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    • 专利摘要:
    The present invention describes novel pyrazole compounds of formula IIa: Formula IIIa In the above formula, R 1 is T-ring D, ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl; R x and R y together with their insertion atoms form a fused unsaturated or partially unsaturated 5 to 7 membered ring having 0 to 3 heteroatoms; R 2 and R 2 ′ are as defined herein. The compounds are useful as protein kinase inhibitors, especially inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer's disease.
    公开号:KR20030061466A
    申请号:KR10-2003-7008387
    申请日:2001-12-19
    公开日:2003-07-18
    发明作者:베빙턴데이비드；샤리에장-다미엥；골렉줄리안；밀러앤드류；네그텔로날드
    申请人:버텍스 파마슈티칼스 인코포레이티드；
    IPC主号:
    专利说明:

    Pyrazole compounds useful as protein kinase inhibitors}
    [1] Cross Reference to Related Applications
    [2] This application claims priority to US Provisional Application No. 60 / 257,887, filed Dec. 21, 2000 and US Provisional Application No. 60 / 286,949, filed Apr. 27, 2001, incorporated herein by reference.
    [3] Field of invention
    [4] FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, the present invention relates to compounds that are inhibitors of Aurora-2 protein kinases. The invention also relates to a method for treating diseases associated with protein kinases, in particular diseases associated with Aurora-2, for example cancer.
    [5] Background of the Invention
    [6] Research and development of new therapeutics has made significant progress in recent years by better understanding the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been studied extensively is protein kinases.
    [7] Protein kinases mediate intracellular signal transduction. To do this, protein kinases transfer the phosphoryl group from nucleoside triphosphate to protein receptors involved in the signaling pathway. By providing extracellular and other stimuli through numerous kinases and pathways, various cellular responses can occur within the cell. Examples of such stimuli include environmental and chemical stress signals (eg osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, H 2 O 2 ), cytokines (eg interleukin-1 (IL-1) and tumor necrosis factor α) (TNF-α)], and growth factors such as granulocyte macrophage-colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF). Extracellular stimulation can trigger one or more cellular responses associated with cell growth, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.
    [8] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Therefore, considerable efforts have been made in the medical chemistry field to identify protein kinase inhibitors that are effective as therapeutic agents.
    [9] Aurora-2 is a serine / threonine protein kinase that has a close effect on human cancers such as colon, breast and other solid tumors. These kinases are believed to be related to protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may serve to control the precise separation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormal events. 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.
    [10] 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 has a close effect on various diseases including diabetes mellitus, Alzheimer's disease, CNS disorders such as manic and neurodegenerative diseases, and myocardial hypertrophy. WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117. These diseases may be caused by, or may result in, the abnormal operation of certain cellular signaling pathways in which GSK-3 plays a role. GSK-3 has been found to modulate the activity of numerous regulatory proteins by phosphorylation. These proteins include glycogen synthase, a microtubule-related protein Tau, gene transcription factor β-catenin, and translational initiation factor e1F2B, as well as ATP citrate lyase, acin, heat shock factor-1, which are rate limiting enzymes required for glycogen synthesis , c-Jun, c-Myc, c-Myb, CREB and CEPBα. These various protein targets are closely related to GSK-3 in many aspects related to cell metabolism, proliferation, differentiation and development.
    [11] In the GSK-3 mediated pathway associated with type II diabetes treatment, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 acts as a negative regulator of insulin-induced signals. Usually, the presence of insulin inhibits GSK-3 mediated phosphorylation and inactivates glycogen synthase. Due to this inhibition of GSK-3, glycogen synthesis and glucose uptake are increased (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 response, glycogen synthesis and glucose uptake do not increase despite relatively high blood insulin concentrations. This results in abnormally high blood glucose levels over a rapid and long period of time, eventually leading to cardiovascular disease, kidney failure and blindness. These patients do not develop normal insulin-induced inhibition of GSK-3. It has also been reported that GSK-3 is overexpressed in type II diabetic patients. WO 00/38675. Thus, therapeutic inhibitors of GSK-3 are quite useful for treating diabetic patients who are impaired in their insulin response.
    [12] GSK-3 activity has also been associated with Alzheimer's disease. This disease is characterized by well-known β-amyloid peptides and intracellular neurofibrillary tangle formation. This neurofibrillary tangle contains a superphosphorylated Tau protein, where Tau is phosphorylated at the abnormal site. GSK-3 has been shown to phosphorylate these abnormal sites in cellular and animal models. Moreover, 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 neurofibrillary tangle development and Alzheimer's disease progression.
    [13] Another substrate of GSK-3 is β-catenin, which is degraded after phosphorylation by GSK-3. Decreased levels of β-catenin have been reported in schizophrenic patients, which has 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)].
    [14] As GSK-3 becomes biologically important, attention is currently focused on therapeutically effective GSK-3 inhibitors. Small molecules that inhibit GSK-3 have recently been reported (WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)).
    [15] For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have been targeted for treatment of these diseases. However, these various protein kinases often function with different biological pathways. For example, certain quinazoline derivatives have recently been reported as inhibitors of p38 kinases (WO 00/12497 (Scios)). This compound has been reported to be useful for treating diseases that are characterized by enhanced p38-α activity and / or TGF-β activity. Although p38 activity has a close effect on a wide range of diseases, including diabetes, p38 kinases have not been reported as a component of the insulin signaling pathway that regulates glycogen synthesis or glucose uptake. Thus, unlike GSK-3, p38 inhibition cannot be expected to enhance glycogen synthesis and / or glucose uptake.
    [16] There is a continuing need to develop new therapies to treat human diseases. Protein kinases Aurora-2 and GSK-3, respectively, are of interest because of their important roles in cancer and diabetes, and of particular interest in the development of new therapeutics.
    [17] Description of the invention
    [18] It has been found by the present invention that the compounds of the present invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, in particular inhibitors of Aurora-2. These compounds are compounds of formula (I), or pharmaceutically acceptable derivatives or prodrugs thereof:
    [19]
    [20] In the above formula,
    [21] Z 1 is nitrogen or CR 8 ,
    [22] Z 2 is nitrogen or CH, wherein at least one of Z 1 and Z 2 is nitrogen;
    [23] R x and R y are independently selected from TR 3 and LZR 3 , or R x and R y have 0 to 3 ring heteroatoms selected from oxygen, sulfur and nitrogen together with their intervening atoms To form a fused unsaturated or partially unsaturated 5 to 7 membered ring, wherein each substitutable ring carbon on the fused ring formed by R x and R y is independently substituted by oxo, TR 3 or LZR 3 , Each substitutable ring nitrogen on the ring formed by R x and R y is independently substituted by R 4 ;
    [24] Q is -N (R 4 )-, -O-, -S-, -C (R 6 ' ) 2- , 1,2-cyclopropanediyl, 1,2-cyclobutanediyl and 1,3-cyclobutane Diyl;
    [25] R 1 is T- (ring D);
    [26] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [27] T is a valence bond or a C 1-4 alkylidene chain, wherein if Q is —C (R 6 ′ ) 2 —, the methylene units of the C 1-4 alkylidene chain are —O—, —S—, —N (R 4 )-, -CO-, -CONH-, -NHCO-, -SO 2- , -SO 2 NH-, -NHSO 2- , -CO 2- , -OC (O)-, -OC (O ) Is optionally substituted by NH- or -NHCO 2- ;
    [28] Z is a C 1-4 alkylidene chain;
    [29] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [30] R 2 and R 2 ' are independently selected from -R, TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [31] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [32] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [33] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [34] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [35] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [36] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [37] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with a nitrogen atom represent a 5-6 membered heterocyclyl or heteroaryl ring; Forming;
    [38] Each R 6 ′ is independently selected from hydrogen and a C 1-4 aliphatic group, or two R 6 ′ on the same carbon atom together form a 3-6 membered carbocyclic ring;
    [39] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring and ;
    [40] R 8 is —R, —halo, —OR, —C (═O) R, —CO 2 R, —COCOR, —NO 2 , —CN, —S (O) R, —SO 2 R, —SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (Optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 4 ) 2 .
    [41] As used herein, the terms as defined herein will apply unless otherwise indicated. "Optionally substituted" is used interchangeably with the expression "substituted or unsubstituted" or "unsubstituted". Unless otherwise indicated, an optionally substituted group may have one substituent at each substitutable position of that group, and each substitution is independent of each other.
    [42] As used herein, the term “aliphatic” refers to a straight, branched or cyclic C 1 -C 12 hydrocarbon containing one or more unsaturated units that are not fully saturated or aromatic. Suitable aliphatic groups include, for example, substituted or unsubstituted straight, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or cycloalkyl ( Alkenyl). The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl" and "alkoxycarbonyl" used alone or as part of a larger moiety include straight and branched chains containing from 1 to 12 carbon atoms. All are included. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety include both straight and branched chains containing 2 to 12 carbon atoms. The term “cycloalkyl”, used alone or as part of a larger moiety, includes cyclic C 3 -C 12 hydrocarbons containing one or more unsaturated units that are not fully saturated or aromatic.
    [43] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to alkyl, alkenyl or alkoxy as may be substituted by one or more halogen atoms. The term "halogen" means F, Cl, Br or I.
    [44] The term "hetero atom" means nitrogen, oxygen or sulfur, which includes oxidized forms of nitrogen and sulfur, and all basic nitrogen in quaternized forms. The term "nitrogen" also includes substitutable nitrogens of heterocyclic rings. As an example, in saturated or partially unsaturated rings having 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen is N (for 3,4-dihydro-2H-pyrrolyl), NH (pyrrolidinyl ) Or NR + (for N-substituted pyrrolidinyl).
    [45] As used herein, the terms “carbocycle”, “carbocyclyl”, “carbocyclo” or “carbocyclic” refer to aliphatic ring systems having 3 to 14 members. The term “carbocycle”, “carbocyclyl”, “carbocyclo” or “carbocyclic” may refer to an optionally substituted ring, whether saturated or partially unsaturated. The term "carbocycle", "carbocyclyl", "carbocyclo" or "carbocyclic" also includes aliphatic rings fused to one or more aromatic or non-aromatic rings, such as in decahydronaphthyl or tetrahydronaphthyl. A corresponding radical or point of attachment is on the aliphatic ring.
    [46] The term "aryl", used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to an aromatic ring group having 5 to 14 members, Examples are phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-anthrasyl and 2-anthrasyl. The term "aryl" may also refer to an optionally substituted ring. The term "aryl" may be used interchangeably with the term "aryl ring". “Aryl” also includes fused polycyclic aromatic ring systems in which the aromatic ring is fused with one or more rings. Examples thereof include 1-naphthyl, 2-naphthyl, 1-anthrasyl and 2-anthrasyl. Also included within the scope of the term “aryl” as used herein are groups in which an aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phenanthridinyl or tetrahydronaphthyl, with the corresponding radical or attachment Is on the aromatic ring.
    [47] As used herein, the terms “heterocycle”, “heterocyclyl” or “heterocyclic” include one or more ring carbons, preferably one to four ring carbons, each substituted with a hetero atom such as N, O or S, respectively. 5 to 14 membered, preferably 5 to 10 membered, non-aromatic ring systems. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl , 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3] -dioxalanyl, [1,3] -dithiolanyl, [1,3] -dioxa Nyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4- Thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-pipe Ridinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxola Nyl, benzothiolanyl and benzothianil. Also included within the scope of the term “heterocyclyl” or “heterocyclic” as used herein are non-aromatic heteroatoms, such as in indolinyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The -containing ring is a group that is fused with one or more aromatic or non-aromatic rings, wherein the radical or point of attachment is above the non-aromatic hetero atom-containing ring. The term “heterocycle”, “heterocyclyl” or “heterocyclic” may refer to an optionally substituted ring, whether saturated or partially unsaturated.
    [48] The term “heteroaryl”, used alone or as part of a larger moiety, such as in “heteroaralkyl” or “heteroarylalkoxy”, refers to a 5-14 membered heteroaromatic ring group. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3 -Pyrrolyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3 -Pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimi Dazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl Or benzoisoxazolyl. Also included within the scope of the term “heteroaryl” as used herein is a group in which a heteroaromatic ring is fused with one or more aromatic or non-aromatic rings, with the radical or point of attachment above the heteroaromatic ring. Examples thereof include tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [3,4-d] pyrimidinyl. The term “heteroaryl” may also refer to an optionally substituted ring. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “hetero aromatic”.
