ZA200301701B - Pyrazole compounds useful as protein kinase inhibitors. - Google Patents
Pyrazole compounds useful as protein kinase inhibitors. Download PDFInfo
- Publication number
- ZA200301701B ZA200301701B ZA200301701A ZA200301701A ZA200301701B ZA 200301701 B ZA200301701 B ZA 200301701B ZA 200301701 A ZA200301701 A ZA 200301701A ZA 200301701 A ZA200301701 A ZA 200301701A ZA 200301701 B ZA200301701 B ZA 200301701B
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- ZA
- South Africa
- Prior art keywords
- ring
- optionally substituted
- substituted
- aliphatic
- phenyl
- Prior art date
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Description
PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS
, CROSS REFERENCE TO RELATED APPLICATIONS . This application claims priority to US ’ Provisional Patent Application 60/232,795 filed September 15, 2000, US Provisional Patent Application -60/257,887 filed December 21, 2000 and US Provisional Patent
Application 60/286,949 filed April 27, 2001, the contents of which are incorporated herein by reference.
The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of
GSK-3 and Aurora-2 protein kinases. The invention also relates to methods of treating diseases associated with these protein kinases, such as diabetes, cancer and
Alzheimer’s disease.
The search for new therapeutic agents has been greatly aided in recent years by better understanding of : the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases. ’ Protein kinases mediate intracellular signal , 25 transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There -1-
SUBSTITUTE SHEET (RULE 26)
A are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet . radiation, bacterial endotoxin, H,0,), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor a (TNF- } a), and growth factors (e.g. granulocyte macrophage- colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.
Many diseases are associated with abnormal : cellular responses triggered Toy protein kinase-mediated events. These diseases include autoimmune diseases, : inflammatory diseases, neurological and neurodegenerative . 20 diseases, cancer, cardiovascular diseases, allergies and : asthma, Alzheimer’s disease or hormone-related diseases.
Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play: * 30 a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora- -2-
SUBSTITUTE SHEET (RULE 26)
2 protein has been found to be overexpressed. See . Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a . : serine/threonine protein kinase comprised of a and B isoforms that are each encoded by distinct genes [Coghlan
RN N ~~ "et al., Chemistry & Biology, 7, 793-803 (2000); Kim and
Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)].
GSK-3 has been implicated in various diseases including diabetes, Alzheimer’s disease, CNS disorders such as manic depressive disorder and nevrodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117). These : 15 diseases may be caused by, or result in, the abnormal + operation of certain cell signaling pathways in which
GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for : glycogen synthesis, the microtubule associated protein
Tau, the gene transcription factor PB-catenin, the translation initiation factor elF2B, as well as ATP ‘citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c¢-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant + for the treatment of type II diabetes, insulin-induced ’ 30 signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated . a
SUBSTITUTE SHEET (RULE 26)
phosphorylation and deactivation of glycogen synthase. " The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, , 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994) ; Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); . Massillon et al., Biochem J. 299, 123-128 (1994)].
However, in a diabetic patient where the insulin response
Bn ~~ Tis impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675].
Therapeutic inhibitors of GSK-3 are therefore potentially : useful for treating diabetic patients suffering from an impaired response to insulin. : : -
GSK-3 activity has also been associated with
Alzheimer’s disease. This disease is characterized by the well-known P-amyloid peptide and the formation of : intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites.
GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition : of GSK-3 has been shown to prevent hyperphosphorylation of Tau in.cells [Lovestone et al., Current Biology 4. * 30 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997) 1. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease. a
SUBSTITUTE SHEET (RULE 26)
Another substrate of GSK-3 is P-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of f-catenin have been reported in schizophrenic ‘ patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J.
BN © 7 7 Neuropathol. Exp, 56, 70-78 (1997)]. :
As a result of the biological importance of
GSK-3, there is current interest in therapeutically effective GSK-3 inhbitors. Small molecules that inhibit
GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)].
For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported ‘recently as inhibitors of p38 kinase (WO 00/12497 to
Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-a activity and/or enhanced TGF-p activity. While p38 activity has been implicated in a wide variety of : diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake.
Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake. : ] There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases aurora-2 and GSK-3 are especially attractive . -5-
SUBSTITUTE SHEET (RULE 26)
targets for the discovery of new therapeutics due to their important role in cancer, diabetes, Alzheimer’s disease and other diseases.
. It has now been found that compounds of this invention and pharmaceutical compositions thereof are - ~~ T “effective as protein kinase inhibitors, particularly as inhibitors of aurora-2 and GSK-3. These compounds have the general formula I:
R2
R?
NF hw
HN” N
AN 2 n, A ~, 7
I or a pharmaceutically acceptable derivative or prodrug thereof, wherein: 7! to z* are as described below;
Ring A is selected from the group consisting of: }
YY A
R* ~N : R* ~N
N RY ZZ ~ J N
WR NN CR ROW, WR NON a b c | d
A ES
: : I 1 SON Ri ) R IAN
RANA | A PN )
R® , N FE “N -6-
SUBSTITUTE SHEET (RULE 26)
e £ ag h . N. } and R® ; i _ 5 _ }
G is Ring C or Ring Dj;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R?, any substitutable non- ortho carbon position on Ring C is independently substituted by -R°, and two adjacent substituents on - Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, : oxo, or -R%;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered - 20 bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected ‘from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R°, and at any substitutable ring nitrogen by -R?, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R® is hydrogen at each ortho carbon position of Ring Dj; . R* is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci.e¢ aliphatic group, said phenyl, heteroaryl, -7-
SUBSTITUTE SHEET (RULE 26) :
. and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R®, said C;.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R! ~and an adjacent substituent taken together with their . intervening atoms form said ring fused to Ring C;
R* and RY are independently selected from T-R?}, or R* and — —— — RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable ° carbon on said fused ring formed by R* and RY is substituted by oxo or T-R?}, and any substitutable nitrogen on said ring formed by R* and RY is substituted by R?*; a.
T is a valence bond or a C:., alkylidene chain;
R? and R* are independently selected from -R, -T-W-R®, or
R? and R?* are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and RY is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R*® and R? is substituted by R*; : :
Rr? is selected from -R, -halo, -OR, -C(=O)R, -CO:R, : ~COCOR, -COCH,COR, -NO,, -CN, -S(O)R, -S(0),R, -SR, -N(R*),, -CON(R’),, -SO.N(R’),, -OC(=O)R, -N(R’)COR, -N(R’) CO, (optionally substituted C;.¢ aliphatic), . : -N(R*)N(R*),, -C=NN(R'),, -C=N-OR, -N(R’)CON(R’), -N(R7)SO,N(R7) 2, -N(R*)SO,R, or -OC(=O0)N(R’);; ’ each R is independently selected from hydrogen or an optionally substituted group selected from C;¢ . SE _a- © SUBSTITUTE SHEET (RULE 26)
aliphatic, Ce.10 aryl, a heteroaryl ring having 5-10 ] ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R* is independently selected from -R’, -COR’, -CO,(Ci.¢ aliphatic), -CON(R’),, or -SO,R’, or two R® on the same , nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
N : 5 each R® is independently selected from -R, halo, -OR, -C{(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SO,R, -SR, -N(R%),, -CON(R%)},, -SO.N(R*),, -OC(=O)R, -N(R*®)COR, -N(R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R*),, -C=NN(R*),, -C=N-OR, -N(R®)CON(R%),, ° -N(R*) SO,N(R*),, -N(R!)SO.,R, or -OC(=O)N(R%),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; -
V is -O-, -S-, -S0-, -8S0,-, -N(R®)S0O,-, -SO,N(R®)-, -N(R®)-, -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, : -N(R®) CON (R®) -, -N(R®)SO,N(R®)-, -N(R®)N(R®)-, -C(O)N(R®) -, -OC(O)N(R®)-, -C(R®),0-, -C(R®),S-, -C(R®)280-, -C(R®);80,-, -C(R®)2SON(R®)-, -C(R®)N(R®)-, -C(R®) N(R?) C(O) -, -C(R®),N(R®)C(0)O-, -C(R®)=NN(R®)-,-C(R®) =N-0-, -C(R®),N(R®)N(R®)-, -C(R) oN (RS) SON (RS) -, or -C(R®) ,N (R®) CON(R®) -;
Wis -C(R®),0-, -C{(R®).S-, -C(R®),80-, -C(R®),S0,-, ~-C(R®),80,N(R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)0C (0) -, -C(R®)OC(O)N(R)-, -C(R®).N(R®)CO-, -C(R®),N(R®) C(0)O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, -C(R®).N(R®)N(R®) -, -C(R®).N(R®)SO,N(R®)~, . -C(R®) ,N(R®) CON (R®) -, or -CON(R®)-; . each R® is independently selected from hydrogen or an optionally substituted C;.; aliphatic group, or two R® ’ groups on the same nitrogen atom are taken together -9- : SUBSTITUTE SHEET (RULE 26)
with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C,¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; } ~~. each .R®.is independently selected from an optionally substituted C;, aliphatic group, -OR®, -SR®, -CORS, ~ 10 -SO,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or -CO,R®%; and
R’ is selected from -R, halo, -OR, -C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SO;R, -SR, -N(R!),, -CON(R*),, -SO.N(R*),, -OC(=0)R, -N(R?)COR, -N(R?)CO, (optionally substituted Cs aliphatic), -N(R*)N(R),, -C=NN(R?),, -C=N-OR, -N(R*)CON(R*),, -N(R*)SO.,N(R%),, -N(R*)SO,R, or © -0C(=0)N(R%),. oo
As used herein, the following definitions shall apply unless otherwise indicated. The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “ (un) substituted. ” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term “aliphatic” as used herein means straight-chain, branched or cyclic C;-C;», hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic. ‘ 30 For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic oo ) alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or -10-
SUBSTITUTE SHEET (RULE 26)
(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms “alkenyl” and “alkynyl” used : alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve ] carbon atoms. The term “cycloalkyl” used alone or as part of a larger moiety shall include cyclic C3;-Cai hydrocarbons which are completely saturated or which . contain one or more units of unsaturation, but which are not aromatic.
The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or I.
The term “heteroatom” means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
Also the term “nitrogen” includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR' (as in N-substituted pyrrolidinyl).
The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” as used herein means an aliphatic ring system having three to fourteen members. : 30 The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” whether saturated or partially unsaturated, also refers to rings that are optionally substituted.
The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or -11- "SUBSTITUTE SHEET (RULE 26)
“carbocyclic” also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.
