolol4,5-bjpyridine (100 mg, 0.5 mmol), 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline (204 mg, 0.55 mmol), and tetrakistriphenylphosphine palladium(0) (29 mg, 0.025 imol) in 1,4-dioxane (3.0 10 mL) was heated at 100 "C for 18 h. The reaction was filtered to collect the precipitate. The solid was triturated in hot ethanol to give an off-white solid, which still contained some minor impurities. The off-white solid was triturated in hot ethanol to give the title product as a beige solid (22 mg, 14%). MS(ES)+ m/e 325.1 IM+H I". I5 The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 197: MS(ES) Example Structure N N N 198 324 NN N /NN 199 N, 325 N N N N 200 N 32. N - 116- N 201 ~ Nz -~r 324 NN N N NN 202 -N - 379 0 N N 203 A 391 o N Schenme 7: H H B r Br C O E bZ Br N N2 Hi I I 1-: - ID R3 N N R3 R3 R3 5 Conditrions: a) dietliy let hoxymei Ili ylene ima Ioiatc. 140 TC. then IDowt herin A. 200 "C-, b) 6 N sodimiin hydroxide, etha nol. ic flux: c) Dowthicrm A. 260 'C: d1) phosphorous oxycl ordc. rdlix; c) his (piiiacolato)d ihoroii. palladiuimi catliyst, [potassiumi acclatc. dioxane. heat; Ownu hicimiyI (142) hiomnide. palladium catalyst, 2 M' aqueous potissiulur carboniate. l thieni ;iiyl (111) hoioiiic a;ii/ester. palladiuim catalyst. 2 NI ;iqileois potassium cait-Nuimt. uiixmii. lieii. Exampic 204 2-ar-nino-N,N-(dimcl.hyI-5-18-mcthy1-4-(4-pyiifliyl)-6-qlilolilyI 1-3 pyitidinesull'onamide 15 - 117- N IllN N 0', H N NN Ns/ N a) ethyl 6-brorno-4-hydroxy-8-methyl-3-quinolinecarboxylate 5 A mixture of 4-bromo-2-nethylanil ine (1.50 g, 8.04 mmol) and diethylethoxymethylene malonate (1.74 g, 8.04 mmol) was heated at 140 "C with stirring in an oil bath for 5.0 h. The reaction was transferred to a heating mantle, diluted with Dowtherm A (4 mL), and heated at 260 "C for I h. The reaction was cooled. diluted with hexanes, and the suspension was stirred overnight at room 10 temperature. The suspension was filtered and the filtered solid was washed with hexanes and dried in a Buchner funnel to give the title compound (1.90 g, 76%) as a tan solid. MS(IS)* rn/e 310 [M+-H. b) 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid 15 A mixture of ethyl 6-brono-4-hydroxy-8-methyl-3-quinolinecarboxylate (1.89 g, 6.(9 mmol) and 6 N NaOl-l (1.22 g, 30.45 rmol, 5.1 mnL) in ethanol (30 mL) was heated at reflux for 2.0 h and concentrated in vacuo. The residue was diluted with water and acidified with 6 N ICI to pI 4. The resulting solid was filtered, washed with water and diethyl ether, and dried overnight in a Buchner 20 tunnel to give the title compound (1.72 g, 99%) as a tan solid. MS(ES)' m/c 2X2 [IM+H J. c) 6-brono-8-methyl-4-quinolinol A mixture of 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid (1.80 25 g, 6.36 mmol) and Dowtherm A (10 mL) was heated at 260 "C for 1.0 h. The reaction was cooled, triturated with hexanes, filtered and dried in a Buchner funnel to give the title compound (1.43 g, 95%) as a tan solid. MS(ES) m/e 238|M+H l. - 118 d) 6-bromo-4-chloro-8-methylquinoline A mixture of* 6-bromo-8-nethyl-4-quinolinol (1.42 g, 5.95 mmol) and phosphorous oxychloride (10.95 g, 71.40 mmol) was heated at Ieliux for I h, cooled, poured onto ice, and neutralized by addition of 30% ammonium hydroxide. The 5 resulting solid was filtered and dried in a vacuum oven to givc the title compound (1.45g, 95%) as a tan solid. MS(ES)' m/c 256 [M+l-l. e) 2-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl -3 pyridinesulfonamide 10 A mixture of 6-bromo-4-chloro-8-methylquinoline (0.3(X) g, 1.170 immol), bis(pinacolato)diboron (0.297 g, 1.170 mmol), dichlorol ,1' bis(diphenylphosphino)ferrocenelpalladium (11) dichloromethane adduct (0.029 g, 0.035 nmol), and solid anhydrous potassium acetate (0.459 g, 4.676 mninol) in dry 1,4-dioxane (8 mL) was heated at reflux for 70 minutes. The oil bath was 15 temporarily removed and to the reaction was added 2-arnino-5-hromo-N,N dimethyl-3-pyridinesulfonamide (0.327 g, 1.17 mmol), dichlorol 1,1' bis(diphenylphosphino)ferroccnelpalladium (11) dichloromethane adduct (0.047 g, 0.058 rnmol), and 2 M aqueous potassium carbonate (0.646 e, 4.676 nimol, 2.34 nL). The reaction was heated at reflux for 8) minutes. The oil bath was 20 temporarily removed and to the reaction was added 4-(4,4,5,5-teiramethyl-1,3,2 dioxaborolan-2-yl)pyridine (0.240 g, 1.17 mmol), dichlorol l,1' bis(diphenylphosphino)ferrocenepalladium (11) dichloromethane adduct (0.047 g, 0.058 mmol), 2 M aqueous potassium carbonate (0.485 g, 3.51 immol, 1.76 mlL), and 1,4-dioxanc (6 nL). The reaction was heated at reflux for 17 h and concentrated in 25 vacuo. The residue was triturated with 10% MeO-l:EtOAc (45 mL), filtered through filter paper, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (7% MeOH:EtOAc) to give the title compound (0.135 g, 28%) as a yellow powder. MS(ES)* m/e 420 IM+-I1. 30 The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 204: - 119 - IVS( ES) Example Structure IMN N "I N N N

