AU2006201392B2 - Isoxazoles and Their Use as Inhibitors of Erk - Google Patents

Description

VO

0 0 0 0, Name of Applicant:

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Vertex Pharmaceuticals Incorpoiated CULLEN CO Patent Trade Mark Attorneys, 239 George Street Brisbane Qld 4000 Australia Isoxazoles and Their Use as Inhibitors of Erk Address for Service: Invention Title: The following statement is a full description of this invention, including the best method of performing it, known to us: 0

(NO

c FIELD OF THE INVENTION 0 The present invention is in the field of medicinal chemistry and relates to isoxazole compounds Ci that are protein kinase inhibitors, especially inhibitors C) of ERK, compositions containing such compounds and 5 methods of use. The compounds are useful for treating.

SD cancer and other diseases that are alleviated by protein S.kinase inhibitors.

BACKGROUND OF THE INVENTION Mammalian mitogen-activated protein (MAP)l kinases are serine/threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J Biol. Chem. 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK (extracellular signal regulated kinase), JNK (Jun N-terminal kinase) and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellular stress,such as heat shock, hyperosmolarity, ultraviolet radiation; lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., .1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaud et al., 1995, J Biol. Chem.

270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad.

Sci. USA 92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al.. 1996, Kidney Int. 49, 1187).

ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thrl83 and \D Tyr185 are phosphorylated by the upstream MAP kinase o kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995, J.

o Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78, 1027), and transcription factors such as ATF2 S(Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 ,(Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc.

0 10 Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et D al., 1995, Proc. Soc. Exp.Biol. Med. 210, 162). ERK2 is 0 also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993, Science 260, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589).

AKT, also known as protein kinase B, is a serine/threonine kinase that plays a central role in promoting the survival of a wide range of cell types [Khwaja, A.,..Nature, pp. 33-34 (1990)]. It has been shown by Zang, et al, that human ovarian cancer cells display elevated levels of AKT-1 and AKT-2. Inhibition of AKT induces apoptosis of these human ovarian cancer cells which demonstrates that AKT may be an important target for ovarian cancer treatment [Zang, Q. et al, Oncogene, 19 (2000)] and other proliferative disorders.

The AKT pathway has also been implicated in motoneuronal 00 survival and nerve regeneration [Kazuhiko, et al, The Journal of Neuroscience, 20 (2000)] SUS patent 5,470,862 discloses an isoxazole compound as an intermediate in the preparation of IO 5 intravenous anesthetics.

There is a high unmet medical need to develop protein kinase inhibitors, especially ERK and AKT Cc inhibitors especially considering the currently available, relatively inadequate treatment options for NO 10 the majority of these conditions.

Accordingly, there is still a great need to develop potent inhibitors of protein kinase, including ERK and AKT inhibitors, that are useful in treating various conditions associated with protein kinase activation.

It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.

Throughout this specification, the term "comprising" and its grammatical equivalents shall be taken to have an inclusive meaning unless the context of use indicates otherwise.

DESCRIPTION OF THE INVENTION It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK and AKT. These compounds have the general formula I: 3 00 CKI Ht A'b IND XT-R 2

RI

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: (1 Ht is a heteroaryl ring selected from pyrrol-3-yl, pyrazol-3-yl, [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, (1 or tetrazol-5-yl; said pyrrol-.3-yl and pyrazol-3-yl 3a IN each having R 3 and QR 4 substituents, and said triazole o substituted by either R 3 or QR 4 A-B is N-0 or 0-N; R is selected from R 5 fluorine, N(Rs) 2 OR, NRCOR,

CON(R

5 2

SO

2 R, NRS02R, or SO 2

N(R)

2 O T and Q are each independently selected from a valence bond or a linker group; each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to 0 six carbons; O R 2 is selected from hydrogen, CN, fluorine, or an o optionally substituted group selected from aryl, heteroaryl, heterocyclyl, an acyclic aliphatic group having one to six carbons, or a cyclic aliphatic group having four to ten carbons; wherein R 2 has up to one L- W substituent and up to three R 8 substituents; L is a C1-6 alkylidene chain which is optionally substituted, and wherein up to two methylene units of L are optionally replaced by -CONH-, -CONHNH-, -C02-, -NHC02-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -SO 2

-NH-,

-SO

2 NH-, -NHSO 2 NH-, or -NHSO 2 W is selected from R 9

CH(R

9 2

CH(R

9

)N(R

9 2 or N(R 9 )2;

R

3 is selected from R, OH, OR, N(R) 2 fluorine, or CN;

R

4 is selected from -R 6 -NH, -NHR 6

-N(R

6 2 or -NR (CH) yN (R 2 each R 5 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons or two R 5 on the same nitrogen may be taken together with the nitrogen to form a four to eight membered ring having one to three heteroatoms; each R 6 is independently selected from R 5

-(CH

2 )yCH(R 7 2 or -(CH2) yR; y is 0-6; O each R' is an optionally substituted group independently selected from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; each R 8 is independently selected from halogen, -OR', CA

-NO

2 -CN, -N(R 5 2 -NRC(O)R', -NRC(0)N(R 5 2 Cn -NRCO 2 -NRNRC(0)R', -NRNRC(O)N(R 5 2 -NRNRC0 2

R',

o

-C(O)-CH

2 -C0 2 10 -C(0)N(R 2 -OC(O)N(Rs) 2 -S(0) 2

-SO

2 N(Rs) 2

S-NRSO

2

N(R

s 2

-NRSO

2

-C(=S)N(R

s 2 or -C(=NH)N(R 5 2 wherein each R' is independently selected from hydrogen, or an optionally substituted group selected from aliphatic, heteroaryl, heterocyclyl, or phenyl; and each R 9 is independently selected from RS, R 8 or an optionally substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl.

As used herein, the following definitions shall apply unless' otherwise indicated. In addition, unless otherwise indicated, functional group radicals are independently selected.

The term "aliphatic" as used herein means straight-chain, branched or cyclic CI-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic.

For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both ND straight and branched chains containing one to twelve 0 carbon atoms. The terms "alkenyl" and "alkynyl" used Salone 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 C 3

-C

12 hydrocarbons which are completely saturated or which C contain one or more units of unsaturation, but which are not aromatic.

C 10 The terms "haloalkyl", "haloalkenyl" and o "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case Ci may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I.

The term "heteroatom" means N, O, or S and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. It also includes and -NR wherein R is as defined infra.

The term "carbocycle", "carbocyclyl", or "carbocyclic" as used herein means an aliphatic ring system having three to fourteen members. The term "carbocycle", "carbocyclyl", or "carbocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted. The terms "carbocyclyl" or "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 "aryloxyalkyl", refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, l-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. The term "aryl" also refers to rings that are

IND

0 optionally substituted. The term "aryl" may be used C- interchangeably with the term "aryl ring". "Aryl" also includes fused polycyclic aromatic ring, systems in which San aromatic ring is fused to one or more rings. Examples o 5 include l-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. Also included within the scope of the term CA "aryl", as it is used herein, is a group in which an Cc) aromatic ring is fused to one or more non-aromatic rings, o such as in a indanyl, phenanthridinyl, or D 10 tetrahydronaphthyl, where the radical or point of o 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 3-1Hbenzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2morpholinyl, 3-morpholinyl, 4-morpholinyl, 2thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, l-phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term "heterocyclyl" or "heterocyclic", as it is used herein, is a group in which a non-aromatic heteroatom-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 ND attachment is on the non-aromatic heteroatom-containing o ring. The term "heterocycle", "heterocyclyl", or ci S"heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or C\ "heteroarylalkoxy", refers to heteroaromatic ring groups Ce -having five to fourteen members. Examples of heteroaryl C 10 rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2o imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- C isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, 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 tetrahydroquinoline, tetrahydroisoquinoline, and pyrido[3,4-d]pyrimidinyl.

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 omay-contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R 0 -ORO, -SRO, 1,2-iethylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl substituted Ph, substituted -O(Ph), C -CH 2 substituted -CH2(Ph), -CH 2

CH

2 substituted M -CH 2

CH

2

-NO

2 -CN, -N(R 0 2 -NRoC(O)Ro, -NROC(O)N(R) 2 -NRoCO 2 RO, -NRONROC (O)RO, -NRONROC (O)N(R) 2

-NRNRCO

2

R

0 C 10 -C(0)CH 2 C(O)R, -CO0Ro, -C(O)RO, -C(0)N(R 0 2

-OC(O)N(R

0 -S(0) 2 Ro, -SO2N(R 0 2 -S(0)RO, -NROSO 2

N(R)

2 -NRoSO 2 R, -C(=S)N(R 0 2 2

-(CH

2 )yNHC(0)R 0

(CH

2 yNHC CH (V-Ro) (RO) wherein RO is H, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, substituted -CH 2 or substituted -CH2(Ph); y is 0-6; and V is a linker group. Examples of substituents on the aliphatic group or the phenyl ring 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 may 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: =NNHR, =NN(R*) 2 =NNHC(O)R*, =NNHCO(alkyl),

=NNHSO

2 (alkyl), or =NR t where each R t is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of ND substituents on the aliphatic group include amino, o alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, Salkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, Shydroxy, haloalkoxy, or haloalkyl.

Suitable substituents on the nitrogen of an aromatic or non-aromatic heterocyclic ring include -R, M -N(R 2 -CO2R, -C(0)C(O -C(O)CH2C(O)R,

-SO

2 R, -SO 2

N(R+)

2 2 2 and o -NR+S02R'; wherein R is H, an aliphatic group, a Ssubstituted aliphatic group, phenyl substituted Ph, substituted CH 2 substituted CH2(Ph), 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, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

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 -CH2-, -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. Examples of linkers include a saturated or unsaturated Ci- 1 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -CONH-, -CONENH-, -CO2-, -NHC02-, -NHCONH-, -OC(0)NH-, -NHNH-, -NHCO-, -SO2-, -NH-,

-SO

2 NH-, or -NHS02-.

O The term "alkylidene chain" refers to an C optionally substituted, straight or branched carbon chain p_ 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 Cq permissible only if such a combination results in a Cstable or chemically feasible compound. A stable Scompound or chemically feasible compound is one that is Sks 10 not substantially altered when kept at a temperature of °C or less, in the absence of moisture or other ci chemically reactive conditions, for at least a week.

It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; 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 13C- or "C-enriched carbon are within the scope of this invention.

One embodiment of this invention relates to compounds wherein A-B is N-O, shown by formula II: I N Ht 0 0

N

T-R

2

R

1 0- .II or a pharmaceutically acceptable derivative or prodrug C- thereof, wherein R 1

R

2

R

3

R

4 T, and Q are as described above. Preferred embodiments of formula II are shown o below for the Ht ring being pyrrol-3-yl pyrazolci 3-yl [1,2,4]triazol-3-yl [1,2,3]triazol- S4-yl and tetrazol-5-yl (II-E).

C H H H N Q-R 4 N Q-R 4 N .NQ

R

4

'N

pR p, P. N N 2 N\ I N T-R T-R 2

T-R

2 R R R' II-A II-B II-C H H ,N N N 'N N 'N t N 2 2

-R

2 T R 2 Ri R II-D II-E Preferred compounds of formulae II-A, II-B, II- C, II-D, and II-E include those having one or more, and most preferably all, of the following features: Q is

-CO

2 or -CONH-; T is a valence bond, -NHC(O)-, or -NHCH 2

R

I is hydrogen or NHR; R 2 is an optionally substituted aryl ring, preferably a phenyl ring, and more preferably a phenyl ring having up to one L-W substituent and up to three R 8 substituents; W is selected from R 9

CH(R

9 2

CH(R')N(R

9 2 or N(R 9

R

3 is hydrogen; R 4 is selected from -R 6

-NH

2

-NHR

6 or -NR 6 (CH)yN(R 6 2

R

6 is R s

-(CH

2 )yCH(R 7 2 or o yR 7 and/or R 7 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

Preferred R 8 substituents on the R 2 phenyl group include halo, nitro, haloalkyl, hydroxyalkyl, C 1 -6 aliphatic, alkoxy, amino, and heterocyclyl. Examples of C preferred L groups include -CH 2

-CH

2 NH-, -CH 2

NHC(O)-,

-CH

2

CH

2 NH-, -CH20-, -CH 2 C(O)NH-, -CH 2

NHCH

2

CH

2

NHC(O)-,

and -CHa 2 C CH 2

CH

2 NHC Preferred W groups include

-CH(C

1 6 aliphatic)NC(0) (C 1 aliphatic), -CH (CH 2 OH)NC (C 16 aliphatic), -CH(CH 2 SH)NC(O) (C 1 6 aliphatic), -N(C.