The term “aryl” used alone or as part of a . larger moiety as in “aralkyl”, “aralkoxy”, or saryloxyalkyl”, refers to aromatic ring groups having ~ five to fourteen members, such as phenyl, benzyl, phenethyl, 1l-maphthyl, 2-naphthyl, l-anthracyl and 2- anthracyl. The term “aryl” also refers to rings that are optionally substituted. The term “aryl” may be used interchangeably with the term “aryl ring”. “Aryl” also Co includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include l-naphthyl, 2-naphthyl, l-anthracyl and 2- anthracyl. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
The term “heterocycle”, “heterocyclyl”, or ) “heterocyclic” as used herein includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1H- benzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3- vl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, [1,3] -dioxalanyl, [1,3]-dithiolanyl, [1,3] -dioxanyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- -12- © SUBSTITUTE SHEET (RULE 26)
morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4- thiomorpholinyl, 1l-pyrrolidinyl, 2-pyrrolidinyl, 3- : ~ pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-
BN piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1- : phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and ) _ _._benzothianyl. Also included within the scope of the term “heterocyclyl” or “heterocyclic”, as it is used herein, : 10 is a group in which a non-aromatic heterocatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term “heterocycle”. “heterocyclyl”, or “heterocyclic” whether saturated or partially unsaturated, also refers to rings that are optionally substituted. . -
The term “heteroaryl”, used alone or as part of : 20 a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl oo rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2- : imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- - 25 isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1l-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2- thiazolyl, 4-thiazolyl, S5-thiazolyl, 5-tetrazolyl, 2- . 30 triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, : quinolinyl, benzotriazolyl, benzothiazolyl, } benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, -13-
SUBSTITUTE SHEET (RULE 26)
isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term “heteroaryl”, as it is used herein, is a group in which a heteroatomic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic } ‘ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido(3,4-dlpyrimidinyl. ~The term “heteroaryl” also refers to rings that are = optionally substituted. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heterocaralkyl group include a halogen, -R°, -OR°, -SR°, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -0 (Ph), substituted -0O(Ph), -CH; (Ph), substituted -CH, (Ph), -CH,CH,(Ph), substituted -CH,CH, (Ph), -NO,, -CN, -N(R°)., -NR°C(O)R°, -NR°C(O)N(R°®)., -NR°CO,R°, -NR°NR°C(0O)R°, -NR°NR°C(O)N(R°),, -NR°NR°CO.R°, -C(0) C(O)R®, -C(O)CH,C(O)R®, -CO,R°, -C(O)R°, -C(O)N(R%),, 25 . -OC(O)N(R®°)5, -S(O)2R°, -SO,N(R°),, -S(O)R°, -NR°SO,;N(R°),, -NR°SO,R®, -C(=S)N(R°)2, -C(=NH)-N(R°®),, -(CH,}yNHC(O)R®, - (CHz) yNHC (0) CH(V-R®) (R°) ; wherein R° is hydrogen, a substituted or unsubstituted aliphatic group, an } unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -0(Ph), substituted -O(Ph), - -CH, (Ph), or substituted -CH,(Ph); y is 0-6; and V is a linker group. Examples of substituents on the aliphatic ~14-
SUBSTITUTE SHEET (RULE 26)
group or the phenyl ring of R° include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, : hydroxy, haloalkoxy, or haloalkyl.
An aliphatic group or a non-aromatic _. _ _heterocyclic ring nay contain one or more substituents.
Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic "ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =0, =8, =NNHR', =NN(R"),, =N-, =NNHC(O)R', =NNHCO, (alkyl), —NNHSO, (alkyl), or =NR*, where each R" is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
Suitable substituents on the nitrogen of a non- aromatic heterocyclic ring include -R*, -N(R%)., -C(O)RY, -CO,R*, -C(0)C(O)R*, -C(O)CH,C(O)R*, -SO.R", -SO;N(R'):, -C(=S)N(R%),, -C(=NH)-N(R*),, and -NR'SO,R*; wherein R' is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, _ -0(Ph), substituted -0(Ph), CH,(Ph), substituted CH, (Ph), : 30 or an unsubstituted heteroaryl or heterocyclic ring.
Examples of substituents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, : aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, i ‘ -15-
Co SUBSTITUTE SHEET (RULE 26)
dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. : 5 . The term “linker group” or “linker” means an . organic moiety that connects two parts of a compound.
Linkers are typically comprised of an atom such as oxygen - or sulfur, a unit such as -NH-, -CH,-, -C(0)-, -C(O)NH-, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms. Examples of linkers include a saturated or unsaturated C,.¢ alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -C(0)-, -C(0)C(0)-, -CONH-, -CONHNH-, -CO,-, -0C(O)-, -NHCO,-, -0-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S-, -S0-, -803-, -NH-, -80,NH-, or -NHSO,-.
The term “alkylidene chain” refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group.
A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable : compound or chemically feasible compound is one in which the chemical structure is not substantially altered when : kept at a temperature of 40 °C or less, in the absence of - 30 moisture or other chemically reactive conditions, for at least a week.
Unless otherwise stated, structures depicted : - herein are also meant to include all stereochemical forms -16-
SUBSTITUTE SHEET (RULE 26)
of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures } depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of ‘a carbon by a ¥C- or *C-enriched carbon are within the scope of this invention.
Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of the . protein kinase inhibitor effective to inhibit a protein kinase, particularly GSK-3, in a biological sample or in a patient. In another embodiment, compounds of this : 20 invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or. prevent a GSK-3-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient. oo The term "GSK-3-mediated condition" or "disease", as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, . 30 without limitation, diabetes, Alzheimer's disease,
Huntington's Disease, Parkinson's Disease, AIDS- associated dementia, amyotrophic lateral sclerosis (AML), -17-
SUBSTITUTE SHEET (RULE 26)
multiple sclerosis (MS), schizophrenia, cardiomycete ‘hypertrophy, reperfusion/ischemia, and baldness.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, . which method comprises administering to the patient a therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer’s disease. Another method relates to inhibiting the phosphorylation of B-catenin, which is useful for treating schizophrenia...
Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a
GSK-3 inhibitor of formula I. 20 . Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said : compound . : 25 Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a ] 30 compound of formula I or a pharmaceutical composition “thereof. : : The term "Aurora-2-mediated condition" or "disease", as used herein, means any disease or other -18-
SUBSTITUTE SHEET (RULE 26)
deleterious condition in which Aurora is known to play a role. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor.
Such conditions include, without limitation, cancer. The : term "cancer" includes, but is not limited to the . following cancers: colon and ovarian.
Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 inhibitor of formula I, or a composition thereof.
Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated diseases with a CDK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a : . therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof. -
The term "CDK-2-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which CDK-2 is known to play a role. The term "CDK-2-mediated condition" or "disease" also means those diseases or conditions that are : alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation, cancer,
Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, : psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M. . 30 and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245 (2000) ; Mani, S., Wang, C., Wu, K., Francis, R. and oo Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);
Fry, D.W. and Garrett, M.D., Current Opinion in -19-
SUBSTITUTE SHEET (RULE 26)
: Oncologic, Endocrine & Metabolic Investigational Drugs, : 2, 40-59 (2000).
Another aspect of the invention relates to inhibiting CDK-2 activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition : comprising said compound.
Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated diseases with an ERK-2 inhibitor, which method comprises . administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula ] : I or a pharmaceutical composition thereof.
The term “ERK-mediated condition”, as used
Therein means any disease state or other deleterious ) condition in which ERK is known to play a role. The term’ "ERK-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a ERK-2 inhibitor. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly,
Alzheimer’s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. The term “cancer” includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, - | bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, -20-
SUBSTITUTE SHEET (RULE 26)
papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders,
Hodgkin’s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon- ] rectum, large intestine, rectum, brain and central ~ nervous system, and leukemia. ERK-2 protein kinase and its implication in various diseases has been described [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997,
Am. J. Respir. Cell Mol. Biol. 16, 589].
Another aspect of the invention relates to .
Co inhibiting ERK-2 activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition : comprising said compound.
Another aspect of this invention relates to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula : 30 I or a pharmaceutical composition thereof. : The term “AKT-mediated condition”, as used - herein, means any disease state or other deleterious condition in which AKT is known to play a role. The term -21-
SUBSTITUTE SHEET (RULE 26)
"AKT-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment . with a AKT inhibitor. BAKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The . association of AKT, also known as protein kinase B, with various diseases has been described [Khwaja, A., Nature, "pp. 33-34, 1990; zang, Q. Y., et al, Oncogene, 19 2000; : Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000].
Another aspect of the invention relates to inhibiting AKT activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof. : : The term “Src-mediated condition”, as used herein means any disease state or other deleterious condition in which Src is known to play a role. The term nSrc-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment : : with a Src inhibitor. Such conditions include, without + limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and : 30 Paget's disease. Src protein kinase and its implication in various diseases has been described {[Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693 (1991);
Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, -22-
SUBSTITUTE SHEET (RULE 26)
Drugs of the Future 2000, 25(7), 717, (2000); Talamonti,
J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys.
Res. 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 : (1986) ; Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, . Adv. Cancer Res., ‘76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993) ; Wiener, Clin. Cancer Res., 5, 2164 (1999); - © Staley, Cell Growth Diff., 8, 269 (1997)].
Another aspect of the invention relates to inhibiting Src activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
The term "pharmaceutically acceptable carrier, ‘adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
The term "patient" includes human and veterinary subjects. : : : The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof ; preparations of an enzyme suitable for in vitro = assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
The amount effective to inhibit protein kinase, for example, GSK-3 and Aurora-2, is one that measurably - 30 inhibits the kinase activity where compared to the activity of the enzyme in the absence of an inhibitor. : Any method may be used to determine inhibition, such as, -23- . :
SUBSTITUTE SHEET (RULE 26)
for example, the Biological Testing Examples described below.
Pharmaceutically acceptable carriers that may } be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum : stearate, lecithin, “serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, | } polyethylene-polyoxypropylene-block polymers, : polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of - this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile oo injectable preparation may also be a sterile injectable -24- : SUBSTITUTE SHEET (RULE 26)
solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and } solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In : addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation . of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, "especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and © 20 other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of : pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. :
The pharmaceutical compositions of this ‘invention may be orally administered in any orally } acceptable dosage form including, but not limited to, ) capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used . include lactose and corn starch. ‘Lubricating agents, such as magnesium stearate, are also typically added.
For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When : -25- : - ©. SUBSTITUTE SHEET (RULE 26)
aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions - of this invention may be administered in the form of suppositories for rectal administration. These can be
I prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials : include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including : diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used. . For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical : administration of the compounds of this invention include, but are not limited to, mineral oil, liquid : 30 petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or -26- : SUBSTITUTE SHEET (RULE 26)
cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited } to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, : benzyl alcohol and water.
For ophthalmic use, the pharmaceutical : compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, : 10 as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated ] in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical } formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, : fluorocarbons, and/or other conventional solubilizing or : dispersing agents.
In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified diseases or disorders. :
A "pharmaceutically acceptable derivative or - 30 prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound ) Co of this invention which, upon administration to a recipient, is .capable of providing, either directly or ~-27- : SUBSTITUTE SHEET (RULE 26)
indirectly, a compound of this invention or an ) inhibitorily active metabolite or residue thereof.
A Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a . patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic |. system) relative to the parent species.
Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids “and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, ~ hemisulfate, heptanoate, hexanoate, hydrochloride, : 25° hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, . 30 succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in ‘ themselves pharmaceutically acceptable, may be employed : | in the preparation of salts useful as intermediates in oo -28-
Co | SUBSTITUTE SHEET (RULE 26) :
obtaining the compounds of the invention and their . pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N'(C,., alkyl), } salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds © disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
Preferably, the compositions should be formulated so that © 15 a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition.
Depending upon the particular protein kinase- mediated condition to be treated or prevented, additional : 30 therapeutic agents, which are normally administered to treat or prevent: that condition, may be administered : together with the inhibitors of this invention. For example, in the treatment of diabetes other anti-diabetic -29-
SUBSTITUTE SHEET (RULE 26)
Claims (68)
1. Use of a compound of formula VI for inhibiting GSK-3 or Aurora activity in a patient: R? i | : ow HNN NN “IE VI or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2, 4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R%, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R%; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or SUBSTITUTED SHEET (RULE 26) 350 Amended Sheet - 2004-05-25 heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or
-R%, and at any substitutable ring nitrogen by -R?, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R® is hydrogen at each ortho carbon position of Ring D; R! is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl E ring, or Ci.¢ aliphatic group, said phenyl, heteroaryl, " and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R?, said Cis aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R* and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RY is T-R*'; T is a valence bond or a C;.4 alkylidene chain; R?® and R? are independently selected from -R, -T-W-R®, or } : R? and R? are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? _ | and R*" is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R®> and R?> is substituted by R*; R?" is an optionally substituted group selected from Cis aliphatic, Ci_1p carbocyclyl, Cs-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring : a having 5-10 ring atoms; oo each R is independently selected from hydrogen or an optionally substituted group selected from Cig : 351 SUBSTITUTE SHEET (RULE 26)
aliphatic, Ce-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R* is independently selected from -R’, -COR’,
-CO, (optionally substituted Cj; aliphatic), -CON(R’)a,
: or -SO,R7, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R®° is independently selected from -R, halo, -OR, -C(=0)R, -CO;R, -COCOR, -NO,, -CN, -S(O)R, -SOzR, -SR, -N(R*%),, -CON(R*),, -SO,N(R%),, -OC(=0)R, -N(R*)COR, -N(R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R%*),, -C=NN(R%),, -C=N-OR, -N(R*)CON(R?), -N(R%) SON (R*),, -N(R*)SO,R, or -OC(=O)N(R'),, or R° and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
V is -O-, -S-, -SO-, -SO0;-, -N(R®)S0,-, -SO,N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, “MN (RS) SON (RS) -, -N(RS)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®);S-, -C(R®)280-, -C(R®)280;-, ~C(R®)280:N (R®) -, -C(R®)N(R®)-, -C(R®).N(R®)C(O)-,
-C(R®),N(R®)C(0)0O-, -C(R®°)=NN(R®)-, -C(R®)=N-O-, -C(R®) ,N(R®)N(R®) -, -C(R®).N(R®)SO,N(R®)-, or -C(R®) ,N(R®) CON (R®) -;
W is -C(R®),0-, -C(R®),S-, -C(R®),80-, -C(R®),S0;-, -C(R®)2S0,N (R®) -, -C(R®),N(R®)-, -CO-, -CO,-, —-C(R®)OC(O)- , —C(R®)0OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®).N(R®)C(O)O-, -C(R®) =NN (R®) -, -C(R®)=N-0-, -C(R®),N(R®)N(R®)-, -C(R®) ,N (R®) SO,N (R®) -, -C(R®),N (R®)CON(R®)-, or -CON(R®)-;
‘ each R® is independently selected from hydrogen, an optionally substituted C;., aliphatic group, or two R® groups on the same nitrogen atom are taken together
352 SUBSTITUTE SHEET (RULE 26)
with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C,.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and ) each R® is independently selected from an optionally substituted C;.4 aliphatic group, -OR®, -SRS, -CORS, -SO,R®, . -N(R®),, -N(R®)N(R®),, -CN, =NO,,.-CON(R®);, or -COR®. ~
2. The use according to claim 1, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, gquinolinyl or isoquinolinyl ring, and R! is -halo, an optionally substituted C,_¢ aliphatic group, phenyl, ~-COR®, -OR®, -CN, -SO,R®, -SO,NH,, -N(R®),, -CO,R®, ~CONH;, -NHCOR®, ~OC (0) NH,, or ~NHSO,R®; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro- 1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) RY is T-R®, wherein T is a valence bond or a methylene; and (c) R* is hydrogen and R’? is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C;-¢ aliphatic group, or R? and R? are taken 353 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
3. The use according to claim 2, wherein: (a) Ring C is an optionally substituted ring . selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring
: . system, the bicyclic ring system .is selected from a naphthyl, - . guinolinyl or isoquinolinyl ring, and R! is -halo, an optionally substituted C,.¢ aliphatic group, phenyl, -CORS, -ORS, -CN, -SO;R®, -SO,NH,, -N(R®);, -CO,RS, -CONH,, -NHCOR®, -0OC (O)NH,, or ~NHSO,RS; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro- 1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; : (b) RY is T-R*, wherein T is a valence bond or a methylene; and } B i ~ Co 3 a BN Se - - —-- N (c) R? is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci-¢ aliphatic group, or R? and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
4. The use according to claim 2, wherein said compound has one or more features selected from the group consisting of: 354 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
(a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R* is -halo, a C;-¢ haloaliphatic group, a C;-¢ aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,
. 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-- oo dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; (b) RY is T-R?', wherein T is a valence bond or a methylene and R¥ is an optionally substituted group selected : from C,_¢ aliphatic, Cs_.¢ carbocyclyl, Cg.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5- ring atoms; (c) R? is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci-¢ aliphatic group, or R? and R?* are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -halo, -CN, -NO,, ~N (RY) , optionally substituted C;.¢4 aliphatic group, -OR, -C(O)R, -CO;R, —-CONH(R), -N(R')COR, -SO,N(R'),, or -N(R*)SO:R.
5. The use according to claim 4, wherein: {a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and rR} 355 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 is -halo, a C;-¢ haloaliphatic group, a Cj;-¢ aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl: (b) RY is T-R3®', wherein T is a valence bond or a methylene and R®* is an optionally substituted group selected
: . © from Ci. aliphatic, Cj3.¢ carbocyclyl, Ce.10 aryl, a heteroaryl so - ring having 5-10 ring atoms, or a heterocyclyl ring having 5- ring atoms; (c) R? is hydrogen and R® is hydrogen or a substituted or unsubstituted group selected from aryl, or a
Ci.¢ aliphatic group, or R? and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -halo, -CN, -NO;, ~N (R%) 2, optionally substituted C;-¢ aliphatic group, -OR, -C(O)R, -COpR, -CONH(R®), -N(R*)COR, -SO,N(R%),, or -N(R*)SO;R.
6. The use according to claim 4, wherein said compound has one or more features selected from the group consisting of: (a) RY is T-R?®', wherein T is a valence bond or a methylene and R¥ is an optionally substituted group selected from C,.¢ aliphatic, Cs.¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring: (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and 356 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is —~halo, a C;-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, } 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, guinolinyl, or naphthyl; : Lo : (c) R?* and R? ‘are taken together with their : So intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R%),, -C;.4 alkyl, =-C;_, haloalkyl, - NO;, -0(C;-4 alkyl), -CO2(Ci.4 alkyl), -CN, -S0,(Ci-4 alkyl), - SO,NH,, -OC(O)NHz, -NH280,(Cy-4 alkyl), ~NHC(O) (Ci4 alkyl), - C(O})NH,, or -CO(C;_4 alkyl), wherein the (C;-4 alkyl) is a straight, branched, or cyclic alkyl group; and (d) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -Cl, -F, -CN, -CFj, } -NH;, -NH(C;-4 aliphatic), -N(C-4 aliphatic),, -0(Ci-4 aliphatic), Ci-4 aliphatic, and -CO,(C;-q aliphatic).
7. The use according to claim 6, wherein: (a) RY is T-R3, wherein T is a valence bond or a methylene and R}' is an optionally substituted group selected : from C,_¢ aliphatic, Ci.¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -~halo, a Ci;-q aliphatic group opticnally substituted with 357 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; (c) R? and R* are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally
: . Co substituted with -halo, -N(R*),, ~C;.4 alkyl, -C;.4 haloalkyl, - . Co NO;, -0O(Cj-4 alkyl), =-CO,(Cj-4 alkyl), -~CN, =S0,(C;-4 alkyl), - SO;NH,, -OC(O)NH;, -NH250;,(Cy-4 alkyl), —-NHC(O) (Cy-4 alkyl), = C(O)NH;, or -CO{(Ci_4 alkyl), wherein the (C;_4 alkyl) is a straight, branched, or cyclic alkyl group; and (d) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -Cl, -F, -CN, -CFj, ~NHp, -NH(Ci.4 aliphatic), -N(Ci-q aliphatic)s, -O(Ci-4 aliphatic), Cj.4 aliphatic, and -CO(Ci.4 aliphatic).
8. The use according to any of claims 1-7, for inhibiting GSK3 activity in a patient.
9. Use of a compound of formula VI for treating a disease that is alleviated by treatment with a GSK-3 inhibitor: R2 R? Tw HNT N Or IE VI 358 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein:
G is Ring C or Ring D;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R’, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally
} substituted by halo, oxo, or -R%;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxc or -R’, and at any substitutable ring nitrogen by -RY, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R°> is hydrogen at each ortho carbon position of Ring D;
359 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
R' is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R%®, said C;-¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or RY and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RY is T-R*'; T is a valence bond or a C,_4 alkylidene chain; R? and R? are independently selected from -R, -T-W-R%, or R?> and R? .are taken together with their intervening - atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R® and R? is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R? and R?® is substituted by R*; R?' is selected from an optionally substituted group selected from C;.¢ aliphatic, Ciz-10 carbocyclyl, Cs-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from Cig aliphatic, Ce.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R? is independently selected from -R7, -COR’, -CO, (optionally substituted C;-s aliphatic), -CON(R’)g, or -SO,R’, or two R* on the same nitrogen are taken 360 SUBSTITUTE SHEET (RULE 26)
together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R®> is independently selected from -R, halo, -OR, -C(=0)R, -CO;R, -COCOR, -NO,, -CN, -S(O)R, -SO:R, -SR, -N(R%*),, -CON(R%),, -SO,N(R%*),, -OC(=0)R, -N(R*)COR, -N(R*) CO, (optionally substituted Ci;.¢ aliphatic), -N(R*)N(R*),, -C=NN(R*),, -C=N-OR, -N(R)CON(R?),
-N(R*) SO.N(R*),, -N(R*)SO,R, or -OC(=0)N(R%),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
V is -O-, -S-, -S0-, -80,-, -N(R®)S0,-, -SO,N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, -N(R®) SO,N(R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®)20-, -C(R®)28-, -C(R®)280-, -C(R®),S0:-,
-C(R®) 280,N (R®) -, -C(R®),N(R®)-, -C(R®).N(R°)C(O)-, -C(R®).N(R®)C(0)0O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, -C(R®).N(R®)N(R®) -, -C(R®).N(R®)SO,N(R®)-, or -C(R®) ;N (R®) CON (R®) -;
W is -C(R®),0-, -C(R®),S-, -C(R®).S0-, -C(R®),S0;-, -C(R®) ,S0.N(R®) -, -C(R®),N(R®)-, -CO-, -COp-, —C(R®)OC(O)- , —-C(R®)OC(O)N(R®)~-, -C(R®),N(R®)CO-, -C(R®).N(R®)C(0)O-, -C(R®) =NN (R®) -, -C(R®)=N-0-, -C(R®),N(R®)N(R®)-, ~C(R®) ,N(R®) SON (R®) -, -C(R®),N(R®)CON(R®)-, or -CON(R®)-;
each R® is independently selected from hydrogen, an optionally substituted C;., aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and : 361 SUBSTITUTE SHEET (RULE 26)
each R® is independently selected from an optionally substituted C;_;, aliphatic group, -ORS, -SRS, -COR®, -SO,R®, -N(R®),, -N(R®)N(R®);, -CN, -NO,, -CON(R®),, or —CO.R®.