H

2 N N 206 424 N F N' N N N

H

2 N N N' N NN N N. H IN N 12F Scheme 8: RI H2N N Br, a R1 b N -, -2 RI H 2N N R N 1&00 N Coniditioins: a) bis(piiiacolao)dihoroii. poLaSSlilill acCUtC. pilhIaII~iili CMdl I iOX0lic. Iic;fl IiCIi 5 5 hromo-2-pyridinain mc, pal lid itun catalyst, 2 M pouias iiin carhoiac, d joXanck. Ic at; h) Cl orosui I Wiic acid. 0 T- riliix; c) R 1 .R-INR. pyridine. dioxane. ft - 50 T. Eixamplc 211 10( 3-( I -piperidinylsulfonyl)-5-14-(4-pyr-idinyl)-6-qulinolinyl j-2-pyiridinartininc N C H>N NN NN at) 5-I 4-(4-pyr-idinlyl)-6)-quinolinyl l-2-pyr-idinamiiinc 1.5 To at I L pressure vessel was added 6-br-orno-4-(4-pyr-idinlyl)qttinloline (I2 4.08S mmol), bis(pinacolato)diboron (12.8 g,50.5 mmol), anhydr'ous potaSsium acetate (8.24 g, 84.16 niniol), II I '-bis(diphcniylphosphino)-lcrmi-cencjI dichloiropatlladiurnl(lI)-coi-nplex with dichlororncthane( 1: 1) ( 1.372 g), 1.68 irnrnol) and anhydlious dioxane (420 mL). The reaction vessel was purged with nitrogen, capped 20 and heated Lit I(X) TC for 15 hours. LCM S indicated 96% conversion to a itureU' Of the desired boronate ester MS(E--S)i rn/c 333.2 1IM+1-11' and boronic acid MS(E-S)+ rn/c 250.9 1IM -1-I -121 - To the reaction mixture above was added 5-brorno-2-pyridinarnine (7.28 g, 42.08 m mol), I ,1 '-bis(di phenylphosph ino)-fi rrocene ldic hloiopal ladium(lIIl) complex with dichloromethane(l1:1) ( 1.7 18 ,, 2.1 ivnol), 2 M aqueois K 2 C0 3 (3X) nL). The reaction was heated at 100 "C for 21 hours. After cooling to rooin 5 temperaturC, the organic layer was separated and concentrated in vacuo. The residue was triturated with water, and dissolved in dichloromethane. This solution was filtered through a plug of silica, washing continuously with dicholormethane and ethanol. Concentration in vacuo provided the title compound as a yellow powder (8.767 g, 70% yield). MS(ES)+ m/e 299.0 IM+-li*. 10 b) 2-amino-5-[4-(4-pyri dinyl)-6-quinolinyll-3-pyri dinesilfonyl chloride To cold (0 C) chlorosulfonic acid (15 mL) under vigorous stirring was added 5-14-(4-pyridinyl)-6-quinolinyll-2-pyridinamine (4.348 g, 14.57 mmol) portionwise. The reaction mixture was then heated at reflex for 1 6 hrs. Upon 15 cooling to room temperature, LCMS indicated 47% of the title compound MS(E3S)+ in/c 396.9 [M+* and 37% of sulfonic acid by-product MS(IS)+ rn/c 379.1 IM+]". A 2 rnL aliquot of this 0.456M solution of the title compound was used in the next reaction without further workup. 20 c) 3-( I-piperidinylsulflonyl)-5-14-(4-pyridinyl)-6-quinolinyl|1-2 -pyridi nainine To a cold (5 "C) solution of the 0.456 M solution of 2-arnino-5-14-(4 pyridinyl)-6-quinolinylj-3-pyridinesulfonyl chloride (2 mL, 0.912 iimmol) in chlorosulfonic acid from above was added anhydrous dioxane (1 mL) and piperidine (1.8 mL, 18.24 mniol). After 30 minutes of stirring, pyridine (I mL, 12.3 mmol) was 25 added and the reaction mixture stirred for an additional hour at room temperature. The reaction mixturte was concentrated in vacuo, the residue dissolved in CI-C12 and the pI adjusted to 14 using 6 N NaOl- (aq). The solution was extracted with CI-1 2 Cl 2 (x4) and the combined organic layers dried (Na2SO.I), filtered and conentrated in vacuo. The resulting residue was purified twice by silica gel 30 chromatography (0-5% MeOll in EtOAC) to give the title compound as a pale yellow solid (269 ing, 66%I yield). MS(ES)+ i/e 446.3 I M+-l 1'. - 122 - The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 211: M S(ES) Example Structure N N N 212 446 N -N N N N 213 ' 406 N N N N N NN N N N N N 215 N ON N N N N N 215~ 2N N N N -123 - N N N 217 453N NN N 2118 43 219 -432 Scheme 9: cI RI Ri N 'l N ' a NC) 'N _' b R 'I:N ' Cond itions: a) aiyl ( RI) horon ic acid or aryl ( RI) horona~tc. pall adium i catalyst. 2 NI poui ss iiin 5 carhonalc. dioxmiic, lical; h) his(piitacolalo)dilxwoi, potassliumt acclAc. pa llaiii Cataliyst. dlioxatic. Iwatl; thicii hictcroaryI ( R2) hiornidc. palladium catalyst. 2 MI potassium carhom:tc. hicat. E'xampic 220) 10( Preparation of 6-(] 1-1-ben/,irnidazol-2-yI)-4-(4-pyi-idi nyl)qulinoli ne N I N I* N - 124 a) 4-(4-pyridinyl)-6-quinolinecarbonitrile A mixture of 4-chloro-6-qu In necarboni tr IC (8.7 g, 46.2 mmol). 4 pyridineboronic acid (8.52 g, 69.3 nmol), tetrakis(triphenylphosphine)palladium(0) 5 (2.67 g, 2.31 mmol) and 2 M potassium carbonate (69.3 ml.., 3 eq) in 1,4-dioxane (380 ml.) is heated at reflux for 3.5 hours. The dioxane is evaporated and the crude product purified by silica gel chromatography eluting with methylene chloride/methanol 0-4 %. A yield of 10.23 g (95%) of the title compounds was obtained. 10 b) 1 H-benzimidazol-2-yl)-4-(4-py ridinyl)quinoline A mixture of 4-(4-pyridinyl)-6-quinolinecarbonitrile, (23] mg, I mmol) 1,2 diaminobenzene (108 mg, I mmol) and polyphosphoric acid (1.4 g) was heated in 15 the microwave at 250 C for 1.5 hours. The reaction was poured onto water which was neutralized with bicarbonate. The product was filtered, washed with water, and dried. The product was fuither purified by dissolving in hot melhanol, filtering and cooling to obtain crystals. The yield was 47.7 m,, 30c. MS(ES)+ n/c 323 I M+I 11'. 20 The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 220: MS(ES) Example Structure M 1' N N 221 323 N N -125 - NQN N N N N NN N-N NN N N 224 \ 3245 NN N N1 NNN Br a Br b R2 N) N"N Cond itioins: .) cyclic Sleconidary aminc.e diincthy I fonmmmride. licat: b) hi s,(pIiacO lato)d iKhnroii. 5 potassiumi accetc. pal ladinum catLalyst. dioxanc . licat: t~he licroary I (MR2) hioi nide palIlad ium i catalyst. 2 M polassiti n carbon ale. lieal Example 225 10( 4-( I pipcr-idinyl)-6-(4,4.5,5-tetirarneihyl- I ,3.2-dioxabor-olan-2-y1)q~linoline N a) 6-brorno-4-( I -pipcridinyl)quinolinc To a solution of 4-chor-o-6-br-ornoquiinoline (726 mo, 3 mmol) In 3 ml. of' I niethyl-2-pyirolidinone was added piperidine (5! 