6 s aliphatic) 2 -heterocyclyl (e.g.

pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl), -CH(C 1 6 aliphatic)NH 2

-CH(C

1 -6 aliphatic)NC(O)O(C.I-6 aliphatic), -CH 2 CN, and -CH 2

N(C

16 aliphatic)2.

When R 4 is R 6 preferred R' groups include pyrrolidin--yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl wherein each group is optionally substituted. When R 4 is -NHR' or -N(R6) 2 preferred R6 groups further include (CH 2 )yR 7 and -(CHi),CH(R 7 2 Examples of preferred R' and R7 include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, tetrahydrofuran-2yl, cyclohexyl, phenyl, -CH 2 1OH, -(CH 2 2 OH, and isopropyl, .wherein each group is optionally substituted.

Exemplary structures of formula II-A, wherein R1 and R3 are each hydrogen, are set forth in Table 1 below.

H

N Q-R4

P

N

I

T-R

2

I-A

Va 0 0 ci 0 Table 1. Compounds of Formula Il-A No. TR ILA-2 2-chlorophenyl CONHCH 2 (Ph) HIA-3 2-chiorophenyl CO(morpholin-y1) ILA-4 4-methoxyphenyl CONHCH 2 (pyridin-4-yl) 3-fluorophenyl CONI{CH 2 (pyridin-4-yl) IU-6 '3-mhetboxyphenyl CONHCH 2 (pyridin-4-yl) IIA-7 2,5-dimethoxyphenyl CONHdlljpyridin-4-yl) HFA-S 3,4-difluorophenyl CONHCH 2 (,pynidin-4-yl) IIA-9 2,3-difluarophenyl CONlICH2jpyndin-4-yl) 2,5-difuorophenyl

'CONHCH

2 (PYridin-4-yl) HLA-li1 4-methoxyphenyl CONH4CH 2 z(pyridin-3-yl) HA- 12 3-fluorophenyl CONHCH2pyzidin-3-yl) HJA- 13 3-niethoxyphenyl CONIICH 2 (pyridin-3-yl) HTA- 14 2,5-dimethoxyphenyl CONll fljpyridin-3-yl) 3 1 4-difluorophenyl CONHCHj(pyridin-3-yl) lErA- 16 .2,3-difluorophenyl CQNTJCH 2 (pyridin-3-yi) HA- 17 2,5-difluorophenyl CONHCH2(pyridin-3-yI) HIA-18 4-methoxyphenyl CONHCH2(tetrahydrofuran-2-yl) EHA-19 3-fluorophenyl CONTICH 2 (tetrahydroftiran-2-yl) 3-methoxyphenyl CONHCH (tetrahydrofuran-2-y) HIA-21 2,5-dimethoxyphenyl CONIICII 2 (tetrahydrofuran-2-yl) HA-22 3,4-difluorophenyl CONH-CH 2 (teurahydrofuran-2-yl) IIIA-23 2,3-difluorophenyl CQNHCH2(tetrahydrofuran-2-yl) 114A-24 2,5-difluorophenyl CONHCH7jtetrahydrofuran-2-yi) 4-fluorophenyl CQNHCH 2 (1-Et-pyrroidin-2-yl) flA-26 4-methoxyphenyl CONHCH 2 1-Et-pyrrolidin-2-yl) IIA-27 3-fluorophenyl CONHCH 2 (1-Et-pyrrolidin-2-yl) IIA-28 3-methoxyphenyl CQNHCH 2 (1-Et-pyrrolidin-2-yl) UIA-29 2,5-dimethoxyphenyl CONHCH 2 (1-E-t-pyrrolidin-2-yl) 3,4-difluorophenyl CQNHCH 2 (1-Et-pyrrolidin-2-yl) IIA-31I 2,3-difluorophenyl CQNHCFJ 2 1-Et-pyrrolidin-2-yl) IIIA-32 2,5-difluorophenyl CONHCH 2 (l-Et-pyirolidin-2-yI) IIA-33 4-fluorophenyl CO(morphoin-4-yI) UIA-34 4-methoxyphenyl CO(morpholin-4-yI) 3-fluorophenyl CQ(norphoin4-y)

C)

Va 0 0 ci 0 No. T-JR 2 -4 LIA-36 3-mothoxyphenyl CO0rnorpholin-4-yl) ITA-37 2,5-dimethoxyphenyl CO(rnorpholin-4-yI) IJA-38 2,3-difluoraphenyl CO(morpholin-4-yl) LIA-39 2.5-difluorophenyt CO(morpholin-4-yi) 4-fluorophenyl CO(4-Me-piperazin-1-y) JIIA-4 1 4-methoxyphenyl CO(4-Me-piperazin-1-yI) IIA-42 3-fluorophenyl CO(4-Me-piperazin-1-yI) UaA-43 3-methoxyphenyl CO(4-Me-piperazin-1-yl) IIA-44 2,5-dimethoxyphenyl CO(4-Me-piperazin- l-yI) 2,3-difluorophenyl CO(4-Me-piperazin-1-yI) IJA-46 2,5-dffluorophenyl CO(4-Me-pipcrazin-I -yI) EIA-47 3-chiorophenyl CONHCH2jpyridin-4-yl) HA-48 3-chiorophenyl CONHCH2(yridin-3-y) IIA-49 3-chiorophenyl CONHCH 2 (tetrahydrofuran-2-yl) 3-chlorophenyl CONHCH2(1-Bt-pyrrolidin-2-yI) HIA-51 3-chlarophenyl CO(4-Me-piperazin- I-yI) HIA-52 4-chlorophenyl CONHCH 2 (pridin-4-y) IIA-53 4-chiorophenyl CONHCH.

2 (yridin-3-y1) EHA-54 4-chlorophenyl CONHCI42(tetrahych'ofuran-2-yi) 4-chlorophenyl CONHCH 2 (1-Et-pyrrolidin-2-yl) RLA-56 4-chlorophenyl CO~morpholin-4-yi) IIA-57 4-chlorophenyl CO(4-Me-piperazin-1-yi) ELA-58 3,4-dichlorophenyl CONHCH2(pyridin-3-yl) IIA-59 3,4-diciorophenyl CQNHCH, 2 (1-Et-pyrrolidin-2-yl) 3,4-dichloropheniyl CO~morpholin-4-yl) UIA-61 3,4-dichlorophenyl CO(4-Me-piperazin-1-yl) EIA-62 2-F-3-chloropbenyl CONHCH 2 (pyridin-4-yi) IIA-63 2-E-3-chlorophenyl CONHCH 2 (pyridin-3-y1) EIA-64 2-P-3-chlorophenyl CQNHCH;,(tetrahydrofuran-2-yi) 2-F-3-chlorophenyl CONHCH2P-Et-pyrrolidin-2-yl) EIA-66 2-F-3-chlorophenyl CO(morpbolin-4-yl) EUA-67 2-P-3-chlorophenyl CO(4-Me-piperszin-1-yi) ELA-68 3-CT4-fluorophenyl CONHCHj(pyridin-4-yl) IJA-69 3-C14-fluorophenyl CONHCH 2 (pyridin-3-yl) 3-C14-fluorophenyl CQNHCH 2 (tetrahydrofuran-2-yl) HIA-71 3-CI-4-fluorophenyl CONHCH 2 (1-Et-pyrrolidin-2-yI) Va 0 0 ci 0 ci en 0 ci Va 0 0 ci No. T-R 2 HA±-72 3-CI4-fluorophenyl. CQ(morpholin-4-yI) UIA-73 3-CI4-fluorophenyi CQ(4-Me-piperazin- 1-yI) EIA-74 3.4-dimethoxyphenyl CONIICH 2 (pyridin-4-yl) 11IA-75 3,4-dimetboxyphenyl CONHCH 2 (pyridin-3-y1) IIA-76 3,4-dimetlioxyphenyl CONHCH 2 (tetrahydrofuran-2-yI) IIA4-77 3,4-dimethoxyphenyl CONHCH 2 (1-Et-pyrrolidin-2-yi) IIIA-79 3,4-dimethoxyphenyl CO~morpholin-4-yl) 11±A-79 3,4-dimethoxyphenyl CO(4-Me-piperazin-1-yl) 11±A-80 4-henzolll.3]diaxol-5-yl CQNHCI{ 2 (pyridin-4-yI) IIA4-81 4-benzo[1,3]dioxol-5-yI CONHCH 2 (pyridin-3-yl) IJA-82 4-benzo[1,3jdioxol-5-yl CONHCFJ 2 (ttrahydrofuran-2-yl) 11±A-83 4-benzo[I ,3jdioxol-5-yI CONHCI- 2 (1-Et-pyrrolidin-2-yl) 11±A-84 4-bcnzo(1,3jdioxol-5-yl CO(morpholin-4-yI) 4-beuzo[1,3]dioxol-5-yl CO(4-Me-piperazin-1-yl) 11A-86 3,5-dichiorophenyl CONHCH 2 (pyridin-4-yI) II±A-87 3,5-dichlorophenyl CONHCH 2 (pyridin-3-yI) HA±-88 3,5-dichlorophenyl CONHCH2(tetrahydrofuran-2-yl) 11A-89 i 3,5-dichlorophenyl CONHCH 2 (1I-Et-pyrrolidin-2-yI) 11±A-90 3,5-dichlorophenyl CO(morpholin-4-yI) IIIA-91 3,5-dichloraphenyl CQ(4-Me-piperazin-1-yl) 11±A-92 3-C14-SO 2

NH

2 -phenyl CO(morpbolin-4-yl) 11±4-93 3-clilorophenyl CO(morpholin-4-yI) 11±A-94 phenyl ipyridin-4-yl 2-chlorophenyl morpholin-4-yl E1±A-96 2-chlorophenyl CH7T 2 (iorpholin-4-yl) IIA4-97 4-rnethoxypheriyl CFT 2 Cpyridin-4-y]) 11A-98Hr l) cI

H

0 0 11±A-99

YH

Nr IIA-100

H

0 0 0 N~t

Va 0 0 ci 0 ci en 0 ci Va 0 0 ci No. T-R 2 Q-R 4 0 H[A- 112 3-chlorophenyl 0 II9A-113 2-fluoro-3-chloropeonyl 0 E[A- 114 2-fluoro-3-chlorophenyl

O

0 HA-i 15 3-chloirophenyl ON CH, H[A- 176 3,4-dimethoxyphenyl HA- 118 3,4-dimethoxyphenyl

O

HIA-i198 3-dmetoyiphenyl HA- 10 2-luor-3-clorobCHy 0 ITIA-1219 2-lo3-hiophenyl lk IIA-122 2-fluoro-3-chlorophenylO N k EIA-122 2-la3-chlorophenyl Va 0 0 ci 0 No. T-R 2 0-114 ELA-124 3,4-ditiathoxyphenyl IIA-125 2-fluoro-3-chlorophenyl k IIA-126 2-fluoro-3-chlorophenyl

N

0 IIA-127 3,4-dimethaxyphenyl tk~~Z 6H O IIA-128

H

F

HIA- 129 3,5-dichlorophenyl 0ot

H

YkN'kh IIA-130 phenyl D N H0 HTA-131 phenyl Qo IIA-132 phenyl -K IIA-133 phenyl e JJIA-135 3,4-dimethoxyphenyl JN.-...Z9 Va 0 0 ci 0 ci en 0 ci Va 0 0 ci No. T-R 2 Q-R 4 IIA-136 3A4-dimethoxyphenyl 0 IIA-137 3,4-dimiethoxyphenylN EIA-138 3-methyiphenyl IA-139 3-methyiphenyl