10. The use according to claim 9, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and = : two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -halo, an optionally substituted C,.¢ aliphatic group, phenyl, -CORS®, -OR®, -CN, -SO,R®, -SO;NH,, -N(R®),, -CO;R®, -CONH,, -NHCOR®, -OC(O)NH,, or -NHSO,R®; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro- 1H-indolyl, isoquineclinyl, quinolinyl, or naphthyl ring; {(b} RY is T-RY, wherein T is a valence bond or a methylene; and (c) R* is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C;-¢ aliphatic group, or R? and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
11. The use according to claim 10, wherein: 362 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
{a} Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -halo, an optionally substituted C,.¢ aliphatic group, phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,;NH,, -N(R®),, -CO,R®, -CONH,, -NHCORS®, -OC (O)NH,, or -NHSO,R®; or Ring D is an optionally substituted
Co . ring selected from a phenyl, pyridinyl, pipeéridinyl, So : piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro- 1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) RY is T-R*', wherein T is a valence bond or a methylene; and (c) R?* is hydrogen and R® is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci-¢ aliphatic group, or R® and R* are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
12. The use according to claim 10, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and rR! is -halo, a Cie haloaliphatic group, a Ci. aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring 363 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, gquinolinyl, or naphthyl; (b) RY is T-R?®', wherein T is a valence bond or a methylene and R* is an optionally substituted group selected from Cz.¢ carbocyclyl, Ce.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; : " (c) R¥ is hydrogen and R? is hydrogen ora Lo : substituted or unsubstituted group selected from aryl, or a Ci-¢ aliphatic group, or R? and R® are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R°, wherein each R® is independently selected from -halo, -CN, -NO,, -N(R!),, optionally substituted C;.¢ aliphatic group, -OR, -C(0O)R, -CO,R, -CONH(R'), -N(R)COR, -SO,N(R*),, or -N(R?)SO:R.
13. The use according to claim 12, wherein: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -halo, a C;_g haloaliphatic group, a Ci. aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro~1H~isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; 364 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
(b) RY is T-R®', wherein T is a valence bond or a methylene and RY is an optionally substituted group selected from Cig aliphatic, Ci.¢ carbocyclyl, Ce.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5- ring atoms; (c) R? is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci-¢ aliphatic group, or R? and R?® are taken together with CL their intervening atoms to form a substituted or - : : unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R>, wherein each R® is independently selected from -halo, -CN, -NOg, -N(R*),, optionally substituted C,_¢ aliphatic group, -OR, -C(0)R, -CO,R, ~-CONH(R'), -N(R')COR, ~SO;N(R*)2, or -N(R")SO;R.
14. The use according to claim 12, wherein said compound has one or more features selected from the group consisting of: (a) RY is T-R*®', wherein T is a valence bond or a methylene and R® is an optionally substituted group selected from C;.¢ aliphatic, Ci3-¢ carbocycliyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -halo, a Ci-4 aliphatic group opticnally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, : 365 : SUBSTITUTED SHEET (RULE 26) : Amended Sheet — 2004-05-25
1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; (c) R? and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R%);, -Ci-4 alkyl, -Ci.4 haloalkyl, - NO», —O(Ci-4 alkyl), -CO2(Ci-4 alkyl), -CN, -S0,(C;-4 alkyl), -
. SO3NH;, -OC(O)NH,;, -NH,50,(C;-4 alkyl), =-NHC(O) (Ci-4 alkyl), -
: .C(O)NH;, or -CO(C;-4 alkyl), wherein.thé (C;-4 alkyl) is a _ straight, branched, or cyclic alkyl group; and (d) Ring D is substituted by oxo or R°, wherein each R® is independently selected from -Cl, -F, -CN, -CFj, -NH,;, -NH(C;., aliphatic), -N(C,-4 aliphatic),, -0(Ci-4 aliphatic), Ci-4 aliphatic, and -C0;(C;.4 aliphatic).
15. The use according to claim 14, wherein: (a) RY is T-R>', wherein T is a valence bond or a methylene and R* is an optionally substituted group selected from C,.¢ aliphatic, Cj-¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring: (pb) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C. and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -halo, a Cj.4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; 366 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
(c) R? and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R%),, -C,.4 alkyl, -C;.q haloalkyl, - NO;, -0O(Cj-4 alkyl), -CO2(Cy-4 alkyl), -CN, -SO0,(C;-4 alkyl), - SO,NH;, -OC(O)NHz, -NH2S0,(Cy-4 alkyl), -NHC(O) (Ci-4 alkyl), = C(O)NHp, or -CO(Ci.4 alkyl), wherein the (Ci4 alkyl) is a straight, branched, or cyclic alkyl group; and
: . (d) Ring D is substituted by oxo or R®, wherein _ : each R® is independently selected from -Cl, -F, -CN, -CFs, -NH;, ~-NH(C;-4 aliphatic), -N(C;-4 aliphatic),, -0(Ci-q aliphatic), Ci-4 aliphatic, and -CO;(C,-4 aliphatic).
16. The use according to any of claims 9-15 in combination with a second therapeutic agent.
17. The use according to any of claims 9-15, wherein said disease is diabetes.
18. The use according to any of claims 9-15, wherein sald disease is Alzheimer’s disease.
19. The use according to any of claims 9-15, wherein said disease is schizophrenia. :
20. Use of a compound of formula VI for enhancing glycogen synthesis in a patient in need thereof: 367 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
R? i Tw HNN NS NE VI or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein:
G is Ring C or Ring D;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R?, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R8;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R>, and at any substitutable ring nitrogen by -R*, provided that when Ring D is a six-membered aryl or
368 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 heteroaryl ring, -R®> is hydrogen at each ortho carbon position of Ring Dj;
R' is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci;.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R%®, said Ci.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R' and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RY is T-R*'; T is a valence bond or a Cy.4 alkylidene chain; R®* and R?' are independently selected from -R, -T-W-R®, or R? and R* are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and R? is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R® and R?* is substituted by R*; R’' is selected from an optionally substituted group selected from C;.¢ aliphatic, C;.10 carbocyclyl, Ce-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C;_g aliphatic, Cs-10 aryl, a heteroaryl ring having 5-10 - ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R* is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R7)g2, 369 SUBSTITUTE SHEET (RULE 26)
or -SO,R7, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R®> is independently selected from -R, halo, -OR, -C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SOzR, -SR, -N(R*)2, -CON(R*),, -SO;N(R%),, -OC(=O)R, -N(R%)COR, -N (R*) CO, (optionally substituted C;.¢ aliphatic), -N (R*)N(R*),, -C=NN(R*),, -C=N-OR, -N(R*)CON(R*), -N (R*) SO.N (R*),, -N(R*)SO,R, or -OC(=0)N(R*),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -S-, -8O-, =-S0,-, -N(R®)S0,-, -SO,N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, -N (R®) SON (R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®),8-, -C(R®),S0-, -C(R®).S0;-, ~C(R®) 280:N(R®) -, -C(R®),N(R®)-, -C(R®).N(R®)C(O)-, -C(R®),N(R®)C(0)0O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, ~C(R®),N(R®)N(R®) -, -C(R®),N(R®)SO,N(R®)-, or -C (R®) oN (R®) CON (R®) -; W is —C(R®),0-, -C(R®)2S-, -C(R®),80-, -C(R®),S0,-, -C (R®) 2S0,N (Rf) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(O)- , —C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(R®)C(0Q)O-, -C(R®) =NN (R) -, -C(R®)=N-0-, -C(R®).N(R®)N(R®)-, -C (R®) ;N (R®) SON (R®) =, -C(R®),N(R®)CON(R®)~, or -CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted C;., aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the 370 SUBSTITUTE SHEET (RULE 26)
nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C;-4 aliphatic group, -OR®, -SRS, -COR®, -SO,RS, -N(R®),, -N(R®°)N(R®),, -CN, -NO,, -CON(R®),, or -CO;RS.
21. Use of a compound of formula VI for lowering blood levels of glucose in a patient in need thereof: 2 R? Tw HN” ON NS : NN) VI or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, . pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R', any non-ortho carbon position on Ring C is optionally and independently substituted by -R®, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, 371 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 said fused ring being optionally substituted by halo, oxo, or -R%; Ring D is a 5-7 membered monocyclic ring or 8-10 membered . bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R%, and at any substitutable ring nitrogen by -R*, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R® is hydrogen at each ortho carbon : position of Ring Dj;
R! is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C;_¢ aliphatic group, said phenyl, heteroaryl,
and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R%?, said C;.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or rR? and an adjacent substituent taken together with their : intervening atoms form said ring fused to Ring C;
RY is T-RY;
T is a valence bond or a C;., alkylidene chain;
R? and R? are independently selected from -R, -T-W-R®, or
R? and R? are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms : | selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and R?' is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R® and R?' is substituted by R*; 372 SUBSTITUTE SHEET (RULE 26)
R? is selected from an optionally substituted group selected from C;.¢ aliphatic, Cs.i0 carbocyclyl, Cs-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a : heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from Cis aliphatic, Cg-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R* is independently selected from -R’, -COR’, -CO, (optionally substituted C,_¢ aliphatic), -CON(R)., or -SO,R’, or two R*! on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R®> is independently selected from -R, halo, -OR, -C(=0)R, -CO3R, -COCOR, -NO;, -CN, -S(O)R, -SO:R, -SR, -N(R*),, -CON(R*),, -SO,N(R%*),, -OC(=O)R, -N(R*)COR, -N(R*) CO, (optionally substituted C;_¢ aliphatic), -N(R*)N(R*),, -C=NN(R*),, -C=N-OR, -N(R®)CON(R?),, -N(R*) SO.N (R*),, -N(R*)SO;R, or -OC(=0)N(R*),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -S-, -SO-, -80,-, -N(R®)SO;-, -SO.N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N(R®)CON(R®)-, -N (R®) SON (R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®)20-, -C(R®),8-, -C(R®),S0-, -C(R®),S0,-, -C(R®) 280.N (R®) -, -C(R®).N(R®)-, -C(R®),N(R®)C(O)-, -C(R®),N(R®)C(0)0O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, -C(R®)N(R®)N(R®)-, -C(R®),N(R®)SO.N(R®)-, or -C(R®) 2N (R®) CON (R®) - ; W is -C(R®)20-, -C(R®),S-, -C(R®)2S0-, -C(R®),S0,-, -C(R®)280,N (R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(O)- , —C(R®)OC(O)N(R®) -, -C(R®),N(R®)CO-, -C(R®),N(R®)C(0O)O-, 373 SUBSTITUTE SHEET (RULE 26)
-C(R®)=NN(R®)-, -C(R®)=N-0-, -C(R®),N(R®)N(R®)-, ~C(R®),N (R®) SOaN (R®) =, ~C (R®) oN (R®) CON (R®) =, or —-CON (R)-; each R® is independently selected from hydrogen, an optionally substituted C;.4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C,.4 aliphatic group, -ORS, -SRS, ~COR®, -SO,R®, ~N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or -CO.R°®.