10 rno, 6 mrmol). T'he reaction1 WaS - 126 heated to 150 C for 5 h.The solvents were removed in vacuo at 100 " and the residue dissolved in methylene chloride and washed with water. The rnethylene chloride was dried with sodium sulfate and concentrated. The residue was triturated with hexane and the solid filtered off to give 6-bromo-4-(I-piperidinyl) quinoline 5 (877 mg, 73%). b) 6-(7,7a-dihydro- II--pyrazolol3,4-bpyridin-5-yl)-4-( I -piperidinyl)quinoline To a solution of 6-bromo-4-(I-piperidinyl)quinoline (429 mg, 1.47 mmol) in 10 dioxane (4 mL) was added 4,4,4',4'.5,5,5',5-octamethyl-2,2'-bi-1,3,2-dioxaborolane (373 mg, 1.76 mnol), potassium acetate (441 mg, 4.5 inmol), and PdCI2(dppf)2 (36 mg, 0.045 mmol). The reaction was heated to 150 "C for 30 minutes to give crude 4-(I-piperidinyl)-6-(4,4,5.5-tetrarnethyl-1,3.2-dioxaborolan-2-yl)quinoline. The reaction was then cooled and 5-bromo-7,7a-dihydro-1-1-pyrazolol3,4-blpyridine 15 (348 mg. 1.76 mmol) was added, followed by PdCI2(dppt)2 (36 mg, 0.045 mmol) and 2 M potassium carbonate (2.25 mL). The reaction was heated at 150 "C for 30 min, at which time the dioxane was evaporated and the crude product triturated water and collected by filtration. The crude product was partially purified by I IPLC chromatography acetonitrile/water/0. 1% TFA. At this point the product was 85% 20 pure. It was free based with sodium carbonate and further purified by silica gel chromatography cluting with methylene chloride/0-2% (methanol/concentrated ammonium hydroxide solution 9/1) to obtain the title compound (29 mg, 0 6%). MS(ES)+ n/c 330 [M+-11 4 . 25 The following compounds were or can be prepared following the general procedurCs used to prepare the compound of Example 225: - 127- M S(PJ.S) Example Structure N NN 226 N'I 332 N NN) 227 N ~ N 345 N N N Q 228 < , 330 N N 229 < , 332 N N Scheme 11: 5 N2 Nz N -, Coniditioins: a) H-siIioil chide~l(I. pyidic. nilh y IciiechlI oride. - 128 - Example 230 2,4-dilluoro-N- { 5-4-(4-pyridinyl)-6-quinolinyl 1-3-pyridinyl } ben z.enesulfonamide N F 0- O SsN H F N a) 2,4-dilluoro-N-{5-14-(4-pyridiriyl)-6-quinolinyl 1-3 pyridinyl} benzenesul fonanide I0 A solution of 5-14-(4-pyridi nyl)-6-quinaliinyll-3-pyridinimi ne (82 mg, 0.27 mmol) in anhydrous pyridine (2.0 ml) was treated with neat 2,4 difluorobenzenesuIlfonyl chloride in one portion. The reaction was stirred at room temperature for 30 minutes then was purified directly by prep-HPLC. The combined, desired fractions were cvaporatcd under reduced pressure to remove 15 organic solvents then diluted with small portions of brine and saturated aqueous sodium bicarbonate. The basic solution was extracted with ethyl acetate then the extracts were dried over anhydrous sodium sulfate and evaporated Under reduced pressure. The resulting colorless film was crystallized From methylene chloride and diethyl ether. The solids were collected by Filtration, rinsed with diethyl ether then 20 vacuum dried to afford the title compound (219 mg, 48%) as a white solid. MS(ES)+ im/e 475 1 MH . The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 230: -129 - MIS( ES) Example Structure IM+lII N N / N N N 0 232 -. . I 445 S S. N N fN 233 P~~ 1I 458 NN N N 234 I499 0 N N N 235 Iq N' 419 NN N N 236 N403 NN N N_ 238 .~N~ N453 H N -130- '312 457 313 457 0 314 469 NN I N 313 ;' 457 NN N 316 0'/ N 489 N 315 0 N3N 317 464 N F 318 ~ N507 N 319 0" N N 507 I N N. 0~ -) ', N 320 00K ~440.1 N SN N N / N S - N 0 0 N 32IS 471 .2 ,N N -132- N N NN N 324 N 483.1 S-() N N N N 325 4 406.3 N N N N N 0 326 N N 418.3 N N NN N o o N N 328 o O498.2 N S, 329 4 49 SN N NN N NN 330 0453 N -11 N N -133- N 331 F7 N. | | N N N 332 Y- S, 500.3 -N N N 0 0 333 547.0, 549.1 N N N 334 N- s N 512.2 N N N 335 N 498.2 N N N 336 N 457.1 N N 337 N N N 525.4 - 134 ojN N14 N N 338F O SsN N N N 339 I429.1 O N ~ 0 S" N N N N 340 429.1 N N N N 340 /0 I507 N N 342 e, g/-,50 N CN N N : F,I 343 N F N 344 O\1)432 S'N Somec non-comnmercially available heteroaryl (R41) bromides were prepared and couIpled to the corresponding boronic ester or boronic acid as no-.ted above. -135 - Scheme 12: H2N r abe B RR,N Br BI CI1. Er .X Br 000 5 Conditions: a) Chlorostironic acid, 0 C-reriux; h) Morphotine, pyrdine. dioxane. 5C- 0 - 50 "C. Example 239 3-(4-inorphol i nylsulf onyl)-5-|4-(4-pyrid iniyl)-6-quoinoilinyl -2-pyridinaimine N O H2N N N, 0 0 10 N a) 2-anino-5-bromo-3-pyridinesulfonyl chloride ro a cooled (0 C) solution of chlorosulfonic acid (58 mL) under vigorous stirring was added 5-brorno-2-pyridinamine (15 g, 86.7 rnmol) portionwise. The 15 reaction mixture was then heated at rellux for 3 hrs. Upon cooling to room tcmnperature. the reaction mixture was poured over ice (-100 g) with vigorous stirring. The resulting yellow precipitate was collected by suction filtration, washing with cold water and petroleum ether to provide the title compound as an orange yellow solid (18.1 g, 77% yield). MS(ES)+ rn/c 272.8 IM+H l'. 20 b) 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine To a solution of 2-anino-5-bromo-3-pyridinesulfonyl chloride (0.50 g, 1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5 C was added (0.16 mL, 1.84 mmol) of morpholine followed by (0.174 mL, 2.15 mmol) of pyridine. The reaction 25 mixture was stirred at room temperature for 2 hrs and then heated at 50 "C for I hour. After cooling to room temperature, a white precipitate formed which was collected by suction filtration, washing with water and petroleum ether to give the - 136 title compound as an off-white solid. (0.539 g, 91% yield). MS(ES)+ rn/c 323.9 | M+H I1*. c) 3-(4-morpholinylsul'onyl)-5-[4-(4-pyridinyl)-6-quinolinyll-2-pyridinamnine 5 A mixture of 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine (0.296 g. 0.92 mmol), 4-(4-pyridinyl)-6-(4,4,5,5-tetranethyl- 1,3,2-dioxaborolan-2 yl)quinoline (0.306 mg, 0.92 mmol), [1,l'-bis(diphenylphosphino) ferroceneldichloropalladium(II)-complex with dichloromethane(1:1) (37.6 rng, 0.046 mmol), 2 M aqueous K 2