H

EIA-140 3-inethyiphenyl IIA-141 2-fluoro,3-chlorophcnyl JIA-142 3-clilorophenyl

H

0 EUA- 143 3-chiorophenylN _0 IIA- 144 3-chlorophenylIr flA-145 3-chlorophenyl 0 IIA-146 3-chlorophenyl Qk N N O 0 tIA-147 HOA- 148 pheniyl A0 phenyl 0 ?Z N: Lt Va 0 0 ci 0 No. T-R 2 0 HIA- 149 3,4-dimethoxyphenyl 0 IIA-150 3,4-dimethoxyphenyl 0F HA- 151 3-methylphenyl 0 HA-152 3-methyiphenyl ?k HA-154 phenylN 0 HA-I154 phenylQ 0 HA-155 34dnexphenyl0 4 0 IA- 157 3,4-dimethoxyphenyl O N~ 0 0 fl.A-158 3-methylphenyl HIA-159 3-methyiphenylY UIA-160 3-ohiorophenyl r N Va 0 0 ci 0 ci en 0 ci Va 0 0 ci No. T-R 2 Q-R 4

OH

UIA-161 phenyl0

CH

IIA- 162 3-chiorophenyl IIA- 163 3,4-dimethoxyphenylN 0 IIA-164 3-chiorophenyl 0 DaA-166 phenylH 08 UIA-167 phenyl -tk KDN y CHa 0

H

LtA-168 3,4-dimethaxypheny! rN LIA-169 3,4-dimethoxyphenyl OtC Ho 0 EUA- 170 3,4-dimethoxyphenylO

N-

0 IIA-172 3-methyiphenyl 07 ~4-~&.~ALg.flS 1 Va 0 0 ci 0 No. T-R 2

Q-R

4 IIIA-173 3-methyiphenyl 0 HIA-i174 3-methyiphenyl 0o ITA- 175 3-methyiphenyl IIA-176 3-mnethiyiphenyl Zk KAm CHS 0 HEA- 177 2-tluora,3-chlorophenyl

O

0 IJA-178 2-fluaro,3-chlorophenyl JIA-179 2-fluoro,3-chlorophenyl ~yH 0~~.H 0 RA-180 2-fluoro,3-chlorophenyl 0CH A-181 phenyl 63 6H 0 E[A- 182 3-chiarophenyl ec rC 0 IIA-183 3-chlorophenylN IIA-184 3-chiorophenyl -KANh II Pif;rl i:

O

0 0

C

O

Another embodiment of this invention relates to compounds wherein A-B is O-N, shown by formula III: -i 7~3

ID

o \Ht e XN T- R 2

II

or a pharmaceutically acceptable derivative or prodrug C\ thereof, wherein R 2 T, and Q are as described above.

Preferred embodiments of formula III are shown below for Cq the Ht ring being pyrrol-3-yl (III-A), pyrazol-3-yl (IIIo [1,2,4jtriazol-3-yl (III-C), [1,2,3]triazol-4-yl C (III-D), and tetrazol-5-yl (III-E).

H H H N -R 4 N Q-R 4 N Q R4 N R N

N

R

N s pa o,N N T- R 2 2

T-R

2 R R'

R

III-A III-B III-C H H N'N'N N'N 0

OIT-R

2 0 T-_R 2

R

1

R

1 III-D III-E Preferred compounds of formulae III-A, III-B, III-C, III-D, and III-E include those having one or more, and most preferably all, of the following features: Q is -CO0-, or -CONH-; T is a valence bond, or -NHCH 2

R

1 is hydrogen or NHR; R 2 is an optionally substituted aryl ring, preferably a phenyl ring, and more preferably a phenyl ring having up to one L-W substituent and up to three R 8 substituents; W is selected from R 9

CH(R

9 2

CH(R)N(R')

2 or N(R 9 2

R

3 is hydrogen; R 4 is selected from -R 6 -NHa, -NHR 6 -N(R6)2, or -NR 6 (CH2)yN(R 6 2

R

6 is R 5

-(CH

2 )yCH(R 7 2 or

IND-(CH

2 )yR 7 and/or R' is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

Preferred Re substituents of the R 2 phenyl group, if present, include halo, nitro, haloalkyl, o hydroxyalkyl, C3,5 aliphatic, alkoxy, amino, and heterocyclyl. Preferred L groups include -CH 2

-CH

2

NH-,

-CH

2 NHC(O)-, -NIH-, -CH 2

CH

2 NH-, -CH 2

-CH

2

C(O)NH-,

-CH2NHCH 2

CH

2 NHC and -CH 2 NHC CH 2

CH

2 NHC Preferred W groups include -CH(C 1 6 aliphatic)NC(o)

(C

1 s aliphatic), -CH(CH20H)NC(0) (ClS aliphatic), -CH (CH2SH)NC(O) aliphatic), N(C-6 aliphatic)2, heterocyclyl pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl),

-CH(C

1 -6 aliphatic)NH 2

-CH(C

1 -6 aliphatic)NC(0)O(C 1 -5 aliphatic), -CH 2 CN, and

CH

2

N(C

1 6 aliphatic)2.

When R is R 6 preferred R 6 groups include pyrrolidin-1-yl, morpholin-4-yl, piperidin-l-yl, and piperazin-l-yl wherein each group is optionally substituted. When R 4 is -NHR 6 or -N(R 6 2 preferred R' groups further include (CH 2 and -(CH2)yCH(R 2 Examples of preferred R 6 and R 7 include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, tetrahydrofuran-2yl, cyclohexyl, phenyl, -CH 2 0H, -(CH 2 2 OH, and isopropyl, wherein each group is optionally substituted.

Exemplary structures of formula IIl-A, wherein R' and R 3 are each hydrogen, are set forth in Table 2 below.

ii Va 0 0 ci 0 111-A Table 2. Compounds of Formula 111-A No. T-R 2 -4 mA-iphenyl CQN(Me) 2 IIIA-2 2-chlorophenyl CONHCH 2 (Ph) IA-3 2-chlorophenyl CO(morpholin-4-yI) JJTA-4 4-methoxyphenyl CQNHCH 2 (pyiridin-4-yI) 3-tluorophenyl CONWHH(pyridin-4-yI) mIA-6 3-methoxyphenyl

CONHCH

2 (pyridin-4-yI) IIIA-7 2,5-dimethoxyphenyl CQNHCH 2 (pynidin-4-yl) MfA-8 3,4-difluorophenyl CONHCH 2 (pynidin-4-yl) MLA-9 2,3-difluorophenyl CONIICH 2 (Pynidin-4-yi) 2,5-difluoruphenyl CQNIICH 2 (pyridin-4-yi) lilIA-i1 4-methaxyphenyl CONT{CH2(Pyridin-3-yi) UTA-12 i3-fluorophenyl COtWHCH2(Pyridin-3-yi) ITA- 13 3-methoxyphenyl CQNHCH 2 (pyxidin-3-yI) IJIA-14 2,5-dinethoxyphenyl CONHCH2(pyridin-3-y1) 3,4-difluorophenyl CONHCH 2 (pynidin-3-yl) IJIA-16 2,3-difluarophenyl CON2HCH 2 (pynidzn-3-yI) uA- 17 2,5-drnluoropheny1 CONHCH 2 (pyridin-3-yi) MJA-18 4-methoxyphenyl CQNHCHa(tetrahydrofuran-2-yl) DIA-19 2,5-difluorophenyl CONHCHa.(1-Ht-pyrrolidin-2-yl) 4-fluorophenyl CQ(morphoin-4-yl) UITA-21 4-fluorophenyl CQ(4-Me-piperazin-l-yI) According to another embodiment, the present invention relates to compounds of formula IV: Ht

N

0

T-R

2

HN

R

IV

or a pharmaceutically acceptable derivative or prodrug thereof, wherein R 1

R

2 T, and Q are as described above.

Preferred embodiments of formula IV are shown below for the Ht ring being pyrrol-3-yl pyrazol-3-yl (IV- [l,2,4]triazol-3-yl [1,2,3]triazol-4-yl (IVand tetrazol-5-yl (IV-E).

H H H N QR4 N Q-R4 ,N O' -R a IN

HN

'R

IV-A IV-B IV-C IV-D IV-E Preferred compounds of formulae IV-A, IV-B, IV- C, IV-D, and IV-E include those having one or more, and most preferably all, of the following features: Q is -CO2-, or -CONH-; T is a valence bond, -NHC(O)-, or -NHCH 2

R

2 is an optionally substituted aryl ring, more preferably a phenyl ring having up to one L-W substituent and up to three R 8 substituents; R 3 is hydrogen; R 4 is selected from -R 6

-NH

2

-NHR

6

\O

-N (R62, or -NR 6

(CH

2 )yN(R 6 2 R6 is R 5

-(CH

2

CH(R

7 2 or N -(CH 2 yR 7 and/or R7 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group.

Preferred RO substituents of the R phenyl group, if present, include halo, nitro, haloalkyl, hydroxyalkyl, C3-6 aliphatic, alkoxy, amino, and n heterocyclyl.

o When R is R 6 preferred R 6 groups include C pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-l-yl wherein each group is optionally substituted. When R 4 is -NHR6 or -N(R 6 preferred R 6 groups further include (CH2)yR and -(CH 2 )yCH(R 7 2 Examples of preferred R 6 and R7 include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, tetrahydrofuran-2yl, cyclohexyl, phenyl, -CH 2 0H, (CH 2 2 OH, and isopropyl, wherein each group is optionally substituted.

Exemplary structures of formula IV-A, wherein R3 is hydrogen, are set forth in Table 3 below.

H

N -R 4 ,O R

NI

T- R 2 RR HNR

IV-A

Table 3. Compounds IV-A No. R T-R 2

Q-R

IVA-1 H phenyl CON(Me)2 IVA-2 H phenyl CO 2 Et IVA-3 H 3-NO2-phenyl CONHNI 2 IVA-4 H henyl CO(pyrrolidin-1-yl) Me phenyl CONHCH2(Ph) IVA-6 H 3-NO 2 -phenyl CO 2 t IVA-7 H 4-C-phenyl CO 2 Et IVA-s Me 4-Me-phenl CO IVA-9 H 3-NH-phenyl C Et H 3-OMe-phenyl CO 2

E

Va 0 0 ci 0 ci en 0 ci Va 0 0 ci No. R T-R 2 Q-R 4 WVA-il H 4-F-phenyl 0E IVA-12. H 4-N0 2 -phenyi CO 2 Et IVA-13 Et 3-lphenl CO 2 )Et IVA4-14 H 3-P-phenyl CO 2 Et WVA-IS H Phenyl 002H1 1VA-16 Me 3 lphenyl CONHCH 2 (pynidin-4-yl) JVA-17 H NVA-1S H 5-F-phenyl CONHCH 2 (tetrahydrofuran-2-yi) [EVA- 19 Me 5,6-F 2 -phenyl C0(4-Me-piperidin- l-y') IFVA-20 H- 4- CI-.phenyl CONHCH 2 (pyrid-4-yl) IVA-21 H 4,5-(QMe) 2 -phenyl o HtC CHS IVA-22 Me 4,5-01,-phenylN H o TVA-23 H 3-CI-phenyl H H IEVA-24 Me IVA-2 H[C O CI H TVA-27 H 0ONMH) It According to another embodiment, the present invention relates to compounds, wherein T is a valence bond and R 2 'is a phenyl ring substituted with L-W and up to three R 8 of f ormula V:

G)

I

ii. i

OO

VD

c Ht R L w Ra v en or a pharmaceutically acceptable derivative or prodrug o thereof, wherein R, -R 1

R

3

R

4

R

8 L, and W are as IND described above. Preferred embodiments,are shown below o for the Ht ring being pyrrol-3-yl pyrazol-3-yl (V- [1,2,4]triazol-3-yl [1,2,3]triazol-4-yl and tetrazol-5-yl H H H N Q-R 4 N Q-_R4 AN Q-R p VA p VB V N H H N I N I N S N- -N

S

L-w W L-W L L-W R R R R V-A V-B V-C H H N N R8 RB V-D V-E Preferred compounds of formulae V-A, V-B, V-C, V-D, and tetrazol-5-yl V-E include those having one or more, and most preferably all, of the following features: Q is -C0 2 or -CONH-; R 1 is hydrogen or NHR; W is selected from R 9

CH(RS)

2

CH(R')N(R

9 2 or

N(R

9 2

R

3 is hydrogen; R 8 if present, is halogen,

-NO

2 -CN, or -N(R 5 2

R

4 is selected IND from -R 6

-NH

2 -NHR6, -N (R 6 2 or -NR 6

(CH

2 yN(R 6 2

R

6 0 is R 5

-(CH

2 )yCH(R 2 or -(CH 2 yR'; and/or R' is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group.