22. Use of a compound of formula VI for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof: R2 : R? Tw HN ON SN A 20 RY N VI or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein: 374 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
G is Ring C or Ring Dj;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring,
wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R’>, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, OoX0O, Or -R%;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R’, and at any substitutable ring nitrogen by -R?, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R®> is hydrogen at each ortho carbon position of Ring D;
R' is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C,.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R?, said C;.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or rR? and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
RY is T-R*®';
375 SUBSTITUTE SHEET (RULE 26)
T is a valence bond or a C;.4 alkylidene chain;
R? and R? are independently selected from -R, -T-W-R°®, or R? and R* are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R?
: and R? is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R? and R?* is substituted by R*;
R®' is selected from an optionally substituted group selected from C;.¢ aliphatic, Ci.i0 carbocyclyl, Cs-1g aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R is independently selected from hydrogen or an optionally substituted group selected from C,_ aliphatic, Cs.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R* is independently selected from -R’, -COR’,
-CO, (optionally substituted C;.¢ aliphatic), -CON(R’):, or -SO,R7, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R® is independently selected from -R, halo, -OR, ~-C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S{(O)R, -SOzR, -SR, -N(R*),, -CON(R*),, -SO.N(R*),, -0C(=0)R, -N(R®)COR,
-N (R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R*),, -C=NN(R!),, -C=N-OR, -N(R*)CON(R*), -N (R*) SO,N (R*),, -N(R?)SO.R, or -0OC(=0)N(R*),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; 376 SUBSTITUTE SHEET (RULE 26)
V is -0-, -S-, -SO-, -SO,-, -N(R®)SO;-, =-SO;N(R®)-, -N(R®)-, -CO-, -CO,-, -N{R®)cO-, -N(R®)C(O)O-, -N(R®)CON(R®)-, ~N (R®) SON (R®)-, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)~, -C(R®),0-, -C(R®),S-, -C(R®);50-, -C(R®),S0,-, ~C(R®) 250.N (R®) =, -C(R®)2N(R®)~, -C(R®),N(R®)C(O)~, ~C(R®),N(R®)C(0)0O~, -C(R®)=NN(R®)-, -C(R®)=N-0O-, ~C(R®),N(R®)N(R®)~, =C(R®),N{R®) SO,N(R®)~, or ~C(R®) oN (R®) CON (R®) ~; W is -C(R®),0-, -C(R®),S-, -C(R®),50~, -C(R®),S0,-, ~C(R®)2S0,N (R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(0O)-, ~C(R®)OC (0) N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(R®)C(O)O-, -C(R®)=NN (R®) =, -C(R®)=N-0-, -C(R®);N(R®)N(R®)-, ~C(R®) ,N (R®) SO,N (R®)-, -C(R®),N(R®)CON(R®)-, or -CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted C;., aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; . each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C;.4 aliphatic group, -0OR®, ~SRE, -CORS, -SO,R, ~N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or -CO;R®.
23. Use of a compound of formula VI for inhibiting the phosphorylation of B-catenin in a patient in need thereof: 377 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
R? i ow HNN NSN v VI or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein:
G is Ring C or Ring D;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -RY, any non-ortho carbon position on Ring C is optionally and independently substituted by -R°, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 hetercatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R%; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R®, and at any substitutable ring nitrogen by -R?, provided that when Ring D is a six-membered aryl or 378 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 heteroaryl ring, -R® is hydrogen at each ortho carbon position of Ring D;
R' is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C,.s aliphatic group, said phenyl, heteroaryl,
and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R®, said C,.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, Or rR? and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring Cj; RY is T-R’; T is a valence bond or a C,., alkylidene chain; R? and R? are independently selected from -R, -T-W-R®, or R?> and R? are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and R* is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R? and R? is substituted by R%; R’' is selected from an optionally substituted group selected from C,.¢ aliphatic, Ci;.;p carbocyclyl, Ce-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C;_¢ aliphatic, Ce-10 aryl, a heteroaryl ring having 5-10 . ring atoms, or a heterocyclyl ring having 5-10 ring. atoms; oo each R?! is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R’), 379 SUBSTITUTE SHEET (RULE 26)
or -SO,R’, or two R® on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R® is independently selected from -R, halo, -OR, -C(=0)R, -CO3R, -COCOR, -NO,, -CN, -S(O)R, -SO;R, -SR, -N(R%*),, -CON(R*),, -SO,N(R%),, -OC(=0)R, -N(R®)COR, -N(R*) CO, (optionally substituted C,;.¢ aliphatic), -N(R*)N(R?),, -C=NN(R!),, -C=N-OR, -N(R)CON(R*), -N(R*) SON (R*),, -N(R*)SO,R, or -OC(=0)N(R%),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -S8-, -SO-, -SO0,-, -N(R®)S0,-, -SO,N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, -N(R®) SO,N(R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®)2S8-, -C(R®),S0-, -C(R®),S0;-, -C(R®) 280,N (R®) -, -C(R®)N(R®)-, -C(R®).N(R®)C(O)-, © -C(R®).N(R®)C(0)O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, -C(R®) ,N(R®)N(R®) -, -C(R®),N(R®)SO,N(R®)-, or -C (R®) ,N (R®) CON (R®) -; W is -C(R®),0-, -C(R®),S-, -C(R®),S80-, -C(R®).S0;-, -C(R®) 2S0,N (Rf) -, -C(R®),N(R®)-, -CO-, -CO:-, -C(R®)OC(O)- , —C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(R®)C(O)O-, -C(R®) =NN (R°) -, -C(R®)=N-0O-, -C(R®).N(R®)N(R®)-, -C(R®) ;N(R®) SO,N (R®) -, -C(R®),N(R®)CON(R®)-, or -CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted C;.4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the 380 SUBSTITUTE SHEET (RULE 26)
nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C34 aliphatic group, -ORS, ~SRS, -COR®, -SO,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO;, -CON(R®),, or —-CO;R®.
24. Use of a compound of formula VI for treating a disease that is alleviated by treatment with an aurora inhibitor: R2 Up NH HNN oy IE \'2% or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from ~R?, any non-ortho carbon position on Ring C is optionally and independently substituted by -R°, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 381 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R%;
. Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl,
: . heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R°, and at any substitutable ring nitrogen by -R*, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R’> is hydrogen at each ortho carbon position of Ring D; R' is selected from -halo, -CN, -NO,, T-V-R°, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci. aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R?, said Ci.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or rR! and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RY is T-R®; T is a valence bond or a Ci. alkylidene chain; R? and R? are independently selected from -R, -T-W-R°®, or R? and R? are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each ' substitutable carbon on said fused ring formed by R? and R?> is substituted by halo, oxo, -CN, -NO,, -R’, or } -V-R®, and any substitutable nitrogen on said ring formed by R? and R?* is substituted by R*; 382 SUBSTITUTE SHEET (RULE 26)
R? is selected from an optionally substituted group selected from C;.¢ aliphatic, Cs-10 carbocyclyl, Cs-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a . heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally. substituted group selected from Cj. aliphatic, Cs-30 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R* is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R’),, or -SO,R’, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R® is independently selected from -R, halo, -OR, -C(=0)R, -COyR, -COCOR, -NO,, -CN, -S(O)R, -SO:R, -SR, -N(R*),, -CON(R"),, -SO:N(R*),, -OC(=0)R, -N(R*)COR, -N(R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R*),, -C=NN(R%),, -C=N-OR, -N(R*)CON(R?),, -N (R*) SO,N (R*),, -N(R*)SO,R, or -OC(=0)N(R'),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -S-, -S0-, -S0,-, -N(R®)S0,-, -SO.N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, -N(R®) SO,N (R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®),S-, -C(R®),S0-, -C(R®),S0;-, -C(R®)280,N (R®) -, -C(R®).N(R®)-, -C(R®).N(R®)C(O)-, -C(R®),N(R®)C(0)0-, -C(R®)=NN(R®)-, -C(R®)=N-O-, ~C(R®)-N(R®)N(R®) -, -C(R®),N(R®)SON(R®)-, or -C (R®) ,N (R®) CON (R®) -; W is -C(R®),0-, -C(R®),S-, -C(R®),S0-, -C(R®),S0,-, ~C(R®) 280,N (R®) -, -C(R®)aN(R®)-, -CO-, -COp-, -C(R®)0C(O)- , —C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(R®)C(O)O-, 383 SUBSTITUTE SHEET (RULE 26)
~C(R®)=NN(R®) -, -C(R®)=N-0-, -C(R®).N(R®)N(R)-, ~C (R®) ,N (R®) SON (R®) =, -C(R®),N(R®)CON(R®)-, or -CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted C;_4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an , Co optionally substituted C;.¢ aliphatic group, or twd R’ on A the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally : substituted C;.4 aliphatic group, -ORS, -SRS, ~CORS, -SO,R, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or -CO,R®.
25. The use according to claim 24 in combination with a second therapeutic agent.
26. The use according to claim 24 wherein said disease is cancer.
27. A compound of formula VI: ” R? = To
HN. N Oo) TE VI 384 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein:
G is Ring C or Ring D; :
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R>, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R%;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R%, and at any substitutable ring nitrogen by -R%, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R’> is hydrogen at each ortho carbon position of Ring D;
R! is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C,.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R%®, said Ci; aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or rR!