    [49] The aryl (including aralkyl, aralkoxy, aryloxyalkyl, etc.) or heteroaryl (including heteroaralkyl, heteroarylalkoxy, etc.) groups may contain one or more substituents. Examples of suitable substituents on unsaturated carbon atoms of aryl, heteroaryl, aralkyl or heteroaralkyl groups include halogen, -R 0 , -OR 0 , -SR 0 , 1,2-methylenedioxy, 1,2-ethylenedi Oxy, protected OH (e.g. acyloxy), phenyl (Ph), substituted Ph, -O (Ph), substituted -O (Ph), -CH 2 (Ph), substituted -CH 2 (Ph) , -CH 2 CH 2 (Ph), substituted -CH 2 CH 2 (Ph), -NO 2 , -CN, -N (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 CO 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 (O) 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 ,-(CH 2 ) y NHC (O) CH (VR 0 ) (R 0 ), wherein R 0 is each hydrogen, substituted or unsubstituted aliphatic group, unsubstituted heteroaryl or hetero Cyclic ring, phenyl (Ph), substituted Ph, -O (Ph), Hwandoen -O (Ph), -CH 2 ( Ph) , and substituted -CH 2 (Ph) independently selected from; y is 0 to 6; V is a linker group]. Examples of substituents on the phenyl ring or aliphatic group of R 0 include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylamino Carbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
    [50] Aliphatic groups or non-aromatic heterocyclic rings may contain one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic or non-aromatic heterocyclic ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: = O, = S, = NNHR * , = NN (R * ) 2 , = N-, = NNHC (O) R * , = NNHCO 2 (alkyl), = NNHSO 2 (alkyl) or = NR * where R * is each hydrogen, an unsubstituted aliphatic group And substituted aliphatic groups]. Examples of substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy , Nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
    [51] Examples of suitable substituents on the nitrogen of the non-aromatic heterocyclic ring include -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 each hydrogen, aliphatic group, substituted aliphatic group, phenyl (Ph), substituted Ph, -O (Ph), Independently selected from substituted —O (Ph), —CH 2 (Ph), substituted —CH 2 (Ph) and unsubstituted heteroaryl or heterocyclic ring. Examples of the substituent on the phenyl ring or aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyl Oxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
    [52] The term "linking group" or "linker" refers to an organic moiety that connects two parts of a particular compound. The linking group is typically composed of atoms such as oxygen or sulfur, units such as -NH-, -CH 2- , -C (O)-, -C (O) NH-, or atomic chains such as alkylidene chains. . The molecular weight of the linking group is typically in the range of about 14 to 200, preferably 14 to 96 and up to about 6 atoms in length. Examples of linking groups include optionally substituted saturated or unsaturated C 1-6 alkylidene chains, wherein one or two saturated carbons of the chain are -C (O)-, -C (O) C (O)- , -CONH-, -CONHNH-, -CO 2 - , -OC (O) -, -NHCO 2 -, -O-, -NHCONH -, - OC (O) NH-, -NHNH-, -NHCO-, Optionally substituted by -S-, -SO-, -SO 2- , -NH-, -SO 2 NH- or -NHSO 2- .
    [53] The term "alkylidene chain" refers to an optionally substituted carbon straight or branched chain that may be fully saturated or have one or more unsaturated units. Optional substituents are as defined above for aliphatic groups.
    [54] Combinations of substituents or variables can only be tolerated if such combinations can produce stable or chemically suitable compounds. A stable compound or chemically suitable compound is one in which the chemical structure is substantially unmodified when maintained for at least one week at temperatures below 40 ° C. in the absence of moisture or other chemically reactive conditions.
    [55] Unless otherwise indicated, structures shown herein are understood to include all stereochemical forms of such structures, ie, the R and S configuration for each asymmetric center. Accordingly, enantiomeric and diastereomeric mixtures as well as single stereochemical isomers of the compounds of the present invention are within the scope of the present invention. Unless stated otherwise, the structures presented herein are understood to include different compounds only in the presence of one or more isotope enhanced atoms. For example, compounds having a structure of the present invention are within the scope of the present invention except when hydrogen is replaced by double hydrogen or tritium or carbon is replaced by 13 C- or 14 C-enhanced carbon.
    [56] Compounds of formula (I) or salts thereof may be formulated into the composition. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of protein kinase inhibitor effective to inhibit protein kinases, particularly Aurora-2, in a biological sample or patient. A pharmaceutical composition comprising a compound of the invention and an amount of protein kinase inhibitor effective to treat or prevent Aurora-2-mediated disease and a pharmaceutically acceptable carrier, adjuvant or vehicle is formulated to be suitable for patient administration. Can be.
    [57] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing the Aurora-2 mediated disease using an Aurora-2 inhibitor. It is about a method.
    [58] As used herein, the term "aurora-2-mediated disease" or "aurora-2-mediated condition" means any disease or other adverse disease state in which it is known that the Aurora plays a role. The term “aurora-2-mediated disease” or “aurora-2-mediated condition” also means a disease or condition that is ameliorated by treatment with an Aurora-2 inhibitor. Such conditions include, but are not limited to, colon cancer, breast cancer, gastric cancer and ovarian cancer.
    [59] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in a biological sample, comprising contacting the biological sample with an Aurora-2 inhibitor of Formula I or a composition thereof.
    [60] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula I or a composition comprising such a compound.
    [61] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof It is about how to.
    [62] As used herein, the term "GSK-3-mediated disease" or "GSK-3-mediated condition" means any disease or other adverse disease state 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, myocardial hypertrophy, reperfusion Ischemia and baldness, but is not limited thereto.
    [63] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [64] 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 GSK-3 inhibitor of Formula (I).
    [65] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of formula (I) or a composition comprising such a compound.
    [66] Another aspect of the invention involves treating or preventing a CDK-2-mediated disease using a CDK-2 inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof It is about how to.
    [67] As used herein, the term "CDK-2-mediated disease" or "CDK-2-mediated condition" means any disease or other adverse disease state in which CDK-2 is known to play a role. The term "CDK-2-mediated disease" or "CDK-2-mediated condition" also refers to a disease or condition that is alleviated by treatment with a CDK-2 inhibitor. Such conditions include, but are not limited to, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia and autoimmune diseases such as rheumatoid arthritis [FIS: 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 Investigation Drugs, 2, 40-59 (2000)].
    [68] Another aspect of the invention relates to a method of inhibiting CDK-2 activity in a patient or biological sample, comprising administering to a patient a compound of Formula I or a composition comprising such a compound.
    [69] Another aspect of the invention involves treating or preventing an ERK-2-mediated disease using an ERK-2 inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof It is about how to.
    [70] As used herein, the term "ERK-2-mediated disease" or "ERK-2-mediated condition" means any disease or other adverse disease state in which ERK-2 is known to play a role. The term "ERK-2-mediated disease" or "ERK-2-mediated condition" also refers to a disease or condition that is alleviated by treatment with an ERK-2 inhibitor. These conditions include cardiovascular diseases including cancer, seizures, diabetes, hepatomegaly, cardiac hypertrophy, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, and asthma, including asthma , Inflammation, neurological disorders and hormone-related diseases. The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, neck cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinocyte tumor , Lung cancer, epidermoid cancer, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenocarcinoma, pancreatic cancer, adenocarcinoma, thyroid cancer, acinar carcinoma, undifferentiated carcinoma, papilloma carcinoma, germ cell, melanoma, sarcoma, bladder carcinoma, liver Carcinoma and Bile Pathway Cancer, Kidney Carcinoma, Myeloid Disorders, Lymphatic Disorders, Hodgkin's, Hair Cells, Narrow and Oral Pharynx (Oral), Lips, Tongue, Mouth, Pharynx, Small Intestine, Colon, Colon, Rectal, Brain and central nervous system, and leukemia. ERK-2 protein kinases and their close influence on various diseases are described in the following literature: Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589].
    [71] Another aspect of the invention relates to a method of inhibiting ERK-2 activity in a patient or biological sample, comprising administering to a patient a compound of Formula I or a composition comprising such a compound.
    [72] Another aspect of the invention relates to a method of treating or preventing an AKT-mediated disease using an AKT inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof will be.
    [73] As used herein, the term "AKT-mediated disease" or "AKT-mediated condition" means any disease or other adverse condition in which AKT is known to play a role. The term "AKT-mediated disease" or "AKT-mediated condition" also means a disease or condition that is alleviated by treatment with an AKT inhibitor. AKT mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer and neurodegenerative disorders. It has been described in the following literature that AKT, also known as protein kinase B, is involved in various diseases. Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y., et al, Oncogene, 19 2000; Kazuhiko, N., et al., The Journal of Neuroscience, 20 2000].
    [74] Another aspect of the invention relates to a method of inhibiting AKT activity in a patient or biological sample, comprising administering to a patient a compound of Formula I or a composition comprising such a compound.
    [75] Another aspect of the invention relates to a method for treating or preventing Src-mediated diseases using Src inhibitors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof will be.
    [76] As used herein, the term "Src-mediated disease" or "Src-mediated condition" means any disease or other adverse condition in which Src is known to play a role. The term "Src-mediated disease" or "Src-mediated condition" also means a disease or condition that is ameliorated by treatment with an Src inhibitor. Such conditions include, but are not limited to, treatment of symptoms of hypercalcemia, osteoporosis, osteoarthritis, cancer, bone metastasis, and Paget's disease. Src protein kinases and their close influence on various diseases are described in the following literature (Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25 (7), 717, (2000); Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys. Res. 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, Cell Growth Diff., 8, 269 (1997)].
    [77] Another aspect of the invention relates to a method of inhibiting Src activity in a patient or biological sample, comprising administering to a patient a compound of Formula I or a composition comprising such a compound.
    [78] Another aspect of the invention relates to a method for treating or preventing Lck-mediated diseases using Lck inhibitors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof will be.
    [79] As used herein, the term "Lck-mediated disease" or "Lck-mediated condition" means any disease or other adverse condition in which Lck is known to play a role. The term "Lck-mediated disease" or "Lck-mediated condition" also means a disease or condition that is alleviated by treatment with an Lck inhibitor. Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia. It has been described in the literature that Lck is involved in a variety of diseases (Molina et al., Nature, 357, 161 (1992)).
    [80] Another aspect of the invention relates to a method of inhibiting Lck activity in a patient or biological sample, comprising administering to a patient a compound of Formula I or a composition comprising such a compound.
    [81] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that can be administered to a patient with a compound of the invention and does not disrupt its pharmacological activity.
    [82] The term “patient” includes humans and veterinary subjects.
    [83] The term "biological sample" as used herein includes cell cultures or extracts thereof; Enzyme preparations suitable for in vitro assays; Biopsied material obtained from a mammal or extracts thereof; And blood, saliva, urine, feces, semen, tears or other body fluids, or extracts thereof.
    [84] An amount effective to inhibit protein kinases such as Aurora-2 and GSK-3 is an amount that inhibits kinase activity to a measurable level compared to inhibiting the activity of the enzyme in the absence of the inhibitor. Inhibition can be measured using any method, for example, the following biological test examples can be used.
    [85] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions are generally known in the art. These 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 glycerides of saturated vegetable fatty acids. Mixtures, water, salts or electrolytes such as protamine sulfate, disodium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based materials, polyethylene glycols, sodium Carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycols and wool fats, including but not limited to.
    [86] The compositions of the present invention can be administered via oral, parenteral, inhalation spray, topical, rectal, nasal, intranasal, intravaginal or implanted reservoirs. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intramuscular, sternum, intravesical, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously.
    [87] Sterile injectable forms of the compositions of the invention may be aqueous or oily suspensions. These suspending agents can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Such sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example 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, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, such as natural pharmaceutically acceptable oils, in particular those oils as polyoxyethylation variants thereof, for example olive oil or castor oil. Do. These oil solutions or suspensions may contain long chain alcohol diluents or dispersants, such as carboxymethyl cellulose, or similar dispersants commonly used in the formation of pharmaceutically acceptable dosage forms, including emulsions and suspending agents. Other commonly used surfactants such as tween, span, and other emulsifiers or bioavailability enhancing agents commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used in the formulation. have.
    [88] The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are typically added as well. Useful diluents for oral administration in capsule form include lactose and dried corn starch. If an aqueous suspending agent is required for oral use, the active ingredient is combined with an emulsifying agent and suspending agent. If desired, certain sweetening, flavoring or coloring agents may be added.
    [89] 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 with the agent a non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
    [90] The pharmaceutical compositions of the invention may also be administered topically, particularly when the target to be treated is a site or organ readily accessible by topical application (including ophthalmic, skin or underlying organ disease). Suitable formulations for topical administration can be readily prepared for each of these sites or organs.
