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    • 专利摘要:
    The present invention relates to compounds of formula (I) useful as protein kinase inhibitors. Formula I In Formula I above, Z 1 and Z 2 are each independently nitrogen or CH, Rings A, T m R 1 , QR 2 , U n R 3 and Sp are as described in the specification. The compounds are particularly useful as inhibitors of ERK2 and are useful for treating diseases of mammals that can be alleviated by protein kinase inhibitors, in particular diseases such as cancer, inflammatory diseases, restenosis, diabetes and cardiovascular diseases.
    公开号:KR20030074814A
    申请号:KR10-2003-7010503
    申请日:2002-02-08
    公开日:2003-09-19
    发明作者:차오징룽；그린제레미；헤일마이클；말타이프랑소와；스트럽쥬디；탕칭；아로노프알렉스
    申请人:버텍스 파마슈티칼스 인코포레이티드；
    IPC主号:
    专利说明:

    Heterocyclic inhibitors of ER2 and uses thereof
    [1] Cross Reference of Related Application
    [2] This application claims priority documents of US Provisional Application No. 60 / 267,818, filed February 9, 2001 and US Provisional Application No. 60 / 328,768, filed October 12, 2001, which is incorporated by reference in its entirety. .
    [4] Mammalian mitogen activating protein (MAP) 1 kinase is a serine / threonine kinase that mediates intracellular signal transduction pathways. Cobb and Goldsmith, 1995, J Biol. Chem., 270 , 14843; Davis, 1995, Mol. Reprod. Dev. 42 , 459. MAP kinase lineages share sequence similarity and maintained structural domains and include ERK2 (extracellular signal regulated kinase), JNK (Jun N-terminal kinase) and p38 kinase. JNK and p38 kinases are activated in response to pro-inflammatory cytokines TNF-α and interleukin-1, and by cellular stresses such as heat shock, hyperosmoemia, ultraviolet radiation, lipopolysaccharides, and protein synthesis inhibitors. 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, ERK is activated by mitogen and growth factors (Bokemeyer et al., 1996, Kidney Int. 49 , 1187).
    [5] ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thr183 and Tyr185 are phosphorylated by the upstream MAP kinase kinase, MEK1 (See Anderson et al., 1990, Nature 343 , 651; Crews et al. , 1992, Science 258 , 478). Upon activation, ERK2 contains a number of protein kinases Rsk90 (Bjorbaek et al., 1995, J. Biol. Chem. 270 , 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78 , 1027). Regulatory Proteins and ATF2 (Raingeaud et al., 1996, Mol. Cell Biol. 16 , 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc) Transcription factors such as Natl.Acad. Sci. USA 90 , 10952) and c-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210 , 162). ERK2 is also a down target of Ras / Raf dependent pathways (Moodie et al., 1993, Science 260 , 1658) and can help to alternate signals from these potentially carcinogenic proteins. ERK2 has been shown to play a role in negative growth regulation of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57 , 628), and overexpression of ERK2 in human breast cancers has been reported (Sivaraman et al. , 1997, J Clin. Invest. 99 , 1478). Activated ERK2 is also involved in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting the role of these kinases in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16 , 589).
    [6] Aurora-2 is a serine / threonine protein kinase that has been linked to human cancers such as colon, breast and other solid tumors. This kinase is considered to be involved in protein phosphorylation results that regulate the cell cycle. In particular, Aurora-2 may play a role in regulating the precise separation of chromosomes during mitosis. Deregulation of the cell cycle can cause cellular proliferation and other abnormalities. In human colon cancer tissues, Aurora-2 protein has been found to be overexpressed. Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.
    [7] Glycogen synthase kinase-3 (GSK-3) is a serine / threonine protein kinase consisting of α and β isoforms, each encoded by separate genes. Coghlan et al., Chemistry & Biology, 7 , 793- 803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10 , 508-514 (2000)]. GSK-3 is involved in a variety of diseases including diabetes mellitus, Alzheimer's disease, CNS diseases such as mood swings and neurodegenerative diseases, and cardiomyocete hypertrophy (see WO 99/65897; WO 00/38675; And Haq et al., J. Cell Biol. (2000) 151,117 . Such diseases may be caused by, or induce aberrant dysfunction of the specific cellular signaling pathways on which GSK-3 acts. GSK-3 has been found to phosphorylate to regulate the activity of many regulatory proteins. These proteins include glycogen synthase, microtubule-associated protein Tau, gene transcription factor β-catenin, translation initiation factor elF2B, as well as ATP citrate cleavage enzymes, axin, heat shock factor-1, and c, which are required for glycogen synthesis. -Jun, c-Myc, c-Myb, CREB and CEPBα. These various protein targets involve GSK-3 in many aspects of cell metabolism, proliferation, differentiation and development.
    [8] In a GSK-3 mediated pathway suitable for treating Type II diabetes, insulin induced signaling leads to cellular glucose uptake and glycogen synthesis. According to this pathway, GSK-3 is a negative regulator of insulin induced signals. In general, the presence of insulin inhibits GSK-3 mediated phosphorylation and inactivates glycogen synthase. Inhibition of GSK-3 results in increased glycogen synthesis and glucose uptake (Klein et al., PNAS, 93 , 8455-9 (1996); Cross et al., Biochem. J., 303 , 21-26 (1994); Cohen, Biochem. Soc. Trans., 21 , 555-567 (1993); Massillon et al., Biochem J. 299 , 123-128 (1994). However, in diabetic patients with impaired insulin responses, despite relatively high blood insulin concentrations, glycogen synthesis and glucose uptake cannot be increased. This eventually leads to abnormally high blood glucose levels with acute long-term action, which can lead to cardiovascular disease, kidney failure and blindness. In such patients, normal insulin induced inhibition of GSK-3 cannot occur. In addition, in patients with type II diabetes, GSK-3 has been reported to be overexpressed (WO 00/38675). Thus, therapeutic inhibitors of GSK-3 are considered useful for treating diabetic patients suffering from impaired responses to insulin.
    [9] GSK-3 activity has also been linked to Alzheimer's disease. This disease is characterized by the formation of well-known β-amyloid peptides and intracellular neurofibrillary tangles. Nerve fiber concentrates contain hyperphosphorylated Tau protein, in which Tau is phosphorylated at the abnormal site. GSK-3 has been shown to phosphorylate at these abnormal positions in cellular and animal models. In addition, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells (Lovestone et al., Current Biology 4 , 1077-86 (1994); Brownlees et al., Neuroreport 8 , 3251-55 (1997). Thus, GSK-3 activity is believed to be able to promote the production of neurofibrillary concentrates and the progression of Alzheimer's disease.
    [10] Another substrate of GSK-3 is β-catenin, which degrades after phosphorylation by GSK-3. It has been reported that β-catenin concentrations are reduced in schizophrenic patients, and the reduced β-catenin concentrations have also been associated with other diseases associated with increased neuronal cell death. Zhong et al., Nature, 395 , 698-702 (1998); Takashima et al., PNAS, 90 , 7789-93 (1993); Pei et al., J. Neuropathol. Exp 56 , 70-78 (1997)].
    [11] As a result of the biological importance of GSK-3, therapeutically effective GSK-3 inhibitors are currently of interest. Small molecules that inhibit GSK-3 have recently been reported (see WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)).
    [12] Aryl substituted pyrroles are known in the literature. In particular, tri-aryl pyrrole (see US Pat. No. 5,837,719) is described as having glucagon antagonist activity. 1,5-Diarylpyrazole is described as a p38 inhibitor (see WO 9958523).
    [13] There is a very unmet medical need to develop new therapies useful for treating various conditions related to ERK2 activation. For many of these conditions, currently available treatment options are inadequate.
    [14] Therefore, there is a great interest in new and effective inhibitors of protein kinases, including ERK2 inhibitors, useful for treating various conditions associated with protein kinase activation.
    [3] FIELD OF THE INVENTION The present invention relates to the field of pharmaceutical chemistry, in particular pyrazole compounds which are inhibitors of protein kinase inhibitors, in particular ERK, compositions containing such compounds and methods of use thereof. The compounds are useful for the treatment of cancer and other diseases that are alleviated by protein kinase inhibitors.
    [15] It has now been found that the compounds of the present invention and compositions thereof are effective as protein kinase inhibitors, in particular as inhibitors of ERK2. Such compounds correspond to compounds of formula (I) or pharmaceutically acceptable derivatives thereof:
    [16]
    [17] In Formula I above,
    [18] Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Rings A and QR 2 are bonded to Sp at non-adjacent positions, Sp has up to 2 R 6 substituents, provided that 2 substitutions in Sp Possible carbocyclic atoms are not substituted at the same time with R 6 ;
    [19] Z 1 and Z 2 are each independently selected from N and CH;
    [20] T and Q are each independently selected from a binding group;
    [21] U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    [22] m and n are each independently 0 or 1;
    [23] R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    [24] R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 ,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , -N (R 4 ) 2 And -NR 4 (CH 2 ) y N (R 4 ) 2 ;
    [25] y is 0 to 6;
    [26] R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    [27] Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    [28] R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    [29] R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [30] R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [31] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [32] R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    [33] w is each independently selected from 0-4.
    [34] As used herein, unless otherwise stated, the following definitions apply. The phrase "optionally substituted" is used interchangeably with the term "substituted or unsubstituted" and the term "(un) substituted". Unless stated otherwise, an optionally substituted group may have a substituent at each substitutable position of the group, and each substituent is independent of each other.
    [35] As used herein, the term “aliphatic” or “aliphatic group” includes straight or branched C 1 -C 12 hydrocarbon chains that are fully saturated or contain one or more unsaturated units, or contain one or more unsaturated units that are not fully saturated or aromatic ( Also referred to herein as “carbocycle” or “cycloalkyl”), monocyclic C 3 -C 8 hydrocarbons or acyclic C 8 -C 12 hydrocarbons, wherein bicyclic has a single point of attachment to the rest of the molecule Individual rings in the click ring system have 3 to 7 circles). For example, suitable aliphatic groups include straight or branched chains or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl However, it is not limited thereto.
    [36] The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl" and "alkoxycarbonyl" used alone or as part of a macro moiety refer to both straight and branched chains containing 1 to 12 carbon atoms. Include. The terms "alkenyl" and "alkynyl", used alone or as part of a macro moiety, include both straight and branched chains containing 2 to 12 carbon atoms.
    [37] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean alkyl, alkenyl or alkoxy which may be optionally substituted with one or more halogen atoms. The term "halogen" means F, C1, Br or I.
    [38] The term "hetero atom" means nitrogen, oxygen or sulfur and includes oxidized forms of nitrogen and sulfur and quaternized forms of basic nitrogen. The term "nitrogen" also includes substitutable nitrogens of heterocyclic rings. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (p As in rolledinyl) or NR + (as in N-substituted pyrrolidinyl).
    [39] The term "aryl", used alone or as part of a macro moiety, is a monocyclic, bicyclic having a total of 5 to 14 ring members as in "aralkyl", "aralkoxy" or "aryloxyalkyl" And tricyclic ring systems, wherein at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring".
    [40] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein refers to 5 to 14 rings, wherein at least one ring member is a hetero atom and each ring in the system contains 3 to 7 ring members. By non-aromatic, monocyclic, bicyclic or tricyclic ring system having a circle.
    [41] The term “heteroaryl”, used alone or as part of a macro moiety, refers to monocyclic, bicyclic and tricyclic having a total of 5 to 14 ring members as in “heteroaralkyl” or “heteroarylalkoxy”. Means a click ring system, wherein at least one ring in the system contains at least one hetero atom as aromatic, and each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
    [42] The aryl (including aralkyl, aralkoxy, aryloxyalkyl, etc.) or heteroaryl (including heteroaralkyl, heteroarylalkoxy, etc.) groups may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl or heteroaralkyl group are halogen, -R 0 , -OR 0 , -SR 0 , 1,2-methylene-dioxy, 1,2-ethylenedioxy , Protected OH (e.g. acyloxy), phenyl (Ph), substituted Ph substituted with R 0 , -O (Ph), O- (Ph) substituted with R 0 , -CH 2 (Ph), R the -CH 2 (Ph) optionally substituted with 0, -CH 2 CH 2 (Ph ), a -CH 2 CH 2 (Ph), -NO 2, -CN, -N (R 0) is substituted by R 0 2, - NR 0 C (O) R 0 , -NR 0 C (O) N (R 0 ) 2 , -NR 0 CO 2 R 0 , -NR 0 NR 0 C (O) R 0 , -NR 0 NR 0 C ( O) N (R 0 ) 2 , -NR 0 NR 0 C0 2 R 0 , -C (O) C (O) R 0 , -C (O) CH 2 C (O) R 0 , -CO 2 R 0 , -C (O) R 0 , -C (O) N (R 0 ) 2 , -OC (O) N (R 0 ) 2 , -S (0) 2 R 0 , -SO 2 N (R 0 ) 2 , -S (O) R 0 , -NR 0 SO 2 N (R 0 ) 2 , -NR 0 SO 2 R 0 , -C (= S) N (R 0 ) 2 , -C (= NH)- N (R 0 ) 2 ,-(CH 2 ) y NHC (O) R 0 and-(CH 2 ) yNHC (O) CH (VR 0 ) (R 0 ), wherein R 0 are each independently hydrogen , Optionally substituted C 1-6 aliphatic group, unsubstituted May to June heteroa Aryl or heterocyclic ring, phenyl (Ph), —O (Ph) and —CH 2 (Ph) —CH 2 (Ph), y is 0 to 6 and V is a bonding group. Substituents on aliphatic groups of R 0 are NH 2 , NH (C 1-4 aliphatic), N (C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic groups, OH, O- (C 1-4 aliphatic) , N0 2 , CN, CO 2 H, C0 2 (C 1-4 aliphatic), -0 (halo C 1-4 aliphatic) and halo C 1-4 aliphatic.
    [43] Aliphatic groups or non-aromatic heterocyclic rings may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or nonaromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of the aryl or heteroaryl group, and are as follows: = O, = S, = NNHR * , = NN (R * ) 2 , = N-, = NNHC (O) R * , = NNHC0 2 (alkyl), = NNHS0 2 (alkyl) or = NR * (where R * are each independently hydrogen and optionally substituted C 1- 6 aliphatic). Substituents on aliphatic groups of R * are NH 2 , NH (C 1-4 aliphatic), N (C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic groups, OH, O- (C 1-4 aliphatic) , N0 2 , CN, CO 2 H, C0 2 (C 1-4 aliphatic), -0 (halo C 1-4 aliphatic) and halo C 1-4 aliphatic.
    [44] The non-aromatic heterocyclic ring on the nitrogen side of the substituent is -R + , -N (R + ) 2 , -C (O) R + , -CO 2 R + , -C (O) C (O) R + ,- C (O) CH 2 C (O) R + , -SO 2 R + , -SO 2 N (R + ) 2 , -C (= S) N (R + ) 2 , -C (= NH) -N (R + ) 2 and -NR + SO 2 R + , where R + is hydrogen, optionally substituted C 1-6 aliphatic group, optionally substituted phenyl (Ph), optionally substituted -O (Ph), optionally substituted -CH 2 (Ph), optionally substituted -CH 2 CH 2 (Ph) or unsubstituted 5 to 6 membered heteroaryl or heterocyclic ring). Substituents on aliphatic groups or phenyl rings of R + are NH 2 , NH (C 1-4 aliphatic), N (C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic groups, OH, O- (C 1- 4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), —O (halo C 1-4 aliphatic), and halo C 1-4 aliphatic.
    [45] The term "alkylidene chain" means an optionally substituted straight or branched carbon chain which may be fully saturated or may have one or more unsaturated units. Optional substituents are the same as described above for aliphatic groups.
    [46] The term "spacer group" refers to a group that isolates and adapts other moieties bound thereto such that the compound advantageously interacts with functional groups in the active site of the enzyme. As used herein, spacer groups separate and adapt Ring A and QR 2 within the active site so that they can form advantageous interactions with functional groups present in the active site of the ERK2 enzyme. When the spacer group is a five-membered heteroaromatic ring, rings A and QR 2 bind to nonadjacent positions “B” and “C” as illustrated below, and the five-membered ring is linked to ring A at point “D”, and “E” At the point it is coupled to QR 2 .
    [47]
    [48] Preferably, the distance between "D" and "C" is 3.7 ms, the distance between "D" and "E" is 5.O ms, the distance between "B" and "C" is 2.2 ms and "B" and "E". The distance of "is 3.5 microseconds, and the said distances are each ± 0.2 microseconds.
    [49] The spacer group itself may also form further interactions within the active site, further enhancing the inhibitory activity of the compound. For example, when Sp is pyrrole, pyrrole-NH can form additional hydrogen bonds within the active site of the ERK2 enzyme.
    [50] The term "binding group" refers to an organic moiety that connects two parts of a compound. The binder typically consists of atoms such as oxygen or sulfur, units such as —NH—, —CH 2 —, —CO—, or chains of atoms such as alkylidene chains. The molecular mass of the binder is usually in the range of about 14 to 200. Examples of binders include optionally substituted saturated or unsaturated C 1-6 alkylidene chains, wherein up to two saturated carbons in the chain are optionally -C (O)-, -C (O) C (O) -, -CONR 7 , -CONR 7 NR 7- , -CO 2- , -OC (O)-, -NR 7 CO 2- , -O-, -NR 7 CONR 7- , -OC (O) NR 7 -, -NR 7 NR 7- , -NR 7 CO-, -S-, -SO-, -SO 2- , -NR 7- , -SO 2 NR 7 -or -NR 7 S0 2- .
    [51] As used herein, binding group Q binds Sp and R 2 . Q may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. Q is -C (0)-, -C0 2- , -OC (O)-, -C (O) C (O)-, -CONH-, -C0 2 NH-, -CONHNH-, -NHCO-, -OC (O) NH-, or -NHCO 2 - carbonyl-containing moiety, such as, or -S0 2 -, -SO 2 NH- or -NHSO 2 - when a sulfonyl-containing glass, such as the date, the carbonyl or sulfonyl oxygen Forms a hydrogen bond with lysine 54 at the ERK2 binding position. When Q is an NH containing moiety such as -CH 2 NH- or -NHNH-, the NH-group forms a hydrogen bond with aspartic acid residue 167 at the ERK2 binding position. When Q is an alkyl chain, a hydrophobic group such as -0- or -S-, Q forms additional hydrophobic interactions within the ERK2 binding site.
    [52] R 2 forms a hydrophobic interaction with the side chain carbons of lysine 54 and aspartic acid 167 in particular within the binding site of ERK2. R 2 may also form hydrophobic interactions with glycine rich loops consisting of amino acid residues 33 to 38. When R 2 is substituted, the substituents can form additional interactions within the binding site to enhance the inhibitory activity of the compound. For example, when the substituent on R 2 is a hydrogen bond donor or hydrogen bond acceptor, the above substituents form a hydrogen bond with an enzymatically bound water molecule present within the bond site.
    [53] As used herein, the binding group T, when present, binds Sp and R 1 . T can also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. T is -CO-, -CO 2 -, -OCO-, -COCO-, -CONH-, -CO 2 NH-, -CONHNH-, -NHCO- , or -NHCO 2 - carbonyl-containing group, such as, or - In the case of sulfonyl containing groups such as S0 2- , -S0 2 NH- or -NHS0 2- , carbonyl or sulfonyl oxygen forms a hydrogen bond with the NH of glutamine 105 at the ERK2 binding position. When T is an NH containing group such as -CH 2 NH- or -NHNH-, the NH group forms a hydrogen bond with the carbonyl of glutamine 105. When T is an alkyl chain, a hydrophobic group such as -0- or -S-, T forms additional hydrophobic interactions with glutamine 105 as well as the side chain carbons of isoleucine 84.
    [54] Binding interactions between the compounds of the invention described herein and the ERK2 binding sites are measured by molecular modeling programs known to those skilled in the art. Such molecular modeling programs include QUANTA (Molecular Simulations, Inc., Burlington, Mass., 1992) and SYBYL (Molecular Modeling Software, Tripos Associates, Inc., St. Louis, Mo., 1992]. As used herein, amino acid numbering for the ERK2 enzyme corresponds to the Swiss-Prot database description for Accession # P28482. The Swiss-Froat database is an international protein sequence database distributed by the European Biotechnology Institute (EBI), Geneva, Switzerland. The database is an Internet address www. ebi. ac. You can find it at uk / swissprot.
    [55] Compounds of the present invention are limited to chemically suitable and stable compounds. Thus, the combination of substituents or variables in such compounds is only allowed if such combinations lead to stable or chemically suitable compounds. Stable compounds or chemically suitable compounds are those in which the chemical structure does not substantially change upon standing for at least one week in the absence of moisture and other chemically reactive conditions at temperatures below 40 ° C.
    [56] Unless stated otherwise, a structure described herein also means including all stereochemical forms of the structure, ie, the R and S configuration for each asymmetric center. Thus, enantiomeric and diastereomeric mixtures as well as the single stereochemical isomers of the present invention are included within the scope of the present invention. Unless stated otherwise, it is meant that the structures described herein also include different compounds only in the presence of one or more isotope-rich atoms. For example, within the scope of the present invention are compounds having structures present other than when hydrogen is substituted by dihydrogen or tritium or carbon is substituted by 13 C- or 14 C-rich carbon.
    [57] The compound of formula (I) or salt thereof can be formulated into a composition. In a preferred embodiment, the composition is a pharmaceutically acceptable composition. In one embodiment, the composition comprises an amount of protein kinase inhibitor effective to inhibit protein kinase, particularly ERK-2, in a biological sample or patient. In another embodiment, a pharmaceutical composition comprising a compound of the invention, and a pharmaceutical composition comprising an amount of a protein kinase inhibitor effective to treat or inhibit an ERK-2 mediated condition and a pharmaceutically acceptable carrier, adjuvant or vehicle Can be formulated for administration.