CO

3 (5 mL) and dioxane (5 mL) was heated at 100 "C 10 for 18 h. After cooling to room temperature, the organic layer was separated and the aqueous portion extracted three times with EtOAc. The combined organic layers were dried (Na 2

SO

4 ), filtered and concentrated in vacuo. The residue was purified twice by silica gel chromatography (eluent: 1)1-5% MeOH in C- 2 Cl 2 and ii) 0-20% MeOH- in CI- 2 C1 2 ) to provide the title compound as a white solid (150 mc, 37% 15 yield). iMS(ES)+rm/c 448.0 [M+H|*j. Scheme 13: 0 o Br Br B B a Br H b Br N c Br N N F, -_ N N F N N N N H 20 Conditions: a) i) LDA. TIF. -78 "C; ii) N-fonnylpiperidine. -78 'C: b) i pinacol. p-TsOH. hcnzcne, reflux: ii) anhydirous hydrazine, DIPEA. EtOH, reflux: c) cone aq HCI (36.5%-3S%). EtOH. 1-10. 60 0 C to rt. - 137- Example 240 5-bromo- I H-pyrazolol3,4-blpyridine Br N 5 N N a) 5-biomo-2-fluoro-3-pyridinecarbaldehyde Following the procedure described in W02(X)6015 124 and trituration of the crude product in hexanes instead of crystallization from cyclohexane afforded the 10 title compound as an off-white solid (68%). MS(ES)+ rn/e 203.8, 205.7 1 M+-l '. b) 5-brono-3-(4,4,5,5-tetranethyl- 1,3-dioxolan-2-v)-2(11H)-pyridinone hydrazone Following the procedure described in W02006015124 without the addition of* hydrogen chloride provided the title compound as a yellow solid. MS( ES)+ rn/e 15 317.9 IM+-|*. This crude material was used directly in the next tep. c) 5-bromo-I 1-H-pyrazolo[3,4-bpyridine Following the procedure described in W02006015124 provided the title compound as a yellow solid (94%, 2 steps). MS(ES)+ rn/e 197.7, 199.7 IM+H]I*. 20 Scheme 14: a b I0 l ON H 2 N Br R NRr Conditions: a) tii(l)chloride. concentrated HCI. room teinpcmaturc- h) R-sulfonyl chloride, pyridiie. mnethylene chloride. - 138 - Example 241 N-(5-bromo-2-chloro-3-pyridinyl)benzenesul lonamide CI N HN X Br 5 a) 3-anino-5-brono-2-chloropyridine To a stirred suspension of 5-brono-2-chloro-3-nitropyridine (20.0 g, 84.2 mnMol) in conc. HCl (90 mL) was added SnC-20 (60.0 u, 266 rnMol) portionwise over 2 h. (The reaction got very warm to the touch.) The reaction was stirred at RT for 18 h, poured onto ice, and basified with aq. 6 N NaO-l (300 mL). 10 The resultant slurry was filtered, washed with 120, and dried under vacuum to give the title compound (15.53 g, 89%) as an off-white solid: IH NMR (400 MHz, DMSO-d 6 ) 6 ppm 7.66 (d, J= 2.3 Hz, 1 1-), 7.30 (d, J = 2.3 I-Iz, 1 -1), 5.90 (br. s., 2 -1); MS (ES) n/e 206.7 (M + H)*. 15 b) N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide To a stirred solution of 3-amino-5-bromo-2-chloropyridine (5.0 g. 24 iMol) in CIH 2 Cl 2 (50 nL) was added pyridine (3.0 rnL, 37 mMol) followed by benzenesulfonyl chloride (4.5 mL, 35 mMol) drop wise over 5 minutes. The reaction was stirred at RT for 18 h and evaporated to dryness under vacuum. 20 Purified by flash chromatography on silica gel (15% hexanes in CH 2 Cl2 then 0 to 5% EtOAc in 15% hexanes in CI-hC 2 ). During evaporation of the solvents the product crashed out. The resultant slurry was diluted with hexane. filtered and dried under vacuum to give the title compound (2.89 g, 34%) as a white solid. IAn overlap fraction which contained 30% starting amine (2.60 g) was also obtained.j: 25 11H N MR (4() M H z, DM SO-d 6 ) 6 ppm 10.61 (br. s., 1 H), 8.41 (d, J = 2.27 Hz, I -1), 7.91 (d, J = 2.27 Hz, I H), 7.73 - 7.77 (m, 2 H), 7.67 - 7.72 (n. 1 1-1), 7.56 - 7.64 (in, 2 H): MS (ES) m/e 346.7 (M + H)+. - 139 - Other non-commrercially available hcteroaryl (RI) bromides were prepared according to thc following lileratUreC procedures and coupled to the corresponding boronic ester as noted above: 5 W020051 10410 was used to prepare intermediates A-C. BrBr Br H,N Moo HMN / 1 / / o S~..N ~ N 0N N 0 S N 0 H NH A B C Scheme 15: RI RI Br R1 OHC N[! . a H CO 2 C ,,G N." b H CO 2 C -T ' .- ~ -Br N N N 0 RI R1 C EtO 2 C 55 d HN, % RB I N N Conitiions: a) rneihy I ( iiiphcnjylphiosplioianiyl idenc )aIcctac. inc [hanoi. it h) hroi n nin mehyIc chloridc. ri; C) ii potassium hydroxide. ciajol. 95 'C, iij siulfiffic alcid. CIIianol . 