    [91] Local application to the lower organs can be carried out with rectal suppositories (see above) or with suitable enema formulations. Topical-dermal patches may also be used.
    [92] For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical administration of a compound 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 in 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.
    [93] When used 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 benzylalconium chloride, or preferably isotonic It can be formulated as a solution in pH adjusted sterile saline. On the other hand, for ophthalmic use, the pharmaceutical composition may be formulated with an ointment such as petrolatum.
    [94] Pharmaceutical compositions of the invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and employ benzyl alcohol or other suitable preservatives, absorption accelerators, fluorocarbons and / or other conventional solubilizers or dispersants that enhance the efficiency of use in vivo. It can be prepared as a solution in saline.
    [95] In addition to the compounds of the present invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of the present invention may be used in the compositions to treat or prevent the aforementioned diseases or disorders.
    [96] A "pharmaceutically acceptable derivative or prodrug" is a pharmaceutical composition of a compound of the invention that, when administered to a recipient, can provide directly or indirectly a compound of the invention or an inhibitory active metabolite or residue thereof. Acceptable salts, esters, salts of esters or other derivatives. Particularly preferred derivatives or prodrugs increase the bioavailability of such compounds when the compounds of the invention are administered to a patient (e.g., allow orally administered compounds to be more readily absorbed into the blood) or Compared to the parent seed, the parent compound enhances the delivery to the biological compartment (eg brain or lymphatic system).
    [97] Pharmaceutically acceptable prodrugs of the compounds of the invention include, but are not limited to, the following derivatives of the compounds of the invention: esters, amino acid esters, phosphate esters, metal salts, sulfonate esters, carbamate and amides.
    [98] 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 acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrate, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, Dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- Hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate , Phosphate, picrate, pivalate, propionate, salicylate, succinate, sulf Pate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic acid, by themselves are not pharmaceutically acceptable, can be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
    [99] Salts derived from suitable bases include alkali metals (eg sodium and potassium), alkaline earth metals (eg magnesium), aluminum and N + (C 1-4 alkyl) 4 salts. The invention also includes quaternized compounds of all basic nitrogen containing groups of the compounds described herein. By such quaternization it is also possible to obtain water or oil-soluble or dispersible products.
    [100] The amount of protein kinase inhibitor that can be combined with a carrier material to produce a single dosage form will vary depending upon the patient being treated and the particular mode of administration. Preferably, the composition should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of inhibitor can be administered to the patient to which the composition is administered.
    [101] Specific dosages and treatment regimens for all specific patients determine the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, release rate, drug combination, and judgment and treatment of the attending physician. It will depend on the severity of the particular disease you receive. The amount of such inhibitor will also be determined depending on the particular compound in the composition.
    [102] Depending on the particular protein kinase mediated disease to be treated or prevented, additional therapeutic agents usually administered to treat or prevent such diseases may be administered in conjunction with the inhibitors of the invention. For example, in treating cancer, other chemotherapeutic or other antiproliferative agents may be combined with the compounds of the present invention to treat cancer. These formulations include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon and platinum derivatives.
    [103] Other examples of agents that may be combined with the inhibitors of the present invention include antidiabetic agents such as insulin or insulin homologues, injectable or inhaled form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers And sulfonyl ureas; 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; Neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, rilusol and antiparkinson's; Cardiovascular disease agents such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; Therapeutic agents for liver diseases such as corticosteroids, cholestyramine, interferon and antiviral agents; Blood disorder treatments such as corticosteroids, anti-leukemic agents and growth factors; And immunodeficiency therapies such as, for example, gamma globulin.
    [104] These additional agents can be administered separately from the protein kinase inhibitor containing composition as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed with the protein kinase inhibitor of the invention in a single composition.
    [105] The compounds of the present invention may exist in the form of substituted tautomers, as in the tautomers i and ii set forth below. Unless indicated otherwise, it is to be understood that what is represented by one tautomer also includes other tautomers:
    [106]
    [107] Wherein R x and R y together form a fused ring, thereby providing a bicyclic ring system containing ring A. Preferred R x / R y rings include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 hetero atoms, which R x / R y rings are optionally substituted. Examples of bicyclic systems containing ring A are shown below as compounds IA to I-BB:
    [108]
    [109]
    [110]
    [111] Wherein Z 1 is nitrogen or C (R 8 ) and Z 2 is nitrogen or C (H)
    [112] Preferred bicyclic ring A systems include IA, IB, IC, ID, IE, IF, II, IJ, IK, IP, IQ, IV and IU, more preferably IA, IB, ID, IE, IJ, IP and IV, most preferably IA, IB, ID, IE and IJ.
    [113] In monocyclic ring A systems, when present, preferred R x groups include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or iso Profile is included. When present, preferred R y groups include TR 3 or LZR 3 [where T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or — N (R 4 ) —, and R 3 is —R, —N (R 4 ) 2 or —OR. Preferred R y groups include 5-6 membered heteroaryl or heterocyclyl rings, for example , 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl; C 1-6 aliphatic, for example methyl, ethyl, cyclopropyl, isopropyl or t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [114] In bicyclic ring A systems, the ring formed by R x and R y may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 / aliphatic group.
    [115] R 2 and R 2 ′ together form a fused ring to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated 6-membered carbocyclo rings, which fused rings are optionally substituted. These are exemplified by the following general formula (I) compounds having pyrazole-containing bicyclic ring systems:
    [116]
    [117] Preferred substituents on the R 2 / R 2 ′ fused ring include one or more of the following: —halo, —N (R 4 ) 2 , —C 1-3 alkyl, —C 1-3 haloalkyl, —NO 2 , -O (C 1-3 alkyl), -CO 2 (C 1-3 alkyl), -CN, -SO 2 (C 1-3 alkyl), -SO 2 NH 2 , -OC (O) NH 2 ,- NH 2 SO 2 (C 1-3 alkyl), —NHC (O) (C 1-3 alkyl), —C (O) NH 2 and —CO (C 1-3 alkyl) [where (C 1-3 Alkyl) is most preferably methyl].
    [118] When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C 1-4 aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or Dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl and (N-heterocyclyl) carbonyl. Examples of such preferred R 2 substituents are methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 2 H, CO 2 CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 OCH 2 Ph, CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHCOOC (CH 3 ) 3 , CONHCH (CH 3 ) 2 , CONHCH 2 CH = CH 2 , CONHCH 2 CH 2 OCH 3 , CONHCH 2 Ph, CONH (cyclohexyl), CON (Et) 2 , CON (CH 3 ) CH 2 Ph, CONH (nC 3 H 7 ), CON (Et) CH 2 CH 2 CH 3 , CONHCH 2 CH (CH 3 ) 2 , CON (nC 3 H 7 ) 2 , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl ), CONH (4-tolyl), CONHCH 3 , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH 2 CH 2 OH, CONH 2 and CO (piperidine- 1-day). Preferred R 2 ' group is hydrogen.
    [119] Particularly useful embodiments for treating Aurora-2-mediated diseases relate to compounds of Formula (IIa), or pharmaceutically acceptable derivatives or prodrugs thereof:
    [120]
    [121] In the above formula,
    [122] R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 7 membered ring having 0 to 3 ring heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [123] R 1 is T- (ring D);
    [124] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [125] T is a valence bond or a C 1-4 alkylidene chain;
    [126] Z is a C 1-4 alkylidene chain;
    [127] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2 -,-N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [128] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [129] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [130] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [131] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [132] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [133] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [134] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [135] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [136] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [137] Preferred rings formed by R x and R y include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This provides a bicyclic ring system containing pyrimidine rings. Examples of preferred pyrimidine ring systems of formula (IIa) are shown below:
    [138]
    [139]
    [140] More preferred pyrimidine ring systems of formula (IIa) include IIa-A, IIa-B, IIa-D, IIa-E, IIa-J, IIa-P and IIa-V, most preferably IIa-A, IIa-B, IIa-D, IIa-E and IIa-J are included.
    [141] The ring formed by R x and R y together may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [142] The R 2 and R 2 ′ groups of formula (IIa) may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following general formula (IIa) compounds having pyrazole containing bicyclic ring systems:
    [143]
    [144] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIa include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl or ethyl.
    [145] When the pyrazole ring system of formula (IIa) is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [146] When ring D of formula (IIa) is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [147] When ring D of formula (IIa) is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindoleyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [148] Preferred TR 5 or VZR 5 substituents on ring D of formula (IIa) include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [149] Preferred compounds of formula (IIa) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [150] (a) R x and R y together with their insertion atoms form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and Each substitutable ring carbon of the fused ring formed by R y is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is selected from R 4 ; Independently substituted;
    [151] (b) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    [152] (c) ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings;
    [153] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring;
    [154] (e) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 .
    [155] More preferred compounds of formula (IIa) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [156] (a) R x and R y together form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring;
    [157] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings; Is;
    [158] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [159] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl and 5-6 membered Selected from heterocyclic, L is -O-, -S- or -N (R 4 )-.
    [160] Even more preferred compounds of formula (IIa) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [161] (a) R x and R y together form a benzo, pyrido, piperidino or cyclohex ring;
    [162] (b) R 1 is a T-ring D, wherein T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring;
    [163] (c) R 2 is hydrogen or C 1-4 aliphatic and R 2 ′ is hydrogen;
    [164] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [165] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring.
    [166] Representative compounds of Formula (IIa) are shown in Table 1 below:
    [167]
    [168]
    [169]
    [170]
    [171]
    [172]
    [173] In another embodiment, the present invention provides a composition comprising a compound of Formula IIa and a pharmaceutically acceptable carrier.
    [174] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula (IIa) or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing the Aurora-2 mediated disease using an Aurora-2 inhibitor. It is about a method.
    [175] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIa or a composition comprising such a compound.
    [176] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IIa or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [177] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IIa) or a pharmaceutical composition thereof It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [178] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IIa or a composition comprising such a compound.
    [179] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIa or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing a CDK-2 mediated disease using a CDK-2 inhibitor. It is about a method.
    [180] Another aspect of the invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a compound of Formula IIa or a composition comprising such a compound.
    [181] Another aspect of the invention relates to a method for treating or preventing Src-mediated diseases using Src inhibitors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIa or a pharmaceutical composition thereof will be.
    [182] Another aspect of the invention relates to a method of inhibiting Src activity in a patient, comprising administering to the patient a compound of Formula IIa or a composition comprising such a compound.
    [183] Another method is to provide a biological sample in an amount effective to inhibit Aurora-2, GSK-3, CDK-2 or Src, Aurora-2, GSK-3, CDK-2 or Src inhibitor of Formula IIa, or a pharmaceutical composition thereof. A method of inhibiting Aurora-2, GSK-3, CDK-2 or Src activity in such a biological sample, including contacting with a.
    [184] Each of the methods described above with respect to the inhibition of Aurora-2, GSK-3, CDK-2 or Src, or the methods of treating the ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula IIa as mentioned above. .
    [185] Another aspect of the invention relates to a compound of formula (IIb), or a pharmaceutically acceptable derivative or prodrug thereof:
    [186]
    [187] In the above formula,
    [188] R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 7 membered ring having 0 to 3 ring heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [189] R 1 is T- (ring D);
    [190] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [191] T is a valence bond or a C 1-4 alkylidene chain;
    [192] Z is a C 1-4 alkylidene chain;
    [193] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [194] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [195] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [196] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [197] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [198] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [199] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [200] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [201] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [202] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [203] Preferred rings formed by R x and R y include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This provides a bicyclic ring system containing pyrimidine rings. Examples of preferred pyrimidine ring systems of formula (IIb) are shown below:
    [204]
    [205]
    [206] More preferred pyrimidine ring systems of formula (IIb) include IIb-A, IIb-B, IIb-D, IIb-E, IIb-J, IIb-P and IIb-V, most preferably IIb-A, IIb-B, IIb-D, IIb-E and IIb-J are included.
    [207] The ring formed by R x and R y together may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [208] The R 2 and R 2 ′ groups of formula (IIb) may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are illustrated in the following formula IIb compounds having pyrazole containing bicyclic ring systems:
    [209]
    [210] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIb include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl or ethyl.
    [211] When the pyrazole ring system of formula (IIb) is monocyclic, preferred R 2 groups include hydrogen or substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [212] When ring D of formula (IIb) is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [213] When ring D of formula (IIb) is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindoleyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [214] Preferred TR 5 or VZR 5 substituents on ring D of formula (IIb) include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [215] Preferred compounds of formula (IIb) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [216] (a) R x and R y together with their insertion atoms form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and Each substitutable ring carbon of the fused ring formed by R y is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is selected from R 4 ; Independently substituted;
    [217] (b) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    [218] (c) ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings;
    [219] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring;
    [220] (e) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 .