Preferred R8 substituents of the R" phenyl group include halo,; nitro, haloalkyl, hydroxyalkyl, Cl.s C aliphatic, alkoxy, amino, and heterocyclyl.

Preferred L groups include -CH 2

-CH

2

NH-,

ci -CH 2 NHC(0)-, -CH 2

CH

2 NH-, -CH20-, -CH2C(0)NH-, 3 o -CH 2

NHCH

2

CH

2 NHC and -CH 2 NHC CH 2

CH

2 NHC Preferred W groups include -CH(C 16 aliphatic)NC(0) (CI. aliphatic), -CH(CH 2 0H)NC(Q) (CI.6 aliphatic), -CH(CH 2 SH)NC(0) aliphatic) N(C 1 6 aliphatic) 2 heterocyclyl pyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidinyl), -CH(C 1 -6 aliphatic)NH 2 -CH(C1- aliphatic)NC(0)0 (C 16 aliphatic), -CH2CN, and

-CH

2 N(C-6 aliphatic)2.

When R 4 is R 6 preferred R' groups include pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-l-yl wherein each group is optionally substituted. When R4 is -NHR' or -N(R 6 2 preferred R 6 groups further include (CH 2

)YR

7 and -(CH 2 )CH(R 2 Examples of preferred R 6 and R 7 include pyridin-3-yi, pyridin-4-yl, imidazolyl, furan-2-yl, tetrahydrofuran-2yl, cyclohexyl, phenyl, -CH 2 OH, -(CH2)2 OH, and isopropyl, wherein each group is optionally substituted.

Exemplary structures of formula V-A, wherein R 3 is hydrogen and T is a valence bond, are set forth in Table 4 below.

IND

0

H

V-A

Table 4. Compounds of Formula V-A Va 0 0 ci 0 ci en 0 ci Va 0 0 ci 0

C

(I

2' .!.r~:2~;rj;i~,;iaraRS~ Va <D 0 0 Cq ci ^*t 0D The present compounds may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I, II, III, and IV below. These schemes are illustrated for the pyrrole compounds of this invention and, by analogy, are applicable for the preparation of compounds having the other Ht rings.

N0D Scheme I o H 0 H 0 HO (N /NUL N

N

S13/ CCi 3

R'-NH

2

N-R'

SO1 3 0 H R R 4 2 SH 0 H 0 N N N 0 N-R

HN-R'

S H (d) Me2N N I o 5 6 Reagents and conditions: PhCH2COC1, AIC 3

CH

2 C1 2 minutes, room temperature DMF, 24 hrs, room temperature (Me 2 N) 2CH-Ot-Bu, THF, 48 hrs, room temperature H2N-OH-HCl, K 2 C0 3 EtOH, 12 hrs, reflux An array of compounds of formula II-A are prepared in the following manner, as shown in Scheme I above. In step a series of separate Friedel-Crafts intermediates 2 are prepared from 2-trichloroacetyl pyrrole by treating a concentrated solution of the pyrrole and the appropriate acyl chloride with AlC1 3 in dichloroethane at 250C. After 1 hour, the resulting ii slurry is purified by chromatography to afford compounds of formula 2.

In step each compound 2 is first dissolved in DMF. A separate solution of 1.2 equivalents of each of six amines 3 in DMF is also prepared. Using a Bohden parallel synthesizer, each compound 2 is treated with each amine 3. The reactions are performed at ambient temperature for 24 hours then concentrated in vacuo to afford compounds of formula 4.

In step the concentrates of compound 4 are dissolved in THF. Using the Bohden parallel synthesizer, each compound 4 is then treated with a solution of Va S(Me 2

N)

2 CHO-t-Bu in THF. The resulting mixtures are again

C

stirred at ambient temperature for 48 hours then Oconcentrated in vacuo to afford compounds of formula SIn step the concentrates of compound 5 are first dissolved in ethanol. Using the Bohden parallel synthesizer, each compound 5 is treated with K 2

CO

3 and

QH

2 NOH-HC1. The resulting mixtures are stirred under reflux for 12 hours then concentrated in vacuo to afford compounds of formula 6.

10 Each compound is purified by preparatory HPLC o (Gilson) on a C18 reverse-phase column eluted with a gradient of 10-90% MeCN TFA) in water over minutes. The details of the conditions used to prepare the compounds as described in Scheme I are set forth in the Examples.

Scheme II 00 0 N 0 N H N I

N\

H

Z NaOEt, EtOH 0 HOO

O

7 8 11IA-22 As shown in Scheme II above :using the preparation of compound IIIA-22 as an example, .compounds of formula III-A may be prepared according to the methods of Zohdi, et al, J. Chem. Res., Synop (1991) 11, pp 322- 323.

N Scheme III oH 0 H 0 H o H a N b

N

SH

H

O Br N N

H

(eage0 d( i' e y r aLne (d H -LCO HN -R' 1 1 0 0 H Brederick's reagent hydrazine HIN-OH-HCI, KCO3,

H

Reagents and conditions: potassium phthalimide (b) Brederick's reagent hydrazine H 2 N-OH-HCl, K 2 C0 3 EtOH, 12 hrs, reflux benzyl bromide benzoyl chloride Scheme III above depicts a general method for preparing compounds of formula I wherein T is NH 2 NH2CH2, or NH 2 In step the bromoacetyl compound 9 is treated with potassium phthalimide to form the protected amino compound 10. Compound 10 is then treated with Brederick's reagent to form the enaminone compound 11.

In step the enaminone 11 is condensed with hydroxylamine to form the isoxazole compouns which is treated with hydrazine in step to remove the phthalimide protecting group to afford the amino compound 12. The amino compound 12 may be derivatised with a variety of reagents to afford various compounds of formula I wherein T is other than a valence bond. For example, compound 12 is treated with a benzyl bromide derivative in step to afford the benzylamine compound

\O

S13. In step the amino compound 12-is treated with a C benzoyl chloride derivative to afford the benzamide Scompound 14. Other compounds of formula I wherein T is other than a valence bond may be prepared by methods o 5 substantially similar to those shown in Scheme III above by modifications of which are well known to those skilled in the art.

o Scheme

IV

IN R9 H H 0 16 OH R9 0 b N H R N

H

F19 N l- N

H

N

Reagents and conditions: 3-C1-4-(R 9 2 aminomethyl- PhCH 2 COCI, A1C1 3

CH

2 C1 2 2 hours, RT DMF, 24 hrs, room temperature (Me 2

N)

2 -Ot-Bu, THF, 24 hrs, room temperature H 2 N-OH-HC1, K 2 C0 3 EtOH, 12 hrs, reflux Scheme IV above shows a general synthetic route that may be used for preparing compounds of formula V-A.

These compounds may be prepared by methods substantially similar to those described in Scheme I above.

According to another embodiment, the invention provides a method of inhibiting ERK or AKT kinase activity in a biological sample. This method comprises the step of contacting said biological sample with a compound of formula I: 0 t c

AQ

T-R

2

R

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: -3 Ht is a heteroaryl ring selected from pyrrol-3-yl, O pyrazol-3-yl, [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl; said pyrrol-3-yl and pyrazol-3-yl Seach having R 3 and QR 4 substituents, .and said triazole substituted by either R 3 or QR 4 A-B is N-O or 0-N;

R

1 is selected from R 5 fluorine, N(RS) 2 OR, NRCOR,

CON(R

5 2

SO

2 R, NRSO 2 R, or SO 2

N(R

5 2 T and Q are each independently selected from a valence bond or a linker group; each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons; R2 is selected from hydrogen, CN, fluorine, or an optionally substituted group selected from aryl, heteroaryl, heterocyclyl, an acyclic aliphatic group having one to six carbons, or a cyclic aliphatic'group having four to ten carbons; wherein R 2 has up to one L- W substituent and up to three R 8 substituents; L is a C 1 -6 alkylidene chain which is optionally substituted, and wherein up to two methylene units of L are optionally replaced by

-CONH-,

-CONHNH-, -CO 2 -NHC02-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -S02-, -NH-,

-SO

2 NH-, -NHSO 2 NH-, or -NHSO2-; W is selected from R 9

CH(R

9 2

CH(R

9

)N(R

9 2 or N(RS)2;

IND

R

3 is selected from R, OH, OR, N(R) 2 fluorine, or CN;

C

I

R

4 is selected from -R 6

-NH

2

-NHR

6

-N(R

6 2 or e, -NR 6 (CH2) yN (R 6 2 each R s is independently selected from hydrogen or an o optionally substituted aliphatic group having one to six carbons or two R 5 on the same nitrogen may be taken c together with the nitrogen to form a four to eight _membered ring having one to three heteroatoms; Seach R 6 is independently selected from R 5

-(CH

2 )yCH(R 7 2 or -(CH 2 yR 7 o 5 y is 0-6; each R 7 is an optionally substituted group independently selected from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; each R 8 is independently selected from halogen, -OR',

-NO

2 -CN, -N(R 5 2 -NRC(O)R', -NRC(O)N(R 5 2 -NRC0 2 -NRNRC(O)R', -NRNRC(O)N(RS)2, -NRNRCOaR',

-C(O)CH

2 -C02R', -C(0)N(RS) 2

-OC(O)N(RS)

2 -S(0) 2

-SO

2 N(Rs) 2

-NRSO

2 N(Rs) 2

-NRSO

2

-C(=S)N(R

5 2 or -C(=NH)N(R 5 )2; wherein each R' is independently selected from hydrogen, or an optionally substituted group selected from aliphatic, heteroaryl, heterocyclyl, or phenyl; and each R 9 is independently selected from R 5

R

8 or an optionally substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl.

According to a preferred embodiment, the invention relates to a method of inhibiting ERK or AKT kinase activity in a biological sample comprising the step of contacting said biological sample with a compound

I

I

ND of formula formula II, III, IV, or V; more preferably o with a compound of formula II-A, III-A, IV-A, or V-A; and Smost preferably, with a compound listed in Tables 1-4.