    [58] The term "patient" includes human and veterinary subjects.
    [59] As used herein, the term "biological sample" refers to cell cultures or extracts thereof, enzyme preparations suitable for in vitro assays; Biopsied materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.
    [60] Another aspect of the invention involves administering to a patient suffering from an ERK-2 mediated disease a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable composition comprising the compound. The present invention relates to a method of treating or suppressing a disease.
    [61] As used herein, the term "ERK-2 mediated symptoms" or "diseases" means diseases or other deleterious symptoms in which ERK-2 is known to play a role. The term "ERK-2 mediated symptom" or "disease" also means a disease or condition that is alleviated by treatment with an ERK-2 inhibitor. These symptoms include cardiovascular diseases including cancer, seizures, diabetes, hepatomegaly, cardiac hypertrophy, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic diseases including asthma, Inflammation, nervous system disorders and hormone related diseases. The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratin Polar cell carcinoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papilloma carcinoma, normal carcinoma, melanoma, sarcoma, Bladder Carcinoma, Liver Carcinoma, Bile Passage, Kidney Carcinoma, Bone Marrow Disease, Lymphoid Disease, Hodgkin's Disease, Hairy Cell Carcinoma, Narrow Cavity and Pharyngeal Cancer (Oral), Thoracic Cancer, Sulfur Cancer, Oral Cancer, Pharyngeal Cancer, Small Intestine Cancer , Colon-rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer and leukemia.
    [62] The methods of the present invention are particularly useful for treating diseases that are alleviated by using ERK-2 or other protein kinases. Although compounds of the invention have been designed as ERK-2 inhibitors, it has been found that certain compounds of the invention also inhibit other protein kinases such as GSK-3, Aurora-2, Lck, CDK-2 and AKT-3.
    [63] Another aspect of the invention relates to a method of inhibiting ERK-2 activity in a biological sample, including contacting the biological sample with a compound of formula (I) or a pharmaceutically acceptable composition comprising the compound.
    [64] Another aspect of the invention relates to a method of inhibiting ERK-2 activity in a patient, comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable composition comprising the compound.
    [65] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable composition comprising the compound to a patient suffering from Aurora-2 mediated disease. The present invention relates to a method of treating or suppressing a disease.
    [66] As used herein, the term "aurora-2 mediated symptom" or "disease" means a particular disease or other deleterious condition in which it is known to play a role. The term “aurora-2 mediated symptom” or “disease” also means a disease or condition that is alleviated by treatment with an Aurora-2 inhibitor. Such symptoms include, but are not limited to cancer. The term "cancer" includes, but is not limited to, colon cancer, breast cancer, gastric cancer and ovarian cancer.
    [67] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in a biological sample, including contacting the biological sample with a compound of formula (I) or a pharmaceutically acceptable composition comprising the compound.
    [68] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of Formula I or a pharmaceutically acceptable composition comprising the compound.
    [69] Another aspect of the invention comprises administering a therapeutically effective compound of formula (I) or a pharmaceutically acceptable composition comprising the compound to a patient suffering from GSK-3 mediated disease, wherein GSK-3 A method of treating or inhibiting a mediated disease.
    [70] As used herein, the term "GSK-3 mediated symptoms" or "diseases" refers to certain diseases or other harmful symptoms or situations in which GSK-3 is known to play a role. These diseases or conditions include diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, mycotic thickening, reperfusion / ischemia and alopecia, This is not restrictive.
    [71] One aspect of the invention is directed to a method of improving glucose synthesis and / or lowering blood glucose levels in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable composition thereof. It is about. The method is particularly useful for diabetics. Another method relates to a method of inhibiting the production of hyperphosphorylated Tau protein, which is useful for inhibiting or alleviating the progression of Alzheimer's disease. Another method relates to a method of inhibiting phosphorylation of β-catenin useful for treating schizophrenia.
    [72] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in a biological sample, including contacting the biological sample with a compound of formula (I).
    [73] Another aspect of the invention relates to a method of inhibiting a patient's GSK-3 activity, comprising administering to a patient a compound of Formula (I) or a pharmaceutically acceptable composition comprising the compound.
    [74] Inhibiting ERK-2, Aurora-2, CDK-2, GSK-3, Lck or AKT-3 kinase activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of this purpose include, but are not limited to, transfusion, organ transplantation, biological sample storage, and biological assays.
    [75] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" means a non-toxic carrier, adjuvant or vehicle that, together with a compound of the present invention, can be administered to a patient without disrupting its pharmacological activity.
    [76] An amount effective to inhibit protein kinases, such as Aurora-2 and GSK-3, is an amount that inhibits the determination of kinase activity as compared to the activity of the enzyme in the absence of the inhibitor. In determining the inhibition rate, methods such as, for example, the biological test examples described below can be used.
    [77] Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, Potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, for example protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pi Lollidon, cellulose based materials, polyethylene glycols, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycols and wool.
    [78] The compositions of the present invention may be administered via oral, parenteral, inhalational spray, topical, rectal, nasal, intraoral, vaginal or inserted reservoirs. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intraarticular, synovial, intrasternal, intradural, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously.
    [79] Sterile injectable formulations of the compositions of the invention may be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques well known in the art. Sterile injectable preparations may also be present as sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, non-irritating nonvolatile oils including synthetic mono- or di-glycerides can be used. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, such as pharmaceutically acceptable natural oils such as olive oil or castor oil. These oil solutions or suspensions may also contain long chain alcohol diluents or dispersants, such as carboxymethyl cellulose, or similar dispersants conventionally used in the formulation of pharmaceutically acceptable dosage forms comprising emulsions or suspending agents. . Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used to prepare pharmaceutically acceptable solids, liquids or other dosage forms are also included. It can be used for formulation purposes.
    [80] The pharmaceutical compositions of the present invention may be administered orally in orally acceptable dosage forms, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants, for example magnesium stearate, are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspending agent is required for oral use, the active ingredient is mixed with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
    [81] Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. They can be prepared by mixing the formulation with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cacao oil, beeswax and polyethylene glycols.
    [82] The pharmaceutical compositions of the present invention may also be administered topically, especially when the therapeutic target comprises a region or organ readily accessible for topical application, including eye, skin or lower intestinal disease. Suitable topical formulations for each of these areas or organs are readily prepared.
    [83] Topical application to the lower intestine can be carried out in rectal suppository formulations (see above) or in suitable enema formulations. Topical-transdermal patches may also be used.
    [84] For topical application, the pharmaceutical composition may be formulated with a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
    [85] For ophthalmic use, the pharmaceutical composition is formulated as a finely divided suspension in isotonic pH adjusted sterile saline with or without preservatives such as benzylalkonium chloride, or preferably as a solution in isotonic pH adjusted sterile saline. Can be converted. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.
    [86] The pharmaceutical compositions of the present invention may also be administered by inhalation or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and brine using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants It can be prepared as an aqueous solution.
    [87] In addition to the compounds of the present invention, pharmaceutically acceptable derivatives of the compounds of the present invention may also be used in the compositions to treat or inhibit the diseases or disorders identified above.
    [88] A “pharmaceutically acceptable derivative” is a pharmaceutically acceptable salt, ester, ester of a compound of the invention which, when administered to a recipient, can provide, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof. Salts or other derivatives thereof. Particularly preferred derivatives are those which increase the bioavailability of the compound when administered to a patient (e.g., orally administered so that the compound is more readily absorbed into the blood) or the biological compartment of the parent compound (e.g. brain Or lymphatic system).
    [89] Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dode Sulphate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydro Oxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, Phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfes Nitrate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic acid, are basically not pharmaceutically acceptable, but can be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
    [90] Salts derived from suitable bases include alkali metal (eg sodium and potassium), alkaline earth metal (eg magnesium), ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also contemplates quaternization of certain basic nitrogen containing groups of the compounds described herein. Water or oil soluble or dispersible products can be obtained by such quaternization.
    [91] The amount of protein kinase inhibitor that can be mixed with the carrier material to produce a single dosage form will vary depending on the patient to be treated and the particular mode of administration. Preferably, the composition should be formulated such that the inhibitor can be administered to a patient receiving such composition at a dosage of 0.01 to 100 mg / kg body weight per day.
    [92] Specific dosages and treatment regimens for particular patients determine the activity, age, weight, general state of health, sex, diet, time of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated for the particular compound used. It should also be understood that it depends on the various factors involved. The amount of inhibitor also depends on the particular compound in the composition.
    [93] Kinase inhibitors of the present invention or pharmaceutical compositions thereof may also be incorporated into the compositions for implantable medical devices such as prosthetics, artificial valves, vascular implants, stents and catheter coatings. For example, vascular stents have been used to overcome restenosis (restenosis of vascular walls after injury). However, patients using stents or other implanted devices are at risk of clots forming and platelet activation. This undesirable effect can be prevented or alleviated by precoating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and general methods of making coated implantable devices are described in US Pat. Nos. 6,099,562, 5,886,026 and 5,304,121. Coatings are typically biocompatible polymeric materials such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating is optionally further coated with a suitable surfacing paint, such as fluorosilicone, polysaccharides, polyethylene glycols, phospholipids or combinations thereof to impart sustained release properties to the composition. Implantation apparatus coated with the kinase inhibitor of the present invention is another embodiment of the present invention.
    [94] Depending on the specific protein kinase mediated condition to be treated or inhibited. Additional therapeutic agents typically administered to treat or inhibit the condition may be administered with an inhibitor of the invention. For example, in the treatment of cancer, other chemotherapeutic or other antiproliferative agents may be mixed with the protein kinase inhibitors of the invention to treat cancer. These preparations include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon and platinum derivatives.
    [95] Examples of other agents that may also be combined with inhibitors of the invention include diabetes such as insulin or insulin homologues, glitazones, α glucosidase inhibitors, biguanides, insulin sensitizers and sulfonyl ureas in injectable or inhaled form. remedy; Anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; Immunomodulators and immunosuppressants such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; Neurotropic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, rilusol and antiparkinson's drugs; therapeutic agents for cardiovascular diseases such as β-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; Agents for treating liver diseases such as corticosteroids, cholestyramine, interferon and antiviral agents; Agents for treating blood disorders such as corticosteroids, anti-leukemic agents and growth factors; And therapeutic agents for immunodeficiency diseases such as γ globulin.
    [96] The additional agents described above may be administered as part of a multiple dosage regimen separately from the protein kinase inhibitor containing composition. Alternatively, the formulation may be part of a single dosage form mixed with the protein kinase inhibitor of the invention in a single composition.
    [97] Compounds of the invention may alternatively exist in tautomeric forms. Unless stated otherwise, descriptions of tautomers include other.
    [98] Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein ring A is a pyridine of formula (II), a pyrimidine of formula (III) or a triazine ring of formula (IV).
    [99]
    [100]
    [101]
    [102] In Formulas II to IV above,
    [103] Sp, T m R 1 , R 2 , U n R 3 , Q and T are the same as defined above.
    [104] Examples of suitable Sp groups of formula I include pyrrole of formula a, imidazole of formula b, pyrazole of formula c, triazole of formula d, oxazole of formula e, isoxazole of formula f, 1 of formula g, 3-thiazole, 1,2-thiazole of formula h, furan of formula i and thiophene of formula j, wherein each of the groups a to j is optionally substituted with R 6 .
    [105]
    [106] Preferred T of Formula (I)mROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, and C1-6 Aliphatic groups and optionally substituted groups selected from 5- to 6-membered aryl or heteroaryl rings. ROneWhen this is optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. Desirable TmROneGroups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3And CH2NHCH3to be. More preferred T of formula (I)mROneThe groups are those listed in Table 1 below.
    [107] Preferred R 3 groups of formula I are selected from hydrogen, carbocyclyl, —CH (R 8 ) R, or C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings Optionally substituted group. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl. When R 3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, SO 2 NH 2 and methylene dioxy. When R 3 is -CH (R 8 ) R, examples of this group include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl. Preferred U n groups, when present, are —CH 2 —, —O—, —NR 7 —, —NHCO— and —NHCO 2 —. More preferred U n R 3 groups are those listed in Table 1 below.
    [108] When R 2 is R 5 , preferred R 5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl [1,4 ] Diazepan-1-yl, 4-phenyl-piperazin-1-yl, wherein each group is optionally substituted. When R 2 is (CH 2 ) y R 5 , (CH 2 ) y CH (R 5 ) 2 or -N (R 4 ) 2 , preferred R 5 groups are pyridin-3-yl, pyridin-4-yl, Imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, -CH 2 OH,-(CH 2 ) 2 0H And isopropyl, wherein each group is optionally substituted. Preferred substituents on R 5 are —OH, pyridyl, piperidinyl and optionally substituted phenyl. When R 2 is-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , the preferred R 8 groups are R 7 and OR 7 , for example OH and CH 2 OH, with preferred R 5 as described above. As shown. Preferred-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 of formula I are -CH (OH) CH (OH) phenyl and -CH (Me) CH (OH) phenyl. Other preferred -QR 2 groups are those listed in Table 1 below.
    [109] Preferred compounds of formula (I)
    [110] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [111] (b) T m R 1 is hydrogen, amino, OH, a 3-6 membered carbocyclyl, or an optionally substituted group selected from a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring;
    [112] (c) when Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH- ;
    [113] (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH When (R 8 ) CH (R 5 ) 2 ;
    [114] (e) when R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ; And
    [115] (f) one or more of the features selected from the group consisting of when R 5 is an optionally substituted group selected from a C 1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl and a 5-6 membered heterocyclyl, further It is preferably a compound having at least one, most preferably all.
    [116] More preferred compounds of formula I are
    [117] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl, benzyl or isoxazolyl groups;
    [118] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ;
    [119] (c) when Q is -CO-, -CONH-, -SO 2- , or -SO 2 NH-;
    [120] (d) R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , wherein R 8 Is OH or CH 2 OH; And
    [121] (e) R 5 is -CH 2 OH,-(CH 2 ) 2 OH, isopropyl, or pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazine-1 -Yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl Or 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl and benzyl, an optionally substituted group selected from the group consisting of one or more, more preferably Preferably a compound having at least one, most preferably all.
    [122] Preferred embodiments of the invention relate to compounds of formula (I ') or pharmaceutically acceptable derivatives thereof.
    [123]
    [124] In Formula I 'above,
    [125] Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein rings A and Q'R 2 ' are bonded to Sp at non-adjacent positions, and Sp has up to two R 6 substituents, provided that Two substitutable carbon ring atoms are not substituted at the same time with R 6 ;
    [126] Z 1 and Z 2 are each independently selected from N and CH;
    [127] Q 'is selected from -CO 2- , -C (O) NR 7 -and -SO 2 NR 7- ;
    [128] T is a binding group;
    [129] U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    [130] m and n are each independently 0 or 1;
    [131] R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    [132] R 2 ′ is selected from — (CH 2 ) y CH (R 5 ) 2 and — (CH 2 ) y CH (R 8 ) CH (R 5 ) 2 ;
    [133] y is 0 to 6;
    [134] R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    [135] Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    [136] R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    [137] R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [138] R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [139] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [140] R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    [141] w is each independently selected from 0-4.
    [142] Examples of suitable Sp groups of formula I 'include pyrrole of formula a, imidazole of formula b, pyrazole of formula c, triazole of formula d, oxazole of formula e, isoxazole of formula f, 1 of formula g , 3-thiazole, 1,2-thiazole of formula h, furan of formula i and thiophene of formula j, wherein each of the groups a to j is optionally substituted with R 6 .
    [143]
    [144] Accordingly, the present invention relates to a compound of formula (I ') or a pharmaceutically acceptable derivative thereof, wherein ring A is a pyridine of formula (II'), a pyrimidine of formula (III ') or a triazine ring of formula (IV').
    [145]
    [146]
    [147]
    [148] In the above formulas II 'to IV',
    [149] Sp, T m R 1 , Q'R 2 ' and U n R 3 are the same as defined above.
    [150] Preferred R 5 groups of the formula I 'are R or OR 7 . Examples of such groups are OH, CH 2 OH, carbocyclic, or optionally substituted 5 or 6 membered aryl or heteroaryl rings such as phenyl, pyridyl and cyclohexyl. Preferred R 8 groups of formula I 'are R and OR 7 , wherein R is an optionally substituted group selected from C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings )to be. Examples of such groups include phenyl, methyl, ethyl, OH and CH 2 OH. Preferred substituents on the aryl or heteroaryl ring which is R 5 are halogen, haloalkyl, OR 0 and R 0 .
    [151] Preferred T of Formula (I ')mROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or C1-6 And an optionally substituted group selected from aliphatic groups and 5-6 membered aryl or heteroaryl rings. ROneWhen this is optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. Desirable TmROneGroups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3And CH2NHCH3It includes. More preferred T of formula (I ')mROneThe groups are those listed in Table 1 below.
    [152] Preferred R 3 groups of the formula (I ′) are hydrogen, carbocyclyl, —CH (R 8 ) R, or C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings. An optionally substituted group selected. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl. When R 3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, SO 2 NH 2 and methylene dioxy. When R 3 is -CH (R 8 ) R, examples of this group include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl. Preferred U n groups, when present, are —CH 2 —, —O—, —NR 7 —, —NHCO— and —NHCO 2 —. More preferred U n R 3 groups of the formula I 'are those listed in Table 1 below.
    [153] Preferred compounds of formula I '
    [154] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [155] (b) T m R 1 is hydrogen, amino, OH, a 3-6 membered carbocyclyl, or an optionally substituted group selected from a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring; And
    [156] (c) one or more of the features selected from the group consisting of where R 5 is R or OR 7 , wherein R is a carbocyclic or optionally substituted 5 or 6 membered aryl or heteroaryl ring, more preferably Is a compound having at least one, most preferably all.
    [157] More preferred compounds of formula I '
    [158] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl, benzyl or isoxazolyl groups;
    [159] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ; And
    [160] (c) one or more of the features selected from the group consisting of when R 5 is OH, CH 2 OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q 'is -C (O) NH- More preferably at least one, most preferably all.
    [161] Another preferred embodiment of the invention relates to a compound of formula (I ") or a pharmaceutically acceptable derivative thereof.
    [162]
    [163] In Formula I "above,
    [164] Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Rings A and C (O) NHCH [(CH 2 ) 1-2 OH] R 5 are bonded to Sp at nonadjacent positions, and Sp is 2 Having up to R 6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted with R 6 ;
    [165] Z 1 and Z 2 are each independently selected from N and CH;
    [166] T is a binding group;
    [167] U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    [168] m and n are each independently 0 or 1;
    [169] R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    [170] R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    [171] Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    [172] R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    [173] R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [174] R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [175] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [176] R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    [177] w is each independently selected from 0-4.
    [178] Examples of suitable Sp groups of formula I ″ include pyrrole of formula a, imidazole of formula b, pyrazole of formula c, triazole of formula d, oxazole of formula e, isoxazole of formula f, 1 of formula g , 3-thiazole, 1,2-thiazole of formula h, furan of formula i and thiophene of formula j, wherein each of the groups a to j is optionally substituted with R 6 .
    [179]
    [180] Accordingly, the present invention relates to a compound of formula I '' or a pharmaceutically acceptable derivative thereof, wherein ring A is a pyridine of formula II '', a pyrimidine of formula III '' or a triazine ring of formula IV ''.
    [181]
    [182]
    [183]
    [184] In the above formulas II '' to IV '',
    [185] Sp, T m R 1 , U n R 3 and R 5 are the same as defined above.
    [186] Preferred T of Formula (I)mROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or C1-6 And an optionally substituted group selected from aliphatic groups and 5-6 membered aryl or heteroaryl rings. ROneWhen this is optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. Desirable TmROneExamples of groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3And CH2NHCH3This includes. More preferred T of formula (I)mROneThe groups are those listed in Table 1 below.
    [187] Preferred R 3 groups of formula I ″ are hydrogen, carbocyclyl, —CH (R 8 ) R, or C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings An optionally substituted group selected Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl When R 3 is optionally substituted phenyl Preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, S0 2 NH 2 and methylene dioxy, when R 3 is -CH (R 8 ) R, Examples of such groups include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl is included. Preferred U n groups, if present, are -CH 2- , -O-, -NR 7- , -NHCO- and -NHCO 2- . The U n R 3 groups are those listed in Table 1 below.
    [188] Preferred R 5 groups of formula I ″ are optionally substituted 6-membered aryl, heteroaryl and carbocyclic rings such as phenyl, pyridyl and cyclohexyl.
    [189] Preferred compounds of formula I "
    [190] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [191] (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If; And
    [192] (c) is a compound having one or more, more preferably one or more, most preferably all of the features selected from the group consisting of when R 5 is an optionally substituted 6 membered aryl, heteroaryl or carbocyclic ring.
    [193] More preferred compounds of formula I "
    [194] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl or benzyl groups;
    [195] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 and CH, optionally substituted with T m R 1 ; 2 is selected from NHCH 3 ; And
    [196] (c) a compound having one or more, more preferably one or more, most preferably all of the features selected from the group consisting of when R 5 is a cyclohexyl or an optionally substituted phenyl or pyridyl ring.
    [197] Another preferred embodiment of the invention relates to a compound of formula (Io) or a pharmaceutically acceptable derivative thereof.
    [198]
    [199] In Formula Io above,
    [200] Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Rings A and C (O) NHCH (R 8 ) CH (R 5 ) 2 are bonded to Sp at non-adjacent positions, and Sp is 2 or less Having the R 6 substituent of, provided that two substitutable carbon ring atoms in Sp are not substituted at the same time with R 6 ;
    [201] Z 1 and Z 2 are each independently selected from N and CH;
    [202] T is a binding group;
    [203] U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    [204] m and n are each independently 0 or 1;
    [205] R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    [206] y is 0 to 6;
    [207] R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    [208] R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    [209] Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    [210] R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [211] R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    [212] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [213] R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    [214] w is each independently selected from 0-4.