95 'C LI) poLasSiuin iel- hutox idc. ( R8) -hydraz inc. ciaiydroluran ii.i* - 6~5 IC. 15 Eniple 242 I-phenvl-5-14-(4-pyiridinyl)-6-quinolinyI I- I ,2-dihydi-o-3/--pyraiiol-3-one N HN, HN 20 6 14D a) methyl 3-14-(4-pyridinyl)-6-quinolinyll-2-propenoate A mixture of 4-(4-pyridinyl)-6-qIuinolinecarbaldehyde (2.29 g, 9.78 mmol), 5 methyl (triphenylphosphoranylidene)acetate (3.30 g, 9.78 mmol) in MeOH (75 mL) was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the resulting residue was purified by silica gel chromatography (1% McOH in EtOAc) to give the title compound (2.71 g, 95 %) as a white solid. MS(ES)+ mle 291 [M+- 1*. b) methyl 2,3-dibromo-3-14-(4-pyridinyl)-6-quinolinyllipropanoate A solution of methyl 3-14-(4-pyridinyl)-6-quinolinyll-2-propenoate (2.71 g, 9.33 mmol) in dichlorornethane (90 ml) was treated with neat bromine (4.80 ml. 15 9.33 mmol) then stirred at room temperature for 4 hours. Evaporation undcr reduced pressure gave the title compound (4.20 g, 100 %) as a yellow solid. MS(ES)+ rn/e 451 IM+ -I. c) ethyl 3-14-(4-pyridinyl)-6-quinolinyll-2-propynoate 20 A slurry of methyl 2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinylipropanoate (4.20 g, 9.33 mmol) in ethanol (120 ml) was treated with solid potassium hydroxide pellets in one portion then heated at 95 "C for 2 hours. The reaction was cooled to room temperature then evaporated under reduced pressure. The resulting residue 25 was diluted with ethanol (90 ml) and concentrated -I SO 4 (3 ml) then heated at 95 "C for 3.5 hours. Cooled to room temperature then concentrated under reduced pressure. The resultiniIg wet residue was taken into a minimum of water ihen made neutral with the addition of saturated aqueous Nal-CO, solution. This solution was extracted with EtOAc and the extracts were dried over anhydrois sodium sulfate, 30 filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc) to give the title compound (1.68 g, 60 %) as a pale yellow solid. MS(ES)+ rn/c 303 [M+Hj+. - 141 d) I-phenyl-5-[4-(4-pyridinyl)-6-quinolilyll-1,2-dihydro-3H-pyiazol-3-one A solution of phenylhydrazine (0.093 ml, 0.95 mnol) in anhydrous THF (4.0 5 ml) was treated with a I M solution of potassium tert-butoxide in TI-F (1.89 ml, 1.89 mmol). The resulting solution was added to a solution of ethyl 3-14-(4-pyridinyl)-6 quinolinyll-2-propynoatc (0.268 g, 0.95 mmol) in THF (10 ml). The resulting brown solution was stirred at room temperature for I hour then at 65 "C for I hour. The resulting orange slurry was cooled to room temperature then concentrated under 10 reduced pressure. The resulting residue was taken into saturated aqueous Nal-CO, then extracted into methylene chloride and the extracts were dried over sodium sulfate then evaporated under reduced pressure. The resulting oil was purified by HPILC (acetonitrile/water. 5 - 80% gradient). The product was concentrated to a residue then recrystallized from ethanol to give the title compound (0.020 g, 6 %) as 15 a white solid. MS(ES)+ n/c 365 1M+-I. The following compounds were or can be prepared following the general procedures used to prepare the compound of Example 242: MS(ES) Example Structure IM+H l' N 0 HN, 243 379 N 1- 3 C\/ N 244 HN N 399 C l - N -142 - N 0N 245 HN3 N 246 HN30 I | Following the procedure used to prepare Example 242, 2-ethyl-6-14-(4-pyridinyl)-6 quinolinyl 1-4(l 1i)-pyrimidinone was or can be prepared by substituting ethylamidine hydrochloride for hydrazine. MS(ES)+ rn/e 329 [M+1-1+. 5 MS(ES) Example Structure IM+II 247 N N N329 's N Following the procedure used to prepare Example 242, 2-phenyl-5-14-(4-pyridinyl) 6-quinolinyll-I,2-dihydro-3H-pyrazol-3-one was or can be prepared by substituting 10 an alkynyl methyl ester for the alkynyl ethyl ester. MS(ES)+ m/c 365 IM+-lI*. IMS(ES) Example Structure I |M+1-il* N 01 N , 248 \-I 'N 365 N - 143 - Scheme 16: R1 RI Br a Br b R2 N.' rb .N ConICdiis: a) aryl (RI) stinnane. palladium catalyst. dioxime, heat: h) his(pinlacolto)ihron. 5 potassium acetate. palladium catalyst. dioxane. heal: then he teroaryl (1(2) hromide. palladium enItalyst. saturated aqicous N a 2