The term "biological sample", as used herein includes cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and C blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

h Another aspect of this invention relates to a method for treating a disease in a patient that is Salleviated by treatment with an ERK or AKT protein kinase Ci inhibitor, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I: Ht

A/O

T-R

2

R

1

I

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Ht is a heteroaryl ring selected from pyrrol-3-yl, pyrazol-3-yl, [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl; said pyrrol-3-yl and pyrazol-3-yl each having R 3 and QR 4 substituents, and said triazole substituted by either R 3 or QR 4 A-B is N-O or O-N;

R

I is selected from R s fluorine, N(R) OR, NRCOR,

CON(RS)

2

SO

2 R, NRSO 2 R, or SO 2

N(RS)

2 T and Q are each independently selected from a valence bond or a linker group; 0 each R is independently selected from hydrogen or an (c optionally substituted aliphatic group having one to O six carbons;

R

2 is selected from hydrogen, CN, fluorine, or an o optionally substituted group selected from aryl, heteroaryl, heterocyclyl, an acyclic aliphatic group C having one to six carbons, or a cyclic aliphatic group en having four to ten carbons; wherein R 2 has up to one Lo W substituent and-up to three R 8 substituents; IKD L is a C1-s alkylidene chain which is optionally o substituted, and wherein up to two methylene units of L are optionally replaced by -CONH-, -CONHNH-, -C02-, -NHC02-, -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -SO2-, -NH-,

-SO

2 NH-, -NHS02NH-, or -NHSO 2 W is selected from R 9

CH(R')

2

CH(R

9

)N(R

9 or N(R 9 2

R

3 is selected from R, OH, OR, N(R) 2 fluorine, or CN;

R

4 is selected from -R 6

-NH

2

-NHR

6

-N(R

6 2 or

-NR

6

(CH

2 yN 2; each R 5 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons or two R 5 on the same nitrogen may be taken together with the nitrogen to form a four to eight membered ring having one to three heteroatoms; each R 6 is independently selected from R 5

-(CH

2 )yCH(R 7 2 or -(CH 2 )yR 7 y is 0-6; each R 7 is an optionally substituted group independently selected from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; each R 8 is independently selected from halogen, -OR',

-NO

2 -CN, -N(R 5 2 -NRC(0)R', -NRC(O)N(R 5 2 o -NRCO 2 -NRNRC(0)R', -NRNRC (0)N (R 5 2

-NRNRCO

2

R',

o -C(O)CH 2

-C

2 S-C(O)N(Rs) 2

-OC(O)N(R

5 2 -S(0) 2

-SO

2

N(R

5 2

-NRSO

2

N(R

s 2

-NRSO

2

-C(=S)N(R

5 2 or -C(=NH)N(R 2 wherein each R' is independently selected from hydrogen, or an optionally substituted group selected C from aliphatic, heteroaryl, heterocyclyl, or phenyl; and each R 9 is independently selected from R s

R

8 or an optionally substituted group selected from aryl, Saralkyl, aralkoxy, heteroaryl, heteroaralkyl, C heterocyclyl, or heterocyclylalkyl.

A preferred embodiment comprises administering a compound of formula II, III, IV, or V, more preferably a compound of formula II-A, III-A, IV-A, or V-A, and most preferably, a compound listed in Tables 1-4.

Pharmaceutical compositions useful for such methods are described below and are another aspect of the present invention.

The present method is especially useful for treating a disease that is alleviated by the use of an inhibitor of ERK. The activity of the compounds as protein kinase inhibitors, for example as ERK inhibitors, may be assayed in vitro, in vivo or in a cell line. Using ERK as an example, in vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of activated ERK. Alternate in vitro assays quantitate the ability of the inhibitor to bind to ERK and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/ERK complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with ERK bound to known

IND

Sradioligands. One may use any type or isoform of ERK, depending upon which ERK type or isoform is to be inhibited.

The protein kinase inhibitors of this o invention, or pharmaceutical salts thereof, may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions effective to treat or prevent C a protein kinase-mediated condition which comprise the .D protein kinase inhibitor in an amount sufficient to C measurably inhibit protein kinase activity ERK or AKT activity) and a pharmaceutically acceptable carrier, are another embodiment of the present invention. The term "measurably inhibit", as used herein means a measurable change in activity between a sample containing said inhibitor and a sample containing only protein kinase.

The compounds of this invention are inhibitors of ERK and AKT kinase as determined by enzymatic assay.

The details of the conditions used for the enzymatic assays are set forth in the Examples hereinbelow.

Accordingly, these compounds are useful for treating ERKor AKT-mediated diseases or conditions.

The term "ERK-mediated disease" or "condition", as used herein means any disease or other deleterious condition in which ERK is known to play a role. 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 hormonerelated diseases. The term "cancer" includes, but is not limited to the following cancers: breast, ovary, cervix, D prostate, testis, genitourinary tract, esophagus, larynx, 0 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, ^C papillary carcinoma, seminoma, melanoma, sarcoma, bladder Oh carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, c 10 Hodgkin's, hairy cells, buccal cavity and pharynx (oral), O lip, tongue, mouth, pharynx, small intestine, colon- Ci rectum, large intestine, rectum, brain and central nervous system, and leukemia.

The term "AKT-mediated disease" or "condition", as used herein, means any disease or other deleterious condition in which AKT is known to play a role. AKTmediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders.

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 disorders.

A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a

IND

Smammal by allowing an orally administered compound C to be more readily absorbed into the blood) or which O enhance delivery of the parent compound to a biological compartment the brain or lymphatic system) o 5 relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, Sesters, amino acid esters, phosphate esters, metal salts o and sulfonate esters.

o 10 Pharmaceutically acceptable salts of the o 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, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, 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 obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal sodium and potassium), alkaline earth metal magnesium), ammonium and N(CI- 4 alkyl) 4 salts. This invention also envisions the quaternization IND of any basic nitrogen-containing groups of the compounds o disclosed herein. Water or oil-soluble or dispersible Sproducts may be obtained by such quaternization.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum C stearate, lecithin, serum proteins, such as human serum O albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts o or electrolytes, such as protamine sulfate, disodium Ci 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 an 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 injectable preparation may also'be a sterile

.N

VO

o injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example Sas a solution in 1,3-butanediol. Among'the acceptable vehicles and solvents that may be employed are water, O 5 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 0 synthetic mono- or di-glycerides. Fatty acids, -such as 10 oleic acid and its glyceride: derivatives-are'useful in

D

o the preparation of injj J saeatural:-.

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 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 aqueous suspensions are required for oral use, the active IN ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositi ons of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating 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

IND

o include cocoa butter, beeswax and polyethylene glycols.0 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 a re 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.

Topicdlly-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 petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one cr more pharmaceutically acceptable

INI

carriers. Suitable carriers include, but are not limited CA to, mineral oil, sorbitan monostearate, polysorbate 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, as solutions in isotonic, pH adjusted sterile saline, Seither with or without a preservative such as NO 10 benzylalkonium chloride. Alternatively, for ophthalmic Suses, 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.

The amount of ERK or AKT inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between about 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 ND administration, rate of excretion, drug combination, and O the judgment of the treating physician and the severity Sof the particular disease being treated. The amount of inhibitor will also depend upon the particular compound in the composition.

The kinase inhibitors of this invention or -c pharmaceutical compositions thereof may also be ^O incorporated into compositions for coating an implantable 1- medical device, such as prostheses, artificial valves, Cq 10 vascular grafts, stents and catheters. Vascular stents, o for example, have been used to overcome restenosis (re- Ci narrowing of the vessel wall after injury).. However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a composition comprising a kinase inhibitor.

Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Implantable devices coated with a kinaae inhibitor of this invention are another embodiment of the present invention.

According to another embodiment, the invention provides methods for treating or preventing an ERK- or AKT-mt.)diated condition comprising the step of administering to a patient one of the above-described

IND

o pharmaceutical compositions. The term "patient", as used herein, means an animal, preferably a mammal, and most i preferably a human.

Preferably, that method is used to treat or O 5 prevent a condition selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell Slung cancer, stroke, diabetes, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease or disorder described above.

Depending upon the particular ERK- or AKTmediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the ERK or AKT inhibitors of this invention. For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the inhibitors of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of therapeutic agents the inhibitors of this invention may also be combined with include, without limitation, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors ND such as acetylcholinesterase inhibitors, MAO inhibitors, O interferons, anti-convulsants, ion channel blockers, Sriluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents fortreating liver disease such as corticosteroids, cholestyramine, interferons, and C anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth Cq 10 factors; agents for treating diabetes such as insulin, o insulin analogues, alpha glucosidase inhibitors, C biguanides, and insulin sensitizers; and agents for treating immunodeficiency disorders such as gamma globulin.

These additional therapeutic agents may be administered separately, as part of a multiple dosage regimen, from the kinase inhibitor-containing composition. Alternatively, these agents may be part of a single dosage form, mixed together with the inhibitor in a single composition.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXAMPLES

Example 1 Compounds of formula II-A were prepared in the following manner in parallel fashion, as shown in Scheme I depicted above. In step a series of separate Friedel-Crafts intermediates 2 were prepared from 2trichloroacetyl pyrrole by treating a concentrated solution of the pyrrole (1 equivalent) and the o appropriate acyl chloride (1 equivalent) with AlC13 (1 Sequivalent) in minimal dichloroethane at 25 0 C. After 1 hour, the resulting slurry was purified by silica gel chromatography to afford compounds of formula 2.

In step each compound 2 was first dissolved in DMF. A separate solution of 1.2 equivalents C of each of six amines 3 in DMF was also prepared. Using a Bohden parallel synthesizer, each compound 2 was Cq treated with each amine 3. The reactions were performed C. 0 10 at ambient temperature for 24 hours then concentrated in C-i vacuo to afford compounds of formula 4.

In step the concentrates of compound 4 were dissolved in THF. Using the Bohden parallel synthesizer, each compound 4 was then treated with a solution of (Me2N) 2 CH-O-t-Bu (10 equivalents) in THF. The resulting mixtures were again stirred at ambient temperature for 48 hours then concentrated in vacuo to afford compounds of formula In step the concentrates of compound were first dissolved in ethanol. Using the Bohden parallel synthesizer, each compound 5 was treated with

K

2 C0 3 (2 equivalents) and H 2 NOH-HC1 (2.0 equivalents).

The resulting mixtures were stirred at reflux for 12 hours then concentrated in vacuo to afford compounds of formula 6.

Each compound was purified by preparatory HPLC (Gilson) on a C1i reverse-phase column eluted with a gradient of 10-90% MeCN TFA) in water over minutes. The characterization data for these compounds is summarized in.Table 5 below and includes LC/MS, HPLC, and "H NMR data.

Unless otherwise indicated, the HPLC method used for the determination of retention time is as follows: on a YMC ODS-AQ 55 120A column with a size of Va 0 0 ci 0 3.0 x 150 mm, a gradient of water:MeCN, 0.1% TFA (95:5 0:100) was run over 15 minutes at 1 mL/min and 214 nm.

As used herein, the term "Rt" refers to the retention time, in minutes, obtained for the compound using the HPLC method as indicated.

Where applicable, 'H NMR data is also summarized in Table 5 below wherein designates H NMR data is available and was found to be consistant with structure.

SCompound numbers correspond to the compound numbers listed in Table 1.

Table 5. Characterization Data for Selected Compounds Compound No HPLC Puity M+I M-1 Rt(min) HNMR HA- 1 282 100 8.6 Y 3 358 356 75 9.61 6 363 361 100- 381 379 93 16 381 379 100- 17 381 379 100- 23 374 372 100- 24 374 372 100 29 425 423 98 401 399 100 31 401 399 98- 32 401 399 100 36 354 352 96 37 384 38 360 358 100- 39 360 358 42 355 354 100 43 365 363 100- 44 397 92 373 371 100- 46 373 371 100 47 354 352 85 7.92 Y 48 379 377 84 7.96 Va 0 0 ci 0 Compound No HPLC Purity M+1 M-1 Rh (min) 1fl NMR E[A- 49 372 370 90 9.82 399 397 87 8.37 51 371 369 83 7.56 52 379 377 100 8.02 53 379 377 100 7.83 54 372 370 95 9.91 399 397 95 8.44 56 358 356 73 9.64 57 371 369 83 7.66 58 413 411 93 8.6 59 433 431 100 9.09 392 390 74 10.35 61 405 403 70 8.26 62 397 395 100 7,99 63 397 395 100 7098 64 390 388 100 9.75 417 415 89 8.42 66 86 9.54 67 389 387 68 7.67 68 89 8-1 69 100 8.13 390 81 10.01 71 417 415 100 8.56 72 376 374 96 9.75 73 389 387 62 7.78 74 405 403 97 6.9 405 403 93 6.9 76 398 396 85 8.43 77 425 423 100 7.27 78 384 382 83 8.1 79 397 395 98 6.59 389 387 too 7.29 81 389 387 100 7.29 82 382 380 100 8.91 83 409 407 100 7.7 84 368 88 8.65 Va

<D

0 0 ci

C

ct en 0 ci Va 0

<D

0 0i Compound No HPLC Purity M+1 M-1 R((min) 1HNMR HA- 85 381 379 80 6.97 86 413 411 100 8.69 87 413 411 100 8.67 88 406 404 72 10.84 89 433 431 100 9.13 90 392 390 72 10.54 91 405 403 74 8.26 92 92 Y 93 358 356 100 Y Example 2 ERK Inhibition Assay: Compounds were assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay,(Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated with various concentrations of the compound in DMSO for 10 min. at 30°C in 0.1 M HEPES buffer, pH containing 10 mM MgC12, 2.5 mM phosphoenolpyruvate, 200 jM NADH, 150 pg/mL pyruvate kinase, 50 pg/mL lactate dehydrogenase, and 200 pM erktide peptide. The reaction was initiated by the addition of 65 pM ATP and the rate of decrease of absorbance at 340 nM was monitored. The percent inhibition values were determined at an inhibitor concentration of 10 pM.