    [221] More preferred compounds of formula (IIb) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [222] (a) R x and R y together form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring;
    [223] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings; Is;
    [224] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [225] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 Selected from the membered heteroaryl, L is -O-, -S- or -N (R 4 )-.
    [226] Even more preferred compounds of formula (IIb) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [227] (a) R x and R y together form a benzo, pyrido, piperidino or cyclohex ring;
    [228] (b) R 1 is a T-ring D, wherein T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring;
    [229] (c) R 2 is hydrogen or C 1-4 aliphatic and R 2 ′ is hydrogen;
    [230] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [231] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring.
    [232] Representative compounds of formula (IIb) are shown in Table 2 below:
    [233]
    [234] In another embodiment, the present invention provides a composition comprising a compound of Formula IIb and a pharmaceutically acceptable carrier.
    [235] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIb or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing Aurora-2 mediated diseases using Aurora-2 inhibitors. It is about a method.
    [236] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIb or a composition comprising such a compound.
    [237] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IIb or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [238] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIb or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [239] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IIb or a composition comprising such a compound.
    [240] Another method includes contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula (IIb), or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. It relates to a method of inhibiting -2 or GSK-3 activity.
    [241] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for treating ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula (IIb) as mentioned above.
    [242] Another aspect of the invention relates to a compound of formula (IIc), or a pharmaceutically acceptable derivative or prodrug thereof:
    [243]
    [244] In the above formula,
    [245] R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 7 membered ring having 0 to 3 ring heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [246] R 1 is T- (ring D);
    [247] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [248] T is a valence bond or a C 1-4 alkylidene chain;
    [249] Z is a C 1-4 alkylidene chain;
    [250] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [251] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [252] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [253] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [254] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [255] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [256] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [257] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [258] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [259] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [260] Preferred rings formed by R x and R y include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This provides a bicyclic ring system containing pyrimidine rings. Examples of preferred pyrimidine ring systems of formula (IIc) are shown below:
    [261]
    [262]
    [263] More preferred pyrimidine ring systems of formula (IIc) include IIc-A, IIc-B, IIc-D, IIc-E, IIc-J, IIc-P and IIc-V, most preferably IIc-A, IIc-B, IIc-D, IIc-E and IIc-J.
    [264] The ring formed by R x and R y of Formula (IIc) may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [265] The R 2 and R 2 ′ groups of formula (IIc) may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are illustrated in the following formula IIc compounds having pyrazole containing bicyclic ring systems:
    [266]
    [267] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIc include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [268] When the pyrazole ring system of formula (IIc) is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [269] When ring D of formula (IIc) is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [270] When ring D of formula (IIc) is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindoleyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [271] Preferred TR 5 or VZR 5 substituents on ring D of Formula (IIc) include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [272] Preferred compounds of formula (IIc) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [273] (a) R x and R y together with their insertion atoms form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and Each substitutable ring carbon of the fused ring formed by R y is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is selected from R 4 ; Independently substituted;
    [274] (b) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    [275] (c) ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings;
    [276] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring;
    [277] (e) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 .
    [278] More preferred compounds of formula (IIc) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [279] (a) R x and R y together form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring;
    [280] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings; Is;
    [281] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [282] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 Selected from the membered heteroaryl, L is -O-, -S- or -N (R 4 )-.
    [283] Even more preferred compounds of formula (IIc) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [284] (a) R x and R y together form a benzo, pyrido, piperidino or cyclohex ring;
    [285] (b) R 1 is a T-ring D, wherein T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring;
    [286] (c) R 2 is hydrogen or C 1-4 aliphatic and R 2 ′ is hydrogen;
    [287] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [288] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring.
    [289] Preferred compounds of formula (IIc) include compounds of formula (IIc '), or pharmaceutically acceptable derivatives or prodrugs thereof:
    [290]
    [291] In the above formula,
    [292] R x and R y , together with their insertion atoms, form a fused benzo ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is independently defined by TR 3 or LZR 3 Substituted;
    [293] R 1 is T- (ring D);
    [294] Ring D is a 5 to 7 membered monocyclic ring or an 8 to 10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [295] T is a valence bond or a C 1-4 alkylidene chain;
    [296] Z is a C 1-4 alkylidene chain;
    [297] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [298] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [299] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [300] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [301] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [302] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [303] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [304] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [305] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [306] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [307] Rings formed by R x and R y of Formula (IIc ′) may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [308] The R 2 and R 2 ′ groups of formula (IIc ′) may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following formula IIc 'compounds having a pyrazole containing bicyclic ring system:
    [309]
    [310] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIc ′ include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl, -NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , —NH 2 SO 2 (C 1-4 alkyl), —NHC (O) (C 1-4 alkyl), —C (O) NH 2 and —CO (C 1-4 alkyl) [where, ( C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [311] When the pyrazole ring system of formula (IIc ') is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [312] When ring D of formula (IIc ') is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [313] When ring D of formula (IIc ') is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindoleyl, indolinyl , Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl This includes.
    [314] Preferred TR 5 or VZR 5 substituents on ring D of Formula (IIc ') include -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O ) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N ( R 4 ) 2 , wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, and 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [315] Preferred compounds of formula IIc 'have at least one of the features selected from the group consisting of, more preferably all of these features:
    [316] (a) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit;
    [317] (b) ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings;
    [318] (c) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring;
    [319] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 .
    [320] More preferred compounds of formula (IIc ') have at least one of the features selected from the group consisting of, more preferably all of these features:
    [321] (a) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings; Is;
    [322] (b) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [323] (c) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 Selected from the membered heteroaryl, L is -O-, -S- or -N (R 4 )-.
    [324] Even more preferred compounds of formula (IIc ') have at least one of the features selected from the group consisting of, more preferably all of these features:
    [325] (a) R 1 is T-ring D, wherein T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring;
    [326] (b) R 2 is hydrogen or C 1-4 aliphatic and R 2 ′ is hydrogen;
    [327] (c) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [328] (d) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring.
    [329] Other preferred compounds of formula (IIc) include compounds of formula (IIc), or pharmaceutically acceptable derivatives or prodrugs thereof:
    [330]
    [331] In the above formula,
    [332] R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 7 membered ring having 0 to 3 ring heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is optionally substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is optionally substituted by R 4 Provided that the fused ring formed by R x and R y is not benzo;
    [333] R 1 is T- (ring D);
    [334] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [335] T is a valence bond or a C 1-4 alkylidene chain;
    [336] Z is a C 1-4 alkylidene chain;
    [337] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [338] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [339] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [340] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [341] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 or -SO 2 R 7 ;
    [342] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [343] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2 -,-N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [344] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [345] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [346] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [347] Preferred rings formed by R x and R y of formula (IIc) include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 1 to 2 hetero atoms, or partially unsaturated carbocyclo rings, such R x / R y The ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. An example of a preferred pyrimidine ring system of formula (IIc) is shown below:
    [348]
    [349] More preferred pyrimidine ring systems of formula IIc "include IIc" -B, IIc "-D, IIc" -E, IIc "-J, IIc" -P and IIc "-V, most preferably IIc" -B, IIc "-D, IIc" -E, and IIc "-J.
    [350] Rings formed by R x and R y of Formula IIc ″ may be substituted or unsubstituted. Suitable substituents include —R, —halo, —O (CH 2 ) 2-4 —N (R 4 ) 2 , —O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4- R, -C (= 0) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic) , -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R or —OC (═O) N (R 4 ) 2 , wherein R and R 4 are as defined above. R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where, R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [351] The R 2 and R 2 ′ groups of formula (IIc ”) together may form a fused ring to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partial Unsaturated 6-membered carbocyclo rings. These are exemplified by the following compound of formula IIc " having a pyrazole-containing bicyclic ring system:
    [352]
    [353] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIc ″ include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl, -NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , —NH 2 SO 2 (C 1-4 alkyl), —NHC (O) (C 1-4 alkyl), —C (O) NH 2 and —CO (C 1-4 alkyl) [where, ( C 1-4 alkyl) is a straight, branched or cyclic alkyl group] Preferably, the (C 1-4 alkyl) group is methyl.
    [354] When the pyrazole ring system of formula (IIc) is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Such preferred R Examples of 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl Preferred R 2 ' group is hydrogen.
    [355] When ring D of formula (IIc) is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [356] When ring D of formula (IIc) is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl , Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl This includes.
    [357] Preferred TR 5 or VZR 5 substituents on ring D of formula (IIc) include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O ) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N ( . R 4) 2 include [where, R is hydrogen, C 1-6 aliphatic, phenyl, a 5 to 6 membered heteroaryl ring and is selected from a 5 to 6-membered heterocyclic ring], the more preferred R 5 substituents Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (mor Pololin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4- 1), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), for example -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, for example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 Aliphatic).
    [358] Preferred compounds of formula (IIc) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [359] (a) a fused unsaturated or partially unsaturated 5-6 membered ring, or partially unsaturated 6-membered carbocyclo, wherein R x and R y together with their insertion atoms have 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen; Forming a ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is independently substituted by oxo, TR 3 or LZR 3 , and each of the ring formed by R x and R y Substitutable ring nitrogen of is independently substituted by R 4 ;
    [360] (b) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit, and ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic selected from aryl and heteroaryl rings Ring;
    [361] (c) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring;
    [362] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 .
    [363] More preferred compounds of formula (IIc) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [364] (a) R x and R y together form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring, wherein said fusion formed by R x and R y Each substitutable ring carbon of the substituted ring is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently substituted by R 4 ;
    [365] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings; Is;
    [366] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [367] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 Selected from the membered heteroaryl, L is -O-, -S- or -N (R 4 )-.
    [368] Even more preferred compounds of formula (IIc) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [369] (a) R x and R y together form a pyrido, piperidino or cyclohex ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is oxo, TR 3 or Independently substituted by LZR 3 , each substitutable ring nitrogen of the ring formed by R x and R y is independently substituted by R 4 ;
    [370] (b) R 1 is a T-ring D, wherein T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring;
    [371] (c) R 2 is hydrogen or C 1-4 aliphatic and R 2 ′ is hydrogen;
    [372] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [373] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring.
    [374] Representative compounds of formula (IIc) are shown in Table 3 below:
    [375]
    [376]
    [377]
    [378]
    [379]
    [380]
    [381]
    [382]
    [383] In another embodiment, the present invention provides a composition comprising a compound of formula IIc, IIc 'or IIc "and a pharmaceutically acceptable carrier.
    [384] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula (IIc, IIc 'or IIc "or a pharmaceutical composition thereof to a patient in need thereof, using Aurora-2 inhibitors A method of treating or preventing a disease.
    [385] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIc, IIc 'or IIc "or a composition comprising such a compound.
    [386] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIc, IIc 'or IIc "or a pharmaceutical composition thereof to a patient in need thereof, wherein the GSK-3-mediated use of a GSK-3 inhibitor The present invention relates to a method of treating or preventing a disease.
    [387] One aspect of the invention involves administering a therapeutically effective amount of a compound of Formula (IIc), (IIc ') or (IIc) or a pharmaceutical composition thereof to a patient in need thereof, thereby enhancing glycogen synthesis and / or blood glucose in such patient This method is particularly useful for diabetics, another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [388] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of formula IIc, IIc 'or IIc "or a composition comprising such a compound.
    [389] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIc, IIc 'or IIc "or a pharmaceutical composition thereof to a patient in need thereof, using a Src inhibitor to treat an Src-mediated disease Or how to prevent it.
    [390] Another aspect of the present invention relates to a method of inhibiting Src activity in a patient, comprising administering to the patient a compound of formula (IIc), (IIc ') or (IIc ") or a composition comprising such a compound.
    [391] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIc, IIc 'or IIc "or a pharmaceutical composition thereof to a patient in need thereof, wherein the ERK-2-mediated ERK-2 inhibitor The present invention relates to a method of treating or preventing a disease.
    [392] 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 IIc, IIc 'or IIc "or a composition comprising such a compound.
    [393] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIc, IIc 'or IIc "or a pharmaceutical composition thereof to a patient in need thereof, wherein the AKT inhibitor is used to treat an AKT-mediated disease. Or how to prevent it.
    [394] Another aspect of the invention relates to a method of inhibiting AKT activity in a patient, comprising administering to the patient a compound of Formula IIc, IIc 'or IIc "or a composition comprising such a compound.