CO

3 . dioxane. heat. Example 345 10 2,4-difluoro-N-{ 2-(methyloxy)-5-14-(4-pyridazinyl)-6-quinolinyl -3 pyridin yl) benzenes ulfonamide N, 0 N F 00 F N 15 a) 6-biomo-4-(4-pyridazinyl)quinoline Dissolved 6-bromo-4-iodoquinoline (17.43 g. 52.2 nnol), 4 (tributylstannanyl)pyridazine (19.27 g, 52.2 mmol), and PdCl2(dppf)-CH2Cl2 20 (2.132 g, 2.61 mmol) in 1,4-dioxane (200 mL) and heated to 105 "C. After 3 h, added more palladium catalyst and heated for 6 h. Concentrated and dissolved in methylene chloride/methanol. Purified by column chromatography (combiflash) with 2% MeOH/EtOAc to 5% MeOH/EtOAc to give the crude title compOund. Trituration with EtOAc furnished 6-bromo-4-(4-pyridazinyl)quinoline (5.8 g, 20.27 25 rnmol, 38.8 % yield). MS(ES)+ rn/c 285.9, 287.9 |M+H I*. b) 2,4-difluoro-N- 2-(methyloxy)-5-14-(4-pyridazinyl)-6-quinolinyl -3 pyridinyl ) benzenesul fonamide - 144- A slurry of 6-bromo-4-(4-pyridazinyl)quinoline (4.8 g, 16.78 inmol), bis(pinacolato)diboron (4.69 g, 18.45 mmol) , PdCI2(dppf)-CI-12C12 (530 mg, 0.649 mnol) and potassium acetate (3.29 g, 33.6 mmol) in anhydrous I,4-dioxane (120 5 ml) was heated at 100 C foI 3 h. The complete disappearance of the starting bromide was observed by LCMS. The reaction was then treated with N-15-bromo-2 (methyloxy)-3-pyridinyll-2,4-ditluorobenzenesulfonamide (6.68 a. 17.61 mmol) and another portion of PdCI2(dppO-CH2CI2 (550 mg, 0.673 mmol), then heated at 110 'C for 16 h. The reaction was allowed to cool to room temperature, filtered, and 10 concentrated. Purification of the residue by chromatography (Analogix: 5% MeOlH / 5% CH2Cl2 / 90% EtOAC) gave 6.5 g (76%) desired product. MS(ES)+ m/c 505.9 [M+- 1*. The following examples were or can be prepared following the general procedure used in Example 345 15 M S( ES) Example Structure IM+tlI, 0 N \ N 346 C'474 N N 346 510 N N F

-

NN N\ 145 348 INTERMEDIATES: Intermediate 1 5 Scheme A: Br N N N OHC c OHC N' N Conditions: a) Tributyl(vinyl)tin, Pd(PPhA)4, dioxane, reflux; b) Os04, NalO 4 , 2,6 10 lutidine, t-BuOH, dioxane, H 2 0, rt; c) (4-pyridyl)boronic acid, Pd(PPh3)4, 2 M

K

2

CO

3 , DMF, 100 OC. 4-(4-pyridinyl)-6-quinolinecarbaldehyde OHC N 15 a) 4-chloro-6-ethenylqluinoline A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Meld. Chem., 21, 268 (1978) ), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and 20 tctrakistriphenylphosphinc palladium (0) (0.62 g, 0.54 mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOI:CI-1 2 Cl 2 ) to give the title compound (5.1 g) as a pale yellow solid. MS (ES)+ - 146 m/e 190 [M+1-]. This material was used directly in the next step. b) 4-ch loro-6-quinolinecarbaldehyde 5 A mixture of 4-chloro-6-cthenylquinoline (5.1 g, 26.88 mmol), 2,6-lutidine (5.76 g, 53.75 mmol), sodium (meta) periodate (22.99 g, 107.51 mmol). and osmium tetroxide (5.48 g of a 2.5% solution in tert-butanol, 0.538 mmol) in 1,4-dioxane:l- 2 0 (350 mL of 3:1 mixture) was stirred for 3.5 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (C-1 2 Cb) 10 to give the title compound (4.26 g, 83% for 2 steps) as a pale yellow solid. MS (EBS)+ m/c 192 [ M+l-l ];. c) 4-(4-pyridinyl)-6-quinolinecarbaldehyde 15 A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), 4 pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K 2

CO

3 (7.02 g, 50.76 mmol, 25.4 mIs of 2M solution) in DMF (100 mL) was heated at 100 "C for 3.0 h and cooled to room temperature. The mixture was filtered through Celite and the Celite was washed 20 with EtOAc. The filtrate was transferred to a separatory funnel, washed with water and saturated NaCl, dried (Na 2 SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% McO-:C-1 2

C

2 ) to give the title compound (2.03 g, 51 %) as a tan solid. MS (ES)+ m/c 235 [M-H1. 25 Intermediate 2 Preparation of 2-amino-5-bromo-NN-dimethyl-3-pyridinesul fonamide /, H Br a) 2-amino-5-bromo-3-pyridinesulfonyl chloride To a cooled (0 "C) solution of chlorosulfonic acid (58 mL) under vigorous 30 stirring was added 5-bromo-2-pyridinamine (86.7 mmol) portionwise. The reaction - 147 mixture was then heated at reflux for 3 hrs. Upon cooling to room temperature, the reaction mixture was poured over ice (-100 g) with vigorous stirring. The resulting yellow precipitate was collected by suction filtration, washing with cold water and petroleum ether to provide the title compound as an orange-yellow solid (18.1 g, 5 77% yield). MS(ES)+ m/e 272.8 [M+HF]. * Other sulfonyl chlorides can be prepared using this procedure by varying the choice of substituted aryl or heteroaryl. 10 b) 2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide To a cold (0 nlC) suspension of 2-amino-5-bromo-3-pyridinesulfonyl chloride (92.1 i mmol) in dry 1.4-dioxane (92 mL) was added pyridine (101.3 mrnol) followed by a 2M solution of dimethylamine in TFI (101.3 mmol). The reaction was allowed to warm to rt for 2 h, heated to 50 G for I h, then cooled to rt. Alter 15 standing for 2 h, the precipitate was collected by filtration and rinsed with a minimal amount of cold water. Drying the precipitate to constant weight under high vacuum provided 14.1 g (55%) of the title compound as a white solid. MS(ES)+ m/c 279.8, 282.0 [M+l]1. 20 *Other sulfonamides were or can be prepared using this procedure by varying the choice of sulfonyl chloride and amine. N N Br H2NB NN B HI NHN H N H S " Br S. Br H S B 00 0 0

H

2 N N O H N H N .NN Hj~ H HO"-** 3 Sr Br H 2 N ~ S~ Bir 00 00 00

H

2 N N H2N N H2N N N H HD N S >Br 'S)')'Br <I rS\) Br 0-0 048 - 148 - H Br N N SHB N SN B NH Br H N S Br Br 0 0 0 0 0z N ~ y H N N NK3XO N BrBr Br F o 6 o HN N O N HN N S:.N Br . Br 0 0 0 0 OF H S1 \\ rB 0 0 Intermediatc 3 Preparation of 2-am ino-iV,N-di meth yl1-5 -(4,4,5,5 -tetramet Ityl- I, 3.2 -d ioxabo rol ail-2 yl)-3-pyridiincsulfonamide