    [215] Examples of suitable Sp groups of formula (Io) include pyrrole of formula (a), imidazole of formula (b), pyrazole of formula (c), triazole of formula (d), oxazole of formula (e), isoxazole of formula (f), 1 of formula g, 3-thiazole, 1,2-thiazole of formula h, furan of formula i and thiophene of formula j, wherein each of the groups a to j is optionally substituted with R 6 .
    [216]
    [217] Accordingly, the present invention relates to a compound of formula (Io) or a pharmaceutically acceptable derivative thereof, wherein ring A is a pyridine of formula (IIo), a pyrimidine of formula (IIIo) or a triazine ring of formula (IVo).
    [218]
    [219]
    [220]
    [221] In the above formulas IIo to IVo,
    [222] Sp, T m R 1 , R 5 , U n R 3 and R 8 are the same as defined above.
    [223] Preferred R 5 group of formula (Io) is R or OR 7 . Examples of such groups include OH, CH 2 OH, carbocyclic, or optionally substituted 5 or 6 membered aryl or heteroaryl rings such as phenyl, pyridyl and cyclohexyl. Preferred R 8 groups of formula Io are R and OR 7 wherein R is an optionally substituted group selected from C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings to be. Examples of such groups include phenyl, methyl, ethyl, OH and CH 2 OH. Preferred substituents on the aryl or heteroaryl ring which is R 5 are halogen, haloalkyl, OR 0 and R 0 .
    [224] Preferred T of Formula (Io)mROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or C1-6 And an optionally substituted group selected from aliphatic groups and 5-6 membered aryl or heteroaryl rings. ROneWhen this is optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. More desirable TmROneGroups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3And CH2NHCH3to be. More preferred T of formula (Io)mROneThe groups are those listed in Table 1 below.
    [225] Preferred R 3 groups of formula Io are selected from hydrogen, carbocyclyl, -CH (R 8 ) R, or C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings Optionally substituted group. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl. When R 3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, SO 2 NH 2 and methylene dioxy. When R 3 is -CH (R 8 ) R, examples of this group include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl. Preferred U n groups, when present, are —CH 2 —, —O—, —NR 7 —, —NHCO— and —NHCO 2 —. More preferred U n R 3 groups of the formula Io are those listed in Table 1 below.
    [226] Preferred compounds of formula (Io)
    [227] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [228] (b) T m R 1 is hydrogen, amino, OH, a 3-6 membered carbocyclyl, or an optionally substituted group selected from a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring; And
    [229] (c) one or more of the features selected from the group consisting of when R 5 is R or OR 7 , wherein R is a carbocyclic or optionally substituted 5 or 6 membered aryl or heteroaryl ring; more preferably Preferably a compound having at least one, most preferably all.
    [230] More preferred compounds of formula (Io)
    [231] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl, benzyl or isoxazolyl groups;
    [232] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ; And
    [233] (c) one or more, more preferably one or more, most preferably all of the features selected from the group consisting of when R 5 is OH, CH 2 OH, carbocyclic, or optionally substituted phenyl or pyridyl rings It is a compound which has.
    [234] Preferred embodiments relate to compounds of Formula III-a or pharmaceutically acceptable derivatives thereof.
    [235]
    [236] Preferred T of Formula III-amROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or C1-6 And an optionally substituted group selected from aliphatic groups and 5-6 membered aryl or heteroaryl rings. ROneWhen this is optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. Such a desirable TmROneExamples of groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3And CH2NHCH3This includes. More preferred T of formula III-amROneThe groups are those listed in Table 1 below.
    [237] Preferred R 3 groups of formula III-a are hydrogen, carbocyclyl, —CH (R 8 ) R, or C 1-4 aliphatic group, 3-6 membered heterocyclic group and 5-6 membered aryl or heteroaryl ring Optionally substituted group selected from: Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl. When R 3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, SO 2 NH 2 and methylene dioxy. When R 3 is -CH (R 8 ) R, examples of this group include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl. Preferred U n groups, when present, are —CH 2 —, —O—, —NR 7 —, —NHCO— and —NHCO 2 —. More preferred U n R 3 groups of formula III-a are those listed in Table 1 below.
    [238] R2R5Where R is the preferred R5Groups include pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl -Piperazin-1-yl, wherein each group is optionally substituted. R2(CH2)yR5, (CH2)yCH (R5)2Or -N (R4)2Where R is the preferred R5Groups are pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, Benzyl, -CH2OH,-(CH2)20H and isopropyl, where each group is optionally substituted. R5Preferred substituents on the phase are -OH, pyridyl, piperidinyl and optionally substituted phenyl. R2Is-(CH2)yCH (R8) CH (R5)2Where R is the preferred R8Group is R7And OR7, For example OH and CH2OH. More preferred -QR2The groups are those listed in Table 1 below.
    [239] Preferred compounds of formula III-a
    [240] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [241] (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If;
    [242] (c) when Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH- ;
    [243] (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH When (R 8 ) CH (R 5 ) 2 ;
    [244] (e) when R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ; And
    [245] (f) one or more, more preferably one or more of the features selected from the group consisting of when R 5 is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl Preferably it is a compound which has all.
    [246] More preferred compounds of formula III-a
    [247] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl or benzyl groups;
    [248] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ;
    [249] (c) when Q is -CO-, -CONH-, -SO 2- , or -SO 2 NH-;
    [250] (d) R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , wherein R 8 Is OH or CH 2 OH; And
    [251] (e) R 5 is -CH 2 OH,-(CH 2 ) 2 OH, isopropyl, or pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazine-1 -Yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl Or 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl and benzyl, an optionally substituted group selected from the group consisting of: Preferably a compound having at least one, most preferably all.
    [252] Preferred compounds of formula III-a include compounds of formula III-a 'or pharmaceutically acceptable derivatives thereof.
    [253]
    [254] Preferred R 5 groups of the formula III-a 'are optionally substituted 6-membered aryl, heteroaryl and carbocyclic rings such as phenyl, pyridyl and cyclohexyl.
    [255] Preferred T of Formula III-a 'mROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or C1-6 And an optionally substituted group selected from aliphatic groups and 5-6 membered aryl or heteroaryl rings. ROneWhen this is optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. Desirable TmROneGroups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3, CH2NHCH3And those listed in Table 1 below.
    [256] Preferred R 3 groups of formula III-a 'are hydrogen, carbocyclyl, -CH (R 8 ) R, or C 1-4 aliphatic group, 3-6 membered heterocyclic group and 5-6 membered aryl or heteroaryl Optionally substituted group selected from rings. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl. When R 3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, SO 2 NH 2 and methylene dioxy. When R 3 is -CH (R 8 ) R, examples of this group include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl. Preferred U n groups, when present, are —CH 2 —, —O—, —NR 7 —, —NHCO— and —NHCO 2 —. More preferred U n R 3 groups of formula III-a 'are those listed in Table 1 below.
    [257] Preferred compounds of formula III-a '
    [258] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [259] (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If; And
    [260] (c) is a compound having one or more, more preferably one or more, most preferably all of the features selected from the group consisting of when R 5 is an optionally substituted 6 membered aryl, heteroaryl or carbocyclic ring.
    [261] More preferred compounds of formula III-a '
    [262] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl or benzyl groups;
    [263] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ; And
    [264] (c) is a compound having one or more, more preferably one or more, most preferably all of the features selected from the group consisting of when R 5 is cyclohexyl or optionally substituted phenyl or pyridyl ring.
    [265] Preferred compounds of formula III-a are further selected from compounds of formula III-ao or pharmaceutically acceptable derivatives thereof.
    [266]
    [267] Preferred R 5 group of formula III-ao is R or OR 7 . Examples of such groups include OH, CH 2 OH, or optionally substituted 6 membered aryl, heteroaryl and carbocyclic rings such as phenyl, pyridyl and cyclohexyl. Preferred R 8 groups of formula III-ao are R and OR 7 wherein R is an optionally substituted group selected from C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings Is). Examples of such groups include phenyl, methyl, ethyl, OH and CH 2 OH.
    [268] Preferred T of Formula III-aomROneGroup is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or C1-6 And an optionally substituted group selected from aliphatic groups and 5-6 membered aryl or heteroaryl rings. ROneWhen this is an optionally substituted phenyl or aliphatic group, the preferred substituents on the phenyl or aliphatic group are R7, Halo, nitro, alkoxy and amino. Desirable TmROneGroups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O) NHCH3And CH2NHCH3This includes. More preferred T of formula III-aomROneThe groups are those listed in Table 1 below.
    [269] Preferred R 3 groups of formula III-ao are hydrogen, carbocyclyl, —CH (R 8 ) R, or C 1-4 aliphatic groups, 3-6 membered heterocyclic groups and 5-6 membered aryl or heteroaryl rings Optionally substituted group selected from: Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl and isopropyl. When R 3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF 3 , OH, SO 2 NH 2 and methylene dioxy. When R 3 is -CH (R 8 ) R, examples of this group include -CH (CH 2 OH) phenyl, -CH (CH 2 0H) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl and -CH (CH 2 0H) CH 2 cyclopropyl. Preferred U n groups, when present, are —CH 2 —, —O—, —NR 7 —, —NHCO— and —NHCO 2 —. More preferred U n R 3 groups of formula III-ao are those listed in Table 1 below.
    [270] Preferred compounds of formula III-ao are
    [271] (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    [272] (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If; And
    [273] (c) is a compound having one or more, more preferably one or more, most preferably all of the features selected from the group consisting of when R 5 is R or OR 7 and R 8 is R 7 or OR 7 .
    [274] More preferred compounds of Formula III-ao are
    [275] (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl or benzyl groups;
    [276] (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ;
    [277] (c) one or more of the features selected from the group consisting of when R 5 is OH, CH 2 OH, phenyl, pyridyl or cyclohexyl and R 8 is methyl, ethyl, OH or CH 2 OH, more preferably Is a compound having at least one, most preferably all.
    [278] Preferred compounds of formula III-a are shown in Table 1 below. More preferred compounds in Table 1 are those of Formula III-a 'or Formula III-ao.
    [279]
    [280]
    [281]
    [282]
    [283]
    [284]
    [285]
    [286]
    [287]
    [288]
    [289]
    [290]
    [291]
    [292]
    [293]
    [294]
    [295]
    [296]
    [297] The above compound of formula III-a is a compound in which ring A is a pyrimidine ring and Sp is a pyrrole ring. The compound of formula I, wherein ring A is a pyridine, pyrimidine, or triazine ring with other Sp rings as described above, is structurally similar to formula III-a, and formulas II-b to II-j shown in Table 2; Formula III-b to Formula III-j, Formula IV-b to Formula IV-j.
    [298]
    [299]
    [300]
    [301]
    [302] The compounds shown in Table 2 above are structurally similar to compounds of formula III-a wherein the pyrrole ring of formula III-a is replaced with each of the following Sp rings: imidazole (b), pyrazole (c), triazole (d ), Oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j). Thus, the preferred QR, T m R 1 and U n R 3 groups in the compounds shown in Table 2 above are as described above for the compounds of Formula III-a.
    [303] In another embodiment, the present invention provides a pharmaceutically acceptable composition comprising the compound set forth in Table 2 above and a pharmaceutically acceptable carrier.
    [304] Another aspect of the invention comprises administering to a patient in need of treatment of an ERK2-mediated disease an therapeutically effective amount of a compound set forth in Table 2 above or a pharmaceutically acceptable composition comprising such a compound, ERK2. -A method for treating or preventing a mediated disease.
    [305] Another aspect of the invention relates to a method for inhibiting a patient's ERK2 activity, comprising administering to a patient a compound shown in Table 2 or a pharmaceutically acceptable composition comprising such a compound.
    [306] Another aspect of the invention comprises administering to a patient in need of treatment of an Aurora-2-mediated disease a therapeutically effective amount of a compound set forth in Table 2 above or a pharmaceutically acceptable composition comprising such a compound. And methods of treating or preventing aurora-2-mediated disease.
    [307] Another aspect of the present invention relates to a method of inhibiting Aurora-2 activity in a patient, comprising administering to a patient a compound shown in Table 2 or a pharmaceutically acceptable composition comprising such a compound.
    [308] Another aspect of the invention comprises administering to a patient in need of treatment of a GSK-3-mediated disease a therapeutically effective amount of a compound set forth in Table 2 above or a pharmaceutically acceptable composition comprising such a compound. And methods for treating or preventing GSK-3-mediated diseases.
    [309] One aspect of the invention is administering to a patient in need of increasing glycogen synthesis and / or lowering blood glucose concentrations a therapeutically effective amount of a compound set forth in Table 2 or a pharmaceutically acceptable composition comprising such a compound. It relates to a method for increasing glycogen synthesis in a patient and / or lowering blood glucose concentration. This method is particularly useful for diabetics. Another method relates to a method of inhibiting the production of hyperphosphorylated Tau protein, which is useful for stopping or delaying the progression of Alzheimer's disease. Another method relates to a method of inhibiting phosphorylation of β-catenin, which is useful for the treatment of schizophrenia.
    [310] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound set forth in Table 2 or a pharmaceutically acceptable composition comprising such compound.
    [311] Another method comprises contacting a biological sample with a compound shown in Table 2 above or a pharmaceutically acceptable composition comprising the compound in an amount effective to inhibit ERK-2, Aurora-2 or GSK-3. To inhibit ERK-2, Aurora-2 or GSK-3 activity in a biological sample.
    [312] Each of the aforementioned methods of inhibiting ERK-2, Aurora-2 or GSK-3, or the method of treating ameliorated disease thereby, is preferably carried out with the preferred compounds set forth in Table 2 above.
    [313] Compounds of the present invention can be prepared by methods commonly known to those skilled in the art for similar compounds, as described in Schemes I-XII and the synthetic examples set forth below.
    [314]
    [315] In Scheme I above,
    [316] Reagents and reaction conditions are as follows:
    [317] (a) T m R 1 CH 2 COCl, AlC1 3 , CH 2 C1 2 , 2 hours, room temperature;
    [318] (b) DMF, 24 h, room temperature;
    [319] (c) (Me 2 N) 2 -CHOt-Bu, THF, 24 h, room temperature;
    [320] (d) guanidine, EtOH, 12 h, reflux;
    [321] (e) thiourea, EtOH, K 2 CO 3 , 12 h, reflux;
    [322] (f) m-CPBA, EtOH; And
    [323] (g) U n R 3 -NH 2 , DMSO, 130 C.
    [324] Scheme I represents a general synthetic route used to prepare pyrrole-3-yl compounds of formula III-a of the present invention wherein R 2 is an optionally substituted phenyl group or aliphatic group. In step (a), optionally substituted acid chloride is combined with compound (1), dichloromethane and aluminum trichloride to form compound (2). When benzoyl acid chloride is used, various substituents on the phenyl ring can be used for the reaction. In addition, lipoma acid chlorlai is often used. Examples of suitable R 2 groups include, but are not limited to, those set forth in Table 1 above.
    [325] Amide (4) is formed by treating compound (2) with amine (3) in DMF. If amine 3 is a primary amine, the reaction proceeds at ambient temperature. If the amine 3 is a secondary amine, the reaction is heated at 50 ° C. to terminate the reaction to give the amide 4.
    [326] In step (c) enamine (5) is formed by treating amide (4) with (Me 2 N) 2 -CHOt-Bu at ambient temperature. Alternatively, the reaction for forming enamine (5) in step (c) is carried out using dimethylformamide-dimethylacetal (DMF-DMA). Reactions using DMF-DMA typically require elevated temperatures to obtain enamines (5), while reactions using (Me 2 N) 2 -OtBu are carried out at ambient temperature to obtain high purity enamines (5 ) Has the advantage of obtaining.
    [327] The formation of the pyrimidine compound (6) in step (d) is carried out by treating the enamine (5) with guanidine at elevated temperature. Alternatively, substituted guanidines can be used to generate amino substituents (8).
    [328] As another method, in step (e), intermediate (5) can be closed with S-methyl thiourea to form 2-thiomethylpyrimidine (7), which is subsequently oxidized to m-CPBA to sulfone Can be formed.
    [329] As illustrated in Table 1, the compounds of formula III-a synthesized in this manner are separated by preparative HPLC (reverse phase, MeCN 10-> 90% in water, 15 minutes). Details of the conditions used to produce these compounds are described in the Examples.
    [330]
    [331] In Scheme II above,
    [332] The reagents used in step (a) are K 2 CO 3 and DMA and the reaction temperature is 100 C.
    [333] In Scheme II, a general method for preparing compound (8) from intermediate (5) and N-substituted guanidine (9) is shown. Intermediate 5 may be prepared according to steps (a), (b) and (c) of Scheme I above. Compound (5) is treated with N-substituted guanidine (9) and potassium carbonate in dimethylacetamide to form compound (8). The reaction can be used on various N-substituted guanidines to form compounds of Formula III-a. Details of the conditions used to prepare these compounds are given in the Examples.
    [334]
    [335] In Scheme III above,
    [336] The reagents and conditions used are as follows:
    [337] (a) pure A1C1 3 , room temperature;
    [338] (b) DMF, 24 h room temperature;
    [339] (c) polyphosphoric acid, 1 hour, 25-140 ° C .;
    [340] (d) POC1 3 , DMF, reflux; And
    [341] (e) NH 2 -U n R 3 , iPrOH, reflux.
    [342] Scheme III depicts a general synthetic route that may be used to prepare pyrrole-3-yl compounds of formula II-a of the present invention. Conversion of intermediate 5 to product 8 can be carried out according to steps (c), (d) and (e) according to the methods described in JACS, 1957, pp 79.
    [343]
    [344] In Scheme IV above,
    [345] The reagents and conditions used are as follows:
    [346] (a) MeOH, pyrimidine, C1 2 ;
    [347] (b) guanidine;
    [348] (c) bromine, acetic acid;
    [349] (d) NaCN, DMF;
    [350] (e) Compound (6), polyphosphoric acid, 1 hour, 25-140 ° C .;
    [351] (f) POC1 3 , DMF, reflux;
    [352] (g) NH 2 -U n R 3 , iPrOH, reflux;
    [353] (h) Se0 2 ; And
    [354] (i) MeNH.
    [355] Scheme IV depicts a general synthetic route that may be useful for preparing the imidazol-4-yl compounds of Formula II-b of the present invention. Conversion of intermediate 5 to product 8 can be carried out via steps (e), (f) and (g) according to the methods described in JACS, 1957, pp 79.
    [356]
    [357] In Scheme V above,
    [358] The reagents and conditions used are as follows:
    [359] (a) MeOH, pyridine, C1 2 ;
    [360] (b) compound (3);
    [361] (c) bromine, acetic acid;
    [362] (d) NaCN, DMF;
    [363] (e) Compound (6), polyphosphoric acid, 1 hour, 25-140 ° C .;
    [364] (f) POC1 3 , DMF, reflux;
    [365] (g) NH 2 -U n R 3 , iPrOH, reflux.
    [366] Scheme V depicts a general synthetic route that may be useful for preparing the imidazol-2-yl compounds of formula II-b 'of the present invention. Conversion of intermediate 5 to product 8 can be carried out via steps (e), (f) and (g) according to the methods described in JACS, 1957, pp 79.
    [367]
    [368] In Scheme VI above,
    [369] The reagents and conditions used are as follows:
    [370] (a) and (b) compound (3);
    [371] (c) compound (5), polyphosphoric acid, 1 hour, 25-140 ° C .;
    [372] (d) POC1 3 , DMF, reflux;
    [373] (e) NH 2 U n R 3 , iPrOH, reflux; And
    [374] (f) cerium-containing ammonium nitrate.
    [375] Scheme VI depicts a general synthetic route that may be useful for preparing the pyrazol-3-yl compounds of Formula II-c of the present invention. Conversion of the intermediate 4 to the product 7 can be carried out via steps (c), (d) and (e) according to the method described in JACS, 1957, pp 79.
    [376]
    [377] In Scheme VII above,
    [378] The reagents and conditions used are as follows:
    [379] (a) 1,1'-carbonyldiimidazole (CDI), triethylamine, THF;
    [380] (b) N-butyllithium, THF, -78 deg.
    [381] (c) compound (6), polyphosphoric acid, 1 hour, 25-140 ° C .;
    [382] (d) POC1 3 , DMF, reflux; And
    [383] (e) NH 2 -U n R 3 , iPrOH, reflux.
    [384] Scheme VII represents a general synthetic route that may be useful for preparing the oxazol-2-yl compounds of Formula II-e ′ of the present invention. Conversion of the intermediate 5 to the product 8 can be carried out via steps (c), (d) and (e) according to the method described in JACS, 1957, pp 79.
    [385]
    [386] In Scheme VIII above,
    [387] The reagents and conditions used are as follows:
    [388] (a) N-butyllithium, TMEDA, -78 ° C;
    [389] (b) t-butyllithium, THF, -78 ° C;
    [390] (c) compound (6), polyphosphoric acid, 1 hour, 25-140 ° C .;
    [391] (d) POC1 3 , DMF, reflux; And
    [392] (e) NH 2 -R, iPrOH, reflux.
    [393] Scheme VIII represents a general synthetic route that may be useful for preparing thiazol-2-yl compounds of formula II-g 'of the present invention. Conversion of the intermediate 5 to the product 8 can be carried out via steps (c), (d) and (e) according to the method described in JACS, 1957, pp 79.
    [394]
    [395] In Scheme IX above,
    [396] The reagents and conditions used are as follows:
    [397] (a) N-butyllithium, Bu 3 SnCl;
    [398] (b) t-butyllithium, THF, -78 deg.
    [399] (c) MeOCO 2 Me;
    [400] (d) Compound (4) and Pd (0);
    [401] (e) compound (6), polyphosphoric acid, 1 hour, 25-140 ° C .;
    [402] (f) POC1 3 , DMF, reflux; And
    [403] (g) NH 2 -U n R 3 , iPrOH, reflux.