: 385 : - SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RY is T-R*'; T is a valence bond or a C;.4 alkylidene chain; R? and R® are independently selected from -R, -T-W-R°, or R? and R?. are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and R? is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R? and R? is substituted by R*; R®' is selected from an optionally substituted group selected from C;.¢ aliphatic, Ci.; carbocyclyl, Ce-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; provided that R?®' is other than morpholin-4-yl; each R is independently selected from hydrogen or an optionally substituted group selected from Cie aliphatic, Cs-10 aryl, a heteroaryl ring having 5-10 - ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R? is independently selected from -R’, -COR’,
IE -CO, (optionally substituted C;.¢ aliphatic), -CON(R’)g, or -SO,R7, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R® is independently selected from -R, halo, -OR, ‘ -C(=0)R, -COs,R, -COCOR, -NO,, -CN, -S(O)R, -SO;R, -SR, -N(R%),, -CON(R%)., -SO,N(R'),, -0C(=0)R, -N(R*)COR, -N(R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R*)2, -C=NN(R*),, -C=N-OR, -N(R*)CON(R?),, 386 SUBSTITUTE SHEET (RULE 26)
-N(R*) SO,N (R*)2, -N(R*)SO;R, or -OC(=0)N(R*)., or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -8-, -SO-, -80,-, -N(R®)S0,-, -SO,N(R®)-, -N(R®)- , -CO-, -CO,-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, ~N(R®) SON (R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, ~C(R®),0-, -C(R®)2S-, -C(R®),80-, -C(R®)2S0:-, -C(R®)280,N(R®) -, -C(R®),N(R®)-, -C(R®).N(R®)C(O)-, -C(R®).N(R®)C(0)O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, -C(R®),N(R®)N(R®)-, -C(R®),N(R®)SO,N(R®)-, or -C(R®) ;N (R®) CON (R®) -; W is -C(R®),0-, -C(R®).S-, -C(R®),S0-, -C(R®),S0:-, -C(R®) ,80,N(R®) -, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(O)- , —C(R®)OC(O)N(R®) -, -C(R®).N(R®)CO-, -C(R®).N(R®)C(0)O-, -C(R®) =NN(R®) -, -C(R®)=N-0-, -C(R®),N(R®)N(R®)-, -C(R®) ,N (R®) SO,N(R®) -, -C(R®),N(R®°)CON(R®)-, or -CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted C;.4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R®? is independently selected from an optionally substituted C;., aliphatic group, -OR®, -SR®, -COR®, -
SO.,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO;, -CON(R®),, or - CO2R®. 387 SUBSTITUTE SHEET (RULE 26)
28. The compound according to claim 27, wherein said compound has one or more features selected from the group consisting of: : (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is - halo, an optionally substituted C,.¢ aliphatic group, phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,NH,, -N(R®),, -CO;R®, - CONH,, -NHCOR®, -OC(O)NH,, or -NHSO,R®°; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, guinolinyl, or naphthyl ring; (b) RY is T-R®', wherein T is a valence bond or a methylene; and (c) R? is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C;.¢ aliphatic group, or R? and R* are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
29. The compound according to claim 28, wherein: (a) Ring C is an optionally substituted ring . selected from phenyl or pyridinyl, wherein when Ring C i and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoguinolinyl ring, and R' is - halo, an optionally substituted Ci.s aliphatic group, 388 SUBSTITUTE SHEET (RULE 26)
phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,NH,, -N(R®),, -CO,R®, - CONH,, -NHCOR®, -OC(O)NH,, or -NHSO.,R®; or Ring D is an optionally substituted ring selected from a phenyl, : pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroguinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) RY is T-R?, wherein T is a valence bond or a methylene; and (¢) R?* is hydrogen and R® is hydrogen or a substituted or unsubstituted group selected from aryl, hetercaryl, or a C;.¢ aliphatic group, or R?® and R?* are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
30. The compound according to claim 28, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -~halo, a Ci.¢ haloaliphatic group, a Cig aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-" dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ; 389 SUBSTITUTE SHEET (RULE 26)
(b) RY is T-R®, wherein T is,a valence bond or a methylene and R* is an optionally substituted group selected from C,.¢ aliphatic, Ci. carbocyclyl, Ce. aryl, a : heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; (c) R* .is hydrogen and R® is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci.¢ aliphatic group, or R® and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R’, wherein each R® is independently selected from -halo, -CN, -NO,, -N(R%),, optionally substituted C;.¢ aliphatic group, -OR, -C(0)R, -CO;R, -CONH(R%), -N(R*)COR, -SO,N(R*),, or -N (R*) SOzR.
31. The compound according to claim 30, wherein: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a Ci.¢ haloaliphatic group, a Cie aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ; (b) RY is T-R®', wherein T is a valence bond or a methylene and R® is an optionally substituted group selected from C;.¢ aliphatic, Cis.¢ carbocyclyl, Ce. aryl, a 390 SUBSTITUTE SHEET (RULE 26)
heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; (c) R?* is hydrogen and R? is hydrogen or a : substituted or unsubstituted group selected from aryl, or a Ci.¢ aliphatic group, or R? and R® are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and (d) Ring D is substituted by oxo or R>, wherein each R®> is independently selected from -halo, -CN, -NO, -N(R*),, optionally substituted C;.¢ aliphatic group, -OR, -C(0O)R, -COR, -CONH(R®), -N(R*)COR, -SO,N(R%), or -N (R*) SOR.
32. The compound according to claim 30, wherein said compound has one or more features selected from the group consisting of: (a) RY is T-R®', wherein T is a valence bond or a methylene and R® is an optionally substituted group selected from C,.¢ aliphatic, Ci-¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a C;.4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; 391 SUBSTITUTE SHEET (RULE 26)
(c) R® and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring . optionally substituted with -halo, -N(R%),, -Ci-s alkyl, - Ci-4 haloalkyl, -NO;, -0(Ci-4 alkyl), -CO,(Cy-s alkyl), -CN, - SO, (Cy_4 alkyl), -SO,NH,, -OC(O)NH,, -NH,SO,(C;., alkyl), -NHC (0) (C;.4 alkyl), -C(O)NH,, or -CO(C;-4 alkyl), wherein the (C;.4 alkyl) is a straight, branched, or cyclic alkyl group; and (d) Ring D is substituted by oxo or R?>, wherein each R® is independently selected from -Cl, -F, -CN, -CF,, -NH,, -NH(C;., aliphatic), -N(Ci-4 aliphatic),, -0(Ci-a aliphatic), C;.q aliphatic, and -CO,(C,-s aliphatic).
33. The compound according to claim 32, wherein: (a) RY is T-R®', wherein T is a valence bond or a methylene and R®* is an optionally substituted group selected from C;.¢ aliphatic, Cs.¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -halo, a C;.4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or ) naphthyl; (c) R? and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring 392 SUBSTITUTE SHEET (RULE 26)
optionally substituted with -halo, -N(R%);, -Ci.s alkyl, =-Ci haloalkyl, =-NOz, -0O(Ci-4 alkyl), -CO2(Ci-4 alkyl), -CN, -S02(Ci-4 alkyl), —SO3NH,, -OC(O)NH;, -NH;S0;(Ci-4 alkyl), -NHC(O) (Ci-4 alkyl), -C(O)NH;, or -CO(C;-4 alkyl), wherein the (C;.4 alkyl) is a straight, branched, or cyclic alkyl group; and (d) Ring D is substituted by oxo or R>, wherein each R® is independently selected from -Cl, -F, -CN, -CFs, -NH,;, -NH(Ci-4 aliphatic), -N(Ci-4 aliphatic), -0(Ci-4 aliphatic), Ci-4 aliphatic, and -CO0;(C;_4 aliphatic).
34. A compound of formula VIa: RZ? rR? HN” N NS N 20 N VIa or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein: G is Ring C or Ring Dy; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4~triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R®, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 hetercatoms selected from oxygen, sulfur or nitrogen, 393 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 said fused ring being optionally substituted by halo, 0X0, Or -R%; Ring D is a 5-7 membered monocyclic ring or 8-10 membered ; bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R°, and at any substitutable ring nitrogen by -R%, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R’> is hydrogen at each ortho carbon position of Ring D;
R' is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C;.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R?, said C;.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R! and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
T is a valence bond or a Cig alkylidene chain;
~ R? and R® are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and R? is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R? and R? is substituted by R*; each R is independently selected from hydrogen or an optionally substituted group selected from C;.¢ aliphatic, Cs-10 aryl, a heteroaryl ring having 5-10 394 : SUBSTITUTE SHEET (RULE 26)
ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R' is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), -CON(R"), or -S0,R’, or two R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from -R, halo, -OR, _C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SO;R, -SR, -N(R%),, -CON(R*),, -SO.N(R*),, -OC(=O)R, -N(R?)COR, -N(R*) CO, (optionally substituted C;.¢ aliphatic), -N(R*)N(R?),, -C=NN(R%),, -C=N-OR, -N(R*)CON(R*)., -N (R?) SO,N (R*),, -N(R*)SO,R, or -0OC(=0)N(R*),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -S-, -SO-, -80,-, -N(R®)SO;-, -SO,N(R°)-, -N(R®)- , -CO-, -CO,~, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, -N(R®) SON (R®) -, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, -C(R®),S-, -C(R®),S0-, -C(R®).S0,-, -C(R®) ,S0N (R®) =, -C(R®).N(R®)-, -C(R®).N(R®)C(O)-, -C(R®),N(R®)C(0)O-, -C(R®)=NN(R®)-, -C(R®)=N-O-, ~C(R®) ,N(R®)N(R®) -, -C(R®),N(R®)SO,N(R®)-, or -C (R®) ,N (R®) CON (R®) -; W is -C(R%).,0-, -C(R®),S-, -C(R®),80-, -C(R®)2S0.-, -C(R®) ,80,N (R®) -, -C(RS),N(R®)-, -CO-, -CO,-, -C(R®)OC(O)- , —C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(R®)C(0O)O-, -C(R®) =NN(R®) -, -C(R®)=N-0-, -C(R®).N(R®)N(R®)-, -C(R®) ,N (R®) SO,N (R®) -, -C(R®),N(R®)CON(R®)-, or -CON(R®)-; each R® is independently selected from hydrogen, an ) optionally substituted C;., aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; 395 SUBSTITUTE SHEET (RULE 26)
each R’ is independently selected from hydrogen or an optionally substituted C,;.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the , nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C;_4 aliphatic group, -OR®, -SR®, -COR®, - SO,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®);, or - CO,R®.
35. The compound according to claim 34, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is ~ halo, an optionally substituted C,;.¢ aliphatic group, phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,NH,, -N(R®),, -CO,R®, - CONH,, -NHCOR®, -OC(O)NH,, or -NHSO,R®; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and (b) R® and R? are taken together with their intervening atoms to form a substituted or unsubstituted ’ benzo, pyrido, pyrimido or partially unsaturated 6- membered carbocyclic ring.
36. The compound according to claim 35, wherein: 396 SUBSTITUTE SHEET (RULE 26)
(a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic . ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -— halo, an optionally substituted C;.¢ aliphatic group,: phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,NH,, -N(R®),, -CO.R®, - CONH,, -NHCOR®, -0OC(O)NH,, or -NHSO,R®’; or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroguinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and (b) R? and R?* are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6- membered carbocyclic ring.
37. The compound according to claim 35, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a Ci haloaliphatic group, a Cis aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- 397 SUBSTITUTE SHEET (RULE 26)
dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or ’ naphthyl; (b) R? and R?® are taken together with their . intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R*),, -Ci.s alkyl, -
Ci.4 haloalkyl, -NO,, -0(Cj-4 alkyl), -CO,(C;.4 alkyl), -CN, - S0;(Cy-4 alkyl), -SO,NH,, -OC(O)NH;, -NH,S0,(Ci.4 alkyl), -NHC (0) (Ci.4 alkyl), -C(O)NH,, or -CO(C;., alkyl), wherein the (C;., alkyl) is a straight, branched, or cyclic alkyl group; and (c) Ring D is substituted by oxo or R°, wherein each R® is independently selected from -halo, -CN, -NO,, -N(R*),, optionally substituted C;.¢ aliphatic group, -OR, -C(O)R, -COR, -CONH(R!), -N(R!)COR, -SO,N(R%)., or -N (R*) SOzR.