    [395] Another method is to provide a biological sample with Aurora-2, GSK-3, Src, ERK- of Formula IIc, IIc 'or IIc "in an amount effective to inhibit Aurora-2, GSK-3, Src, ERK-2 or AKT. A method of inhibiting Aurora-2, GSK-3, Src, ERK-2 or AKT activity in such a biological sample, including contacting with 2 or an AKT inhibitor, or a pharmaceutical composition thereof.
    [396] Each of the methods described above for the inhibition of Aurora-2, GSK-3, Src, ERK-2 or AKT, or methods of treating ameliorated diseases thereby, are preferred compounds of formula IIc, IIc 'or IIc "as mentioned above. Preference is given to using.
    [397] Another embodiment particularly useful for treating Aurora-2-mediated diseases relates to a compound of Formula (IId), or a pharmaceutically acceptable derivative or prodrug thereof:
    [398]
    [399] In the above formula,
    [400] Q 'is selected from -C (R 6' ) 2- , 1,2-cyclopropanediyl, 1,2-cyclobutanediyl and 1,3-cyclobutanediyl;
    [401] R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 7 membered ring having 0 to 3 ring heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [402] R 1 is T- (ring D);
    [403] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [404] T is a valence bond or a C 1-4 alkylidene chain, wherein if Q 'is -C (R 6' ) 2- , the methylene group of the C 1-4 alkylidene chain is -O-, -S-,- N (R 4 )-, -CO-, -CONH-, -NHCO-, -SO 2- , -SO 2 NH-, -NHSO 2- , -CO 2- , -OC (O)-, -OC ( O) NH- or -NHCO 2 -optionally substituted;
    [405] Z is a C 1-4 alkylidene chain;
    [406] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2 -,-N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [407] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [408] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [409] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [410] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [411] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R or —OC (═O) N (R 4 ) 2 ;
    [412] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [413] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [414] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [415] Each R 6 ′ is independently selected from hydrogen and a C 1-4 aliphatic group, or two R 6 ′ on the same carbon atom together form a 3-6 membered carbocyclic ring;
    [416] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [417] Preferred rings formed by R x and R y include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This provides a bicyclic ring system containing pyrimidine rings. Examples of preferred pyrimidine ring systems of formula (IId) are shown below:
    [418]
    [419]
    [420] More preferred pyrimidine ring systems of formula IId include IId-A, IId-B, IId-D, IId-E, IId-J, IId-P and IId-V, most preferably IId-A, IId-B, IId-D, IId-E and IId-J are included.
    [421] Rings formed by R x and R y of Formula (IId) may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [422] The R 2 and R 2 ′ groups of formula (IId) may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are illustrated in the following formula IId compounds having pyrazole containing bicyclic ring systems:
    [423]
    [424] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IId include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2, -O (C 1-4 alkyl), -CO 2 (C 1- 4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2, -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [425] When the pyrazole ring system of formula (IId) is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [426] When ring D of formula (IId) is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [427] When ring D of formula (IId) is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindoleyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [428] Preferred TR 5 or VZR 5 substituents on ring D of formula (IId) include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [429] Preferred Q 'groups of formula (IId) include -C (R 6' ) 2 -or 1,2-cyclopropanediyl, wherein R 6 ' is each independently selected from hydrogen and methyl. More preferred Q 'group is -CH 2- .
    [430] Preferred compounds of formula (IId) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [431] (a) R x and R y together with their insertion atoms form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and Each substitutable ring carbon of the fused ring formed by R y is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is selected from R 4 ; Independently substituted;
    [432] (b) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit, and this methylene unit is optionally replaced by -O-, -NH- or -S-;
    [433] (c) ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl and heteroaryl rings;
    [434] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring;
    [435] (e) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 .
    [436] More preferred compounds of formula (IId) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [437] (a) R x and R y together form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring;
    [438] (b) R 1 is T- (ring D) [where T is a valence bond or methylene unit, and this methylene unit is optionally replaced by —O—, ring D is selected from 5 to 6 selected from aryl and heteroaryl rings A member monocyclic ring or an 8 to 10 membered bicyclic ring;
    [439] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [440] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl and 5-6 membered Is selected from heterocyclic, L is -O-, -S- or -N (R 4 )-;
    [441] (e) Q 'is -C (R 6' ) 2 -or 1,2-cyclopropanediyl, wherein R 6 ' is each independently selected from hydrogen and methyl.
    [442] Even more preferred compounds of formula (IId) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [443] (a) R x and R y together form a benzo, pyrido, piperidino or cyclohex ring;
    [444] (b) R 1 is a T-ring D, wherein T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring;
    [445] (c) R 2 is hydrogen or C 1-4 aliphatic and R 2 ′ is hydrogen;
    [446] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [447] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 or -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring;
    [448] (f) Q 'is -CH 2- .
    [449] Representative compounds of formula (IId) are shown in Table 4 below:
    [450]
    [451]
    [452] In another embodiment, the present invention provides a composition comprising a compound of Formula IId and a pharmaceutically acceptable carrier.
    [453] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IId or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing Aurora-2 mediated diseases using Aurora-2 inhibitors. It is about a method.
    [454] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IId or a composition comprising such a compound.
    [455] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IId or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [456] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IId or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [457] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IId or a composition comprising such a compound.
    [458] Another method includes contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula (IId), or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. It relates to a method of inhibiting -2 or GSK-3 activity.
    [459] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for the treatment of ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula (IId) as mentioned above.
    [460] Another aspect of the invention relates to a compound of formula IIIa, or a pharmaceutically acceptable derivative or prodrug thereof:
    [461]
    [462] In the above formula,
    [463] R x and R y are independently selected from TR 3 and LZR 3 ;
    [464] R 1 is T- (ring D);
    [465] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [466] T is a valence bond or a C 1-4 alkylidene chain;
    [467] Z is a C 1-4 alkylidene chain;
    [468] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2 -,-N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [469] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [470] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [471] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [472] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [473] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [474] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [475] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [476] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [477] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [478] Preferred R x groups of formula IIIa include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or isopropyl.
    [479] Preferred R y groups of formula IIIa include TR 3 or LZR 3 , wherein T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [480] The R 2 and R 2 ′ groups of formula IIIa may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following formula IIIa compounds having pyrazole-containing bicyclic ring systems:
    [481]
    [482] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIIa include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [483] When the pyrazole ring system of Formula IIIa is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [484] When ring D of formula IIIa is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [485] When ring D of formula IIIa is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [486] Preferred TR 5 or VZR 5 substituents on ring D of Formula IIIa include -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [487] Preferred compounds of formula (IIIa) have at least one of the features selected from the group consisting of, more preferably all of these features:
    [488] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group;
    [489] (b) R y is TR 3 or LZR 3 , where T is a valence bond or methylene and R 3 is —R, —N (R 4 ) 2 or —OR;
    [490] (c) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit;
    [491] (d) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [492] (e) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [493] More preferred compounds of formula IIIa have at least one of the features selected from the group consisting of, more preferably all of these features:
    [494] (a) R y is TR 3 or LZR 3 wherein T is a valence bond or methylene, and R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1- 6 aliphatic, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl];
    [495] (b) R 1 is T- (ring D), where T is a valence bond;
    [496] (c) ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [497] (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring;
    [498] (e) L is -O-, -S- or -N (R 4 )-.
    [499] Even more preferred compounds of formula IIIa have at least one of the features selected from the group consisting of, more preferably all of these features:
    [500] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
    [501] (b) R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, Alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido is selected from optionally substituted phenyl and methoxymethyl;
    [502] (c) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, wherein ring D is -halo, -CN, -NO 2 ,- N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) SO 2 R, Is optionally substituted by one or two groups selected from -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ]; ;
    [503] (d) R 2 is hydrogen or substituted or unsubstituted C 1-6 aliphatic and L is —O—, —S— or —NH—.
    [504] Representative compounds of Formula IIIa are shown in Table 5 below:
    [505]
    [506]
    [507]
    [508]
    [509]
    [510] In another embodiment, the present invention provides a composition comprising a compound of Formula IIIa and a pharmaceutically acceptable carrier.
    [511] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIIa or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing the Aurora-2 mediated disease using an Aurora-2 inhibitor. It is about a method.
    [512] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIIa or a composition comprising such a compound.
    [513] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, including administering a therapeutically effective amount of a compound of Formula IIIa or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [514] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering a therapeutically effective amount of a compound of Formula IIIa or a pharmaceutical composition thereof to a patient in need thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [515] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IIIa or a composition comprising such a compound.
    [516] Another aspect of the invention relates to a method for treating or preventing Src-mediated diseases using Src inhibitors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIIa or a pharmaceutical composition thereof will be.
    [517] Another aspect of the invention relates to a method of inhibiting Src activity in a patient, comprising administering to the patient a compound of Formula IIIa or a composition comprising such compound.
    [518] Another method includes contacting a biological sample with an Aurora-2, GSK-3 or Src inhibitor of Formula IIIa, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3 or Src. A method of inhibiting Aurora-2, GSK-3 or Src activity in a biological sample.
    [519] Each of the methods described above for the inhibition of Aurora-2, GSK-3 or Src, or the methods for treating ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula IIIa as mentioned above.
    [520] Another aspect of the invention relates to a compound of formula IIIb, or a pharmaceutically acceptable derivative or prodrug thereof:
    [521]
    [522] In the above formula,
    [523] R x and R y are independently selected from TR 3 and LZR 3 ;
    [524] R 1 is T- (ring D);
    [525] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [526] T is a valence bond or a C 1-4 alkylidene chain;
    [527] Z is a C 1-4 alkylidene chain;
    [528] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [529] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [530] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [531] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [532] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [533] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [534] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [535] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [536] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [537] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [538] Preferred R x groups of formula IIIb include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or isopropyl.
    [539] Preferred R y groups of formula IIIb include TR 3 or LZR 3 , wherein T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [540] The R 2 and R 2 ′ groups of formula IIIb may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following formula IIIb compounds having pyrazole containing bicyclic ring systems:
    [541]
    [542] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIIb include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [543] When the pyrazole ring system of formula IIIb is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [544] When ring D of formula IIIb is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [545] When ring D of formula IIIb is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [546] Preferred TR 5 or VZR 5 substituents on ring D of Formula IIIb include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [547] Preferred compounds of formula IIIb have one or more, more preferably all of these features, selected from the group consisting of:
    [548] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group;
    [549] (b) R y is TR 3 or LZR 3 , where T is a valence bond or methylene and R 3 is —R, —N (R 4 ) 2 or —OR;
    [550] (c) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit;
    [551] (d) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [552] (e) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [553] More preferred compounds of formula IIIb have at least one of the features selected from the group consisting of, more preferably all of these features:
    [554] (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is hydrogen, C 1-6 Aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl];
    [555] (b) R 1 is T- (ring D), where T is a valence bond;
    [556] (c) ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [557] (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring;
    [558] (e) L is -O-, -S- or -N (R 4 )-.
    [559] Even more preferred compounds of formula IIIb have at least one of the features selected from the group consisting of, more preferably all of these features:
    [560] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
    [561] (b) R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, Alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido is selected from optionally substituted phenyl and methoxymethyl;
    [562] (c) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, wherein ring D is -halo, -CN, -NO 2 ,- N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) SO 2 R, Is optionally substituted by one or two groups selected from -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ]; ;
    [563] (d) R 2 is hydrogen or substituted or unsubstituted C 1-6 aliphatic and L is —O—, —S— or —NH—.
    [564] Representative compounds of Formula IIIb are shown in Table 6 below:
    [565]
    [566]
    [567]
    [568] In another embodiment, the present invention provides a composition comprising a compound of Formula IIIb and a pharmaceutically acceptable carrier.
    [569] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIIb or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing the Aurora-2 mediated disease using an Aurora-2 inhibitor. It is about a method.
    [570] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIIb or a composition comprising such a compound.
    [571] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIIb or a pharmaceutical composition thereof It is about how to.
    [572] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIIb or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [573] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IIIb or a composition comprising such a compound.
    [574] Another method comprises contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula IIIb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3, It relates to a method of inhibiting -2 or GSK-3 activity.
    [575] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for treating ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula IIIb as mentioned above.
    [576] Another aspect of the invention relates to a compound of formula IIIc, or a pharmaceutically acceptable derivative or prodrug thereof:
    [577]
    [578] In the above formula,
    [579] R x and R y are independently selected from TR 3 and LZR 3 ;
    [580] R 1 is T- (ring D);
    [581] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [582] T is a valence bond or a C 1-4 alkylidene chain;
    [583] Z is a C 1-4 alkylidene chain;
    [584] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2 -,-N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [585] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [586] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [587] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [588] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [589] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [590] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [591] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [592] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [593] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [594] Preferred R x groups of formula IIIc include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups, for example methyl, ethyl, cyclopropyl or isopropyl.