    [404] Scheme IX represents a general synthetic route that may be useful for preparing thiazol-4-yl compounds of formula II-g of the present invention. Conversion of intermediate 5 to product 8 can be carried out via steps (e), (f) and (g) according to the methods described in JACS, 1957, pp 79.
    [405]
    [406] In Scheme X above,
    [407] The reagents and conditions used are as follows:
    [408] (a) CH 3 0CH 2 CH 2 COC1, A1C1 3 , CH 2 C1 2 , 2.5 hours, room temperature;
    [409] (b) DMF, 24 h, room temperature;
    [410] (c) (Me 2 N) 2 -CHOt-Bu, THF, 24 h, room temperature;
    [411] (d) N-substituted guanidine, EtOH, 12 h, reflux; And
    [412] (e) BBr 3 , CH 2 C1 2 .
    [413] Scheme X represents a general synthetic route used to prepare compounds of Formula III-a wherein T m R 1 is methoxymethyl or hydroxymethyl. In step (a), 3-methoxypropionyl chloride is combined with compound (1), dichloromethane and aluminum trichloride to form compound (2).
    [414] Formation of the amide (4) is carried out by treating compound (2) with amine (3) in DMF. If amine 3 is a primary amine, the reaction proceeds at ambient temperature. If amine 3 is a secondary amine, the reaction is heated at 50 ° C. to terminate the reaction, giving amide 4. The formation of the enamine 5 in step (c) is carried out by treating the amide 4 with (Me 2 N) 2 -CHOt-Bu at ambient temperature.
    [415] The formation of the pyrimidine compound (6) in step (d) is carried out by treating the enamine (5) with guanidine (d) at elevated temperature. Alternatively, the use of substituted guanidines results in amino substituents.
    [416] To form a compound in which T m R 1 is hydroxymethyl, intermediate (6) is treated with BBr 3 in dichloromethane to form compound (7). Those skilled in the art will appreciate that the hydroxymethyl group of compound (7) may be further derivatized to form various compounds of formula III-a. Details of the conditions used to produce these compounds are given in the Examples.
    [417]
    [418] In Scheme XI above,
    [419] The reagents and conditions used are as follows:
    [420] (a) R 2 NH 2 , MeCN, 0-25 ° C., 12 h;
    [421] (b) AlCl 3 , CH 2 C1 2 , 25 ° C .; And
    [422] (c) MeOH: H 2 O (2: 1), 37 ° C.
    [423] Scheme XI represents a general method for preparing triazine compounds of Formula IV-a. Step (a) is carried out in the manner described in step (b) of Scheme I above. Step (b) is carried out in the manner described in step (a) of Scheme I above. The formation of the triazine ring in step (c) can be carried out according to the methods described in the literature. See Hirsch, J .; Petrakova, E .; Feather, M. S .; J Carbohydr Chem [JCACDM] 1995, 14 (8), 1179-1186]. Alternatively, step (c) may be prepared according to the methods described in the literature. See Siddiqui, A. U .; Satyanarayana, Y .; Rao, U. M .; Siddiqui, A. H .; J Chem Res, Synop [JRPSDC] 1995 (2), 43].
    [424]
    [425] In formula (XII) above,
    [426] The reagents used in step (a) are K 2 CO 3 and DMA and the reaction conditions are 100 ° C., 24 hours.
    [427] Using the process for preparing compound (III-a-226) to illustrate, Scheme XII represents a general synthetic route used to prepare compounds of formula III-a wherein U n is NR 7 . Formation of compound (III-a-226) in step (a) is carried out by treating enamine (5) with guanidine (6) at elevated temperature. Alternatively, substituted guanidines are used to generate hydrazino substituents.
    [428] In another embodiment, the present invention provides a pharmaceutically acceptable composition comprising a compound of Formula I ', I ", Io, III-a, III-a' or III-ao and a pharmaceutically acceptable carrier. .
    [429] Another embodiment of the invention provides a therapeutically effective amount of a compound of formula (I ′, I ″, Io, III-a, III-a 'or III-ao or such compound in a patient in need of treatment of an ERK2-mediated disease) It relates to a method for treating or preventing an ERK2-mediated disease, including administering a pharmaceutically acceptable composition comprising a.
    [430] Another aspect of the invention comprises administering to a patient a compound of Formula I ', I ", Io, III-a, III-a' or III-ao or a pharmaceutically acceptable composition comprising such a compound Thus, the present invention relates to a method of inhibiting ERK2 activity of a patient.
    [431] Another aspect of the invention provides a therapeutically effective amount of a compound of Formula I ', I ", Io, III-a, III-a' or III-ao to a patient in need of treatment of aurora-2-mediated disease or A method of treating or preventing aurora-2-mediated disease, including administering a pharmaceutically acceptable composition comprising such a compound.
    [432] Another aspect of the invention comprises administering to a patient a compound of Formula I ', I ", Io, III-a, III-a' or III-ao or a pharmaceutically acceptable composition comprising such a compound Thus, the present invention relates to a method of inhibiting Aurora-2 activity in a patient.
    [433] Another aspect of the invention provides a therapeutically effective amount of a compound of Formula I ', I ", Io, III-a, III-a' or III-ao to a patient in need of treatment of a GSK-3-mediated disease or A method of treating or preventing a GSK-3-mediated disease, including administering a pharmaceutically acceptable composition comprising such a compound.
    [434] One aspect of the invention provides a therapeutically effective amount of Formula I ', I ", Io, III-a, III-a' or III-ao to patients in need of increasing glycogen synthesis and / or lowering blood glucose concentrations. A method for increasing glycogen synthesis and / or lowering blood glucose levels in a patient, comprising administering a compound of formula I or a pharmaceutically acceptable composition comprising such a compound is particularly useful for diabetics. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful for stopping or delaying the progression of Alzheimer's disease, and another method for inhibiting phosphorylation of β-catenin. Method, which is useful for the treatment of schizophrenia.
    [435] Another aspect of the invention includes administering to a patient a compound of Formula I ', I ", Io, III-a, III-a' or III-ao or a pharmaceutically acceptable composition comprising such a compound. The present invention relates to a method of inhibiting GSK-3 activity of a patient.
    [436] Another aspect of the invention provides a therapeutically effective amount of a compound of Formula I ', I ", Io, III-a, III-a' or III-ao to a patient in need of treatment of a CDK-2-mediated disease or A method of treating or preventing a CDK-2-mediated disease, including administering a pharmaceutically acceptable composition comprising such a compound.
    [437] As used herein, the term "CDK-2 mediated symptoms" or "diseases" means any disease or other deleterious condition in which CDK-2 is known to play a part. The term "CDK-mediated symptom" or "disease" also refers to a disease or condition that is ameliorated by treatment with a CDK-2 inhibitor. These symptoms include, but are not limited to, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases (eg, rheumatoid arthritis) See Fischer, PM and Lane, DP, Current Medicinal Chemistry, 7,1213-1245 (2000); Mani, S., Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D. W. and Garrett, M. D., Current Opinion in Oncologic, Endocrine & Metabolic Investigational Drugs, 2,40-59 (2000)].
    [438] Another aspect of the invention provides a therapeutically effective amount of a compound of Formula I ', I ", Io, III-a, III-a' or III-ao or such compound in a patient in need of treatment for a Lck-mediated disease. It relates to a method for treating or preventing a Lck-mediated disease, including administering a pharmaceutically acceptable composition comprising a.
    [439] As used herein, the term "Lck-mediated symptom" or "disease" means any disease or other harmful condition in which Lck is known to play a part. The term “Lck-mediated symptom” or “disease” also means a disease or condition that is alleviated by treatment with an Lck inhibitor. Such symptoms include, but are not limited to, graft rejection, allergic diseases, rheumatoid arthritis and autoimmune diseases such as leukemia. The relationship between Lck and various diseases is described in the literature (Molina et al., Nature, 357, 161 (1992)).
    [440] Another aspect of the invention provides a therapeutically effective amount of a compound of Formula I ', I ", Io, III-a, III-a' or III-ao to a patient in need of treatment of an AKT-3-mediated disease or A method for treating or preventing AKT-3-mediated disease, including administering a pharmaceutically acceptable composition comprising such a compound.
    [441] As used herein, the term "AKT3-mediated symptom" or "disease" means any disease or other harmful condition in which AKT-3 is known to play a part. The term “AKT3-mediated symptom” or “disease” also refers to a disease or condition that is alleviated by treatment with an AKT3 inhibitor. Such symptoms include, but are not limited to, proliferative diseases, cancer and neurodegenerative diseases. The relationship between AKT3 and various diseases is described in the literature (Zang, Q. Y., et al, Oncogene, 19 (2000)) and Kazuhiko, N., et al, The Journal of Neuroscience, 20 (2000).
    [442] Another method is a method for preparing a biological sample in an amount effective to inhibit ERK-2, Aurora-2, CDK-2, Lck, AKT3 or GSK-3 in Formula I ′, I ″, Io, III-a, III- ERK-2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3 activity in a biological sample, including contacting a compound of a 'or III-ao or a pharmaceutically acceptable composition comprising the compound It is about how to suppress.
    [443] Each of the above-mentioned methods of inhibiting ERK-2, Aurora-2, CDK-2, Lck, AKT3 or GSK-3, or a method of treating ameliorated disease thereby, may be represented by the formulas I ', I ", Preference is given to performing with the preferred compounds of Io, III-a, III-a 'or III-ao. More preferably, each of the aforementioned methods is of the formula I', I ", Io, III-a 'or III with preferred compounds of -ao, most preferably with compounds of formula (I ", Io, III-a 'or III-ao).
    [444] To more fully understand the invention described herein, the following examples are presented. It is to be understood that these examples are presented for illustrative purposes only and do not limit the invention in any way.
    [445] Synthetic Example
    [446] For compounds using the HPLC method indicated as “A”, a gradient of water: MeCN, 0.1% TFA (95: 5 → 0: 100) is performed over 1 minute / minute and 22 minutes at 214 nm. For compounds using the HPLC method indicated as "B", a gradient of water: MeCN, 0.1% TFA (90: 10 → 0: 100) is performed over 1 minute at 1 mL / min and 214 nm. Methods A and B each use a YMC ODS-AQ 55 120A column (size: 3.0 × 150 mm). As used herein, the term “R t ” refers to the retention time in minutes with respect to the compound using the designated HPLC method.
    [447] Example 1
    [448]
    [449] 2,2,2-trichloro-1- (4-phenyl acetyl-1 H-pyrrol-2-yl) -ethanone ( 1 ):
    [450] In anhydrous flask, phenylacetyl chloride (1 equiv) is combined with 2-trichloroacetyl pyrrole (1 equiv) in a minimum amount of dichloromethane (DCM) to dissolve the reaction. At ambient temperature, aluminum trichloride (1 equiv) is added to the resulting solution. After 2 hours, the reaction mixture is applied directly to the silica gel column. 10% ethyl acetate in hexanes: Gradient eluted with 50% ethyl acetate to give compound ( 1 ) in 60% yield.
    [451] 1 H NMR (CDCl 3 ) δ4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s, NH).
    [452] HPLC using Method B has an R t of 4.9 minutes.
    [453] LC / MS (M + 1) 330.2, (M-1) 328.1.
    [454] Example 2
    [455]
    [456] 2,2,2-trichloro-1- (4- (3-chlorophenyl) acetyl-1 H-pyrrol-2-yl) -ethanone ( 2 ):
    [457] In anhydrous flask, 3-chlorophenylacetyl chloride (1 equiv) is combined with 2-trichloroacetyl pyrrole (1 equiv) in a minimum amount of dichloromethane (DCM). At ambient temperature, aluminum trichloride (1 equiv) is added to the resulting solution. After 2 hours, the reaction mixture is applied directly to the silica gel column. 10% ethyl acetate in hexanes: Gradient eluted with 50% ethyl acetate to afford compound ( 2 ). HPLC using Method A has an R t of 15 minutes.
    [458] Example 3
    [459]
    [460] 1- [5- (2,2,2-Trichloro-acetyl) -1 H-pyrrol-3-yl) -propan-1-one ( 3 ):
    [461] In anhydrous flask, 3-propionyl chloride (1 equiv) is combined with 2-trichloroacetyl pyrrole (1 equiv) in a minimum amount of dichloromethane (DCM). At ambient temperature, aluminum trichloride (1 equiv) is added to the resulting solution. After 2 hours, the reaction mixture is applied directly to the silica gel column. 10% ethyl acetate in hexanes: Gradient eluted with 50% ethyl acetate to afford compound ( 3 ).
    [462] Example 4
    [463]
    [464] 4-phenylacetyl-1H-pyrrole-2-carboxylic acid benzylamide ( 4 ):
    [465] At ambient temperature, benzylamine (1.2 equiv) is added to a solution of compound 1 (1 equiv) in DMF. After 24 hours, the solvent is evaporated and the crude product 4 is used without purification. HPLC using Method B has an R t of 3.8 minutes.
    [466] FIA / MS (M + 1) 319.3, (M-1) 317.2.
    [467] Example 5
    [468]
    [469] 2- (3-Chlorophenyl) -1- [5- (morpholine) -4-carbonyl) -1H-pyrrol-3-yl] -ethanone ( 5 ):
    [470] At ambient temperature, morpholine (1.2 equiv) is added to a solution of Compound 2 (1 equiv) in DMF. After 24 hours, the solvent is evaporated and the crude product 5 is used without purification.
    [471] FIA / MS (M + 1) 333.3, (M-1) 331.2.
    [472] 1 H NMR was consistent with the expected structure.
    [473] Example 6
    [474]
    [475] 4-propionyl-1H-pyrrole-2-carboxylic acid 3,4-difluorobenzylamide ( 6 ):
    [476] At ambient temperature, 3,4-difluorobenzyl amine (1.2 equiv) is added to a solution of compound 3 (1 equiv) in DMF. After 24 hours, the solvent is evaporated and the crude product 6 is used without purification.
    [477] Example 7
    [478]
    [479] 4- (3-Dimethylamino-2-phenyl-acryloyl) -1 H-pyrrole-2-carboxylic acid benzylamide ( 7 ):
    [480] At ambient temperature, (Me 2 N) 2 CHOt-Bu (3 equiv) is added to a solution of Compound 4 (1 equiv) in THF. After 24 hours, the solvent is evaporated and then the crude product 7 is used without purification.
    [481] 1 H NMR (CDCl 3 ) δ 4.4 (S, 2H), 4.8 (s, NH), 6.8-7.4 (m, 13H).
    [482] Example 8
    [483]
    [484] 2- (3-Chloro-phenyl) -3-dimethylamino-1- [5- (morpholin-4-carbonyl) -1 H-pyrrol-3-yl] -propenone ( 8 ):
    [485] At ambient temperature, (Me 2 N) 2 CHOt-Bu (3 equiv) is added to a solution of Compound 5 (1 equiv) in THF. After 24 hours, the solvent is evaporated and then the crude product 8 is used without purification. HPLC using Method B has an R t of 11.2 min.
    [486] Example 9
    [487]
    [488] 4- (2-Amino-5-methyl-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide (III-a-74):
    [489] Step 1: At ambient temperature, (Me 2 N) 2 CHOt-Bu (3 equiv) is added to a solution of Compound 6 (1 equiv) in THF. After 24 hours, the solvent is evaporated and the crude product is used without purification.
    [490] Step 2: At room temperature, guanidine (3 equiv) is added to the compound solution formed in step 1 (1 equiv) in ethanol, and the resulting mixture is heated at reflux. After 12 h the solvent is evaporated and the crude product is purified by preparative HPLC (reverse phase; 10-90% MeCN in water; 15 min) to afford the desired compound (III-a-74). HPLC using Method B has an R t of 7.9 minutes. 1 H NMR was consistent with the expected structure.
    [491] FIA / MS Obs. M + 1 / M-1.
    [492] Example 10
    [493]
    [494] {4- [2-Amino-5- (3-chlorophenyl) -pyrimidin-4-yl] -1 H-pyrrole-2yl} -morpholin-4-yl-methanone (III-a-72):
    [495] At ambient temperature, guanidine (3 equiv) is added to a solution of compound 8 (1 equiv) in ethanol and then the resulting mixture is heated at reflux. After 12 hours, the solvent is evaporated and then the crude product is purified by preparative HPLC (reverse phase; 10-90% MeCN in water; 15 minutes) to afford the desired compound (III-a-72). HPLC using Method B has an R t of 7.9 minutes. 1 H NMR was consistent with the expected structure.
    [496] FIA / MS Obs. (M + 1) 384.4 amu.
    [497] Example 11
    [498]
    [499] N- (2-hydroxy-1- (S) -phenyl-ethyl) -guanidineHCl:
    [500] Combine (S) -phenylglycineol (0.38 g, 2.7 mmol) and bis-Boc guanidine- (N) -triplate (0.9 g, 2.3 mmol) in methylene chloride (anhydrous, 5 mL), then stir overnight at ambient temperature Let's do it. Completion of the reaction is confirmed by HPLC. The mixture is diluted with ethyl acetate, washed with 2M sodium sulfite and brine, then dried over MgSO 4 , filtered and concentrated in vacuo. The bis-Boc guanidine intermediate is treated with 4N HCl / dioxane (5 mL) and stirred at room temperature until deprotection is complete (48 h) to afford the title compound.
    [501] Example 12
    [502]
    [503] 4- [2- (2-Hydroxy-1- (S) -phenyl-ethylamino) -5-methyl-pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (III-a-155):
    [504] 4- (3-Dimethylamino-2-methyl-acryloyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl) -amide (100 mg, 0.29 mmol) was added to N, N-dimethyl. Combined with N- (S) -phenylglycinol guanidine-HCl (126 mg) and potassium carbonate (121 mg) in acetamide (2 mL). The resulting suspension is heated and stirred at 100 ° C. for 24 hours. The crude material is diluted with ethyl acetate, washed with saturated NaHCO 3 and brine, then dried over MgSO 4 and concentrated in vacuo. Preparative HPLC [Gilson: column = gradient elution with eluent of CombiHT SB-C189, 5 μM, 21.2 × 100 mm, 0.1% TFA / MeCN / H 2 O], followed by preparative TLC (silica, CH 2 Cl 2 In 5% MeOH) to afford compound (III-a-155) as a pale yellow solid (8.0 mg). HPLC (method B), R t = 4.76 min; MS (FIA) 458.2 (M + l), 456.1 (M-1); 1 H NMR was consistent with the expected structure.
    [505] Example 13
    [506]
    [507] 4- (2-Cyclopropylamino-5-methyl-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-carboxy-1- (S) -phenyl-ethyl) -amide (III-a- 162):
    [508] 4- (3-Dimethylamino-2-methyl-acryloyl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl) -amide (100 mg, 0.29 mmol) was added to N, N-dimethyl. Combine with cyclopropyl guanidine-HCl (80 mg) and potassium carbonate (121 mg) in acetamide (2 mL). The resulting suspension is heated and stirred at 100 ° C. for 24 hours. The crude material is diluted with ethyl acetate, washed with saturated NaHCO 3 and brine, then dried over MgSO 4 and concentrated in vacuo. Purification by preparative TLC (silica, 1: 1 EtOAc: hexanes) affords compound (III-a-162) as a yellow solid (7.8 mg).
    [509] HPLC (method B), R t = 4.29 min; LC / MS (m / z) 378.2 (M + l), 376.2 (M-1); 1 H NMR was consistent with the expected structure.
    [510] Example 14
    [511]
    [512] 3-methoxy-1- [5- (2,2,2-trichloro-acetyl) -1 H-pyrrol-3-yl] -propan-1-one:
    [513] To a solution of 2-trichloroacetyl pyrrole (1.0 equiv, 4.67 g, 22 mmol) in methylene chloride (5 mL) was added 3-methoxypropionyl chloride (1.0 equiv, 22 mmol), followed by aluminum trichloride (1.0 equiv, 2.93 g, 22 mmol). A small amount is added. After 2.5 h, the crude mixture is chromatographed on silica gel (2% MeOH in DCM) to give 3.0 g of Friedel-Crafts product. 1 H NMR is consistent with the structure.
    [514] Example 15
    [515]
    [516] 4- (3-Methoxy-propionyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide:
    [517] 3-methoxy-1- [5- (2,2,2-trichloro-acetyl) -1H-pyrrole-3-yl] -propan-1-one (3.0 in acetonitrile (50 mL) cooled to 0 ° C. g, 10 mmol) (S)-(+)-phenyl glycinol (1.2 equiv, 1.65 g, 12 mmol) and the resulting mixture are stirred at room temperature for 3 days. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel (5% MeOH in DCM) to give 5.3 g of the title compound as a white solid.
    [518] HPLC (method B), R t = 4.2 min; LC / MS (m / z) 317.03 (M + l), 315.00 (M-111); 1 H NMR is consistent with the structure.
    [519] Example 16
    [520]
    [521] 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide:
    [522] An excess of 4- (3-methoxy-propionyl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide in THF for 3 days at room temperature to 50 ° C Treated with Bredeck reagent. The solvent is removed under reduced pressure and the concentrate is used directly in the next step.
    [523] HPLC (method B), R t = 5.0 min, “Wide peak”.
    [524] Example 17
    [525]
    [526] 4- (5-methoxymethyl-2-phenylamino-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (III- a-164):
    [527] 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (0.27 mmol) Combine with phenyl guanidine (73 mg) in, N-dimethylacetamide (2 mL) and heat the resulting suspension at 90 ° C. for 35 h. The reaction mixture is diluted with ethyl acetate, washed with saturated NaHCO 3 and brine, then dried over MgSO 4 and concentrated in vacuo. The crude product was purified by preparative HPLC (Gilson: column = CombiHT SB-C189, 5 μΜ, gradient elution with eluent of 21.2 mm x 100 mm, 0.1% TFA / MeCN / H 2 O) to yield the compound as a yellow solid (3.2 mg). (III-a-164).