38. The compound according to claim 37, wherein: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -halo, a C,.¢ haloaliphatic group, a Cis aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoguinolinyl, gquinolinyl, or . naphthyl; (b) R? and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring 398 SUBSTITUTE SHEET (RULE 26)
optionally substituted with -halo, -N(R*)., -Ci.s alkyl, - C;-4 haloalkyl, -NO,, -0(C;.4 alkyl), -CO,(C;.4 alkyl), -CN, - S80; (C1-4 alkyl), -SO2NHa, -OC (O)NH,, -NH,80,(C;-4 alkyl),
. -NHC (0) (C1.4 alkyl), -C(O)NH,, or -CO(C;-4 alkyl), wherein the (Ci. alkyl) is a straight, branched, or cyclic alkyl group; and : (c) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -halo, -CN, -NO, -N(R*),, optionally substituted C;.¢ aliphatic group, -OR, -C(O)R, -CO,R, -CONH(R!), -N(R*)COR, -SO,N(R*),, or -N (R*) SOR.
39. The compound according to claim 37, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a C;.4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, guinolinyl, or naphthyl; (b) R?® and R* are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclic ring optionally : substituted with -halo, -N(R%),, -Cis alkyl, -Ci-s haloalkyl, -NO,, -0(Ci., alkyl), -CO,(C;-4 alkyl), -CN, - SO, (Cy-4 alkyl), -SO,NH,, -OC(O)NH,, -NH,S0;(Cji-4 alkyl), _NHC (0) (Ci, alkyl), -C(O)NH,, or -CO(C;., alkyl), wherein 399 SUBSTITUTE SHEET (RULE 26)
the (C,., alkyl) is a straight, branched, or cyclic alkyl group; and (c) Ring D is substituted by or R®>, wherein each
. R® is independently selected from -Cl, -F, -CN, -CF3, - NH,, -NH(C,.4 aliphatic), -N(C;-4 aliphatic),, -0(Ci_4 aliphatic), C;.4 aliphatic, and -CO;(C,.4 aliphatic).
40. The compound according to claim 39, wherein: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a C;, aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, gquinolinyl, or naphthyl; : (b) R? and R? are taken together with their intervening atoms to form a benzo, pyrido, or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R%)s, -Ci.. alkyl, -Ci.s haloalkyl, -NO,, -0O(Ci.4 alkyl), -CO;(Ci-4 alkyl), -CN, - S80; (C1-4 alkyl), -SO.NH,, -OC(O)NH, -NH,S0,(Cy., alkyl), -NHC (0) (C;.4 alkyl), -C(O)NH;, or -CO(Cj-. alkyl), wherein the (C,., alkyl) is a straight, branched, or cyclic alkyl group; and oo (¢) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -Cl, -F, -CN, -CFs, : -NH,, -NH(C;.s aliphatic), -N(C;.4 aliphatic),, -0(Ci-s ) aliphatic), C,., aliphatic, and -CO,(C;., aliphatic). 400 SUBSTITUTE SHEET (RULE 26)
41. The compound according to claim 40, wherein said compound is selected from the following Table 5 compounds: je H NH NH HN N HN N" HN N NSN NSN NSN ( - - oro Tro oo NZ Fie NF Re VIi-1 VI-2 vIi-3 CH, CHj CHs jo jal Lp HN " HN N HN N NSN NSN NSN XN x ae IX NN N_ = N > N N — S 4 VI-4 VI-5 VIi-6 - a - ~ NH ~ NH Je H HN oh HN NY HN \ NSN NAN NSN - to - oo on, oot N_~ CH N ~ vI-7 vi-8 VI-9 iPr Pr Bu ja ja Low HN NY HN NY HN" N NH ca N& OMe . VI-10 VI-11 vIi-12 401 SUBSTITUTED SHEET (RULE 26) : Amended Sheet — 2004-05-25
Hn Py HL NY HN N' HN \" od i 1 NNN NN N 0 SOY OYTO VI-13 VI-14 VI-15 NH : - H NH HN N' HI W HN N" NSN N SN NSN Ov O00 Ovo F3C F3C Cl VI-16 vI-17 VI-18 F F i. — H — , B, NN NSN fo) NSN 0 on ORO Ske FC FaC vVI-19 vVI-20 vI-21 F b H - H bh H HN oh HN % HN N NSN NSN NSN
{ . - - CY ONO ONO Cl Cl FaC : vIi-22 VI-23 VI-24 402 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
F. b H b H b H HN N nN HN N NSN NSN cl NN OA, CTO OO cl OMe cl NC VI-25 VI-26 VI-27 b H b H b H nN nN — HOCH NYY SNe SARE FaC HN ee HN kc VI-28 VI-29 VI-30 F b H b H - ans nN ans : NSN NSN NN [IS A . (I SASS AS SHENSENT cl HN.
N° FiC VI-31 VI-32 VI-33 F F P : H - H ~ NH HN f nN ans NSN NSN NSN TO OO ono NZ Ec NZ Fc NZ kc VI-34 VI-35 VI-36 403 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
> H - H Pi H HN N HN N HN NY Ay wn wn SYD YD YD Nc N° cl NZ Fc VI-37 VI-38 VI-39 b H A, | b H HN” W HN N HN NY eA CERN CRONE NH NH Ec ZFC NH, VI-40 VI-41 VI-42 D H D H A H HN NY HN N HN N NSN NSN NSN 0 N* NN? SN? Ne FC | Fal VI-43 VI-44 VI-45
F. N < NH NH _ NH HN % HN % HN N" NSN NSN NH ise 0) 0 cl Ci Cl Via-1 VIa-2 VIa-3 404 SUBSTITUTED SHEET (RULE 26) Amended Sheet - 2004-05-25
F N A { ) l | _ _ NH _ NH - NH HN % HN N° HI NY NSN CN NSN Me rN CF, hae hae ie VIia-4 VIa-5 VIa-6 N 2 H b H NH HN % HN \ HY % NSN CN NSN Me Ji . a, TO is CF; NHMe VIa-7 VIa-8 VIa-9 0 Q Ns = be 0 — ~ NH ~ NH _ NH HN % HN % HIN NT NSN NSN oN OMe 0 NH, NHMe VIa-10 VIa-11 VIa-12.
42. A composition comprising a compound according to any of claims 34-41 and a pharmaceutically acceptable carrier.
43. The composition according to claim 42 further comprising a second therapeutic agent. 405 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
44. Use of a composition according to claim 42 for inhibiting GSK-3 or Aurora activity in a patient.
45. The use according to claim 44, wherein said method inhibits GSK3 activity in a patient.
46. Use of a compound according to either of claims 27 or 34 for inhibiting GSK-3 or Aurora activity in a biological sample.
47. Use of a composition according to claim 42 for treating a disease that is alleviated by treatment with a GSK-3 inhibitor.
48. The use according to claim 47 in combination with a second therapeutic agent.
49. The use according to claim 47, wherein said disease is diabetes.
50. The use according to claim 47, wherein said disease is Alzheimer’s disease.
51. The use according to claim 47, wherein said disease is schizophrenia.
52. Use of composition according to claim 42 for enhancing glycogen synthesis in a patient in need thereof. 406 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
53. Use of a composition according to claim 42 for lowering blood levels of glucose in a patient in need thereof.
54. Use of a composition according to claim 42 for inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof. : : "
55. Use of a composition according to claim 42. for a inhibiting the phosphorylation of B-catenin in a patient in need thereof.
56. Use of a composition according to claim 42 for treating a disease that is alleviated by treatment with an aurora inhibitor.
57. The use according to claim 56 in combination with a second therapeutic agent.
58. The use according to claim 56 wherein said disease is cancer.
59. Use of a compound of formula VI for treating diabetes, Alzheimer’s Disease or schizophrenia: R? R? = ow HNN Oo) RY S80 VI 407 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein:
G is Ring C or Ring D;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R%, any non-ortho carbon position on Ring C is optionally and independently substituted by -R’, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R%;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R>, and at any substitutable ring nitrogen by -RY, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R® is hydrogen at each ortho carbon position of Ring D;
R! is selected from -halo, -CN, -NO;, T-V-R®, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci.¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -RS, said C,.¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R' and an adjacent substituent
408 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 taken together with their intervening atoms form said ring fused to Ring C;
RY is T-R%';
T is a valence bond or a C;.4 alkylidene chain;
R? and R%® are independently selected from -R, -T-W-RS, or R? and R?* are taken together with their intervening atoms to
: form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected : © from nitrogen, oxygen, or sulfur, wherein each . = oo .
substitutable carbon on said fused ring formed by R? and R? is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R® and RY is substituted by RY;
R}' is selected from an optionally substituted group selected from C;_¢ aliphatic, Ci.39 carbocyclyl, Ce19 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R 1s independently selected from hydrogen or an optionally substituted group selected from C;.¢ aliphatic,
: Ce-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R* is independently selected from -R’, -COR’, -CO, (optionally substituted C;.¢ aliphatic), ~CON (R7) 5, or -S0,R?, or £wo R* on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R®> is independently selected from -R, halo, -OR, -C(=0)R, -CO,R, -COCOR, -NO,, -CN, -S(O)R, -SO,R, -SR, -N(R%),, -CON(R"),, -SO,N(R"),, -OC(=0)R, -N(R*)COR, -N(R*) CO, (optionally substituted C,.¢ aliphatic), -N(R*)N(R%),, -C=NN(R?),, -C=N-OR, -N(R®)CON(R*),, -N(R*) SO2N (RY) 2, -N(R*)SO,R, or -OC(=0)N(R'),, or R® and an
409 SUBSTITUTED SHEET (RULE 26) Amended Sheet —- 2004-05-25 adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -0-, -S-, -SO-, -S0,-, -N(R®)SO,-, -SO;N(R®)-, -N(R®)-, ~- CO-, -COz-, -N(R®)CO-, -N(R®)C(0)O-, -N(R®)CON(R®)-, - N(R®) SON (R®)-, -N(R®)N(R®)-, -C(O)N(R®)-, —-OC(O)N(R®)-, -C(R®),0-, -C(R®);5-, -C(R®),S0~, -C(R®),S0,-, -C(R®) 250;N (R) =, =C (RS) N(R®)~, ~C(R®),N(R®)C(O)-, -C(R®),N(R®)C(0)O~, -C(R®)=NN(R®)-, -C(R®)=N-O-, : ~ —C(R®)N(R®)N(R®)-, -C(R®),N(R®)SO,N(R®)-, or : So ~C (RS) ,N (R®) CON (R®) - ; W is -C(R®),0-, -C(R®)25~, -C(R®),S0~, -C(R®),S0,-, —C(R®) ,SO,N (R®) =, -C(R®),N(R®)-, -CO-, -CO,-, ~C(R)0C (0) -, - C(R®)OC(O)N(R®)-, -C(R®),N(R®)CO-, -C(R®),N(RE)C (0)O-, -C(R®)=NN(R®)-, -C(R®)=N-0-, -C(R®),N(R®)N(R®)-, ~C (R®) 2N(R®) SON (R®) =, -C(R®),N(R®)CON(R®)-, or —CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted Cj_4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C;_¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C;.4 aliphatic group, -OR®, -SR®, ~CORS®, -SO,R®, -N(R®),, -N(R®°)N(R®),, -CN, -NO,, -CON(R®),, or -CO,RS.