Table 6 shows the results of the activity of selected compounds of this invention in the ERK2 inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as provided a percent inhibition value above 60%; compounds having an activity designated as provided a percent inhibition value between 30 and 0 (j Va 0 0, ci and compounds having an activity designated as "C" provided a percent inhibition value less than Table 6. ERK2 Inhibitory Activity of Selected Compounds No. Activity No. Activity HA-1 B 11±-3 B.

IIA-4 C 14-5 B IIA-6 C 11.4-7 C 11±-8 A 11±-9 A A IA-I1 B EA-12 B UA-13 B B IIA-16 B IIA-17 B IIA-IS C IIA-19 B EUA-20 B IIA-22 C UA-23 B I±A-24 A ILA-25 C 1A-26 C IJA-27 C 1A-28 C IIA-29 C RA.-36 B ELA-37 C E1A-38 B IIA-39 B C IIA-41 C ELA-42 C HA±-43 C IIA-44 C 11±-45 C IIA-46 C 11±-47 A 11A-48 A 11±A-49 B C HA-51 C IIA-52 A IIA-53 B ELA-54 C UA±-55 C IJA-56 C 11A-57 C 1IA-58 B 11A-59 C B IIA-61 C IIIA-62 A IIA-63 A I1±A-64 B IIA-65 C 1JA-66 B I1A-67 C 11±A-68 A ILA-69 B B I[A-71 C IIIA-72 B 11A-73 C IIA-74 B nA±-80 B

I:

i' I' rl Va 0 c en No. Activity No. Activity IIA-SI B UA-82 B IIA-84 C IIA-86 A IIA-87 B IIA-88 B C IIA-91 C EJA-106 B IIA-107 B nA-108 B IIA-109 B B RA-ll B IIA-112 A IIA-113 B EIA-114 A IIA-115 B IA-116 B 114-117 C EhA-118 C hlA-119 B JIA-120 A IIA-121 B LIA-122 C- IA-123 C ELA-124 C IIA-125 C EIA-126 B IIA-127 B IIA-130 B ITA-131 C UJA-132 C IIA-133 B IIA-134 A UIA-135 C IIA-136 C E1A-137 C IrA-138 C JIA-139 C IA-140 B IIA-141 C IIA- 142 C HA- 143 A 14-144 A IIA-145 B lIA-146 B IIA-147 B IIA-148 B IA-149 C D[A-150 B 114-151 B IIA-152 C ITA-153 C IIA-155 B IIA-156 C IIA-157 C IIA-158 B IIA-159 C HA4-160 B IIA-161 C IIA-162 C UA-164 C ELA-165 C IIA-166 C IIA-167 B IIA-171 A UA-172 B IIA-173 C IIA-174 C EIA-175 A JIA-176 C H[A-Ll C EIA-178 C Va 0 0 ci 0 No. Activity No. Activity IIA-179 C IIA-180 C HA-181 C IA-182 B 1IA-183 B IIA-184 C IIA-185 C IIA-186 C IIA-187 C IIA-188 C IIA-189 B IIA-190 C IIA-191 C Example 3 AKT3 Inhibition Assay: Compounds were screened for their ability to inhibit AKT3 using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgC12, 25 mM NaCI 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma Chemicals) and 200 pM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at and 45 nM AKT3. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 pM NADH, 30 pg/ML pyruvate kinase and 10 ug/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed:above, with the exception of AKT3, DTT, and the test compound of interest. 56 pj of the stock solution was placed in a 384 well plate followed by addition of 1 pl of 2 mM DMSO stock containing the test compound (final compound concentration 30 pM). The plate was preincubated for about 10 minutes at 30*C and the reaction initiated by addition of 10 1l of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a minute read time at

T

Va 0 0, ci Table 7 shows the results of the activity of selected compounds of this invention in the AKT3 inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as provided a percent inhibition value above 30%; compounds having an activity designated as provided a percent inhibition value between 20 and and compounds having an activity designated as "C" provided a percent inhibition value less than 20%. All percent inhibition Values were determined at a inhibitor concentration.

Table 7. AKT3 Inhibitory Activity of Selected Compounds No. Activity No. Activity IA-106 B IIA-107 A IlA-108 B IIA-109 A HA-110 B IA-lll B IIA-112 B IIA-113 B IIA-114 A IIA-115 B IIA-116 A IIA-117 A IIA-118 A IIA-119 A IIA-120 A IIA-121 C IIA-122 A IIA-123 A I1A-124 C IIA-125 C IIA-126 B IIA-127 B IIA-131 C IIA-132 B IIA-133 C IIA-134 C IIA-135 C IIA-136 C IIA-139 C IIA-140 C IIA-141 C IIA-142 C IIA-143 A IIA-144 C IIA-145 C IIA-146 C IIA-147 C IIA-148 C IIA-150 C IIA-151 B IIA-153 A IIA-155 C IIA-156 IIA-159 I I I o Va

<D

0 0 ci

C^-

ct en 0 ci Va 0

<D

0 0i No. Activity No. Activity IIA-160 C IIA-161 C IIA-162 C IA-163 A IIA-164 A IIA-165 C IIA-166 C IIA-167 C IIA-171 C IIA-172 B IIA-173 B IIA-174 C IIA-175 C IIA-176 C IIA-177 C IIA-178 C IIA-179 C IIA-180 A IA-181 C IIA-182 B IIA-183 C IIA-184 C HA-185 C IIA-186 C BIA-187 C 11A-188 C IIA-189 B While we of this invention, have described a number of embodiments it is apparent that our basic examples may be altered to provide other embodiments which utilize 5 the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

Claims (22)

1. A compound having the formula: H H N Q-R 4 N Q-R 4 ,O p R N R c N 0 o T-R T-R 2 SR 1 or R II-A III-A Cl or a pharmaceutically acceptable salt thereof, wherein R' is selected from R 5 fluorine, N(R 5 2 OR, NRCOR, CON(R')2, SO2R, NRS02R, or SO 2 N(R 5 2 T and Q are each independently selected from a valence bond or asaturated or unsaturated C 1-6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -CONH-, -CONHNH-, -C0 2 -NHCO 2 -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -SO 2 -SO 2 NH-, or -NHSO 2 each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons; R2 is selected from CN, fluorine, or an optionally substituted group selected from aryl, heteroaryl, heterocyclyl, an acyclic aliphatic group having one to six carbons, or a cyclic aliphatic group having four to ten carbons; wherein R 2 has up to one L-W substituent and up to three R8 substituents; L is a Ci-6 alkylidene chain which is optionally substituted, and wherein up to two methylene units of L are optionally replaced by -CONH-, CONHNH-, -C0 2 -NHCO 2 -NHCONH-, -OC(O)NH-, -NHNH-, NHCO-, -SO2-, -SO 2 NH-, -NHSO 2 NH-, or -NHSO 2 W is selected from R 9 CH(R 9 2 CH(R 9 or N(R)2; R 3 is selected from R, OH, OR, N(R) 2 fluorine, or CN; R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R 6 or -NR6(CH2)yN(R6)2; 64 VO Seach R 5 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons or two R s on the same nitrogen may be taken together with the nitrogen to form a four to eight membered ring having one to three heteroatoms; C, 5 each R 6 is independently selected from R 5 -(CH 2 )yCH(R 2 or -(CH2)yR 7 en y is 0-6; 7 O each R is an optionally substituted group independently selected from R, aryl, aralkyl, IN aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, O heterocyclylalkyl, heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; each R 8 is independently selected from halogen, -NO 2 -CN, -N(R 5 2 NRC(O)R', -NRC(O)N(R 5 2 -NRC02R', -NRNRC(O)R', -NRNRC(O)N(R5)2, NRNRCO 2 -C(O)CH 2 -CO 2 -C(O)N(R 5 2 OC(O)N(R 5 2 -S(O) 2 -SO 2 N(R 5 2 -NRSO 2 N(R 5 2 -NRSO 2 2 or -C(=NH)N(R5)2; wherein each R' is independently selected from hydrogen, or an optionally substituted group selected from aliphatic, heteroaryl, heterocyclyl, or phenyl; and each R 9 is independently selected from R 5 R 8 or an optionally substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl.

2. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: Q is -C0 2 or -CONH-; T is a valence bond, or -NHCH 2 R 1 is hydrogen or NHR; R 2 is an optionally substituted aryl ring having up to one L-W substituent and up to three R 8 substituents; W is selected from R 9 CH(R 9 2 CH(R 9 )N(R 9 2 or N(R)2; R 3 is hydrogen; R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R 6 2 or -NR 6 (CH 2 )yN(R 6 2 R 6 is R 5 -(CH 2 )yCH(R 7 2 or -(CH 2 )yR 7 and O O7 S(i) R is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl. 0

3. The compound according to claim 2, wherein: C 5 Q is -CO2-, or -CONH-; cc) T is a valence bond, or -NHCH 2 o R' is hydrogen or NHR; D R is an optionally substituted aryl ring having up to one L-W substituent and 0 up to three R 8 substituents; W is selected from R 9 CH(R 9 2 CH(R)N(R)2, or N(Rg)2; R 3 is hydrogen; R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R6)2, or -NR 6 (CH 2 ),N(R 6 2 R 6 is R 5 -(CH 2 )yCH(R 7 2 or -(CH 2 )yR 7 and R 7 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

4. The compound according to claim 3, having the formula: H N Q-R 4 R 3 p R NI T- R 2 HN "R IV-A or a pharmaceutically acceptable salt thereof. The compound according to claim 4, wherein said compound has one or more features selected from the group consisting of: Q is -C0 2 or -CONH-; T is a valence bond, or -NHCH 2 R 2 is an optionally substituted aryl ring having up to one L-W substituent and up to three R 8 substituents; R 3 is hydrogen; O 0 S(e) R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R 6 2 or -NR 6 (CH 2 )yN(R6)2; R 6 is R 5 -(CH 2 )yCH(R 7 2 or -(CH 2 )yR 7 and R is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group. C. Cc 6. The compound according to claim 5, wherein: o Q is -CO 2 or -CONH-; 0 T is a valence bond, or -NHCH2-; O R 2 is an optionally substituted aryl ring having up to one L-W substituent and up to three R 8 substituents; R 3 is hydrogen; R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R 6 2 or -NR 6 (CH 2 R 6 is R 5 -(CH 2 )yCH(R 7 2 or -(CH 2 )yR 7 and R 7 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkylgroup.