    [528] LC / MS (m / z) 444.16 (M + l), 442.19 (M-1); HPLC (method B), R t = 5.16 min; 1 H NMR is consistent with the structure.
    [529] Example 18
    [530]
    [531] 4- (5-Hydroxymethyl-2-phenylamino-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (III- a-165):
    [532] To a solution of compound (III-a-164) (15 mg, 0.03 mmol) in dichloromethane (2 mL) cooled to −78 ° C. add BBr 3 (135 μl, 0.13 mmol). After 15 minutes, the reaction is warmed to room temperature. After 45 minutes, the reaction is quenched with saturated sodium carbonate and the resulting mixture is stirred for an additional 30 minutes before extraction with ethyl acetate. The organic layers are combined, washed with brine and then dried over sodium sulfate. The crude mixture is purified by preparative TLC (silica, 7% MeOH in CH 2 Cl 2 ) to afford compound (III-a-165) as a beige solid (1.6 mg).
    [533] HPLC (method B), R t = 4.54 min; LC / MS (m / z) 430.15 (M + l), 428.03 (M-1); 1 H NMR is consistent with the structure.
    [534] Example 19
    [535]
    [536] 4- (2-Amino-5-methoxymethyl-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl-ethyl) -amide (III-a-161):
    [537] In Example 16 the enamine (0.27 mmol) formed above is combined with guanidine.HCl (51 mg) and K 2 CO 3 (100 mg) in N, N-dimethylacetamide (4 mL). The heterogeneous mixture is heated and stirred at 90 ° C. for 35 hours. The crude material is diluted with ethyl acetate, washed with saturated NaHCO 3 and brine, then dried (MgSO 4 ) and concentrated in vacuo. Purified by preparative HPLC (Gilson: Column = CombiHT SB-C189, 5 μΜ, 21.2 mm x 100 mm, gradient elution with eluent of 0.1% TFA / MeCN / H 2 O) to give III-a- as a yellow solid (2.0 mg). Provides 161.
    [538] LC / MS (m / z) 368.12 (M + l), 366.15 (M-1); R t (HPLC) = 3.77 min; 1 H NMR matches the structure.
    [539] Example 20
    [540]
    [541] 4- (2-Mercapto-5-methyl-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide:
    [542] 4- (3-Dimethylamino-2-methoxymethyl-acryloyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (17.6 mmol, 6.0 g) is combined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53 mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension is heated at 90 ° C. for 24 h. The solvent is removed in vacuo, the resulting black solid is diluted with water and the solid is filtered off. The solid is washed twice with ethyl acetate and the aqueous solution is oxidized to pH 5-6 with HCl (2N). The solid formed is filtered off and the aqueous solution is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed in vacuo to yield the title compound as a brown solid (3.0 g, yield: 48%).
    [543] HPLC (method B), R t = 3.7 min; 1 H NMR is consistent with the structure.
    [544] Example 21
    [545]
    [546] 4- (5-Methyl-2-propylsulfanyl-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide:
    [547] 4- (2-mercapto-5-methyl-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl- in aqueous ammonia (15%) at room temperature To ethyl) -amide (7.7 mmol, 2.74 g) is added n-propyl iodide (11.6 mmol, 1.1 mL). The solution is stirred overnight at room temperature. The resulting solid is collected by filtration and then used directly in the next step. 1 H NMR is consistent with the structure.
    [548] Example 22
    [549]
    [550] 4- [5-Methyl-2- (propane-1-sulfonyl) -pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl)- amides:
    [551] The thiopropyl compound (7.7 mmol, 3.05 g) prepared in Example 21 was dissolved in 120 mL of ethanol. To the solution kept at room temperature is added m-CPBA (70% w / w%, 23.1 mmol, 4.0 g). The solution is stirred for an additional 4 hours at room temperature. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate and washed four times with sodium hydroxide (IN) solution. The organic phase is dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (1.7 g, yield: 51% for two steps).
    [552] HPLC (method B), R t = 5.4 min. 1 H NMR is consistent with the structure.
    [553] Example 23
    [554]
    [555] 4- (2-Ethylamino-5-methyl-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide:
    [556] 4- [5-methyl-2- (propane-1-sulfonyl) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S)-in DMSO (1 mL) To a phenyl-ethyl) -amide solution (47 μmol, 20 mg) is added ethylamine (0.5 mmol, 150 μl). The mixture is heated at 130 ° C. for 24 hours to afford the title compound.
    [557] LC / MS (m / z) 366.2 (M + l); HPLC (method B), R t = 4.2 min; 1 H NMR is consistent with the structure.
    [558] Example 24
    [559]
    [560] 4- [2- (N ', N'-dimethyl-hydrazino) -5-methyl-pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S)- Phenyl-ethyl) -amide ( III-a-226 ):
    [561] 4- (3-dimethylamino-2-methoxymethyl-acryloyl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide solution in DMA (2 mL) (0.15 mmol, 50 mg) and dimethyl-N, N-aminoguanidine.2HCl (0.17 mmol, 30 mg) and potassium carbonate (0.36 mmol, 50 mg). The reaction mixture is stirred at 100 ° C. for 48 hours. The solvent is removed under high vacuum "GeneVac" and the residue is subjected to preparative HPLC (Gilson: column = gradient eluting with eluent of CombiHT SB-C189, 5μΜ, 21.2mm x 100mm, 0.1% TFA / MeCN / H 2 O). Then purified using preparative TLC (silica, 5% MeOH in CH 2 Cl 2 ) using “double eluent” to afford compound (III-a-226) as a pale yellow solid (1.3 mg).
    [562] HPLC (method B), R t = 4.03 min; LC / MS (m / z) 381.1 (M + l), 379.1 (M-1); 1 H NMR is consistent with the structure.
    [563] Example 25
    [564]
    [565] Ethanol Guanidine:
    [566] Ethanolamine hydrochloride (200 mg, 2 mmol) is added to a mixture of N, N'-di-boc-N "-triflyguanidine (800 mg, 2 mmol) and TEA (0.28 mL, 2 mmol) in dichloromethane (10 mL). The mixture was stirred overnight, then diluted with EtOAc, washed with sodium sulfite (2M) and saturated sodium bicarbonate, dried over NaSO 4 and concentrated in vacuo The crude residue was concentrated to 20% CH 2 Cl 2 / hexanes. Purification by flash column chromatography eluting gives a white solid (0.56 g, 92%).
    [567] 1 H NMR (CDCl 3 ): δ 4.18 (q, 2H), 1.60 (d, 18H), 1.37 (t, 3H).
    [568] 4M HCl / dioxane (5 mL) is added to the bis-Boc guanidine. The mixture is stirred for 24 hours and then concentrated to give the title compound (0.26 g).
    [569] 1 H NMR (MeOD): δ3.92 (q, 2H), 1.27 (t, 3H), MS (M + 1) 104.
    [570] Example 26
    [571]
    [572] 4- (2-Ethanolamine-5-methyl-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (III-a- 195):
    [573] 4- (3-Dimethylamino-2-methyl-acryloyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxymethyl-1- (S) -phenyl-ethyl) -amide (0.1 in DMF (1 mL)) mmol) and K 2 CO 3 (55 mg, 0.4 mmol) are added to ethanol guanidine hydrogen chloride (0.2 mmol). The resulting suspension is stirred at 90 ° C. for 6 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The crude residue was purified by preparative HPLC (Gilson: column = CombiHT SB-C189, 5 μΜ, gradient elution with eluent of 21.2 mm x 100 mm, 0.1% TFA / MeCN / H 2 O) to give the compound as a yellow oil (21 mg). (III-a-195).
    [574] HPLC (method B), R t = 4.08 min; MS (M + 1) 382.1.
    [575] Example 27
    [576]
    [577] Ethyl Carbamate Guanidine:
    [578] Ethylcarbazate (208 mg, 2 mmol) is added to a solution of N ', N'-di-boc N "-triflilguanide (800 mg, 2 mmol) in dichloromethane (10 mL). The mixture is stirred overnight, and with EtOAc Diluted, washed with sodium sulfite (2M) and saturated sodium bicarbonate, dried over anhydrous NaSO 4 and concentrated in vacuo The crude residue was purified by flash column chromatography eluting with 30% EtOAc / hexanes to give white. Solid (0.55 g) is added 4M HCl / dioxane (5 mL) to this bis-boc guanidine The mixture is stirred for 24 hours and then concentrated to afford the title compound.
    [579] 1 H NMR (MeOD) δ 3.4.18 (d, 2H), 3.26 (s, 1H), 1.28 (t, 3H).
    [580] MS (M + 1) 134.
    [581] Example 28
    [582]
    [583] 4- (2-Ethyl carbamate-5-methyl-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1- (S) -phenyl-ethyl) -amide (III-a -218):
    [584] 4- (3-Dimethylamino-2-methyl-acryloyl) -1 H-pyrrole-2-carboxylic acid (2-hydroxymethyl-1- (S) -phenyl-ethyl) -amide (0.1 in DMF (1 mL)) mmol) and K 2 CO 3 (55 mg, 0.4 mmol) are added ethyl carbamate guanidine hydrogen chloride (0.2 mmol). The resulting suspension is stirred at 90 ° C. for 6 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The crude residue was purified by preparative HPLC (Gilson: column = CombiHT SB-C189, 5 μΜ, gradient elution with eluent of 21.2 mm x 100 mm, 0.1% TFA / MeCN / H 2 O) to give the compound as a yellow oil (10 mg). (III-a-218).
    [585] HPLC (method B), R t = 4.03 min; MS (M + 1) 425.1.
    [586] 1 H NMR (MeOD) 8.08 (s, 1 H), 7.87 (s, 1 H), 7.7 (s, 1 H), 7.24-7.5 (m, 5 H); 5.15 (t, 1 H), 4.2 (m, 2 H), 3.85 (m, 2 H); 2.5 (s, 3 H).
    [587] Example 29
    [588] Other compounds of formula III-a have been prepared using methods substantially similar to the compounds described in Examples 1-28 above and described in Schemes I-XII. Characteristic data for these compounds are summarized in Table 3 below and include LC / MS, HPLC and 1 H NMR data.
    [589] Where applicable, in Table 3 below 1 H NMR data is obtained and indicated as “Y” if found to be consistent with the structure. Compound numbers correspond to the compound numbers listed in Table 1.
    [590]
    [591]
    [592] Biological test
    [593] The activity of the compounds of the invention as protein kinase inhibitors can be assayed in vitro, in vivo or in cell lines. In vitro assays include assays that measure the inhibition of phosphorylation activity or ATPase activity of activated protein kinases. In another in vitro assay, the ability of an inhibitor to bind protein kinases is measured. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, separating the inhibitor / protein kinase complex, and then measuring the amount of bound radiolabel. In addition, inhibitor binding can be measured by a competition test in which a novel inhibitor is incubated with a protein kinase bound to a known radioligand. Details of the conditions used to perform this analysis are described in Examples 30-37.
    [594] Example 30
    [595] ERK Inhibition Assay
    [596] Compounds were analyzed for inhibition of ERK2 using spectroscopically bound enzyme assays (Fox et al (1998) Protein Sci 7, 2249). In this assay, fixed concentrations of activated ERK2 (10 nM) were MgCl 2 10 mM, phosphoenolpyruvate 2.5 mM, NADH 200 μM, pyruvate kinase 150 μg / mL, lactate dehydrogenase 50 μg / mL and erktide Incubate with compounds of various concentrations in DMSO (2.5%) for 10 min at 30 ° C. in 0.1 M HEPES buffer at pH 7.5 containing 200 μM peptide. The reaction was initiated by adding 65 μM of ATP. Absorption reduction was monitored at 340 nM. IC 50 was evaluated from the rate data as a function of inhibitor concentration.
    [597] Table 4 shows the results of the activity of the selected compounds of the invention in the ERK2 inhibition assay. Compound numbers correspond to compound numbers in Table 1. The active compound represented by "A" has an inhibition rate of 33% or less, the active compound represented by "B" has an inhibition rate of 24 to 66%, and the active compound represented as "C" has an inhibition rate of 67 to 100%. The active compound denoted as "D" has a K i of less than 0.10 μM, the active compound denoted as "E" has a K i of 0.1 to 1.0 μM and the active compound denoted as "F" has a K i of greater than 1.0 μM.
    [598]
    [599]
    [600]
    [601] Example 31
    [602] ERK2 Inhibition: Cell Proliferation Assay
    [603] Compounds can be assayed for inhibition of ERK2 by cell proliferation assays. In this assay, the complete medium is prepared by adding 10% fetal bovine serum and penicillin / streptomycin solution to RPMI 1640 medium (JRH Biosciences). Colon cancer cells (HT-29 cell line) are added to each of the 84 wells of each 96 well plate at a distribution density of 10,000 cells / well / 150 μl. Cells are added to the plates by incubating at 37 ° C. for 2 hours. Solutions of test compounds are prepared in complete medium by serial dilution to obtain 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM and 0.08 μM concentrations. Test compound solution (50 μl) is added to each of the 72 cell containing wells. To 12 residual cell containing wells, only complete medium (200 μl) is added to form a control group to measure maximal proliferation. Complete media is added to the remaining 12 empty wells to form a vehicle control group to determine background. Plates are incubated at 37 ° C. for 3 days. The stock solution of 3 H-thymidine [1 mCi / mL, New England Nuclear, Boston, Mass.] Was diluted to 20 μCi / mL in PRMI medium, and 20 μl of the solution was added to each well. do. Plates are further incubated at 37 ° C. for 8 hours, then obtained and analyzed for 3 H-thymidine uptake using a liquid scintillation counter.
    [604] Compounds III-a-116, III-a-139, and III-A-136 each indicate an IC 50 of less than 0.1 μM.
    [605] Example 32
    [606] ERK1 Inhibition Assay
    [607] Compounds were analyzed for inhibition of ERK1 using a spectrophotometrically coupled enzyme system (Fox et al. (1998) Protein Sci 7, 2249). In this assay, the fixed concentration of activated ERK1 (20 nM) was 10 mg of MgCl 2 , phosphoenolpyruvate 2.5 mM, NADH 200 μM, pyruvate kinase 30 μg / mL, lactate dehydrogenase for 10 minutes at 30 ° C. Incubate with various concentrations of compounds in DMSO (2.0%) in 0.1 M HEPES buffer at pH 7.6 containing 10 μg / mL and 150 μM of erctide peptide. The reaction was initiated by adding ATP 140 μM (20 μl). Absorption reduction was monitored at 340 nM. Ki was evaluated from the rate data as a function of inhibitor concentration.
    [608] Examples of compounds found to inhibit ERK1 whose activity is less than 0.1 μM include III-a-202, III-a-204 and III-A-205.
    [609] Example 33
    [610] GSK-3 Inhibition Assay
    [611] The compounds were screened for their ability to inhibit GSK-3β (AA 1-420) activity using a standard bound enzyme system (Fox et al. (1998) Protein Sci 7, 2249). The reaction was carried out in a solution containing 100 mM HEPES (pH: 7.5), 10 mM MgCl 2 , 25 mM NaCl, 300 μM NADH, 1 mM DTT and 1.5% DMSO. The final substrate in the analysis is 20 μM of ATP (Sigma Chemicals, St. Louis, MO) and 20 μM of peptite (HSSPHQS (PO 3 H 2 ) EDEEE, American Peptide, Sunnyvale, CA). . The reaction was carried out at 30 ° C. and GSK-3β20 nM. Final concentrations of bound enzyme system components are phosphoenolpyruvate 2.5 mM, NADH 300 μM, pyruvate kinase 30 μg / mL and lactate dehydrogenase 10 μg / mL.
    [612] Analytical buffer stocks were prepared containing all of the reagents described above, with the exception of ATP and important test compounds. Analytical buffer stocks (175 μL) are incubated in 96-well plates using 5 μL of critical test compound at a final concentration range of 0.002 to 30 μM at 30 ° C. for 10 minutes. Typically, a twelve point titration is performed by preparing a dilution of phosphorus (from 10 mM compound stock solution) with test compound DMSO in the daughter plate. The reaction is initiated by adding 20 μl of ATP (final concentration: 20 μM). The reaction rate is obtained over 30 minutes at 30 ° C. using a Molecular Devices Spectramax plate reader (Sunvale, Calif.). K i values are determined from the rate data as a function of inhibitor concentration.
    [613] Table 5 shows the results of the activity of the selected compounds of the invention in the GSK3 inhibition assay. Compound numbers correspond to compound numbers in Table 1. The active compound indicated as "A" has a K i value of less than 0.1 μM, the active compound indicated as "B" has a K i value of 0.1 to less than 1.0 μM, and the active compound indicated as "C" has a K i value of 1.0 μM Exceeds.
    [614]
    [615] Example 34
    [616] AURORA-2 Inhibition Assay
    [617] Compounds were screened for their ability to inhibit Aurora-2 using standard bound enzyme systems (Fox et al. (1998) Protein Sci 7, 2249) in the following manner.
    [618] HEPES (pH: 7.5) 0.1M, MgCl 2 10mM, DTT 1mM, NaCl 25mM, Phosphoenolpyruvate 2.5mM, NADH 300mM, Pyruvate Kinase 30mg / mL, Lactate Dehydrogenase 10mg / mL, ATP 40mM And DMSO solution of the compound of the present invention at a final concentration of 30 μM to an assay stock buffer containing 800 μM of peptide (LRRASLG, American Peptide, Sunvale, CA). The resulting mixture was incubated at 30 ° C. for 10 minutes. The reaction was initiated by adding 10 μl of Aurora-2 stock solution with a final concentration of 70 nM in the assay. The reaction rate is determined by BioRad Ultramark plate reader; Hercules, Calif., Was used to monitor the absorbance over a 5 minute read time at 30 ° C. at 340 nm. K i values were determined from the rate data as a function of inhibitor concentration. Examples of compounds found to inhibit Aurora-2 include compounds III-a-116, III-a-117, III-a-136, III-a-138, III-a-139, III-a-140 and III -a-141 is included.
    [619] Example 35
    [620] CDK-2 Inhibition Assay
    [621] Compounds were screened for their ability to inhibit CDK-2 using a standard bound enzyme system (Fox et al. (1998) Protein Sci 7, 2249) in the following manner.
    [622] HEPES (pH: 7.5) 0.1 M, MgCl 2 10 mM, DTT 1 mM, NaCl 25 mM, Phosphoenolpyruvate 2.5 mM, NADH 300 mM, Pyruvate kinase 30 mg / mL, Lactate dehydrogenase 10 mg / mL, ATP 100 mM And DMSO solution of the compound of the present invention at a final concentration of 30 μM to an assay stock buffer containing 100 μM of peptide (MAHHHRSPRKRAKKK, American Peptide, Sunvale, CA). The resulting mixture was incubated at 30 ° C. for 10 minutes.
    [623] The reaction was initiated by the addition of 10 [mu] l of CDK-2 / Cyclin A stock, with a final concentration of 25 nM in the assay. The reaction rate was obtained by monitoring the absorbance over a 5 minute read time at 30 ° C. at 340 nm using a Biorad Ultramark plate reader (Hercules, Calif.). K i values were determined from the rate data as a function of inhibitor concentration.
    [624] The following compounds show K i values of at least 0.1 μM for CDK-2: III-a-116, III-a-142, III-a-149 and III-a-152.
    [625] The following compounds show K i values of 0.1-1 μM for CDK-2: III-a-146, III-a-148, III-a-150, III-a-155 and III-a-162 and III- a-174.
    [626] The following compound shows a K i value of 1.0 to 20.0 μΜ for CDK-2: III-a-117, III-a-156 and III-a-159.
    [627] Example 36
    [628] LCK inhibition assay
    [629] Compounds were evaluated as inhibitors of human Lck kinase using assays based on radioactivity or spectrophotometry.
    [630] Lck Inhibition Assay (A): Assay Based on Radioactive Activity
    [631] The compound was expressed and purified from baculo viral cells in bovine thymus Lck kinase of total length [see Upstate Biotechnology, cat. no. 14-106]. Lck kinase activity was monitored by incorporation from ATP into tyrosine based on a random poly Glu-Tyr polymer of a composition with a Glu: Tyr (Sigma, cat number P-0275) 4: 1. The final concentrations of the assay components are: HEPES 0.025M, pH 7.6, MgCl 2 10 mM, DTT 2 mM, BSA 0.25 mg / mL, ATP ( 33 P-ATP 1 to 2 μCi) 10 μM, Poly Glu-Tyr 5 mg / mL And recombinant human Src kinase 1 or 2 units. In conventional assays, all reaction components except ATP are premixed and aliquoted into assay plate wells. Addition of an inhibitor dissolved in DMSO to the well results in a final DMSO concentration of 2.5%. The assay plate is incubated at 30 ° C. for 10 minutes before initiating the reaction with 33 P-ATP. After reacting for 20 minutes, the reaction was quenched with 150 μl of 10% trichloroacetic acid (TCA) containing 20 mM Na 3 PO 4 . The quench sample is then transferred to a 96 well filter plate (Whatmann, UNI-filter GF / F glass fiber filter, cat no. 7700-3310) installed on a filter plate vacuum manifold. The filter plate is washed four times with 10% TCA containing 20 mM Na 3 PO 4 and then four times with methanol. 200 μl of the flash fluid is then added to each well. After the plate was sealed, the amount of radioactive activity associated with the filter was measured on a TopCount scintillation counter. The incorporated radioactive activity is propelled as a function of inhibitor concentration. The data fits a competitive inhibition kinetics model to obtain K i for the compound.
    [632] Lck Inhibition Assay (B): Spectrophotometric Assay
    [633] ADPs generated from ATP by human recombinant Lck kinase catalyzed phosphorylation on poly Glu-Tyr substrates were quantified using a bound enzyme assay (Fox et al. (1998) Protein Sci 7, 2249). In this assay, one NADH molecule is oxidized to NAD in all of the ADP molecules generated in the kinase reaction. The disappearance of NADH can be conveniently performed at 340 nm.