    [595] Preferred R y groups of formula IIIc include TR 3 or LZR 3 , wherein T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [596] The R 2 and R 2 ′ groups of formula IIIc may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are illustrated in the following formula IIIc compounds having pyrazole containing bicyclic ring systems:
    [597]
    [598] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIIc include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [599] When the pyrazole ring system of formula IIIc is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [600] When ring D of formula IIIc is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [601] When ring D of formula IIIc is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [602] Preferred TR 5 or VZR 5 substituents on ring D of Formula IIIc include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [603] Preferred compounds of formula IIIc have at least one of the features selected from the group consisting of, more preferably all of these features:
    [604] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group;
    [605] (b) R y is TR 3 or LZR 3 , where T is a valence bond or methylene and R 3 is —R, —N (R 4 ) 2 or —OR;
    [606] (c) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit;
    [607] (d) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [608] (e) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [609] More preferred compounds of formula IIIc have at least one of the features selected from the group consisting of, more preferably all of these features:
    [610] (a) R y is TR 3 or LZR 3 wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl;
    [611] (b) R 1 is T- (ring D), where T is a valence bond;
    [612] (c) ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [613] (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring;
    [614] (e) L is -O-, -S- or -N (R 4 )-.
    [615] Even more preferred compounds of formula IIIc have at least one of the features selected from the group consisting of, more preferably all of these features:
    [616] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
    [617] (b) R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, Alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido is selected from optionally substituted phenyl and methoxymethyl;
    [618] (c) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, wherein ring D is -halo, -CN, -NO 2 ,- N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) SO 2 R, Is optionally substituted by one or two groups selected from -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ]; ;
    [619] (d) R 2 is hydrogen or substituted or unsubstituted C 1-6 aliphatic and L is —O—, —S— or —NH—.
    [620] Representative compounds of Formula IIIc are shown in Table 7 below:
    [621]
    [622]
    [623]
    [624] In another embodiment, the present invention provides a composition comprising a compound of Formula IIIc and a pharmaceutically acceptable carrier.
    [625] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIIc or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing the Aurora-2 mediated disease using an Aurora-2 inhibitor. It is about a method.
    [626] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIIc or a composition comprising such a compound.
    [627] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IIIc or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [628] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIIc or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [629] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IIIc or a composition comprising such a compound.
    [630] Another aspect of the invention relates to a method for treating or preventing Src-mediated diseases using Src inhibitors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIIc or a pharmaceutical composition thereof will be.
    [631] Another aspect of the invention relates to a method of inhibiting Src activity in a patient, comprising administering to the patient a compound of Formula IIIc or a composition comprising such a compound.
    [632] Another method includes contacting a biological sample with an Aurora-2, GSK-3 or Src inhibitor of Formula IIIc, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3 or Src. A method of inhibiting Aurora-2, GSK-3 or Src activity in a biological sample.
    [633] Each of the methods described above with respect to the inhibition of Aurora-2, GSK-3 or Src, or the methods for the treatment of the alleviated disease thereby, is preferably carried out using the preferred compounds of formula IIIc as mentioned above.
    [634] Another aspect of the invention relates to a compound of formula IIId, or a pharmaceutically acceptable derivative or prodrug thereof:
    [635]
    [636] In the above formula,
    [637] Q 'is selected from -C (R 6' ) 2- , 1,2-cyclopropanediyl, 1,2-cyclobutanediyl and 1,3-cyclobutanediyl;
    [638] R x and R y are independently selected from TR 3 and LZR 3 ;
    [639] R 1 is T- (ring D);
    [640] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [641] T is a valence bond or a C 1-4 alkylidene chain, wherein if Q 'is -C (R 6' ) 2- , the methylene group of the C 1-4 alkylidene chain is -O-, -S-,- N (R 4 )-, -CO-, -CONH-, -NHCO-, -SO 2- , -SO 2 NH-, -NHSO 2- , -CO 2- , -OC (O)-, -OC ( O) NH- or -NHCO 2 -optionally substituted;
    [642] Z is a C 1-4 alkylidene chain;
    [643] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [644] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [645] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [646] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [647] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [648] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [649] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [650] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [651] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [652] Each R 6 ′ is independently selected from hydrogen and a C 1-4 aliphatic group, or two R 6 ′ on the same carbon atom together form a 3-6 membered carbocyclic ring;
    [653] R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [654] Preferred R x groups of formula IIId include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or isopropyl.
    [655] Preferred R y groups of formula IIId include TR 3 or LZR 3 , wherein T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [656] The R 2 and R 2 ′ groups of formula IIId may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following formula IIId compounds having pyrazole-containing bicyclic ring systems:
    [657]
    [658] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IIId include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [659] When the pyrazole ring system of formula IIId is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [660] When ring D of formula IIId is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [661] When ring D of formula IIId is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [662] Preferred TR 5 or VZR 5 substituents on ring D of Formula IIId include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [663] Preferred Q 'groups of formula IIId include -C (R 6' ) 2 -or 1,2-cyclopropanediyl, wherein R 6 ' is each independently selected from hydrogen and methyl. More preferred Q 'group is -CH 2- .
    [664] Preferred compounds of formula IIId have at least one of the features selected from the group consisting of, more preferably all of these features:
    [665] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group;
    [666] (b) R y is TR 3 or LZR 3 , where T is a valence bond or methylene and R 3 is —R, —N (R 4 ) 2 or —OR;
    [667] (c) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit, and this methylene unit is optionally replaced by -O-, -NH- or -S-;
    [668] (d) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [669] (e) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [670] More preferred compounds of Formula IIId have at least one of the features selected from the group consisting of, more preferably all of these features:
    [671] (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is hydrogen, C 1-6 Aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl];
    [672] (b) R 1 is T- (ring D), where T is a valence bond;
    [673] (c) ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [674] (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring;
    [675] (e) L is -O-, -S- or -N (R 4 )-;
    [676] (f) Q 'is -C (R 6' ) 2 -or 1,2-cyclopropanediyl, wherein R 6 ' is each independently selected from hydrogen and methyl.
    [677] Even more preferred compounds of formula IIId have at least one of the features selected from the group consisting of, more preferably all of these features:
    [678] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
    [679] (b) R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, Alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido is selected from optionally substituted phenyl and methoxymethyl;
    [680] (c) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, wherein ring D is -halo, -CN, -NO 2 ,- N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) SO 2 R, Is optionally substituted by one or two groups selected from -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ]; ;
    [681] (d) R 2 is hydrogen or substituted or unsubstituted C 1-6 aliphatic and L is —O—, —S— or —NH—;
    [682] (e) Q 'is -CH 2- .
    [683] Representative compounds of Formula IIId are shown in Table 8 below:
    [684]
    [685]
    [686]
    [687] In another embodiment, the present invention provides a composition comprising a compound of Formula IIId and a pharmaceutically acceptable carrier.
    [688] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IIId or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing Aurora-2 mediated diseases using Aurora-2 inhibitors. It is about a method.
    [689] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IIId or a composition comprising such a compound.
    [690] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IIId or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [691] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IIId or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [692] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IIId or a composition comprising such a compound.
    [693] Another method comprises contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula IIId, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3, It relates to a method of inhibiting -2 or GSK-3 activity.
    [694] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for the treatment of the alleviated diseases thereby, are preferably carried out using the preferred compounds of formula IIId as mentioned above.
    [695] Another aspect of the invention is a compound of Formula IVa, or a pharmaceutically acceptable derivative or prodrug thereof:
    [696]
    [697] In the above formula,
    [698] Z 1 is nitrogen or CR 8 ,
    [699] Z 2 is nitrogen or CH, wherein one of Z 1 and Z 2 is nitrogen;
    [700] R x and R y are independently selected from TR 3 and LZR 3 , or R x and R y together with their insertion atoms are fused unsaturated having 0 to 3 ring hetero atoms selected from oxygen, sulfur and nitrogen or Forms a partially unsaturated 5-7 membered ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is independently substituted by oxo, TR 3 or LZR 3 , and R x and R y Each substitutable ring nitrogen of the ring formed by is independently substituted by R 4 ;
    [701] R 1 is T- (ring D);
    [702] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [703] T is a valence bond or a C 1-4 alkylidene chain;
    [704] Z is a C 1-4 alkylidene chain;
    [705] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [706] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [707] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [708] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [709] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [710] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [711] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [712] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [713] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [714] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [715] R 8 is -R, -halo, -OR, -C (= 0) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 .
    [716] Preferred rings formed by R x and R y of Formula IVa include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred pyridine ring systems of formula IVa are shown below:
    [717]
    [718]
    [719] More preferred pyridine ring systems of formula IVa include IVa-A, IVa-B, IVa-D, IVa-E, IVa-J, IVa-P and IVa-V, most preferably IVa-A, IVa-B, IVa -D, IVa-E and IVa-J. Even more preferred pyridine ring systems of formula IVa are the abovementioned compounds wherein Z 1 is nitrogen and Z 2 is CH.
    [720] Preferred R x groups of formula IVa include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or isopropyl.
    [721] Preferred R y groups of formula IVa include TR 3 or LZR 3 [where T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [722] Rings formed by R x and R y groups of Formula IVa may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [723] The R 2 and R 2 ′ groups of formula IVa may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following compound of formula IVa having a pyrazole containing bicyclic ring system:
    [724]
    [725] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IVa include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [726] When the pyrazole ring system of formula IVa is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [727] When ring D of formula IVa is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [728] When ring D of formula IVa is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [729] Preferred TR 5 or VZR 5 substituents on ring D of Formula IVa include -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [730] When present, preferred R 8 groups of formula IVa include R, OR and N (R 4 ) 2 . Examples of preferred R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 O, (piperidine- 1-yl) CH 2 CH 2 O and NH 2 CH 2 CH 2 O.
    [731] Preferred compounds of formula IVa have one or more, more preferably all of these features, selected from the group consisting of:
    [732] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group, R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene and R 3 is -R, -N (R 4 ) 2 or -OR]; Or R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 6 membered ring having 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [733] (b) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    [734] (c) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [735] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [736] More preferred compounds of formula IVa have at least one of the features selected from the group consisting of, more preferably all of these features:
    [737] (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is hydrogen, C 1-6 Aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl]; Or R x and R y together with their insertion atoms form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring, wherein R x and R y Each substitutable ring carbon of the fused ring formed is independently substituted by oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently substituted by R 4 Become;
    [738] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [739] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [740] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl and 5-6 membered Selected from heterocyclic, L is -O-, -S- or -N (R 4 )-.
    [741] Even more preferred compounds of formula IVa have at least one of the features selected from the group consisting of, more preferably all of these features:
    [742] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, mor Polyyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted Selected from phenyl and methoxymethyl; Or R x and R y , together with their insertion atoms, form a benzo, pyrido, piperidino or cyclohex ring, wherein the ring is —halo, —R, —OR, —COR, —CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R or -SO 2 N (R 4 ) 2 , wherein R is hydrogen or an optionally substituted C 1-6 aliphatic group;
    [743] (b) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, which is —halo, —CN, —NO 2 , —N (R 4 ) 2 , optionally substituted C 1-6 aliphatic, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N ( R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 optionally substituted with one or two groups selected from];
    [744] (c) R 2 is hydrogen and a substituted or unsubstituted group selected from aryl, heteroaryl and C 1-6 aliphatic groups and R 2 ′ is hydrogen;
    [745] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [746] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
    [747] Representative compounds of Formula IVa are shown in Table 9 below:
    [748]
    [749] In another embodiment, the present invention provides a composition comprising a compound of Formula IVa and a pharmaceutically acceptable carrier.
    [750] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IVa or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing the Aurora-2 mediated disease using an Aurora-2 inhibitor. It is about a method.
    [751] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IVa or a composition comprising such a compound.
    [752] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IVa or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [753] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering a therapeutically effective amount of a compound of Formula IVa or a pharmaceutical composition thereof to a patient in need thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [754] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IVa or a composition comprising such a compound.
    [755] Another method includes contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula IVa, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. It relates to a method of inhibiting -2 or GSK-3 activity.
    [756] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for the treatment of ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula IVa as mentioned above.