H

2 N .<N> 5 c) To a solution of 2-amino-5-bromo-NN-dimethyl-3-pyridinesulfonamide (7.14 mmol) in 1,4-dioxane (35 mL) was added 4,4,4',4',5,5,5',5'-octarnethyl-2,2'-bi-1,3,2 dioxaborolanc (7.86 mmol), potassium acetate (28.56 mmol) and II,' bis(diphenylphosphino)-ferroccnc]dichloropalladium(l 1) dichloromethane complex 10 (1:1) (0.571 mmol). The reaction mixture was stirred at 100 "C for 18 h. The reaction was concentrated in vacu, re-dissolved in ethyl acetate (50 ml.) and purified on silica using 60% ethyl acetate/hexanes to yield the title compound as a tan solid (86 %). I H NMR (400 M-lz, DMSO-d 6 ) 6 ppm 8.4 I (d. I H, J = 1.52), - 149 - 7.92 (d, I H, J = 1.77), 2.68 (s, 6 -1), 1.28 (s, 12 -1). * Other boronate or boronic acids can be prepared using this procCdurc by varying the choice of aryl or heteroaryl bromide. 5 Scheme 17: RI el NI 02NaBr a O b 0 2 N Br 0 2 N Br RI R1

H

2 N Br R2 Br 2) H Conditions: a) NaO(Ill), (RI)OH. 0 0 C to room temperature: b) SnCI 2 1- 2 0, ethyl acetate. retlux; 10 c) (R2)SO 2 C], pyridine, 0 oC to room temperatLre. Intermediate 4 Preparation of N-1 5-bromo-2-(methyloxy)-3-pvridinvl 1-2,4 15 difluorobenzenesulfonamide SN F 0 0 )al S N Br F a) 5-bromo-2-(methyloxy)-3-ni.iopyridine 20 To a cooled (0 'C) solution of 5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20% sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h. - 150- The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for I h. The solids were filtered, washed with water (3 x 100 mL) and dried in a vac oven (40 C) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4 % yield) as a pale yellow powder. The original filtrate was concentrated in vacuo 5 and diluted with water (150 mL). Saturated ammonium chloride (25 mL.,) was added and the mixture stirred for I h. The solids were filtered. washed with water, and dried in a vac oven (40 C) to give a second crop of' 5-bromo-2-(methyloxy)-3 nitropyridine (9 g, 38.6 mmol, 18.34 % yield). Total yield = 90%. MS(ES)+ rn/c 232.8, 234.7 [M+-]*. 10 b) 5-bromo-2-(methyloxy)-3-pyridinamine To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(lI) chloride dihydrate (174 g, 772 mmol). The 15 reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 mol% tin (11) chloride dihvdrate and continued to heat at reflux. After 2 h. the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for I h. The mixture was then with methylene chloride (I I.) 20 filtered through Celite. and washed with methylene chloride (500 mL..). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7 % yield). The product was used crude in subsequent reactions. MS(ES)+ rn/c 201.9, 203.9 [M+H '. 25 c) N-[5-bromo-2-(methyloxy)-3-pyridinyll-2,4-difluorobenzenesulfonamide To a cooled (0 C) solution of 5-bromo-2-(methyloxy)-3-pyridinanine (20.3 100 mmol) in pyridine (200 mL) was added slowly 2,4-difluorobenzenesulfonyl 30 chloride (21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h. at which time the reaction was diluted with water (500 mL) and the solids filtered off - 151 and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 50 "C to give N-I5-bromo-2-(methyloxy)-3-pyridinyll-2,4 difluorobenzenesulfonamide (12 g, 31.6 mmol, 3 1.7 % yield) MS(ES)+ rn/e 379.0, 380.9 [M+H I'. 5 *Other N-I5-bromo-2-(alkoxy)-3-pyridinyl Isulfonamides were or can be prepared using this procedure by varying the choice of sulfonyl chloride and alkoxide. 0 N 0I Br Ir Br H H FBr Br Br Cr F 10 Exemplary capsule composition An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the 15 proportions shown in Table I, below. Table I INGREDIENTS A MOUNTS compound of example 1 25 mg Lactose 55 mg Talc 16 mg Magnesium Stearate 4 mg - 152 - Exemplary Injectable Parenteral Composition An injectable form for administering the present invention is produced by 5 stirring 1.5% by weight of compound of example I in 10% by volume propylene glycol in water. Exemlary Tablet Composition I) The sucrose, calcium sulfate dihydrate and an P13K inhibitor as shown in Table Il below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, tale and stearic acid;, screened and compressed into a tablet. 15 Table I INGREDIENTS A MO U NTS compound of example 1 20 mg calcium sulfate dehydrate 30 mg Sucrose 4 mg Starch 2 mg Tale I mg stearic acid 0.5 mg While the preferred embodiments of the invention are illustrated by the 20 above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved. - 153- C-\R~orbl\DCC\KNGkIxM M_I DOC-M15/21112 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not. and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge 5 in the field of endeavour to which this specification relates. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion ofa stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or 10 steps. - 153A -

Claims (16)