    [634] The following are the final concentrations of the assay components: HEPES 0.025M, pH 7.6, MgCl 2 10 mM, DTT 2 mM, Poly Glu-Tyr 5 mg / mL and recombinant human Lck kinase 50 nM. Final concentrations of components of the bound enzyme system were phosphoenolpyruvate 2.5 mM, NADH 200 μM, pyruvate kinase 30 mg / mL and lactate dehydrogenase 10 mg / mL.
    [635] In conventional assays, all reaction components except ATP are premixed and aliquoted into assay plate wells. Addition of an inhibitor dissolved in DMSO to the well results in a final DMSO concentration of 2.5%. The assay plate is incubated at 30 ° C. for 10 minutes and then the reaction is initiated with ATP 150 μM. Absorption rate change over time and reaction rate at 340 nm is monitored with a molecular device plate reader. Kinetic data as a function of inhibitor concentration fit a competitive inhibition kinetics model to obtain K i values for the compound.
    [636] The following compounds show that K i values exceed 1 μM for Lck: III-a-170, III-a-171, III-a-172, III-a-173, III-a-181 and III-a -203.
    [637] The following compounds show K i values for Lck between 1.0 and 20.0 μΜ: III-a-204, III-a-205, III-a-206 and III-a-207.
    [638] Example 37
    [639] AKT3 Inhibition Assay
    [640] Compounds were screened for their ability to inhibit AKT3 using standard bound enzyme assays (Fox et al. (1998) Protein Sci 7, 2249) in the following manner. The assay was performed with a mixture of HEPES (pH: 7.5) 100 mM, MgCl 2 10 mM, NaCl 25 mM, DTT 1 mM and DMSO 1.5%. Final assay concentrations in the assay were ATP 170 μM (Sigma Chemicals) and peptide (RPRAATF, American Peptide, Sunvale, CA). Analyze at 30 ° C. and AKT3 45 nM. Final concentrations of bound enzyme system components are phosphoenolpyruvate 2.5 mM, NADH 300 μM, pyruvate kinase 30 μg / mL and lactate dehydrogenase 10 μg / mL.
    [641] Analytical feedstock buffers are prepared containing all of the reagents described above except for AKT3, DTT and important test compounds. 56 μl of raw material is placed in a 384 well plate, and then 1 μl of 2 mM DMSO containing test compound (final compound concentration: 30 μM) is added. The plate is preincubated at 30 ° C. for about 10 minutes and the reaction is initiated by adding 10 μl of enzyme (final compound concentration: 45 μM) and 1 mM of DTT. Reaction rates are obtained using a Biorad Ultramark Plate Reader (Hercules, Calif.) At 30 ° C. over a 5 minute read time. IC 50 values are determined by titrating standard wells containing analyte mixture and DMSO without compounds with inhibition greater than 50% versus test compound.
    [642] Selected compounds of the invention that inhibit AKT3 include III-a-238.
    [643] Although many embodiments of the invention are shown, it is clear that our basic structure cannot be modified to provide other embodiments using the compounds and methods of the invention. Accordingly, it will be appreciated that the scope of the invention is to be limited by the appended claims rather than by the specific embodiments shown in the examples.
    [644] Annex A: Name of the compound number of formula III-a of Table 1
    [645] 1: 4- (2-amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrole-2 carboxylic acid dimethylamide;
    [646] 2: {4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -pyrrolidin-1-yl-methanone;
    [647] 3: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -pyrrolidin-1-yl-meta Paddy fields;
    [648] 4: 4- (2-amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrole-2 carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [649] 5: [4- (2-amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -morpholin-4-yl-methanone;
    [650] 6: [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] [1,4 '] bipiperidinyl-1'-yl-methanone;
    [651] 7: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1 H-pyrrol-2-yl}-(3-hydroxy-piperidine- 1-yl) -methanone;
    [652] 8: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1H-pyrrole-2-yl}-[1,4 '] bipiperidinyl- 1'-yl-methanone;
    [653] 9: [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] [1,4 '] bipiperidinyl-1'-yl-methanone;
    [654] 10: {4- [2-amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[1,4 '] bipiperidinyl -1'-yl-methanone;
    [655] 11: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-hydroxy-piperidin-1-yl) -methanone ;
    [656] 12: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] [4- (2-fluorophenyl) -piperazin-1-yl] -meta Paddy fields;
    [657] 13: [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] (4-phenyl-piperazin-1-yl) -methanone;
    [658] 14: [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] [4- (4-fluorophenyl) -3,6-dihydro-2H- Pyridin-1-yl] -methanone;
    [659] 15: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] (4-pyridin-2-yl-piperazin-1-yl) -methanone;
    [660] 16: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -H-pyrrol-2-yl} -morpholin-4-yl-methanone;
    [661] 17: 4- [2-amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] 1H-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) amide;
    [662] 18: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] -morpholin-4-yl-methanone;
    [663] 19: 4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -1 H-pyrrole-2 carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [664] 20: 4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) amide;
    [665] 21: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-yl}-[4- (2-fluorophenyl) -piperazine- 1-yl] -methanone;
    [666] 22: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-phenylpiperazin-1-yl) -meta Paddy fields;
    [667] 23: {4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-yl}-[4- (4-fluorophenyl) -3,6 -Dihydro-2H pyridin-l-yl] -methanone;
    [668] 24: {4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-yl}-(3,4-dihydro-lH-isoquinoline-2 -Yl) -methanone;
    [669] 25: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-yl}-(4-pyridin-2-yl-piperazin-1- Yl) -methanone;
    [670] 26: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -morpholin-4-yl-methanone ;
    [671] 27: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-yl}-(4-hydroxy-piperidin-1-yl) -Methanone;
    [672] 28: {4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-yl}-[1,4 '] bipiperidinyl-1'-yl -Methanone;
    [673] 29: 4- (2-amino-5-phenyl-pyrimidin-4-yl) -H-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [674] 30: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-[4- (4-methoxy-phenyl) -piperazin-1-yl] -Methanone;
    [675] 31: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -H-pyrrol-2-yl]-(2-hydroxymethylpiperidin-1-yl) -methanone;
    [676] 32: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(3,4-dihydro-lH-isoquinolin-2-yl) -meta Paddy fields;
    [677] 33: 4- [2-amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [678] 34: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1 H-pyrrol-2-yl}-[4- (4-fluorophenyl) -3,6-dihydro-2H pyridin-l-yl] -methanone;
    [679] 35: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3,4-dihydro-lH- Isoquinolin-2-yl) -methanone;
    [680] 36: 4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [681] 37: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-phenyl-piperazin-1-yl) -methanone;
    [682] 38: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-methyl- [1,4] -diazepan-1-yl ) -Methanone;
    [683] 39: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(3,4-dihydro-lH-isoquinolin-2-yl) -Methanone;
    [684] 40: 4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [685] 41: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-methyl- [l, 4] diazepane- 1-yl) -methanone;
    [686] 42: 4- [2-amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid benzyl-methyl amide;
    [687] 43: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[2- (2-hydroxyethyl) -piperi Din-1-yl] metanon;
    [688] 44: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-phenyl-piperazine-1 -Yl) -methanone;
    [689] 45: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl]-[4- (2-fluorophenyl) -piperazin-1-yl ] -Methanone;
    [690] 46: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl]-(3-hydroxy-piperidin-1-yl) -methanone ;
    [691] 47: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl]-[4- (4-methoxy-phenyl) -piperazine-1- General] -methanone;
    [692] 48: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl]-[4- (4-fluorophenyl) -3,6-dihydro -2H-pyridin-l-yl] -methanone;
    [693] 49: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (2-fluorophenyl ) -Piperazin-l-yl] -methanone;
    [694] 50: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (4-methoxy- Phenyl) -piperazin-1-yl] -methanone;
    [695] 51: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-methyl- [1,4 Diazepan-1-yl) -methanone;
    [696] 52: 1- (4- {4- [2-Amino-5- (3-chloro-2-fluorophenyl) pyrimidin-4-yl] -1H-pyrrole-2-carbonyl} -piperazine-1 -Yl) -ethanone;
    [697] 53: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3,4-dihydro-lH Isoquinolin-2-yl) -methanone;
    [698] 54: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl ) -Methanone;
    [699] 55: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] (4-methyl- [1,4] diazepan-1-yl) -methanone ;
    [700] 56: 1- (4- {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carbonyl} -piperazine-1 -Yl) -ethanone;
    [701] 57: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1H-pyrrol-2-yl}-(4-methyl- [1,4] -Diazepan-1-yl) -methanone;
    [702] 58: [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] (3-hydroxy-piperidin-1-yl) -methanone;
    [703] 59: 4- [2-amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-carboxylic acid methyl- (2-pyridin-2-yl-ethyl) -amide;
    [704] 60: [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-[2- (2-hydroxyethyl) -piperidine-1- General] -methanone;
    [705] 61: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[2- (2-hydroxyethyl ) -Piperidin-l-yl] -methanone;
    [706] 62: 4- [2-amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2- Phenylethyl) -methyl-amide;
    [707] 63: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-pyridin-2-yl- Piperazin-1-yl) -methanone;
    [708] 64: [4- (2-amino-5-phenyl-pyrimidin-4-yl) -H-pyrrol-2-yl]-(4-hydroxy-piperidin-1-yl) -methanone;
    [709] 65: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -H-pyrrol-2-yl}-(4-hydroxy-piperidine- 1-yl) -methanone;
    [710] 66: {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-hydroxy-piperidine -1-yl) -methanone;
    [711] 67: {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] 1H-pyrrole-2-yl}-(4-pyridin-2-yl-piperazine -1-yl) -methanone;
    [712] 68: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (2-hydroxyethyl) -piperazine -1-yl] -methanone;
    [713] 69: 1- {4- [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrole-2-carbonyl] -piperazin-1-yl} -ethanone;
    [714] 70: {4- [2-amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1H-pyrrol-2-yl}-[4- (2-fluorophenyl) -Piperazin-1-yl] -methanone;
    [715] 71: [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] pyrrolidin-1-yl-methanone;
    [716] 72: {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -morpholin-4-yl-methanone;
    [717] 73: 4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrole-2 carboxylic acid benzylamide;
    [718] 74: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3,4-difluorobenzylamide;
    [719] 75: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [720] 76: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 4-fluoro-benzylamide;
    [721] 77: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-benzylamide;
    [722] 78: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 4-methoxy-benzylamide;
    [723] 79: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    [724] 80: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) -amide;
    [725] 81: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) -amide;
    [726] 82: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2 carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    [727] 83: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    [728] 84: 4- (2,5-diaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    [729] 85: 4- (2-amino-5-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    [730] 86: 4- (5-acetylamino-2-aminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    [731] 87: 4- [2-amino-5- (3-methyl-ureido) -pyrimidin-4-yl] -lH pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [732] 88: 4- (2-amino-5-hydroxy-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    [733] 89: 4- (2-amino-5-methylaminomethylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [734] 90: 4- (2-amino-5-hydroxymethylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [735] 91: 4- [2-cyclohexylamino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [736] 92: 4- [2-acetylamino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [737] 93: 4- (5-hydroxy-2-methanesulfonylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [738] 94: 4- (2-Amino-5-methanesulfonyl-pyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro benzylamide;
    [739] 95: 4- (2-amino-5-hydroxymethylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
    [740] 96: 4- (2-cyclohexylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
    [741] 97: 4- [2-amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (pyridin-4-ylmethyl) amide;
    [742] 98: 4- [5- (3,5-dichloro-phenyl) -2-phenylaminopyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 3-trifluoromethyl benzylamide;
    [743] 99: 4- [2-amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [744] 100: 4- [2-amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (benzo [1,3] diosol-5-ylmethyl )-amides;
    [745] 101: 4- [2-amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-dimethylamino-2 pyridin-3-yl-ethyl )-amides;
    [746] 102: 4- [2-amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 4-methanesulfonyl benzylamide;
    [747] 103: 4- [5- (3,5-dichloro-phenyl) -2-phenylaminopyrimidin 4-yl] -lH-pyrrole-2-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amides;
    [748] 104: 4- [5- (3,5-dichloro-phenyl) -2-phenylaminopyrimidin 4-yl] -lH-pyrrole-2-carboxylic acid (2-morpholin-4-yl-2-pyridine-3 -Yl-ethyl) -amide;
    [749] 105: 4- [2-amino-5- (3-fluoro-5-trifluoromethylphenyl) -pyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [750] 106: 4- (2-amino-5-propyl-pyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [751] 107: 4- (2-amino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [752] 108: 4- (5-methyl-2-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) amide;
    [753] 109: 4- (2-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [754] 110: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-dimethylamino-ethyl) -amide;
    [755] 111: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid propylamide;
    [756] 112: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (3-phenyl-propyl) -amide;
    [757] 113: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (naphthalen-1-ylmethyl) -amide;
    [758] 114: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid cyclopropylamide;
    [759] 115: 4- (2-ethylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 2-trifluoromethyl-benzylamide;
    [760] 116: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [761] 117: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [762] 118: 4- (2-ethylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (4-methyl-cyclohexyl) -amide;
    [763] 119: 4- (5-ethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid isopropylamide;
    [764] 120: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-amino-ethyl) -amide;
    [765] 121: 4- (2-aminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [766] 122: 4- (2-aminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    [767] 123: 1-4- [4- (2-ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carbonyl] -piperazin-1-yl} -ethanone;
    [768] 124: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (3-phenyl-propyl) -amide;
    [769] 125: 4- (2-Amino-5-ethylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [2- (6-methoxy-lH-indol-3-yl) -ethyl] -amide;
    [770] 126: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-phenoxyethyl) -amide;
    [771] 127: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (1-methyl-3-phenyl propyl) -amide;
    [772] 128: 4- (5-methyl-2-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (lH-benzoimidazol-2-ylmethyl) -amide;
    [773] 129: 4- (5-methyl-2-methylaminopyrimidin-4-yl) -HH pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methylbutyl) -amide;
    [774] 130: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -lH pyrrole-2-carboxylic acid [1-hydroxymethyl-2- (lH-imidazol-4-yl) -ethyl]- amides;
    [775] 131: 4- (2-amino-5-methylpyrimidin-4-yl) -1H-pyrrole-2 carboxylic acid (tetrahydrofuran-2-ylmethyl) -amide;
    [776] 132: 4- [2- (2-diethylamino-ethylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 3,4-difluoro benzylamide;
    [777] 133: 4- [5-methyl-2- (2-piperidin-1-yl-quinazolin-4-ylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid benzylamide;
    [778] 134: 4- (5-methyl-2-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl]- amides;
    [779] 135: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl]- amides;
    [780] 136: 4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [781] 137: 4- [2- (3-methoxy-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [782] 138: 4- [2- (3-hydroxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [783] 139: 4- [2- (benzo [1,3] dioxol-5-ylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenyl Ethyl) -amide;
    [784] 140: 4- [5-methyl-2- (4-sulfamoyl-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [785] 141: 4- [2- (3-benzyloxy-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [786] 142: 4- [2- (4-hydroxycyclohexylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [787] 143: 4- (5-cyclohexyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [788] 144: 4- (5-cyclopropyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [789] 145: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-fluoro-4-methylphenyl) -2-hydroxyethyl] -amide ;
    [790] 146: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -HH pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    [791] 147: 4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid [1- (3-fluoro-4-methylphenyl) -2- Hydroxyethyl] -amide;
    [792] 148: 4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -Ethyl] -amide;
    [793] 149: 4- [5-methyl-2- (3-trifluoromethylphenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [794] 150: 4- (2-benzylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [795] 151: 4- [2- (3,4-dimethylphenylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [796] 152: 4- [2- (4-benzyloxy-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [797] 153: 4- (2-isopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [798] 154: 4- [5-methyl-2- (2,2,2-trifluoro-ethylamino) pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [799] 155: 4- [2- (2-hydroxy-l-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    [800] 156: 4- [2- (2-methoxyphenylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [801] 157: 4- [5-methyl-2- (4-trifluoromethoxy-phenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    [802] 158: 4- (2-isobutylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [803] 159: 4- [2- (cyclopropylmethyl-amino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [804] 160: 4- (5-methoxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [805] 161: 4- (2-Amino-5-methoxymethylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [806] 162: 4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [807] 163: 4- (5-Methyl-2-propylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [808] 164: 4- (5-methoxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [809] 165: 4- (5-hydroxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [810] 166: 4- [2- (2-hydroxy-1-phenylethylamino) -5-methyl pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    [811] 167: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    [812] 168: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    [813] 169: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenylethyl) -amide;
    [814] 170: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2-phenylethyl) -amide;
    [815] 171: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-hydroxymethyl-2-phenylethyl) -amide;
    [816] 172: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    [817] 173: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    [818] 174: 4- [2- (l-hydroxymethyl-cyclopropylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide ;
    [819] 175: 4- [2- (2-hydroxyethylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [820] 176: 4- [2- (2-hydroxy-l-methylethylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    [821] 177: 4- [2- (2-hydroxypropylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [822] 178: 4- [2- (2-hydroxypropylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [823] 179: 4- [2- (2-hydroxycyclohexylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [824] 121: 4- [2- (2-hydroxy-1-methyl-ethylamino) -5-methyl pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    [825] 121: 4- [2- (3-dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [826] 180: 4- (2-aminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    [827] 181: 4- (2-aminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl amide;
    [828] 183: 4- (2-aminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenylethyl) -methyl-amide;
    [829] 184: {[4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl ester;
    [830] 186: 4- (2-Aminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    [831] 187: 4- (2-ethylamino-5-methoxymethylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [832] 188: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-pyridin-3-yl-ethyl) -amide;
    [833] 189: 4- (2-ethylamino-5-hydroxymethylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [834] 190: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (3-fluoro-5-trifluoromethylphenyl) -2-hydroxyethyl ]-amides;
    [835] 191: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (3-fluorophenyl) -2-hydroxyethyl] -amide;
    [836] 192: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (2-fluorophenyl) -2-hydroxyethyl] -amide;
    [837] 193: 4- [2- (2-cyclopropyl-1-hydroxymethylethylamino) -5 methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    [838] 194: 4- [2- (2,3-dimethylphenylamino) -5-methylpyrimidin 4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [839] 195: 4- (2-ethoxyamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [840] 196: 4- [2- (l-hydroxymethyl-2-methyl-propylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [841] 197: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-oxo-1-phenyl-propyl) -amide;
    [842] 198: 4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    [843] 199: 4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -Ethyl] -amide;
    [844] 200: 4- [2- (2-chloro-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -Ethyl] -amide;
    [845] 201: 4- [2- (2-hydroxy-1-phenylethylamino) -5-methyl pyrimidin-4-yl] -H-pyrrole-2-carboxylic acid [2-hydroxy-1- (3-tri Fluoromethylphenyl) -ethyl] -amide;
    [846] 200: 4- [2- (3-dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl ) -Ethyl] -amide;
    [847] 202: 4- (2-Cyclopropylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide ;
    [848] 203: 4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [2-hydroxy-l- (2-methoxyphenyl) -ethyl] -amide;
    [849] 204: 4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl] -amide;
    [850] 205: 4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    [851] 206: 4- (2-methoxyamino-5-methylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [852] 207: 4- (2-isopropoxyamino-5-methylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [853] 208: 4- [2- (3-dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl)- amides;
    [854] 209: 4- [2- (2-Chloro-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl) -amide;
    [855] 210: 4- [2- (2-hydroxy-1-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl- Ethyl) -amide;
    [856] 211: 4- [2- (2,3-dimethylphenylamino) -5-methylpyrimidin 4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl) -amide;
    [857] 212: 4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-l-m-tolyl-ethyl) -amide;
    [858] 213: 4- (2-acetylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [859] 214: 4- (5-methyl-2-o-tolylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [860] 215: 4- [5-methyl-2- (pyridin-3-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [861] 216: 4- {5-Methyl-2-[(tetrahydrofuran-2-ylmethyl) -amino] pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [862] 217: 4- {5-Methyl-2-[(tetrahydrofuran-2-ylmethyl) -amino] pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [863] 218: N'-4- [5- (2-hydroxy-1-phenylethylcarbamoyl) -lH-pyrrol-3-yl] -5-methylpyrimidin-2-yl} hydrazinecarboxylic acid ethyl ester;
    [864] 219: 4- {5-Methyl-2-[(pyridin-3-ylmethyl) -amino] -pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    [865] 220: 4- (2-cyclopropylmethoxyamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [866] 221: 4- [2- (isoxazol-3-ylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [867] 222: 4- [2- (2-hydroxy-1-methyl-ethylamino) -5-methyl pyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl -Ethyl) -amide;
    [868] 223: 4- (5-methyl-2-o-tolylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    [869] 224: 4- (5-methyl-2-o-tolylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl] -amide;
    [870] 225: 4- [2- (2-hydroxy-ethoxyamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide;
    [871] 226: 4- [2- (N ', N'-dimethyl-hydrazino) -5-methylpyrimidin 4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide ;
    [872] 227: 4- [5-methyl-2- (2-trifluoromethylphenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [873] 228: 4- [5-methyl-2- (morpholin-4-ylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    [874] 229: 4- [5-methyl-2- (5-methyl-isoxazol-3-ylamino) -pyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [875] 230: 4- {2- [l- (3-chloro-4-fluorophenyl) -2-hydroxyethylamino] -5-methylpyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2 -Hydroxy-1-phenylethyl) -amide;
    [876] 231: 4- (5-methyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-fluorophenyl) -2-hydroxyethyl] -amide;
    [877] 232: 4- [2- (1-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxy Oxyethyl] -amide;
    [878] 233: 4- [2- (2-hydroxy-1-hydroxymethyl-ethylamino) -5 methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl] -amide;
    [879] 234: 4- [2- (l-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amides;
    [880] 235: 4- [2- (2-hydroxy-1-hydroxymethyl-ethylamino) -5 methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl )-amides;
    [881] 236: 4- [2- (l-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    [882] 237: 4- [5-methyl-2- (2-methyl-cyclopropylamino) -pyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1 phenylethyl) -amide; And
    [883] 238: 4- (2-Cyanoamino-5-methylpyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide.