    [757] Another aspect of the invention is a compound of Formula IVb, or a pharmaceutically acceptable derivative or prodrug thereof:
    [758]
    [759] In the above formula,
    [760] Z 1 is nitrogen or CR 8 ,
    [761] Z 2 is nitrogen or CH, wherein one of Z 1 and Z 2 is nitrogen;
    [762] R x and R y are independently selected from TR 3 and LZR 3 , or R x and R y together with their insertion atoms are fused unsaturated having 0 to 3 ring hetero atoms selected from oxygen, sulfur and nitrogen or Forms a partially unsaturated 5-7 membered ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is independently substituted by oxo, TR 3 or LZR 3 , and R x and R y Each substitutable ring nitrogen of the ring formed by is independently substituted by R 4 ;
    [763] R 1 is T- (ring D);
    [764] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [765] T is a valence bond or a C 1-4 alkylidene chain;
    [766] Z is a C 1-4 alkylidene chain;
    [767] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [768] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [769] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [770] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [771] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [772] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [773] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [774] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [775] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [776] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [777] R 8 is -R, -halo, -OR, -C (= 0) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 .
    [778] Preferred rings formed by R x and R y in Formula IVb include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 hetero atoms, which R x / R y rings are optionally substituted. This provides a bicyclic ring system containing pyrimidine rings. Examples of preferred pyrimidine ring systems of formula IVb are shown below:
    [779]
    [780]
    [781] More preferred pyrimidine ring systems of formula IVb include IVb-A, IVb-B, IVb-D, IVb-E, IVb-J, IVb-P and IVb-V, most preferably IVb-A, IVb-B, IVb-D, IVb-E and IVb-J. Even more preferred pyrimidine ring systems of formula IVb are the abovementioned compounds wherein Z 1 is nitrogen and Z 2 is CH.
    [782] Preferred R x groups of formula IVb include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or isopropyl.
    [783] Preferred R y groups of formula IVb include TR 3 or LZR 3 , wherein T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [784] Rings formed by R x and R y groups of Formula IVb may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [785] The R 2 and R 2 ′ groups of formula IVb may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are illustrated in the following formula IVb compounds having pyrazole containing bicyclic ring systems:
    [786]
    [787] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IVb include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [788] When the pyrazole ring system of formula IVb is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [789] When ring D of formula IVb is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [790] When ring D of formula IVb is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [791] Preferred TR 5 or VZR 5 substituents on ring D of Formula IVb include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [792] When present, preferred R 8 groups of formula IVb include R, OR and N (R 4 ) 2 . Examples of preferred R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 O, (piperidine- 1-yl) CH 2 CH 2 O and NH 2 CH 2 CH 2 O.
    [793] Preferred compounds of formula IVb have at least one, more preferably all of these features selected from the group consisting of:
    [794] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group, R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene and R 3 is -R, -N (R 4 ) 2 or -OR]; Or R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 6 membered ring having 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [795] (b) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    [796] (c) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [797] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [798] More preferred compounds of formula IVb have at least one of the features selected from the group consisting of, more preferably all of these features:
    [799] (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is hydrogen, C 1-6 Aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl]; Or together with the insertion atoms of R x and R y guides form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring, wherein the formed by R x and R y Each substitutable ring carbon of the fused ring is independently substituted by oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently substituted by R 4 ;
    [800] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [801] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [802] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl and 5-6 membered Selected from heterocyclic, L is -O-, -S- or -N (R 4 )-.
    [803] Even more preferred compounds of formula IVb have at least one of the features selected from the group consisting of, more preferably all of these features:
    [804] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, mor Polyyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted Selected from phenyl and methoxymethyl; Or R x and R y , together with their insertion atoms, form a benzo, pyrido, piperidino or cyclohex ring, wherein the ring is —halo, —R, —OR, —COR, —CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R or -SO 2 N (R 4 ) 2 , wherein R is hydrogen or an optionally substituted C 1-6 aliphatic group;
    [805] (b) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, which is —halo, —CN, —NO 2 , —N (R 4 ) 2 , optionally substituted C 1-6 aliphatic, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N ( R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 optionally substituted with one or two groups selected from];
    [806] (c) R 2 is hydrogen and a substituted or unsubstituted group selected from aryl, heteroaryl and C 1-6 aliphatic groups and R 2 ′ is hydrogen;
    [807] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [808] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 or -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring.
    [809] Representative compounds of Formula IVb are shown in Table 10 below:
    [810]
    [811]
    [812] In another embodiment, the present invention provides a composition comprising a compound of Formula IVb and a pharmaceutically acceptable carrier.
    [813] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IVb or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing Aurora-2 mediated diseases using Aurora-2 inhibitors. It is about a method.
    [814] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IVb or a composition comprising such a compound.
    [815] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IVb or a pharmaceutical composition thereof It is about how to.
    [816] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IVb or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [817] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IVb or a composition comprising such a compound.
    [818] Another method includes contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula IVb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3, It relates to a method of inhibiting -2 or GSK-3 activity.
    [819] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for the treatment of ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula IVb as mentioned above.
    [820] Another aspect of the invention is a compound of Formula IVc, or a pharmaceutically acceptable derivative or prodrug thereof:
    [821]
    [822] In the above formula,
    [823] Z 1 is nitrogen or CR 8 ,
    [824] Z 2 is nitrogen or CH, wherein one of Z 1 and Z 2 is nitrogen;
    [825] R x and R y are independently selected from TR 3 and LZR 3 , or R x and R y together with their insertion atoms are fused unsaturated having 0 to 3 ring hetero atoms selected from oxygen, sulfur and nitrogen or Forms a partially unsaturated 5-7 membered ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is independently substituted by oxo, TR 3 or LZR 3 , and R x and R y Each substitutable ring nitrogen of the ring formed by is independently substituted by R 4 ;
    [826] R 1 is T- (ring D);
    [827] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [828] T is a valence bond or a C 1-4 alkylidene chain;
    [829] Z is a C 1-4 alkylidene chain;
    [830] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [831] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [832] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [833] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [834] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [835] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [836] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [837] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [838] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [839] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [840] R 8 is -R, -halo, -OR, -C (= 0) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 .
    [841] Preferred rings formed by R x and R y of Formula IVc include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred pyridine ring systems of formula IVc are shown below:
    [842]
    [843]
    [844] More preferred pyridine ring systems of formula IVc include IVc-A, IVc-B, IVc-D, IVc-E, IVc-J, IVc-P and IVc-V, most preferably IVc-A, IVc-B, IVc -D, IVc-E and IVc-J. Even more preferred pyridine ring systems of formula IVc are the abovementioned compounds wherein Z 1 is nitrogen and Z 2 is CH.
    [845] Preferred R x groups of formula IVc include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups such as methyl, ethyl, cyclopropyl or isopropyl.
    [846] Preferred R y groups of formula IVc include TR 3 or LZR 3 [where T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [847] Rings formed by R x and R y groups of Formula IVc may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [848] The R 2 and R 2 ′ groups of formula IVc may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following formula IVc compounds having pyrazole containing bicyclic ring systems:
    [849]
    [850] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IVc include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [851] When the pyrazole ring system of formula IVc is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [852] When ring D of formula IVc is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [853] When ring D of formula IVc is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindoleyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [854] Preferred TR 5 or VZR 5 substituents on ring D of Formula IVc include -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [855] When present, preferred R 8 groups of formula IVc include R, OR and N (R 4 ) 2 . Examples of preferred R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 O, (piperidine- 1-yl) CH 2 CH 2 O and NH 2 CH 2 CH 2 O.
    [856] Preferred compounds of formula IVc have at least one of the features selected from the group consisting of, more preferably all of these features:
    [857] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group, R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene and R 3 is -R, -N (R 4 ) 2 or -OR]; Or R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 6 membered ring having 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Substituted with;
    [858] (b) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    [859] (c) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [860] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [861] More preferred compounds of formula IVc have one or more of the features selected from the group consisting of: more preferably all of these features:
    [862] (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is hydrogen, C 1-6 Aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl]; Or R x and R y together with their insertion atoms form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring, wherein R x and R y Each substitutable ring carbon of the fused ring formed is independently substituted by oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently substituted by R 4 Become;
    [863] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [864] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [865] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl and 5-6 membered Selected from heterocyclic, L is -O-, -S- or -N (R 4 )-.
    [866] Even more preferred compounds of formula IVc have one or more of the features selected from the group consisting of, more preferably all of these features:
    [867] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, mor Polyyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted Selected from phenyl and methoxymethyl; Or R x and R y , together with their insertion atoms, form a benzo, pyrido, piperidino or cyclohex ring, wherein the ring is —halo, —R, —OR, —COR, —CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R or -SO 2 N (R 4 ) 2 , wherein R is hydrogen or an optionally substituted C 1-6 aliphatic group;
    [868] (b) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, which is —halo, —CN, —NO 2 , —N (R 4 ) 2 , optionally substituted C 1-6 aliphatic, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N ( R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 optionally substituted with one or two groups selected from];
    [869] (c) R 2 is hydrogen and a substituted or unsubstituted group selected from aryl, heteroaryl and C 1-6 aliphatic groups and R 2 ′ is hydrogen;
    [870] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [871] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
    [872] Representative compounds of Formula IVc are shown in Table 11 below:
    [873]
    [874] In another embodiment, the present invention provides a composition comprising a compound of Formula IVc and a pharmaceutically acceptable carrier.
    [875] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IVc or a pharmaceutical composition thereof to a patient in need thereof, thereby treating or preventing Aurora-2 mediated diseases using Aurora-2 inhibitors. It is about a method.
    [876] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IVc or a composition comprising such a compound.
    [877] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IVc or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [878] One aspect of the invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering a therapeutically effective amount of a compound of Formula IVc or a pharmaceutical composition thereof to a patient in need thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [879] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IVc or a composition comprising such a compound.
    [880] Another method includes contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula IVc, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. It relates to a method of inhibiting -2 or GSK-3 activity.
    [881] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for treating ameliorated diseases thereby, are preferably carried out using the preferred compounds of formula IVc as mentioned above.
    [882] Another aspect of the invention is a compound of Formula IVd, or a pharmaceutically acceptable derivative or prodrug thereof:
    [883]
    [884] In the above formula,
    [885] Z 1 is nitrogen or CR 8 ,
    [886] Z 2 is nitrogen or CH, wherein one of Z 1 and Z 2 is nitrogen;
    [887] Q 'is selected from -C (R 6' ) 2- , 1,2-cyclopropanediyl, 1,2-cyclobutanediyl and 1,3-cyclobutanediyl;
    [888] R x and R y are independently selected from TR 3 and LZR 3 , or R x and R y together with their insertion atoms are fused unsaturated having 0 to 3 ring hetero atoms selected from oxygen, sulfur and nitrogen or Forms a partially unsaturated 5-7 membered ring, wherein each substitutable ring carbon of the fused ring formed by R x and R y is independently substituted by oxo, TR 3 or LZR 3 , and R x and R y Each substitutable ring nitrogen of the ring formed by is independently substituted by R 4 ;
    [889] R 1 is T- (ring D);
    [890] Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    [891] T is a valence bond or a C 1-4 alkylidene chain, wherein if Q 'is -C (R 6' ) 2- , the methylene group of the C 1-4 alkylidene chain is -O-, -S-,- N (R 4 )-, -CO-, -CONH-, -NHCO-, -SO 2- , -SO 2 NH-, -NHSO 2- , -CO 2- , -OC (O)-, -OC ( O) NH- or -NHCO 2 -optionally substituted;
    [892] Z is a C 1-4 alkylidene chain;
    [893] L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [894] R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    [895] R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    [896] R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    [897] R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    [898] R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    [899] V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    [900] W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    [901] Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    [902] Each R 6 ′ is independently selected from hydrogen and a C 1-4 aliphatic group, or two R 6 ′ on the same carbon atom together form a 3-6 membered carbocyclic ring;
    [903] Each R 7 is independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring;
    [904] R 8 is -R, -halo, -OR, -C (= 0) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 .
    [905] Preferred rings formed by R x and R y of Formula IVd include 5, 6 or 7 membered unsaturated or partially unsaturated rings having 0 to 2 heteroatoms, which R x / R y rings are optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred pyridine ring systems of formula IVd are shown below:
    [906]
    [907] More preferred pyridine ring systems of formula IVd include IVd-A, IVd-B, IVd-D, IVd-E, IVd-J, IVd-P and IVd-V, most preferably IVd-A, IVd-B, IVd -D, IVd-E and IVd-J. Even more preferred pyridine ring systems of formula IVd are the abovementioned compounds wherein Z 1 is nitrogen and Z 2 is CH.
    [908] Preferred R x groups of formula IVd include hydrogen, alkyl- or dialkylamino, acetamido, or C 1-4 aliphatic groups, for example methyl, ethyl, cyclopropyl or isopropyl.