7. The compound according to claim 1, having the formula: H N Q-R 4 0o R 3 N I R' L W R 8 V-A or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein said compound has one or more features selected from the group consisting of: Q is -C0 2 or -CONH-; R' is hydrogen or NHR; W is selected from R 9 CH(R 9 2 CH(R9)N(R 9 2 or N(R9)2; R 3 is hydrogen; 67 O 0 k R 8 is halogen, -NO 2 -CN, or -N(R 5 )2; R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R6)2, or -NR 6 (CH 2 ),N(R 6 2 R 6 is R 5 -(CH 2 )yCH(RT)2, or -(CH 2 )yR 7 and R 7 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, C I 5 heteroarylalkyl, heterocyclyl, heterocyclylalkyl group. o 9. The compound according to claim 8, wherein: I0 Q is -C0 2 or -CONH-; O R 1 is hydrogen or NHR; W is selected from R 9 CH(R 9 2 CH(R 9 )N(R 9 2 or N(R9)2; R 3 is hydrogen; R 8 is halogen, -NO 2 -CN, or -N(R)2; R 4 is selected from -R 6 -NH 2 -NHR 6 -N(R 6 2 or -NR 6 (CH 2 )yN(R6)2; R 6 is R 5 -(CH 2 )yCH(R')2, or -(CH 2 )yR 7 and R 7 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group. The compound according to claim 1, wherein said compound is selected from a compound of formula II-A, wherein T-R 2 and Q-R 4 are provided in Table 1: H N Q-R 4 T-R 2 II-A Table 1 No. T-R 2 Q-R 4 IA-1 phenyl CON(Me)2 IIA-2 2-chlorophenyl CONHCH 2 (Ph) IIA-3 2-chlorophenyl CO(morpholin-4-yl) IIA-4 .4-methoxyphenyl CONHCH 2 (pyridin-4-yl) I IA-5 3-fluorophenyl CONHCHz(pyridin-4-yl) IIA-6 3-methoxyphenyl CONHCH 2 (pyridin-4-yl) Va 0 0 ci 0 No. T-R 2 Q-R 4 IIA-7 2,5-dimethoxyphenyl CONHCH- 2 (pyridin-4-yl) I IA-8 3 ,4-difluorophenyl CONHCI- 2 (Pyridin-4-yI) I IA-9 2,3-difluorophenyl CONHCI- 2 (pyridin-4-yI) 2,5-difluorophenyl CONHCH 2 (pyridiri-4-yI) hI-1I 4-methoxyphenyl CONHCI-1(pyridin-3 -yi) IHA- 12 3-fluorophenyl CONHCH- 2 (pyridin-3-yl) IIA- 13 3 -methoxyphenyl CON I-CHII 2 (pyridiri-3 -yl) IhA- 14 2,5-dimerhoxyphenyl CON HCH 2 (pyrid in-3 -yI) 3 ,4-difluorophenyl CONHCH 2 (pyrid in-3 -yl) I IA- 16 2,3-difluorophenyl CONH Cl- 2 (pyridin-3 -yl) IA17 2,5-difluorophenyl CONHCH 2 (pyridin-3-yi) I IA-I8 4-methoxyphenyl CONHCH 2 (tetrahydrofuran-2-yi) I IA- 19 3-fluorophenyl CONHCH 2 (tatrahydrofuran-2-y i) I IA-20 3 -methoxyphenyl CONHCH 2 (t~trahydrofuran-2-yi) I IA-2 1 2,5-dimethoxyphenyl CONHCH 2 (tetrahydrofuran-2-yI) IIA-22 3 ,4-difluorophenyl CONHCH 2 (tetrahydrofuran-2-yI) I IA-23 2,3-difluorophenyl CONHCH 2 (tetrahydrofuran-2-yI) I IA-24 2,5-difluorophenyl CON HCH 2 (tetrahydrofuran-2-yI) 4-fluorophenyl CONHCH 2 I Et-pyrrolidin-2-yI) IIA-26 4-methoxyphenyl CON HCH 2 1 -Et-pyrrol id in-2-yI) IIA-27 3-fluorophenyl CONI-CH 2 l'-Et-pyrrolidiri-2-yI) II A-28 3-methoxyphenyl CONI-CH 2 -Et-pyrrol id in-2-yI) II A-29 2,5-dimethoxyphenyl CONI-CH 2 (I -Et-pyrrol id in-2-yI) 3,4-difluorophenyl CONI-ICH 2 I1.Et-pyrrol id in-2-yI) IIA-31I 2,3-difluarophenyl CONI-CH 2 I, Et-pyrrolid in-2-yl) IIA-32 2,5-difluorophenyl CONHC H 2 (1 IEt-pyrrolidin-2-yl) IIA-33 4-fluorophenyl CO(mo'rpholin-4-yI) IIA-34 4-methoxyphenyl CO(mo rpholin-4-yi) 3-fluorophenyl CO(morpholin-4-yl) I IA-36 3 -methoxyphenyl CO(morpholin-4-yi) IIA-37 2,5-dinwthoxyphenyl CO(morpholin-4-yI) IIA-38 2,3-difluorophenyl CO(mdrpholin-4-yI) I IA-3 2,5-difluorophenyl CO(mo Irphol in-4-yi) I IA-40 4-fluorophenyl CO(4-Me-piperazin- I -yl) Va 0 0 ci 0 No. -2 -4 IIlA-4 I 4-methoxyphenyl CO(4-Me-piperazin- I -yI) 1IIA-42 3 -fluorophenyl CO(4-Me-piperazin- Il-yI) I IA-43 3-methoxyphenyl CO(4-Me -piperazin-1-yl) I IA-44 2,5-dimethoxyphenyl CO(4-Me'4 1 piperazin- I-yI) I IA-45 2,3-di fluorophenyl CO(4-Mel-piperazin- I -yI) I IA-46 2,5-di fluorophenyl CO(4-Me-piperazin- I yl) I IA-47 3-chiorophenyl CONHCH 2 (pyridin-4-yI) I IA-48 3 -chlorophenyl CON I-CH 2 (pyrid in-3 -yI) I IA-49 3 -ch lorophenyl CONHCH 2 (t~trahydrofuran-2-yI) 3-chiorophenyl CON HC H 2 I 'Et-pyrrol idin-2-yi) IIA-51I 3-chiorophenyl CO(4-Me-piperazin- I-yl) I IA-52 4-chiarophenyl CON I-CH 2 (pyridin-4-yI) II A-53 4-chiorophenyl CON HCH 2 (pyridin-3 -yI) iIA-54 4-chiorophenyl CONH CH 2 (te trahydrofuran-2-yI) 4-chiorophenyl CON HCH 2 (I ,rEt-pyrrolidin-2-yi) IIA-56 4-chiorophenyl CO(morpholin-4-yl) II A-57 4-chiorophenyl CO(4-Me- piperazin- I -yl) I iA-58 3 ,4-dichlorophenyl CON HCH 2 (pyridin-3-yI) II A-59 3 ,4-dichlorophenyl CONHCH 2 (I -Et-pyr-rolid in-2-yI) II A-60 3 ,4-dichlorophenyl CO(morphol in-4-yl) IIA-61I 3,4-dichiorophenyl CO(4-NMetpiperazin- I -yl) II A-62 2-F-3 -ch lorophenyl CON HCH 2 (pyrid in-4-yI) II A-63 2-F-3 -chiorophenyl CON HCH 2 (pyridin-3 -yI) II A-64 2-F-3 -chiorophenyl CON HCH 2 (tetrahydrofuran-2-yi) II A-65 2-F-3-chlorophenyl CONHCH 2 I .Et-pyr-rolid in-2-yI) II A-66 2-F-3-ch lorophenyl CO(morphol in-4-yI) II A-67 2-F-3-ch lorophenyl CO(4-Me-piperazin- I -yl) II A-68 3 -C1-4-fluorophenyl CON 1ICH 2 (pyridin-4-yI) II A-69 3 -C1-4-fluorophenyl CON HCH 2 (pyrid in-3 -yI) 3 -CI-4-fluorophenyl CONHCH 2 (tetrahydrofuran-2-yI) I IA-71I 3 -Cl4-fluorophenyl CON HCH,( -Et-pyrrolidin-2-yI) II A-72 3-CI-4-fluorophenyl CO(moipo n--I I IA-73 3-CI-4-fluorophenyl CO(4-Me-piperazin- Il-yI) I IA-74 3 ,4-dimethoxyphenyl CONHCH 2 (pyridin-4-yI) Va 0 0 ci 0 No. T-R 2 I IA-75 3 ,4-dimethoxyphenyl CONHCH 2 (pyridin-3 -yI) I IA-76 3 ,4-dimethoxyphenyl CONHCH 2 (trahydrofuran-2-yI) IIA-77 3,4-dimethoxyphenyl CONHC- 2 I -Et-pyrrolidin-2-yI) I IA-78 3 ,4-dimethoxyphenyl CO(morphol in-4-yI) IIA-79 3,4-dimethoxyphenyl CO(4-M :piperazin- I-y I) 4-benzo[1I,3]dioxol-5-yI CONHC IH,(pyridin-4-yI) I IA-8 1 4-benzo[1I,3]dioxol-5-yI CON I-CI-I 2 pyrid in-3 -yI) I IA-82 4-benzo[1I,3]dioxol-5-yI CONHCL- 2 (etrahydrofuran-2-yi) IIA-83 4-benzo[I ,3]dioxol-5-yI CONHCFI 2 (1 -Et-pyrrolidin-2-yI) I IA-84 4-benzo[ I ,3]dioxol-5-yI CO(morphol in-4-yI) 4-bcnzo[ I ,3]dioxol-5-yI CO(4-Me-piperazin- I -yI) IIA-86 3,5-dichiorophenyl CONI-ICH- 2 (pyrid in-4-yl) I IA-87 3 ,5-dichlorophenyl CONI-CI- 2 (pyrid in-3 -yi) I IA-88 3 ,5-dichlorophenyl CONI-CH 2 (t~trahydrofuran-2-yI) I IA-89 3 ,5-dichlorophenyl CONHCH 2 i -Et-pyrrol idin-2-yI) 3 ,5-dichlorophenyl CO(morpholin-4-yI) I IA-9 1 3 ,5-dichlorophenyl CO(4-Me-piperazin- Il-yI) IIA-92 3-CI-4-SO 2 NFI 2 -phenyl CO(morphol in-4-yl) I IA-93 3-chiorophenyl CO(m'oSrpholin-4-yl) IIA-94 phenyl py ,ridin-4-yI 2-chiorophenyl morpholin-4-yl II A-96 2-chiorophenyl CH 2 (morpholin-4-yl) II A-97 4-methoxyphenyl CI- 2 (pyridin-4-yi) IIA-98 HI0 CI H N YtN N IIA-99 H IH I- IN ci N' 8 0 HH O Va 0 0 ci 0 No. T-R 2 QR4 0 IIII ~H HN OCH, 0 OMe IIA-10 NyLCHNf\ CI 0 IIA-102 N, NC3c H 0 CI3 II-0 N H HNA OH 3 00 0 IIA-103 N -fYNSH YVo 0I H IIA-104 A N N0H -ts 0 O 0 H HNACOl N\ IIA-105 H Nr OH 3 0I H IIA-106 phenyl KNt 0 IIA-107 phenyl t~ No II-O08 3,4-dimethoxyphenyl 0. hIA-i 10 3-chiorophenyl N Va 0 0 ci 0 No. T-R 2 Q- IhA-! 11I 3-methylphenyl IA-I 12 3-chiorophenyl k -C I IA-1 114 2-fluoro-3-chlorophenyl k -chiropeny!N H3 0 HIA-I 16 3,4uo-dehoyphenylN I 0 1 IA-I 17 3-ihoxphenyl 4 0 hIA-I 18 3,4-dimethoxyphenyl JN hIA-I 19 3-dmethoylphenyl U O hIA- 120 2-lo3,-iehorphenyl hA-1 121 2- o3-ehlophenyl N,,O Va 0 0 ci 0 No. T-R 2 Q-R 4 0 IIA-122 2-fluoro-3-chiorophenyl tN 0 IIA-123 3-chiorophenyl O H I IA-i124 3 ,4-dimethoxyphenyi O H I IA-i125 2-fluoro-3-chlorophenyl Z IIA-126 2-fluoro-3-chiorophenyi KN N IIA-1 27 3,4-dimethoxyphenyl a IjsKOi CH 3 OH hIA- 128 3,5-dichlorophenyl C,( VKN; OH H lEA- 129 3,5-dichlorophenyl 0 O H N_ N I1A-131 phenyl H 0 IIA-132 phenyl k Va 0 0 ci 0 No. T-R 2 IIA-133 phenyl Zr 0 IlA-134 phenyl N IIA- 135 3,4-dimethoxyphenyl i H hA.-136 IIA-136 3,4-dimethoxyphenyl Y'-N 0 IIA-137 3-dmethoyiphenyl YNm 0 IIA-138 3-methyipheny) 4AN 00 IIA-149 3-cehorphenyl t jI H IIA-140 3-cehrphenyl e IA- 144 2-lo3-chorophenyl tk 0 N IIA-142 3-chiorophenylZKN _H Va 0 0 ci 0 No. T-R 2 Q-R 4 IIA-146 3-chiorophenyl ,NN U IIA-147 phenyl 020 0 IIA-148 phenyl D YOmp IIA-149 3,4-dimethoxyphenyl k 0 IIA-150 3,4-dimethoxyphenyl II A- 151 3-methylphenyl O Q~f HIA- 152 3-methyiphenyl Y N CH 3 IIA-153 phenyl YN 0 IIA-154 phenyl OH IIA-155 phenyl N 0 IIA-i156 3,4-dimethoxyphenyl (DN N~ Va 0 0 ci 0 No. T-R 2 Q-R 4 hIA- 157 3,4-dimethoxyphenyl ke 0 hA-i 8 3-ethylheny IIA-i159 3-methylphenyl IIA- 160 3-cehlphenyl OH IIA-161 phenyl AS OH IIA-1 62 3-chlorophenylN IIA-163 3,4-dimethoxyphenylN 0N CH 3 0 IIA-164 3clphenyl NA~yO 1IA-16 pheyl N '~O OH3 IIA-165 phenyl Iu O 0 Va 0 0 ci 0 No. T-R 2 QR IIA-I 68 3,4-dimethoxyphenyl 0 IIA-I169 3,4-dimethoxyphenyl N hIA-1 70 3,4-dimethoxyphenyl IIA-171 3-methyiphenyl K O 0 QrkNh IIA-172 3-methyiphenyl (,N 0 IIA-173 3-methyiphenyl tN 0 IIA-174 3-methylphenyl 'a N 0 IIA-175 3-methyiphenyl ON CH 3 0 0 IIA-i177 2-fluoro-3-chiorophenyl k IIA-178 2-fluoro-3-chlorophenyl N OH Va 0 0 ci 0 No. T-R 2 9R IIA-179 2-fluoro-3-chlorophenyl N 0 II-1 80 2-fluoro-3-chlorophenyl N C H 3 OH IIA-1 82 -lphenylN 0 IIA-182 3-chiorophenyl 0 N IIA-183 3-chlorophenyl OHe IIA-i186 3-chlorophenylYN IIA-185~~ 3-hlrohey OH IIA-186 3-mehyirphenyl ZtkN 6H3 OH IIA-189 2-lo3-hlophenyl OHO I IA- 190 2-fl uoro-3 -chilorophenyl Va 0 0 ci 0 No. T-R 2 Q-R 4 &0 IIA-191 phenyl a O II A- 192 3 ,4-dimethoxyphenyl a O IA- 93 3-methyphenyl J NaOH 0 IIA-194 phenyl a N a compound of formula ITT-A, wherein R 1 and R3 are hydrogen and T-R 2 and Q are provided in Table 2: 4-R 4 R3 Ill-A Table 2 No. T-R 2 Q-R 4 lIIA-I phenyl CON(Me) 2 IIIA-2 2-chiorophenyl CONI-CH 2 (Ph) II IA-3 2-chiorophenyl CO(morpholin-4-yI) Ii IA-4 4-methoxyphenyl CONHCH 2 (pyridin-4-yI) II IA-5 3-fluorophenyl CON HCT- 2 (pyridin-4-yl) 11 IA-6 3 -methoxyphenyl CON HCH 2 (pyridin-4-yI) II IA-7 2,5-d imethoxyphenyl CON HCH2(pyridin-4-yI) II IA-S 3 ,4-difiuorophenyl CON HCI- 2 (pyridin-4-yI) Va 0 0 ci 0 No. T-R 2 -4 I11A-9 2,3-difluorophenyl CONHCH 2 (Pyridin-4-yl) II IA- 10 2,5-difluorophenyl CONHCH 2 (pyridin-4-yI) ilA-1I 4-methoxyphenyl CONHC H 2 (pyridin-3-yI) ilA- 12 3-fluorophenyl CONHCH 2 (pyridin-3-yI) II IA- 13 3 -methoxyphenyl CON HCH 2 (pyridin-3-yI) 11IIA- 14 2,5-dimethoxyphenyl CONHCH 2 (pyridin-3 -yI) II IA- 15 3,4-difluorophenyl CONHCH 2 (pyridin-3-yI) II IA- 16 2,3-difluorophenyL CONHCH 2 (pyridin-3-yI) II IA- 17 2,5-ditluorophenyl CON HCH 2 (pyridin-3 -yI) IIIA-1I8 4-methoxyphenyl CONHCI-1 2 tetrahydrofuran-2-yl) liA-01 2,5-difluorophenyl CONHC- 2 I -Et-pyrrolidin-2-yl) I IIA-20 4-fluorophenyl CO(torpholi n-4-yi) IIIA-21I 4-fluorophenyl CO(4-Me-piperazin- I-yl) a compound of formula IV-A, wherein R 3 provided in Table 3: is hydrogen and R, T-R 2 and Q-R 4 are H N Q-R 4 ST-R 2 HN, IV-A Table 3 No. Rt T-R 2 !1Q-R 4 IVA-1 H phenyl CON(NMe) 2 IVA-2 H _pjhenyl !-CO 2 Et IVA-3 H 3-N0 2 -phenyl CONHfNH 2 IVA-4 H phenyl CO(pyrrolidin- l-yl) Me phenyl CONHCH 2 (Ph) IVA-6 H 3-N0 2 -phenyl 'CO 2 Et Va 0 0 cxl 0 No. R T-R 2Q-R4 IVA-7 H 4-C 1-phenyl CO 2 Et IVA-8 Me 4-OMe-pheny1 CO 2 Et IVA-9 H 3-NH 2 -phenyl CO 2 Et H 3-OMe-phenyl CO 2 Et IVA-1I I H 4-F-phenyl CO 2 Et IVA-12 H 4-N0 2 -phenyl CO 2 Et IVA-13 Et 3-Cl-phenyI CO 2 Et IVA-14 H 3-F-phenyl CO 2 Et IVA- 15 H _phenyl C0 2 H IVA-16 Me 3-Ci-phenyl CONHCH 2 (pyridin-4-yl) IVA- 17 H H O IVA- 18 H 5-F-phenyl CON HCI-1 2 (etrahydro furan-2-yI) IVA-19 Me 5,6-Fr-phenyl CO(4-Me-piperidin- I-yI) H 4-Ci-phenyl CONHFCF 2 (pyrid-4-yI) O HN N IVA-2 1 H 4,5-(OMe) 2 -phenyl 0 OH3CCH3 IVA-22 Me 4,5-C1 2 -phenyl 0 Ct-' IV-3 H 3-CI-phenyl O0 o OH IVA-24 H 3-CI-phenyl NHC 'A Me 3,5-C1 2 -phenyl N CI IVA-26 H 0 O 0 CI H IVA-2 H9,H 'ACON(Me) 2 IVA-27 H N 6 ci Va 0 0 ci 0 R L- or a compound of formnula V-A, wherein R 3 is hydrogen and Q-R 4 are provided in Table 4: V-A Table 4 No. R1Q-R 4 VA-I H IC NH 2 CON(Me) 2 VA-2 HN_)C2t VA-3 H N ~C 3 CONHNH 2 00 %rkN C1 VA-4 NHMe NH~H CI CI HO N H 00 NHMe N N 'A-3k N C H VA-6 NHMe N N 'qMe II H Va 0 0 ci 0 O 0 O No. R' Q-R 4 oO HN N VA-17 NH 2 K O-^N CH 3 NN _Me H S a 0 H 3 C C H 3 SVA-18 NH 2 N OEt O cH O VA-19 H N -CH3 OH OH 00 H N_ O 0 VA-21 H oI0 OHH OH H VA-22 Me O NCH, CO Me O CI r N SO2Me H O SM u ^H 0