    权利要求:
    Claims (70)
    [1" claim-type="Currently amended] A method of inhibiting ERK-2 activity, comprising administering a compound of Formula (I) or a pharmaceutically acceptable derivative thereof to a patient in need of inhibition of ERK-2 activity.
    Formula I

    In Formula I above,
    Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Rings A and QR 2 are bonded to Sp at non-adjacent positions, Sp has up to 2 R 6 substituents, provided that 2 substitutions in Sp Possible carbocyclic atoms are not substituted at the same time with R 6 ;
    Z 1 and Z 2 are each independently selected from N and CH;
    T and Q are each independently selected from a binding group;
    U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    m and n are each independently 0 or 1;
    R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 ,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , -N (R 4 ) 2 And -NR 4 (CH 2 ) y N (R 4 ) 2 ;
    y is 0 to 6;
    R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    w is each independently selected from 0-4.
    [2" claim-type="Currently amended] The method of claim 1, wherein Sp is selected from one of the rings of the formulas or pharmaceutically acceptable derivatives thereof.

    [3" claim-type="Currently amended] The compound of claim 2, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) T m R 1 is hydrogen, amino, OH, a 3-6 membered carbocyclyl, or an optionally substituted group selected from a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring;
    (c) when Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH- ;
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH When (R 8 ) CH (R 5 ) 2 ;
    (e) when R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ; And
    (f) having at least one feature selected from the group consisting of R 5 is an optionally substituted group selected from C 1-6 aliphatic groups, phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl Way.
    [4" claim-type="Currently amended] The compound of claim 3, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) T m R 1 is an optionally substituted group selected from hydrogen, amino, OH, 3-6 membered carbocyclyl, or C 1-6 aliphatic group and 5-6 membered aryl or heteroaryl ring,
    (c) Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH-,
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 ,
    (e) R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ,
    (f) R 5 is an optionally substituted group selected from C 1-6 aliphatic groups, phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl.
    [5" claim-type="Currently amended] The compound of claim 3, wherein the compound is
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl, benzyl or isoxazolyl groups;
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ;
    (c) when Q is -CO-, -CONH-, -SO 2- , or -SO 2 NH-;
    (d) R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , wherein R 8 Is OH or CH 2 OH; And
    (e) R 5 is -CH 2 OH,-(CH 2 ) 2 OH, isopropyl, or pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazine-1 -Yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl , 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl and benzyl, optionally substituted group selected from the group consisting of .
    [6" claim-type="Currently amended] The compound of claim 5, wherein the compound is
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and an optionally substituted phenyl, benzyl or isoxazolyl group,
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ,
    (c) Q is -CO-, -CONH-, -SO 2 -or -SO 2 NH-,
    (d) R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , wherein R 8 Is OH or CH 2 OH),
    (e) R 5 is -CH 2 OH,-(CH 2 ) 2 OH, isopropyl, or pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazine-1 -Yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl , 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl and benzyl.
    [7" claim-type="Currently amended] The method of claim 2, wherein the compound is a compound of Formula III-a or a pharmaceutically acceptable derivative thereof.
    Formula III-a

    [8" claim-type="Currently amended] The compound of claim 7, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If;
    (c) when Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH- ;
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH When (R 8 ) CH (R 5 ) 2 ;
    (e) when R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ; And
    (f) R 5 has one or more of the features selected from the group consisting of phenyl, a 5-6 membered heteroaryl and an optionally substituted group selected from 5-6 membered heterocyclyl.
    [9" claim-type="Currently amended] The compound of claim 8, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring ego,
    (c) Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH-,
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 ,
    (e) R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ,
    (f) R 5 is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl.
    [10" claim-type="Currently amended] A method of inhibiting ERK-2 activity in a biological sample, comprising contacting the biological sample with a compound of Formula (I) or a pharmaceutically acceptable derivative thereof.
    Formula I

    In Formula I above,
    Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Rings A and QR 2 are bonded to Sp at non-adjacent positions, Sp has up to 2 R 6 substituents, provided that 2 substitutions in Sp Possible carbocyclic atoms are not substituted at the same time with R 6 ;
    Z 1 and Z 2 are each independently selected from N and CH;
    T and Q are each independently selected from a binding group;
    U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    m and n are each independently 0 or 1;
    R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 ,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , -N (R 4 ) 2 And -NR 4 (CH 2 ) y N (R 4 ) 2 ;
    y is 0 to 6;
    R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    w is each independently selected from 0-4.
    [11" claim-type="Currently amended] The method of claim 10, wherein Sp is selected from one of the rings of the formula or pharmaceutically acceptable derivatives thereof.

    [12" claim-type="Currently amended] The compound of claim 11, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) T m R 1 is hydrogen, amino, OH, a 3-6 membered carbocyclyl, or an optionally substituted group selected from a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring;
    (c) when Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH- ;
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH When (R 8 ) CH (R 5 ) 2 ;
    (e) when R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ; And
    (f) having at least one feature selected from the group consisting of R 5 is an optionally substituted group selected from C 1-6 aliphatic groups, phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl Way.
    [13" claim-type="Currently amended] The compound of claim 12, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) T m R 1 is an optionally substituted group selected from hydrogen, amino, OH, 3-6 membered carbocyclyl, or C 1-6 aliphatic group and 5-6 membered aryl or heteroaryl ring,
    (c) Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH-,
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 ,
    (d) R 4 is R, R 7 or-(CH 2 ) y CH (R 5 ) 2 ,
    (e) R 5 is an optionally substituted group selected from C 1-6 aliphatic groups, phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl.
    [14" claim-type="Currently amended] The compound of claim 12, wherein the compound is
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl, benzyl or isoxazolyl groups;
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ;
    (c) when Q is -CO-, -CONH-, -SO 2- , or -SO 2 NH-;
    (d) R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , wherein R 8 Is OH or CH 2 OH; And
    (e) R 5 is -CH 2 OH,-(CH 2 ) 2 OH, isopropyl, or pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazine-1 -Yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl , 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl and benzyl, optionally substituted group selected from the group consisting of .
    [15" claim-type="Currently amended] The compound of claim 14, wherein the compound is
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and an optionally substituted phenyl, benzyl or isoxazolyl group,
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ,
    (c) Q is -CO-, -CONH-, -SO 2 -or -SO 2 NH-,
    (d) R 2 is-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 , wherein R 8 Is OH or CH 2 OH),
    (e) R 5 is -CH 2 OH,-(CH 2 ) 2 OH, isopropyl, or pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazine-1 -Yl, 4-methyl [1,4] diazepan-1-yl, 4-phenyl-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl , 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl and benzyl.
    [16" claim-type="Currently amended] The method of claim 11, wherein the compound is a compound of Formula III-a or a pharmaceutically acceptable derivative thereof.
    Formula III-a

    [17" claim-type="Currently amended] The compound of claim 16, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If;
    (c) when Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH- ;
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH When (R 8 ) CH (R 5 ) 2 ;
    (e) when R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ; And
    (f) R 5 has one or more of the features selected from the group consisting of phenyl, a 5-6 membered heteroaryl and an optionally substituted group selected from 5-6 membered heterocyclyl.
    [18" claim-type="Currently amended] The compound of claim 17, wherein the compound is
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring ego,
    (c) Q is -CO-, -CO 2- , -CONH-, -SO 2- , -SO 2 NH-, -OC (O) NH-, -C (O) ONH- or -CONHNH-,
    (d) R 2 is -NR 4 (CH 2 ) y N (R 4 ) 2 ,-(CH 2 ) y R 5 ,-(CH 2 ) y CH (R 5 ) 2 or-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 ,
    (e) R 4 is R, R 7 or — (CH 2 ) y CH (R 5 ) 2 ,
    (f) R 5 is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl.
    [19" claim-type="Currently amended] 4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid dimethylamide;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -pyrrolidin-1-yl-methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -pyrrolidin-1-yl-methanone;
    4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] morpholin-4-yl-methanone;
    [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrole-2-yl]-[1,4 '] bipiperidinyl-1'-yl-methanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] 1H-pyrrole-2-yl}-(3-hydroxy-piperidin-1-yl ) -Methanone;
    {4- [2-amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1H-pyrrole-2-yl}-[1,4 '] bipiperidinyl-1' -Yl-methanone;
    [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -1H-pyrrole-2-yl] [1,4 '] bipiperidinyl-1'-yl-methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[1,4 '] bipiperidinyl-1 '-Yl-methanone;
    [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrole-2-yl]-(4-hydroxy-piperidin-1-yl) -methanone;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-[4- (2-fluorophenyl) -piperazin-1-yl] -methanone ;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-phenyl-piperazin-1-yl) -methanone;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl] [4- (4-fluorophenyl) -3,6-dihydro-2H-pyridine- 1-yl] -methanone;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -H-pyrrol-2-yl]-(4-pyridin-2-yl-piperazin-1-yl) -methanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -morpholin-4-yl-methanone;
    4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] morpholin-4-yl-methanone;
    4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (2-fluorophenyl) -piperazine-1 -Yl] -methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-phenyl-piperazin-1-yl) -methanone ;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (4-fluorophenyl) -3,6- Dihydro-2H-pyridin-1-yl] -methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinoline-2- Yl) -methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazin-1-yl ) -Methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -morpholin-4-yl-methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-hydroxy-piperidin-1-yl)- Metanon;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[1,4 '] bipiperidinyl-1'-yl- Metanon;
    4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] [4- (4-methoxy-phenyl) -piperazin-1-yl] -methanone ;
    [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrole-2-yl] (2-hydroxymethylpiperidin-1-yl) -methanone;
    [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] (3,4-dihydro-lH-isoquinolin-2-yl) -methanone;
    4- [2-Amino-5- (3, 4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH pyrrole-2-carboxylic acid benzyl-methyl-amide;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1 H-pyrrol-2-yl}-[4- (4-fluorophenyl) -3 , 6-dihydro-2H-pyridin-1-yl] -methanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3,4-dihydro-lH-isoquinoline -2-yl) methanone;
    4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-phenyl-piperazin-1-yl) -methanone;
    [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-methyl- [1,4] diazepan-1-yl) -meta Paddy fields;
    [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(3,4-dihydro-lH-isoquinolin-2-yl) -meta Paddy fields;
    4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-methyl- [l, 4] diazepane-1- Yl) -methanone;
    4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-carboxylic acid benzyl-methyl-amide;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[2- (2-hydroxyethyl) -piperidine- 1-yl] -methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-phenyl-piperazin-1-yl ) -Methanone;
    [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -1H-pyrrole-2-yl] [4- (2-fluorophenyl) -piperazin-1-yl] -meta Paddy fields;
    [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] (3-hydroxy-piperidin-1-yl) -methanone;
    [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] [4- (4-methoxy-phenyl) -piperazin-1-yl]- Metanon;
    [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -1H-pyrrol-2-yl] [4- (4-fluorophenyl) -3,6-dihydro-2H- Pyridin-1-yl] -methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (2-fluorophenyl)- Piperazin-1-yl] -methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (4-methoxy-phenyl) -Piperazin-1-yl] -methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -1 H-pyrrol-2-yl}-(4-methyl- [1,4] dia Jepan-1-yl) methanone;
    1- (4- {4- [2-amino-5- (3-chloro-2-fluorophenyl) pyrimidin-4-yl] -1H-pyrrole-2-carbonyl} -piperazin-1-yl ) -Ethanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3,4-dihydro-lH-iso Quinolin-2-yl) -methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(3-hydroxy-piperidin-1-yl)- Metanon;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-(4-methyl- [1,4] diazepan-1-yl) -methanone;
    1- (4- {4- [2-amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1H-pyrrole-2-carbonyl} -piperazin-1-yl ) -Ethanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1H-pyrrol-2-yl}-(4-methyl- [1,4] diazepan -1-yl) -methanone;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -H-pyrrol-2-yl]-(3-hydroxy-piperidin-1-yl) -methanone;
    4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid methyl- (2-pyridin-2-yl-ethyl) -amide;
    [4- (2-Amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrol-2-yl]-[2- (2-hydroxyethyl) -piperidin-1-yl] -Methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[2- (2-hydroxyethyl)- Piperidin-1-yl] -methanone;
    4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenylethyl ) -Methyl-amide;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-pyridin-2-yl-piperazine -1-yl) -methanone;
    [4- (2-Amino-5-phenyl-pyrimidin-4-yl) -1 H-pyrrol-2-yl] (4-hydroxy-piperidin-1-yl) -methanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-hydroxy-piperidine-1- Yl) -methanone;
    {4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-(4-hydroxy-piperidine-1 -Yl) -methanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] -1 H-pyrrol-2-yl}-(4-pyridin-2-yl-piperazine- 1-yl) methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl}-[4- (2-hydroxyethyl) -piperazine-1 -Yl] -methanone;
    1- {4- [4- (2-amino-5-m-tolyl-pyrimidin-4-yl) -lH-pyrrole-2-carbonyl] -piperazin-1-yl} -ethanone;
    {4- [2-Amino-5- (3,4-dimethoxy-phenyl) -pyrimidin-4-yl] 1H-pyrrole-2-yl}-[4- (2-fluorophenyl) -piperazine -1-yl] -methanone;
    [4- (2-amino-5-phenyl-pyrimidin-4-yl) -1H-pyrrole-2-yl] pyrrolidin-1-yl-methanone;
    {4- [2-Amino-5- (3-chloro-phenyl) -pyrimidin-4-yl] -lH-pyrrol-2-yl} -morpholin-4-yl-methanone;
    4- (2-amino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid benzylamide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 4-fluoro-benzylamide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3-chloro-benzylamide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 4-methoxy-benzylamide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- (2,5-Diaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (2-Amino-5-methylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (5-acetylamino-2-aminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- [2-Amino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (2-Amino-5-hydroxy-pyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (2-amino-5-methylaminomethylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (2-amino-5-hydroxymethylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- [2-cyclohexylamino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluorobenzylamide;
    4- [2-acetylamino-5- (3-methyl-ureido) -pyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluorobenzylamide;
    4- (5-hydroxy-2-methanesulfonylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluorobenzylamide;
    4- (2-Amino-5-methanesulfonyl-pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3-chloro-4-fluoro-benzylamide;
    4- (2-amino-5-hydroxymethylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
    4- (2-cyclohexylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid 3,4-difluoro-benzylamide;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (pyridin-4-ylmethyl) -amide;
    4- [5- (3,5-Dichloro-phenyl) -2-phenylaminopyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid 3-trifluoromethylbenzylamide;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (benzo [1,3] diosol-5-ylmethyl) amide ;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-dimethylamino-2-pyridin-3-yl-ethyl) -amides;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid 4-methanesulfonyl-benzylamide;
    4- [5- (3,5-Dichloro-phenyl) -2-phenylaminopyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl)- amides;
    4- [5- (3,5-Dichloro-phenyl) -2-phenylaminopyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-morpholin-4-yl-2-pyridine-3- Mono-ethyl) -amide;
    4- [2-Amino-5- (3-fluoro-5-trifluoromethylphenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- (2-Amino-5-propyl-pyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    4- (5-Methyl-2-methylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    4- (2-Methylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-pyridin-3-yl-ethyl) -amide;
    4- (2-Ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-dimethylamino-ethyl) -amide;
    4- (5-methyl-2-phenylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid propylamide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-phenyl-propyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (naphthalen-1-ylmethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid cyclopropylamide;
    4- (2-ethylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid 2-trifluoromethyl-benzylamide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-Ethylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (4-methyl-cyclohexyl) -amide;
    4- (5-ethyl-2-phenylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid isopropylamide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-amino-ethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid benzyl-methyl-amide;
    4- (2-Aminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    1- {4- [4- (2-ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carbonyl] -piperazin-1-yl} -ethanone;
    4- (2-Ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-phenyl-propyl) -amide;
    4- (2-Amino-5-ethylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [2- (6-methoxy-lH-indol-3-yl) -ethyl] -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-phenoxyethyl) -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (1-methyl-3-phenyl-propyl) -amide;
    4- (5-Methyl-2-methylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (lH-benzoimidazol-2-ylmethyl) -amide;
    4- (5-Methyl-2-methylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methyl-butyl) -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [l-hydroxymethyl-2- (lH-imidazol-4-yl) -ethyl] -amide ;
    4- (2-amino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (tetrahydrofuran-2-ylmethyl) -amide;
    4- [2- (2-Diethylamino-ethylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid 3,4-difluorobenzylamide;
    4- [5-Methyl-2- (2-piperidin-1-yl-quinazolin-4-ylamino) -pyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid benzylamide;
    4- (5-methyl-2-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl] -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl] -amide;
    4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (3-methoxy-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (3-hydroxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (Benzo [1,3] dioxol-5-ylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amides;
    4- [5-Methyl-2- (4-sulfamoyl-phenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [2- (3-benzyloxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [2- (4-Hydroxy-cyclohexylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (5-cyclohexyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (5-cyclopropyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [1- (3-fluoro-4-methylphenyl) -2-hydroxyethyl] -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-fluoro-4-methylphenyl) -2-hydroxy Ethyl] -amide;
    4- [2- (3-Fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl ]-amides;
    4- [5-Methyl-2- (3-trifluoromethylphenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-benzylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (3,4-Dimethylphenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [2- (4-benzyloxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (2-isopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [5-Methyl-2- (2,2,2-trifluoro-ethylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amides;
    4- [2- (2-hydroxy-l-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-methoxy-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [5-Methyl-2- (4-trifluoromethoxy-phenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-isobutylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (Cyclopropylmethyl-amino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (5-methoxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-Amino-5-methoxymethylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (5-Methyl-2-propylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-hydroxy-l-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenylethyl) -methyl-amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-hydroxymethyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-hydroxymethyl-2-phenylethyl) -amide;
    4- (2-Ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- (2-Ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- [2- (l-hydroxymethyl-cyclopropylamino) -5-methyl-pyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy 1-phenylethyl) -amide;
    4- [2- (2-hydroxyethylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (2-hydroxy-l-methyl-ethylamino) -5-methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- [2- (2-hydroxy-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (2-hydroxy-propylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (2-Hydroxy-cyclohexylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (5-hydroxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    {[4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl ester;
    4- [2- (2-hydroxy-l-methyl-ethylamino) -5-methyl-pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- [2- (3-Dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    4- (2-ethylamino-5-methoxymethylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-pyridin-3-yl-ethyl) -amide;
    4- (2-ethylamino-5-hydroxymethylpyrimidin-4-yl) -1H pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-Ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [1- (3-fluoro-5-trifluoromethylphenyl) -2-hydroxyethyl]- amides;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [l- (3-fluorophenyl) -2-hydroxyethyl] amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (2-fluorophenyl) -2-hydroxyethyl] amide;
    4- [2- (2-cyclopropyl-1-hydroxymethyl-ethylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    4- [2- (2,3-Dimethylphenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (2-Ethoxyamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (l-hydroxymethyl-2-methyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-oxo-1-phenyl-propyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    4- [2- (3-Fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl ]-amides;
    4- [2- (2-Chloro-phenylamino) -5-methylpyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl ]-amides;
    4- [2- (2-hydroxy-1-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-1- (3-trifluoro Methylphenyl) -ethyl] -amide;
    4- [2- (3-Dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl)- Ethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (2-methoxyphenyl) -ethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- (2-methoxyamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-isopropoxyamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (3-Dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- [2- (2-Chloro-phenylamino) -5-methylpyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- [2- (2-hydroxy-1-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amides;
    4- [2- (2,3-Dimethylphenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- (2-acetylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (5-Methyl-2-o-tolylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [5-Methyl-2- (pyridin-3-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- {5-Methyl-2-[(tetrahydrofuran-2-ylmethyl) -amino] pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- {5-Methyl-2-[(tetrahydrofuran-2-ylmethyl) -amino] -pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    N '-{4- [5- (2-hydroxy-l-phenylethylcarbamoyl) -lH-pyrrol-3-yl] -5-methylpyrimidin-2-yl} -hydrazinecarboxylic acid ethyl ester;
    4- {5-Methyl-2-[(pyridin-3-ylmethyl) -amino] -pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide ;
    4- (2-cyclopropylmethoxyamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (isoxazol-3-ylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-cyanoamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-Hydroxyl-methyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl )-amides;
    4- (5-Methyl-2-o-tolylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- (5-methyl-2-o-tolylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [l- (3-chloro-phenyl) -2-hydroxyethyl] amide;
    4- [2- (2-hydroxy-ethoxyamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (N ', N'-Dimethyl-hydrazino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide ;
    4- [5-Methyl-2- (2-trifluoromethylphenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [5-Methyl-2- (morpholin-4-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [5-Methyl-2- (5-methyl-isoxazol-3-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl)- amides;
    4- {2- [l- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -5-methylpyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydr Oxy-1-phenylethyl) -amide;
    4- (5-methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [l- (3-fluorophenyl) -2-hydroxyethyl] amide;
    4- [2- (l-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl ]-amides;
    4- [2- (2-Hydroxy-l-hydroxymethyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl)- 2-hydroxyethyl] -amide;
    4- [2- (l-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrol-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide ;
    4- [2- (2-Hydroxyl-hydroxymethyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    4- [2- (l-Hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide; And
    4- [5-Methyl-2- (2-methyl-cyclopropylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide A method for inhibiting a patient's ERK-2 activity, comprising administering a compound selected from the patient.
    [20" claim-type="Currently amended] A compound of formula (I ') or a pharmaceutically acceptable derivative thereof.