1. 2. A compound according to claim I, wherein the compound is a compound of formula (l)(G): N (RsMR (R)n N R4 - 154 - (1)(G) in which each RI, R3, R4 and R5 is independently selected from: hydrogen, halogen, 5 acyl, amino, substituted amino, arylamino, acylamino. hetercycloalkylamino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7hetcrocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, 10 substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, acyloxy, and aryloxy: n is 1-2, m is 0-3; or R5 is R6, wherein R6 is -SO2NR80 or -NSOzR80 in which R80 is selected from a group consisting of: CI -C6ulkyl, C I -C6cycloalkyl, CI C6hetcrocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, 15 substituted Cl-C6hetcrocycloalkyl, aryl optionally fused with a five-membered nng or substituted with one to Five groups selected from a group consisting of: Cl -C6alkyl, Cl -C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or -(CH-1 2 )COOl, or heteroaryl optionally fused with a five-membered ring or substituted with one to five 20 groups selected from a group consisting of: Cl-C6alkyl, CI-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or (CHz)nCOOH, wherein n is 0-2, or a pharmaceutically acceptable salt thereof.
2. 3. A compound according to claim I, wherein the compound is a 25 compound of formula (1)(K): N OM R1 R6 N (1)(K) - 155 - in which RI is selected from a group consisting of: heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, 5 arylamino, acylamino, hetercycloalkylamino, alkoxy, CI-6alkyl and substituted CI-6alkyl; cach R5 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, cyano, hydroxyl, alkoxy; m is 0-1, 10 R6 is -SO2NRSO or -NSO 2 R8O. in which R80 is selected from a group consisting of: Cl -C6alkyl, C I -C6cycloalkyl, Cl -C6heterocycloalkyl, substituted Cl-C6alkyl, substituted Cl(-C6cycloalkyl, substituted Cl-C6hcterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five 15 groups selected from a group consisting of: CI-C6alkyl, CI-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl. alkoxy, oxo or -(C12)XC001, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, 20 alkoxy, oxo. or -(CH 2 )nCOO-1, wherein n is 0-2; or a pharmaceutically acceptable salt thereof.
3. 4. A compound according to claim 1, wherein the compound is a compound of formula (1)(M): 25 N (O R1 (Rs) R6 N (1)(M) - 156 - in which R I is selected from a group consisting of: heteroaryl. substituted heteroaryl, hetcrocycloalkyl, substituted hcterocycloalkyl, amino, substituted amino, arylarnino, acylamino, hetercycloalkylamino, alkoxy, Cl-6alkyl and substituted 5 CI-6alkyl; each R5 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI -6alkyl, substituted CI-6alkyl, cyano, hydroxyl. alkoxy; 10 m is 0-l; R6 is -NSO 2 R80, wherein R80 is selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, Cl-C6heterocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally 15 fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl. alkoxy. oxo or (ClH 2 )COOl, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl 20 C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(CH2),COOH-I, wherein n is 0-2; or a pharmaceutically acceptable salt thereof.
4. 5. A compound according to claim 1, wherein the compound is a 25 compound of formula (1)(N): N R6 N (I )( N) - 157 - in which Rl is selected from a group consisting of: heteroaryl, substituted hcteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, arylamino, acylamino, hetercycloalkylamino, alkoxy, CI 6alkyl and substituted 5 CI-6alkyl; each R5 is independently selected from: hydrogen, halogen, acyl, amino, substituted amino, CI-6alkyl, substituted CI-6alkyl, cyano, hydroxyl, alkoxy; 10 m is 0-1; R6 is -SO2NR80, wherein R80 is selected from a group consisting of: Cl C6alkyl, Cl-C6cycloalkyl, Cl-C6hcterocycloalkyl, substituted Cl-C6alkyl, substituted Cl-C6cycloalkyl, substituted Cl-C6heterocycloalkyl, aryl optionally 15 fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, Cl-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or (CI-1 2 )COO-, or heteroaryl optionally fused with a five-membered ring or substituted with one to live groups selected from a group consisting of: CI 20 C6alkyl, Cl-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano. hydroxvl, alkoxy, oxo, or -(ClHl 2 )nCOOl, wherein n is 0-2; or a pharmaceutically acceptable salt thereof.
5. 6. The compound of Formula (1)(M). 25 7. The compound of Formuma (1)(N).
6. 8. A method of inhibiting one or more phosphatoinositides 3-kinases (Pl3Ks) in a human; comprising administering to the human in need thereof a therapeutically effective amount of a compound of Formula (I) - 158 - R1 R2 N R4 (R 3 )n (I) or a pharmaceutically acceptable salt thereof; 5 in which R2 is pyridinyl or substituted pyridinyl; R1 is selected from a group consisting of: heterocycloalkyl, substituted heterocycloalkyl, aryl. substituted aryl, heteroaryl and substituted heteroaryl; each R3 and R4 is independently selected from: hydrogen, halogen, acyl, amino, 10 substituted amino, Cl-6alkyl. substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, 15 alkoxy. nitro. acyloxy, and aryloxy; n is 1-2; X is C or N; Y is C, O, N, or S; or a pharmaceutically acceptable salt thereof. 20 9. A method of treating one or more disease states selected from a group consisting of: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, in a human in need 25 thereof, which method comprises administering to such human , a therapeutically effective amount of a compound according to claim 1.
7. 10. A method of treating cancer comprises co-administration a compound according to claim 1; and/or a pharmaceutically acceptable salt thereof; and at -159 - least one anti-neoplastic agent, such as one selected from a group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway 5 inhibitors, non-receptor tyrosine kinase angiogencsis inhibitors, immunotherapeutic agents, proapoptotic agents, and ccll cycle signaling inhibitors. I1. A method of claim 9, wherein the disease state is selected from a group consisting of: multiple sclerosis, psoriasis, rheumatoid arthritis, systemic It lupus crythematosis, inflammatory bowel disease, lung inflammation, thrombosis, brain infection/inflammation, meningitis and encephalitis.
8. 12. A method of claim 9, wherein the disease state is selected from a group consisting of: Alzheimer's disease, Huntington's disease, CNS trauma, stroke and ischemic conditions. 15 13. A method of claim 9, wherein the disease state is selected from a group consisting of: atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure and vasoconstrict ion.
9. 14. A method of claim 9, wherein the disease state is selected from a group consisting of': chronic obstructive pulmonary disease, anaphylactic shock 20 fibrosis, psoriasis, allergic diseases, asthma, stroke, ischemia-reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, antiogenesis, invasion metastasis, melanoma, Karposi's sarcoma, acute and chronic bacterial and virual infections. sepsis, transplantation rejection, graft rejection, glomerulo sclerosis, glomerulo 25 nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung, and lung airways inflammation.
10. 15. A method of claim 9, wherein the disease is cancer.
11. 16. A method of claim 15 wherein the cancer is selected from a group consisting of: brain (gliomas), glioblastomas, leukemias. Bannayan-Zonana 30 syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, -160- melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid.
12. 17. A method of claim 15 wherein the cancer is selected from a group 5 consisting of: ovarian cancer, pancreatic cancer, breast cancer, prostate cancer and leukemia.
13. 18. A method of claim 8, wherein said P13 kinase is a Pl3o..
14. 19. A method of claim 8, wherein said P13 kinase is a P13y.
15. 20. A method of claim 8, wherein said P13 kinase is a P136. 1t 21. A method of claim 9, wherein the compound or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.
16. 22. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier. 15 - 161 -