11. A composition comprising a compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier.

12. The composition according to claim 11, further comprising an additional therapeutic agent. r 00 13. A method of inhibiting ERK or AKT activity in a biological sample, comprising the step of contacting said Sbiological sample with a compound according to any one of claims 1-10 or a composition comprising said compound. IO

14. Use of a compound according to any one of claims 1- C-i 10 for the preparation of a medicament for the treatment Sof an ERK-mediated disease in a patient. ND 10 15. A method of treating an ERK-mediated disease in a patient, said method comprising the step of administering to said patient the compound according to any one of claims 1-10 or the composition according to claim 11.

16. The method according to claim 15, wherein said composition further comprises an additional therapeutic agent.

17. Use of a compound according to any one of claims 1- 10 for the preparation of a medicament for the treatment of a disease in a patient, wherein said disease is selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, or pathologic immune conditions involving T cell activation. -86- 00 18. A method of treating a disease in a patient said 0 method comprising the step of administering to said (N Spatient the compound according to any one of claims 1-10 or the composition of claim 11 or claim 12, wherein said ND 5 disease is selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's C-q disease, cystic fibrosis, viral disease, autoimmune Sdiseases, atherosclerosis, restenosis, psoriasis, Sallergic disorders, inflammation, neurological disorders, \Q 10 a hormone-related disease, conditions associated with Sorgan transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, or pathologic immune conditions involving T cell activation.

19. The method according to claim 18, wherein the disease is cancer. The method according to claim 19, wherein said cancer is selected from 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, 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- -87- 00 rectum, large intestine, rectum; brain and central 0 nervous system; or leukemia.

21. The method according to either of claims 19 or IO 5 wherein said composition further comprises a chemotherapeutic agent.

22. The method according to claim 18, wherein the Sdisease is an autoimmune disease. (N O S23. The method according to claim 22, wherein said (N autoimmune disease is selected from psoriasis, SLE Lupus, cystic fibrosis, or conditions associated with organ transplantation.

24. The method according to claim 18, wherein the disease is a neurodegenerative disease. The method according to claim 24, wherein said neurodegenerative disease is selected from Alzheimer's Disease, Parkinson's Disease, ALS, epilepsy and seizures, Huntington's disease, or stroke.

26. The method according to claim 18, wherein the disease is a cardiovascular disease.

27. The method according to claim 26, wherein said cardiovascular disease is selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure.

28. The method according to either of claims 26 or 27, wherein said composition further comprises a therapeutic agent for treating cardiovascular disease. -88- 00 0 29. The method according to claim 18, wherein the (N Sdisease is an inflammatory disease. 0 5 30. The method according to claim 29, wherein said inflammatory disease is selected from asthma, rheumatoid C arthritis, or atopic dermatitis. S31. The method according to claim 18, wherein the (N ND 10 disease is a liver disease. (N

32. The method according to claim 31, wherein said liver disease is selected from hepatomegaly or hepatic ischemia.

33. A composition for coating an implantable device comprising a compound according to any one of claims 1 to and a carrier suitable for coating said implantable device.

34. An implantable device coated with a composition according to claim 33. A compound of formula II-A or III-A as defined in claim 1 and substantially as hereinbefore described in one or more of the accompanying examples.

36. A method of treating an ERK-mediated disease in a patient or a disease selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions -89- 00 associated with organ transplantation, immunodeficiency 0 disorders, destructive bone disorders, proliferative (N Sdisorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, IO 5 chronic myelogenous leukemia (CML), liver disease, or pathologic immune conditions involving T cell activation, C-i said method comprising the step of administering to said Spatient the compound according to claim \O 10 Dated this 16 t h day of April 2008