    Formula I '

    In Formula I 'above,
    Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein rings A and Q'R 2 ' are bonded to Sp at non-adjacent positions, and Sp has up to two R 6 substituents, provided that Two substitutable carbon ring atoms are not substituted at the same time with R 6 ;
    Z 1 and Z 2 are each independently selected from N and CH;
    T is a binding group;
    Q 'is selected from -CO 2- , -C (O) NR 7 -and -SO 2 NR 7- ;
    U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    m and n are each independently 0 or 1;
    R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    R 2 ′ is selected from — (CH 2 ) y CH (R 5 ) 2 and — (CH 2 ) y CH (R 8 ) CH (R 5 ) 2 ;
    y is 0 to 6;
    R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    w is each independently selected from 0-4.
    [21" claim-type="Currently amended] The compound of claim 20, wherein Sp is selected from one of the rings of the formulas or pharmaceutically acceptable derivatives thereof.

    [22" claim-type="Currently amended] The method of claim 21,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) when T m R 1 is an optionally substituted group selected from hydrogen, amino, OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring; And
    (c) a compound having at least one of the features selected from the group consisting of when R 5 is R or OR 7 , wherein R is a carbocyclic or optionally substituted 5 or 6 membered aryl or heteroaryl ring.
    [23" claim-type="Currently amended] The method of claim 22,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) T m R 1 is an optionally substituted group selected from hydrogen, amino, OH, 3-6 membered carbocyclyl, or C 1-6 aliphatic group and 5-6 membered aryl or heteroaryl ring,
    (c) R 5 is R or OR 7 , wherein R is a carbocyclic or optionally substituted 5 or 6 membered aryl or heteroaryl ring.
    [24" claim-type="Currently amended] The method of claim 22,
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl, benzyl or isoxazolyl groups;
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ; And
    (c) R 5 is OH, CH 2 OH, a carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q 'has at least one of the features selected from the group consisting of -C (O) NH- compound.
    [25" claim-type="Currently amended] The method of claim 24,
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and an optionally substituted phenyl, benzyl or isoxazolyl group,
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ,
    (c) R 5 is OH, CH 2 OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q 'is -C (O) NH-.
    [26" claim-type="Currently amended] The compound of formula I "or a pharmaceutically acceptable derivative thereof.
    Formula I "

    [27" claim-type="Currently amended] The method of claim 26,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If; And
    (c) a compound having at least one of the features selected from the group consisting of when R 5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
    [28" claim-type="Currently amended] The method of claim 27,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring ego,
    (c) R 5 is an optionally substituted 6 membered aryl, heteroaryl or carbocyclic ring.
    [29" claim-type="Currently amended] The compound of formula Io or a pharmaceutically acceptable derivative thereof.
    Formula Io

    [30" claim-type="Currently amended] The method of claim 29,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) T m R 1 is hydrogen, amino, OH, a 3-6 membered carbocyclyl, or an optionally substituted group selected from a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring; And
    (c) a compound having at least one of the features selected from the group consisting of when R 5 is R or OR 7 , wherein R is a carbocyclic or optionally substituted 5 or 6 membered aryl or heteroaryl ring.
    [31" claim-type="Currently amended] The method of claim 30,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) T m R 1 is an optionally substituted group selected from hydrogen, amino, OH, 3-6 membered carbocyclyl, or C 1-6 aliphatic group and 5-6 membered aryl or heteroaryl ring,
    (c) R 5 is R or OR 7 , wherein R is a carbocyclic or optionally substituted 5 or 6 membered aryl or heteroaryl ring.
    [32" claim-type="Currently amended] A compound of Formula III-a 'or a pharmaceutically acceptable derivative thereof.
    Formula III-a '

    In Formula III-a 'above,
    T is a binding group;
    U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    m and n are each independently 0 or 1;
    R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    w is each independently selected from 0-4.
    [33" claim-type="Currently amended] 33. The method of claim 32,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If; And
    (c) a compound having at least one of the features selected from the group consisting of when R 5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
    [34" claim-type="Currently amended] The method of claim 33, wherein
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring ego,
    (c) R 5 is an optionally substituted 6 membered aryl, heteroaryl or carbocyclic ring.
    [35" claim-type="Currently amended] The method of claim 33, wherein
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and optionally substituted phenyl or benzyl groups;
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ; And
    (c) a compound having at least one of the features selected from the group consisting of when R 5 is cyclohexyl or an optionally substituted phenyl or pyridyl ring.
    [36" claim-type="Currently amended] 36. The method of claim 35 wherein
    (a) R 3 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, -CH (CH 2 OH) phenyl, -CH (CH 2 OH) ethyl, -CH (CH 2 OH) 2 , -CH (CH 2 OH) isopropyl, -CH (CH 2 OH) CH 2 cyclopropyl, and an optionally substituted phenyl or benzyl group,
    (b) phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC (O) NHCH 3 optionally substituted with T m R 1 ; And CH 2 NHCH 3 ,
    (c) R 5 is a cyclohexyl or optionally substituted phenyl or pyridyl ring.
    [37" claim-type="Currently amended] A compound of Formula III-ao or a pharmaceutically acceptable derivative thereof.
    Formula III-ao

    In Formula III-ao above,
    T is a binding group;
    U is -NR 7- , -NR 7 CO-, -NR 7 CONR 7- , -NR 7 CO 2- , -O-, -CONR 7- , -CO-, -CO 2- , -OC (O) -, -NR 7 SO 2- , -SO 2 NR 7- , -NR 7 SO 2 NR 7 -and -SO 2- ;
    m and n are each independently 0 or 1;
    R 1 is selected from hydrogen, CN, halogen, R, N (R 7 ) 2 , OR and OH;
    y is 0 to 6,
    R 3 is R 7 , R,-(CH 2 ) y CH (R 8 ) R, CN,-(CH 2 ) y CH (R 8 ) CH (R 5 ) 2 and-(CH 2 ) y CH (R 8 ) N (R 4 ) 2 ;
    Each R is independently selected from an optionally substituted group selected from a C 1-6 aliphatic group, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 3 to 10 ring atoms Become;
    R 4 are each independently R, R 7 , -COR 7 , -CO 2 R, -CON (R 7 ) 2 , -SO 2 R 7 ,-(CH 2 ) y R 5 and-(CH 2 ) y CH (R 5 ) 2 ;
    R 5 are each independently R, OR, CO 2 R, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    R 6 are each independently R 7 , F, Cl, (CH 2 ) y N (R 7 ) 2 , N (R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON (R 7 ) 2 , CON (R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN and SO 2 N (R 7 ) 2 ;
    Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    R 8 is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N (R 4 ) 2 and (CH 2 ) w SR 7 ;
    w is each independently selected from 0-4.
    [38" claim-type="Currently amended] The method of claim 37,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group is one of two groups;
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring If; And
    (c) a compound having at least one of the features selected from the group consisting of when R 5 is R or OR 7 and R 8 is R 7 or OR 7 .
    [39" claim-type="Currently amended] The method of claim 38,
    (a) R 3 is optionally substituted from hydrogen, carbocyclyl, —CH (R 8 ) R, or a C 1-4 aliphatic group, a 3-6 membered heterocyclic group and a 5-6 membered aryl or heteroaryl ring Group,
    (b) an optionally substituted group wherein T m R 1 is selected from hydrogen, N (R 4 ) 2 , OH, a 3-6 membered carbocyclyl, or a C 1-6 aliphatic group and a 5-6 membered aryl or heteroaryl ring ego,
    (c) a compound in which R 5 is R or OR 7 and R 8 is R 7 or OR 7 ;
    [40" claim-type="Currently amended] 4- [2-Amino-5- (3-chloro-2-fluorophenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenylethyl ) -Methyl-amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- (2-Amino-5-methylpyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2-Amino-5- (3,5-dichloro-phenyl) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-dimethylamino-2-pyridin-3-yl-ethyl) -amides;
    4- [5- (3,5-Dichloro-phenyl) -2-phenylaminopyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-morpholin-4-yl-2-pyridine-3- Mono-ethyl) -amide;
    4- [2-Amino-5- (3-fluoro-5-trifluoromethylphenyl) pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide ;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    4- (5-Methyl-2-methylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (1-hydroxymethyl-3-methyl-butyl) -amide;
    4- (5-methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrol-2-carboxylic acid [l-hydroxymethyl-2- (lH-imidazol-4-yl) ethyl] -amide;
    4- (5-methyl-2-methylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl] -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [1- (3-chloro-4-fluorophenyl) -2-hydroxyethyl] -amide;
    4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (3-methoxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (3-hydroxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (Benzo [1,3] dioxol-5-ylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amides;
    4- [5-Methyl-2- (4-sulfamoyl-phenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [2- (3-Benzyloxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [2- (4-Hydroxy-cyclohexylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (5-cyclohexyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (5-cyclopropyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [1- (3-fluoro-4-methylphenyl) -2-hydroxyethyl] -amide;
    4- (5-Methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-fluoro-4-methylphenyl) -2-hydroxy Ethyl] -amide;
    4- [2- (3-Fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl ]-amides;
    4- [5-Methyl-2- (3-trifluoromethylphenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-benzylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (3,4-Dimethylphenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [2- (4-benzyloxy-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (2-isopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [5-Methyl-2- (2,2,2-trifluoro-ethylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amides;
    4- [2- (2-hydroxy-l-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-methoxy-phenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [5-Methyl-2- (4-trifluoromethoxy-phenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-isobutylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (Cyclopropylmethyl-amino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (5-methoxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-Amino-5-methoxymethylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (5-Methyl-2-propylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-hydroxy-1-phenylethylamino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-2-phenylethyl) -methyl-amide;
    4- (2-Ethylamino-5-methylpyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-2-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2 carboxylic acid (2-hydroxy-1-hydroxymethyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2 carboxylic acid (2-hydroxy-1-hydroxymethyl-2-phenylethyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -H'pyrrole-2-carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2 carboxylic acid (3-hydroxy-1-phenyl-propyl) -amide;
    4- [2- (l-hydroxymethyl-cyclopropylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-hydroxyethylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (2-Hydroxy-1-methyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide ;
    4- [2- (2-hydroxy-propylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (2-hydroxy-propylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (2-Hydroxy-cyclohexylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (5-hydroxymethyl-2-phenylaminopyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    {[4- (2-ethylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carbonyl] -amino} -phenyl-acetic acid methyl ester;
    4- [2- (2-Hydroxy-1-methyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide ;
    4- [2- (3-Dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (2-Aminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-methyl-2-phenylethyl) -methyl-amide;
    4- (2-Aminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-methyl-2-phenylethyl) -methyl-amide;
    4- (2-ethylamino-5-methoxymethylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-pyridin-3-yl-ethyl) -amide;
    4- (2-ethylamino-5-hydroxymethylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (3-fluoro-5-trifluoromethylphenyl) -2-hydroxyethyl]- amides;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [l- (3-fluorophenyl) -2-hydroxyethyl] amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (2-fluorophenyl) -2-hydroxyethyl] amide;
    4- [2- (2-cyclopropyl-1-hydroxymethyl-ethylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    4- [2- (2,3-Dimethylphenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- (2-Ethoxyamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (l-hydroxymethyl-2-methyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-oxo-1-phenyl-propyl) -amide;
    4- (2-ethylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl] -amide;
    4- [2- (3-Fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl ]-amides;
    4- [2- (2-Chloro-phenylamino) -5-methylpyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl) -ethyl ]-amides;
    4- [2- (2-hydroxy-1-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-1- (3-trifluoro Methylphenyl) -ethyl] -amide;
    4- [2- (3-Dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [2-hydroxy-l- (3-trifluoromethylphenyl)- Ethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [2-hydroxy-1- (3-trifluoromethylphenyl) -ethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid [2-hydroxy-l- (2-methoxyphenyl) -ethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl] -amide;
    4- (2-cyclopropylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- (2-methoxyamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (2-isopropoxyamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (3-Dimethylamino-phenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- [2- (2-Chloro-phenylamino) -5-methylpyrimidin-4-yl] -1 H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- [2- (2-hydroxy-1-phenylethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amides;
    4- [2- (2,3-Dimethylphenylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- [2- (3-fluorophenylamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- (2-acetylamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- (5-Methyl-2-o-tolylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [5-Methyl-2- (pyridin-3-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- {5-Methyl-2-[(tetrahydrofuran-2-ylmethyl) -amino] pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl)- amides;
    4- {5-Methyl-2-[(tetrahydrofuran-2-ylmethyl) -amino] -pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    N '-{4- [5- (2-hydroxy-l-phenylethylcarbamoyl) -lH-pyrrol-3-yl] -5-methylpyrimidin-2-yl} -hydrazinecarboxylic acid ethyl ester;
    4- {5-Methyl-2-[(pyridin-3-ylmethyl) -amino] -pyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide ;
    4- (2-cyclopropylmethoxyamino-5-methylpyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (isoxazol-3-ylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- (2-cyanoamino-5-methylpyrimidin-4-yl) -H-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amide;
    4- [2- (2-Hydroxyl-methyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl )-amides;
    4- (5-Methyl-2-o-tolylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide;
    4- (5-methyl-2-o-tolylaminopyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl] -amide;
    4- [2- (2-hydroxy-ethoxyamino) -5-methylpyrimidin-4-yl] -1H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [2- (N ', N'-Dimethyl-hydrazino) -5-methylpyrimidin-4-yl] -H-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide ;
    4- [5-Methyl-2- (2-trifluoromethylphenylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide;
    4- [5-Methyl-2- (morpholin-4-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) amide;
    4- [5-Methyl-2- (5-methyl-isoxazol-3-ylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl)- amides;
    4- {2- [l- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -5-methylpyrimidin-4-yl} -lH-pyrrole-2-carboxylic acid (2-hydr Oxy-1-phenylethyl) -amide;
    4- (5-methyl-2-phenylaminopyrimidin-4-yl) -lH-pyrrole-2-carboxylic acid [l- (3-fluorophenyl) -2-hydroxyethyl] amide;
    4- [2- (l-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl) -2-hydroxyethyl ]-amides;
    4- [2- (2-Hydroxy-l-hydroxymethyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid [1- (3-chloro-phenyl)- 2-hydroxyethyl] -amide;
    4- [2- (l-hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrol-2-carboxylic acid (2-hydroxy-1-m-tolyl-ethyl) -amide ;
    4- [2- (2-Hydroxyl-hydroxymethyl-ethylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-1-phenylethyl) -amides;
    4- [2- (l-Hydroxymethyl-propylamino) -5-methylpyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide; And
    4- [5-Methyl-2- (2-methyl-cyclopropylamino) -pyrimidin-4-yl] -lH-pyrrole-2-carboxylic acid (2-hydroxy-l-phenylethyl) -amide Compound selected from.
    [41" claim-type="Currently amended] 41. A composition comprising a compound according to any one of claims 20-40 and a pharmaceutically acceptable carrier.
    [42" claim-type="Currently amended] 42. The composition of claim 41, further comprising an additional therapeutic agent.
    [43" claim-type="Currently amended] Administering a therapeutically effective amount of a composition according to claim 41 to a patient in need of inhibition of ERK2, GSK-3, Aurora, CDK2 or Lck activity, wherein the ERK2, GSK-3, Aurora, CDK2 or Method of Inhibiting Lck Activity.
    [44" claim-type="Currently amended] The method of claim 43, wherein the patient inhibits ERK2 activity.
    [45" claim-type="Currently amended] A method of treating an ERK2-mediated disease in a patient comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of treatment of the ERK2-mediated disease.
    [46" claim-type="Currently amended] 46. The method of claim 45, further comprising administering an additional therapeutic agent to the patient.
    [47" claim-type="Currently amended] 46. The disease according to claim 45, wherein the disease is cancer, seizures, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, atherosclerosis, restenosis, psoriasis, allergic disease, inflammation, nervous system Disorders, hormone related diseases, tissue transplant related diseases, immunodeficiency disorders, destructive bone diseases, proliferative diseases, infectious diseases, apoptosis related diseases, trombone induced platelet aggregation, chronic myeloid leukemia (CML), liver disease, T A etiological immune disease involving cell activation, or a central nervous system disease.
    [48" claim-type="Currently amended] The method of claim 47, wherein the disease is cancer.
    [49" claim-type="Currently amended] 49. The method according to claim 48, wherein the disease is breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocyte tumor, lung cancer, epidermoid carcinoma, Large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal carcinoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, cholestatic passage Inoculation, kidney carcinoma, bone marrow disease, lymphoid disease, Hodgkin's disease, hairy cell carcinoma, stenosis and pharyngeal cancer (oral cavity), carcinoma, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colon-rectal cancer, colon cancer, rectal cancer And cancer selected from brain and central nervous system cancer and leukemia.
    [50" claim-type="Currently amended] 46. The method of claim 45, wherein the disease is cardiovascular disease.
    [51" claim-type="Currently amended] 51. The method of claim 50, wherein the disease is a cardiovascular disease selected from restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction or congestive heart failure.
    [52" claim-type="Currently amended] A method of treating GSK-3-mediated disease in a patient, comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of treatment of the GSK-3-mediated disease.
    [53" claim-type="Currently amended] The method of claim 52, further comprising administering an additional therapeutic agent to the patient.
    [54" claim-type="Currently amended] The method of claim 52, wherein the disease is diabetes.
    [55" claim-type="Currently amended] The method of claim 52, wherein the disease is Alzheimer's disease.
    [56" claim-type="Currently amended] The method of claim 52, wherein the disease is schizophrenia.
    [57" claim-type="Currently amended] A method of increasing glycogen synthesis in a patient comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of an increase in glycogen synthesis.
    [58" claim-type="Currently amended] A method of lowering blood glucose concentration in a patient comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need thereof.
    [59" claim-type="Currently amended] A method of inhibiting hyperphosphorylated Tau protein production in a patient, comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of inhibition of hyperphosphorylated Tau protein production.
    [60" claim-type="Currently amended] A method of inhibiting phosphorylation of β-catenin in a patient comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of inhibition of phosphorylation of β-catenin.
    [61" claim-type="Currently amended] A method of treating Aurora-2-mediated disease in a patient comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of treatment of the Aurora-2-mediated disease.
    [62" claim-type="Currently amended] 62. The method of claim 61, further comprising administering an additional therapeutic agent to the patient.
    [63" claim-type="Currently amended] 62. The method of claim 61, wherein the disease is selected from colon cancer, breast cancer, gastric cancer or ovarian cancer.
    [64" claim-type="Currently amended] A method of treating a CDK-2-mediated disease of a patient, comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of treatment of the CDK-2-mediated disease.
    [65" claim-type="Currently amended] The method of claim 64, wherein the disease is selected from cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune disease.
    [66" claim-type="Currently amended] A method of treating a Lck-mediated disease of a patient, comprising administering a therapeutically effective amount of the composition according to claim 41 to a patient in need of treatment of the Lck-mediated disease.
    [67" claim-type="Currently amended] The method of claim 66, wherein the disease is selected from autoimmune disease or graft rejection.
    [68" claim-type="Currently amended] A method of inhibiting ERK2, Aurora-2, GSK-3, CDK-2 or Lck activity in a biological sample, comprising contacting the biological sample with a compound according to any one of claims 20-40.
    [69" claim-type="Currently amended] A composition for coating an implantation device, comprising a compound according to claim 20 and a carrier suitable for coating the implantation device.
    [70" claim-type="Currently amended] 70. Implantation device coated with a composition according to claim 69.
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    同族专利:
    公开号 | 公开日
    JP4173738B2|2008-10-29|
    BR0207114A|2004-02-25|
    US20040229875A1|2004-11-18|
    RU2003127116A|2005-03-27|
    WO2002064586A3|2003-02-06|
    EP1363906B1|2015-07-15|
    US6743791B2|2004-06-01|
    US20030092714A1|2003-05-15|
    JP2008163045A|2008-07-17|
    AR049239A1|2006-07-12|
    PE20020971A1|2002-10-29|
    NO20033491D0|2003-08-06|
    WO2002064586A2|2002-08-22|
    CA2437767A1|2002-08-22|
    JP2004520402A|2004-07-08|
    AP200302853A0|2003-09-30|
    HK1062298A1|2016-02-26|
    EP1363906A2|2003-11-26|
    MXPA03007049A|2003-11-18|
    US20070265263A1|2007-11-15|
    IL157131D0|2004-02-08|
    CA2437767C|2010-05-04|
    CN1494541A|2004-05-05|
    TWI309650B|2009-05-11|
    KR100857732B1|2008-09-10|
    HU0304052A2|2004-04-28|
    HU0304052D0|2004-01-28|
    NO20033491L|2003-10-08|
    CN100534991C|2009-09-02|
    RU2300377C2|2007-06-10|
    US7253187B2|2007-08-07|
    ES2549677T3|2015-10-30|
    NZ527251A|2006-09-29|
    PL364565A1|2004-12-13|
    HU0304052A3|2010-06-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-02-09|Priority to US26781801P
    2001-02-09|Priority to US60/267,818
    2001-10-12|Priority to US32876801P
    2001-10-12|Priority to US60/328,768
    2002-02-08|Application filed by 버텍스 파마슈티칼스 인코포레이티드
    2002-02-08|Priority to PCT/US2002/003791
    2003-09-19|Publication of KR20030074814A
    2008-09-10|Application granted
    2008-09-10|Publication of KR100857732B1
    优先权:
    申请号 | 申请日 | 专利标题
    US26781801P| true| 2001-02-09|2001-02-09|
    US60/267,818|2001-02-09|
    US32876801P| true| 2001-10-12|2001-10-12|
    US60/328,768|2001-10-12|
    PCT/US2002/003791|WO2002064586A2|2001-02-09|2002-02-08|Heterocyclic inhibitors of erk2 and uses thereof|
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