60. The use according to claim 59, wherein said compound has one or more features selected from the group consisting of: 410 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
(a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -halo, an optionally substituted C;.¢ aliphatic group, phenyl, -CORS, -OR®, ~-CN, -SO,R®, -SO;NH,;, -N(R®),, -CO;R®, -CONH,, —NHCOR®, -OC(O)NH,, or -NHSO,R®; or Ring D is an optionally substituted oo ring selected from a phenyl, pyridinyl, piperidinyl, ‘ oo piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro- 1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) RY is T-R®', wherein T is a valence bond or a methylene; and (c) R* is hydrogen and R? is hydrogen or a : substituted or unsubstituted group selected from aryl, heteroaryl, or. a Ci;-¢ aliphatic group, or R? and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
61. The use according to claim 60, wherein: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R! is -halo, an optionally substituted C;_4 aliphatic group, phenyl, -COR®, -OR®, -CN, -SO,R®, -SO,NH;, -N(R®),, -CO;R®, -CONH,, ~-NHCORS, -OC (O)NH,, or -NHSO,R®; or Ring D is an optionally substituted 411 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro- 1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; (b) RY is T-R3', wherein T is a valence bond or a methylene; and (c) R* is hydrogen and R? is hydrogen or a oo substituted or unsubstituted group selected from aryl, oo heteroaryl, or a Cig aliphatic group, or R? and R? are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring.
62. The use according to claim 60, wherein said compound has one or more features selected from the group consisting of: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R! is -halo, a Ci_-¢ halcaliphatic group, a Cig aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydrogquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; (b) RY is T-R3®', wherein T is a valence bond or a methylene and R® is an optionally substituted ‘group selected from Cj3.¢ carbocyclyl, C¢-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 412 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
(c) R? is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci-¢ aliphatic group, or R? and R® are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and - | td) Ring D is substituted by oxo or R®>, wherein each R® is independently selected from -halo, -CN, -NO,, ~N (RY) 5, optionally substituted Ci-6 aliphatic group, -OR, -C(0)R, -COzR, -CONH(R'), -N(R!)COR, -SO,N(R%),, or -N(R')SO;R.
63. The use according to claim 62, wherein: (a) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R? is -halo, a Ci-¢ haloaliphatic group, a Ci-¢ aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-iscindolyl, 2, 3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; (b) RY is T-R*', wherein T is a valence bond or a methylene and R® is an optionally substituted group selected from Cy.¢ aliphatic, C3.¢ carbocyclyl, Cg10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5- ring atoms; (c) R® is hydrogen and R? is hydrogen or a substituted or unsubstituted group selected from aryl, or a Ci-¢ aliphatic group, Or R? and R®* are taken together with their intervening atoms to form a substituted or 413 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and {(d) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -halo, -CN, -NO,, -N(R%),, optionally substituted Cj;-¢ aliphatic group, -OR, ~ -C(O)R, -COzR, -CONH(R'), -N(R!)COR, ~SO,N (RY), or -N(R*) SO;R.
64. The use according to claim 62, wherein said compound has one or more features selected from the group consisting of: (a) RY is T-R?, wherein T is a valence bond or a methylene and rR} is an optionally substituted group selected from C,.¢ aliphatic, Cj3.¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and Rr! : is ~halo, a C;-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; (c) R? and R? are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R*'),, -Cy.4 alkyl, -C,., haloalkyl, - NO,, -0(Ci-4 alkyl), -COz(Cj-4 alkyl), =-CN, -S0,(Ci-4 alkyl), - SO,NHz, —-OC(O)NH;, -NH3S02(Ci-4 alkyl), -NHC(O) (Ci-4 alkyl), - 414 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
C(O)NHz, or -CO(C;.4 alkyl), wherein the (Cy-4 alkyl) is a straight, branched, or cyclic alkyl group; and (d) Ring D is substituted by oxo or R®, wherein each R® is independently selected from -Cl, -F, -CN, ~CFj, -NH,, -NH(C;-4 aliphatic), -N(Cj-4 aliphatic),, -0(Ci_4 aliphatic), C;-4 aliphatic, and -CO;(C;-4 aliphatic).
65. The use according to claim 64, wherein: co (a) RY ‘is T-R®, wherein T is a valence bord or a : methylene and R}' is an optionally substituted group selected from Ci-¢ aliphatic, Cs-¢ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; (b) Ring C is an optionally substituted ring selected from phenyl or pyridinyl, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and rR? is -halo, a C;-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl; (c) R?® and R¥ are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R*),, -Ci_4 alkyl, -Ci.4 haloalkyl, - NO;, -0(C;-4 alkyl), -CO2(Ci-4 alkyl), -CN, -S50(C;-4 alkyl), - SO,NH,, -0OC(O)NH,, ~-NH;S0,(C;-4 alkyl), -NHC(O) (C;-4 alkyl), - C(O)NH,, or -CO(C;4 alkyl), wherein the (C;_4 alkyl) is a : straight, branched, or cyclic alkyl group; and 415 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
(d) Ring D is substituted by oxo or R®>, wherein each R®> is independently selected from -Cl, -F, -CN, -CFs, ~NH>, -NH (Ci1-4 aliphatic) , —N (C1-4q aliphatic) 2s -0(C1-4 aliphatic), Ci-4 aliphatic, and -CO;(C;-4 aliphatic).
66. The use according to any of claims 59-65 in combination with a second therapeutic agent.
67. Use of a compound of formula VI for treating cancer: 0 R? R2 = NH HN ON 1 RY 280. VI or a pharmaceutically acceptable salt, derivative, or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R!, any non-ortho carbon position on Ring C is optionally and independently substituted by -R°, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, 416 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R%;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen
- " ~ or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or -R°, and at any ' © substitutable ring nitrogen By “RY, provided that when Ring ’ D is a six-membered aryl or heteroaryl ring, -R® is hydrogen at each ortho carbon position of Ring D;
R' is selected from -halo, -CN, -NO,, T-V-R®, phenyl, 5-6 membered heterocaryl ring, 5-6 membered heterocyclyl ring, or Cy-¢ aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -RS, said C;_¢ aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R!' and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
RY is T-R*';
T is a valence bond or a Ci.4 alkylidene chain;
R? and R? are independently selected from -R, ~T-W-R®, or R? and R? are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R? and R®" is substituted by halo, oxo, -CN, -NO,, -R’, or -V-R®, and any substitutable nitrogen on said ring formed by R? and R? is substituted by R*;
417 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
/
R3' is selected from an optionally substituted group selected from C;.¢ aliphatic, Cs3.;9 carbocyclyl, Ce-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R is independently selected from hydrogen or an optionally substituted group selected from C,.¢ aliphatic,
- "7 Cg-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; © each R! is independently selected from -R’, -COrR’, Co
-CO;, (optionally substituted Croc aliphatic), —CON(R') 5, or -SO,R’, or two R® on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R® is independently selected from -R, halo, -OR, -C{(=0)R, -COzR, -COCOR, -NO,, -CN, -S(O)R, -SOzR, -5R, ~N(R*),, -CON(R%),, -SO,N(R*),, -OC(=0)R, -N(R)COR, -N (R*) CO, (optionally substituted Ci-¢ aliphatic), -N(R")N(R*),, -C=NN(R');, -C=N-OR, =-N(R*)CON(R"),, ~N (R?) SON (R") 2, -N(R*)SO,R, or -OC(=0)N(R%),, or R® and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
V is -0-, -S-, -SO-, -SO,-, -N(R®)SO,-, -SO,N(R)-, -N(R®)-, - CO-, -CO,-, -N(R®)CO-, -N(R®)C(O)O-, -N(R®)CON(R®)-, ~N (R®) SON (R®) —, -N(R®)N(R®)-, -C(O)N(R®)-, -OC(O)N(R®)-, -C(R®),0-, —-C(R®),S—, -C(R®),S0-, -C(R®),S02-, -C(R®),SO,N(R®)- , —C(R%)2N(R®)~-, -C(R®)N(R®)C(0)-, -C(R®),N(R®)C(0)O-, ~ C (R®)=NN (R®) ~, -C(R®)=N-0-, -C(R®),N(R®)N(R®)-, ~C (R®) ;N (R®) SON (R®) ~, or -C(R®),N(R®)CON(R®)-;
W is —C(R®),0-, -C(R®);S-, -C(R®),50-, -C(R®),S0,-, ~C (R®) ,S0,N (R®) =, -C(R®),N(R®)-, -CO-, -CO,-, -C(R®)OC(0)-, - C(R®)OC (O)N (R®) —, —-C(R®),N(R®)CO-, -C(R®),N(R®)C(0)O-,
418 SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25
~C(R®)=NN(R®)-, -C(R®)=N-0-, -C(R®)N(R®)N(R®)-, —C (R®) ,N (R®) SON (R®) =, -C(R®),N(R®)CON(R®)-, or -CON(R®)-; each R® is independently selected from hydrogen, an optionally substituted C;.4 aliphatic group, or two R® groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or So hetercaryl ring; each R’ is independently selected from hydrogen or an optionally substituted C,.¢ aliphatic group, or two R’ on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and each R® is independently selected from an optionally substituted C;.4 aliphatic group, -OR®, -SR®, -CORS, -SO,R®, -N(R®),, -N(R®)N(R®),, -CN, -NO,, -CON(R®),, or =-CO,R°.
68. The use according to claim 67 in combination with a second therapeutic agent. 419 : SUBSTITUTED SHEET (RULE 26) Amended Sheet — 2004-05-25 \
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US3133081A (en) * | 1964-05-12 | J-aminoindazole derivatives | ||
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US3998951A (en) * | 1974-03-13 | 1976-12-21 | Fmc Corporation | Substituted 2-arylquinazolines as fungicides |
DE2458965C3 (en) * | 1974-12-13 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | 3-Amino-indazole-N-carboxylic acid derivatives, process for their preparation and pharmaceuticals containing them |
DOP1981004033A (en) * | 1980-12-23 | 1990-12-29 | Ciba Geigy Ag | PROCEDURE TO PROTECT CROP PLANTS FROM PHYTOTOXIC ACTION OF HERBICIDES. |
US5597920A (en) * | 1992-04-30 | 1997-01-28 | Neurogen Corporation | Gabaa receptor subtypes and methods for screening drug compounds using imidazoquinoxalines and pyrrolopyrimidines to bind to gabaa receptor subtypes |
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