    [909] Preferred R y groups of formula IVd include TR 3 or LZR 3 , wherein T is a valence bond or methylene and L is —O—, —S—, —C (R 6 ) 2 O—, —CO— or —N (R 4 )-, wherein R 3 is -R, -N (R 4 ) 2 or -OR]. Preferred R y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl; Alkoxyalkylamino such as methoxyethylamino; Alkoxyalkyl such as methoxymethyl or methoxyethyl; Alkyl- or dialkylamino such as ethylamino or dimethylamino; Alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; Acetamido; And optionally substituted phenyl such as phenyl or halo-substituted phenyl.
    [910] Rings formed by R x and R y groups of Formula IVd may be substituted or unsubstituted. Suitable substituents include -R, -halo, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -OR, -N (R 4 )-(CH 2 ) 2-4 -N (R 4 ) 2 , -N (R 4 )-(CH 2 ) 2-4 -R, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R or -OC ( = O) N (R 4 ) 2 , wherein R and R 4 are as defined above. Preferred R x / R y ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R, -SO 2 N (R 4 ) 2 [where , R is hydrogen or an optionally substituted C 1-6 aliphatic group.
    [911] The R 2 and R 2 ′ groups of formula IVd may form a fused ring together to provide a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and partially unsaturated six-membered carbocyclo rings. These are exemplified by the following compound of formula IVd having a pyrazole containing bicyclic ring system:
    [912]
    [913] Preferred substituents on the R 2 / R 2 ′ fused ring of formula IVd include one or more of the following: -halo, -N (R 4 ) 2 , -C 1-4 alkyl, -C 1-4 haloalkyl,- NO 2 , -O (C 1-4 alkyl), -CO 2 (C 1-4 alkyl), -CN, -SO 2 (C 1-4 alkyl), -SO 2 NH 2 , -OC (O) NH 2 , -NH 2 SO 2 (C 1-4 alkyl), -NHC (O) (C 1-4 alkyl), -C (O) NH 2 and -CO (C 1-4 alkyl) [where (C 1-4 alkyl) is a straight, branched or cyclic alkyl group. Preferably, the (C 1-4 alkyl) group is methyl.
    [914] When the pyrazole ring system of formula IVd is monocyclic, preferred R 2 groups include hydrogen and substituted or unsubstituted groups selected from aryl, heteroaryl and C 1-6 aliphatic groups. Examples of such preferred R 2 substituents are H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. Preferred R 2 ' group is hydrogen.
    [915] When ring D of formula IVd is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
    [916] When ring D of formula IVd is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, Benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl Included.
    [917] Preferred TR 5 or VZR 5 substituents on ring D of Formula IVd include —halo, —CN, —NO 2 , —N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, —OR, —C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 , and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt, -NHCOCH 2 NHCH 3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 N (CH 3 ) 2 , -NHCOCH 2 CH 2 CH 2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 (morpholin-4-yl), -NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), -NHCO 2 (t-butyl), -NH (C 1-4 aliphatic), yes For example, -NHMe, -N (C 1-4 aliphatic) 2 , for example -NMe 2 , OH, -O (C 1-4 aliphatic), for example -OMe, C 1-4 aliphatic, For example methyl, ethyl, cyclopropyl, isopropyl or t-butyl, and -CO 2 (C 1-4 aliphatic).
    [918] When present, preferred R 8 groups of formula IVd include R, OR and N (R 4 ) 2 . Examples of preferred R 8 include methyl, ethyl, NH 2 , NH 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 NH, N (CH 3 ) 2 CH 2 CH 2 O, (piperidine- 1-yl) CH 2 CH 2 O and NH 2 CH 2 CH 2 O.
    [919] Preferred Q 'groups of formula IVd include -C (R 6' ) 2 -or 1,2-cyclopropanediyl, wherein R 6 ' is each independently selected from hydrogen and methyl. More preferred Q 'group is -CH 2- .
    [920] Preferred compounds of formula IVd have at least one of the features selected from the group consisting of, more preferably all of these features:
    [921] (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group, R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene and R 3 is -R, -N (R 4 ) 2 or -OR]; Or R x and R y , together with their insertion atoms, form a fused unsaturated or partially unsaturated 5 to 6 membered ring having 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein R x and R y Each substitutable ring carbon of the fused ring formed by is independently substituted with oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently defined by R 4 Is substituted with;
    [922] (b) R 1 is T- (ring D), where T is a valence bond or a methylene unit, which methylene unit is optionally replaced by -O-, -NH- or -S-;
    [923] (c) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [924] (d) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [925] More preferred compounds of formula IVd have at least one of the features selected from the group consisting of, more preferably all of these features:
    [926] (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , and R is hydrogen, C 1-6 Aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl]; Or together with the insertion atoms of R x and R y guides form a benzo, pyrido, cyclopento, cyclohex, cyclohepto, thieno, piperidino or imidazo ring, wherein the formed by R x and R y Each substitutable ring carbon of the fused ring is independently substituted by oxo, TR 3 or LZR 3 , and each substitutable ring nitrogen of the ring formed by R x and R y is independently substituted by R 4 ;
    [927] (b) R 1 is T- (ring D), wherein T is a valence bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    [928] (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    [929] (d) R 3 is selected from -R, -halo, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl and 5-6 membered Is selected from heterocyclic, L is -O-, -S- or -N (R 4 )-;
    [930] (e) Q 'is -C (R 6' ) 2 -or 1,2-cyclopropanediyl, wherein R 6 ' is each independently selected from hydrogen and methyl.
    [931] Even more preferred compounds of formula IVd have at least one of the features selected from the group consisting of, more preferably all of these features:
    [932] (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, mor Polyyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted Selected from phenyl and methoxymethyl; Or R x and R y , together with their insertion atoms, form a benzo, pyrido, piperidino or cyclohex ring, wherein the ring is —halo, —R, —OR, —COR, —CO 2 R, -CON (R 4 ) 2 , -CN, -O (CH 2 ) 2-4 -N (R 4 ) 2 , -O (CH 2 ) 2-4 -R, -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4 SO 2 R or -SO 2 N (R 4 ) 2 , wherein R is hydrogen or an optionally substituted C 1-6 aliphatic group;
    [933] (b) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, which is —halo, —CN, —NO 2 , —N (R 4 ) 2 , optionally substituted C 1-6 aliphatic, -OR, -C (O) R, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N ( R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 optionally substituted with one or two groups selected from];
    [934] (c) R 2 is hydrogen and a substituted or unsubstituted group selected from aryl, heteroaryl and C 1-6 aliphatic groups and R 2 ′ is hydrogen;
    [935] (d) R 3 is selected from -R, -OR and -N (R 4 ) 2 , wherein R is hydrogen, C 1-6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl Are selected from L and -O-, -S- or -NH-;
    [936] (e) ring D is -halo, -CN, -NO 2 , -N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -C (O) R, -CO 2 R,- CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 , wherein R is hydrogen , C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, and a 5-6 membered heterocyclic ring;
    [937] (f) Q 'is -CH 2- .
    [938] Representative compounds of Formula IVd are shown in Table 12 below:
    [939]
    [940] In another embodiment, the present invention provides a composition comprising a compound of Formula IVd and a pharmaceutically acceptable carrier.
    [941] Another aspect of the invention involves administering a therapeutically effective amount of a compound of Formula IVd or a pharmaceutical composition thereof to a patient in need thereof, using a Aurora-2 inhibitor to treat or prevent an Aurora-2 mediated disease. It is about a method.
    [942] Another aspect of the invention relates to a method of inhibiting Aurora-2 activity in such a patient, comprising administering to the patient a compound of Formula IVd or a composition comprising such compound.
    [943] Another aspect of the invention involves treating or preventing a GSK-3-mediated disease using a GSK-3 inhibitor, comprising administering a therapeutically effective amount of a compound of Formula IVd or a pharmaceutical composition thereof to a patient in need thereof. It is about how to.
    [944] One aspect of the invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose levels in such patients, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition thereof. It is about. This method is particularly useful for diabetics. Another method is to inhibit the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing the progression of Alzheimer's disease. Another method is to inhibit the phosphorylation of β-catenin, which is useful for treating schizophrenia.
    [945] Another aspect of the invention relates to a method of inhibiting GSK-3 activity in such a patient, comprising administering to the patient a compound of Formula IVd or a composition comprising such a compound.
    [946] Another method comprises contacting a biological sample with an Aurora-2 or GSK-3 inhibitor of Formula IVd, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3, It relates to a method of inhibiting -2 or GSK-3 activity.
    [947] Each of the methods described above with respect to the inhibition of Aurora-2 or GSK-3, or the methods for the treatment of the alleviated diseases thereby, are preferably carried out using the preferred compounds of formula IVd as mentioned above.
    [948] Compounds of the present invention can generally be prepared by methods known to those skilled in the art for analogous compounds, as illustrated by the following Schemes I-VII, the following general methods, and the following preparation examples.
    [949]
    [950] Reagents: (a) EtOH, Et 3 N, room temperature; (b) R 1 -QH (Q = S, NH or O) or R 1 -CH 2 -M / catalyst (M is Al, Mg or Sn and the catalyst is Pd 0 or Ni 0 ).
    [951] Scheme I sets forth a general route for preparing compounds of the present invention. Dichlorination starting materials (1) are described in J. Indian. Chem. Soc., 61, 690-693 (1984) or J. Med. Chem., 37, 3828-3833 (1994), can be prepared using methods analogous to those reported. (1), supra, see Bioorg. Med. Chem. Lett, 10, 11, 1175-1180, (2000) or J. Het. Chem, 21, 1161-1167, (1984) to react with aminopyrazole (or aminoindazole) (2) in the manner as described to provide various monochloro intermediates (3). The conditions for translating the chloro group of (3) to R 1 -Q will depend on the nature of the Q linker moiety, which is generally known in the art. See J. Med. Chem, 38, 14, 2763-2773, (1995), where Q is an N-linker, Chem. Parm. Bull., 40, 1, 227-229, (1992), where Q is an S-linker, J. Het. Chem., 21, 1161-1167, (1984), where Q is a 0-linker or Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998), where Q is a C-linker].
    [952]
    [953] Reagents: (a) POCl 3 , Pr 3 N, 110 ° C .; (b) EtOH, Et 3 N, room temperature.
    [954] Scheme II shows another route for preparing compounds of the present invention. Starting material (4) can be prepared in a similar manner as described for cognate compounds. See Chem. Heterocycl. Compd., 35, 7, 818-820 (1999), where Q is an N-linker, Indian J. Chem. Sect. B, 22, 1, 37-42 (1983), where Q is an N-linker, Pestic. Sci, 47, 2, 103-114 (1996), where Q is a 0-linker, J. Med. Chem., 23, 8, 913-918 (1980) (where Q is an S-linker), or Pharmazie, 43, 7, 475-476 (1988) (where Q is a C-linker)] . Chlorination of (4) gives an intermediate (5). J. Med. Chem., 43, 22, 4288-4312 (2000), where Q is an N-linker, Pestic. Sci, 47, 2, 103-114 (1996), where Q is a 0-linker, J. Med. Chem., 41, 20, 3793-3803 (1998), wherein Q is an S-linker, or J. Med. Chem., 43, 22, 4288-4312 (2000), where Q is a C-linker. Transitioning the 4-Cl group in the intermediate (5) to aminopyrazole (or aminoindazole) (2) to provide the compound of the present invention can be carried out according to a known method for cognate compounds. J. Med. Chem., 38, 14, 2763-2773 (1995), where Q is an N-linker, Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997), where Q is an O-linker, Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000), where Q is an S-linker, or J. Med. Chem., 41, 21, 4021-4035 (1998), where Q is a C-linker].
    [955]
    [956] Reagent: (a) POCl 3 ; (b) EtOH, Et 3 N, room temperature; (c) oxone; (d) R 1 -QH (Q = S, NH or O) or R 1 -CH 2 -M / catalyst (M is Al, Mg or Sn and the catalyst is Pd 0 or Ni 0 ).
    [957] Scheme III shows another alternative route for preparing compounds of the present invention. The starting material 6 can be chlorinated to provide the intermediate 7. The 4-chloro group in (7) was transposed to aminopyrazole (or aminoindazole) (2) to obtain an intermediate (8), and then the methylsulfanyl group was oxidized to give methylsulfone (9). do. This methylsulfonyl group of (9) can be easily transposed to R 1 -OH to afford the desired product I. See J. Am. Chem. Soc., 81, 5997-6006 (1959) (where Q is an N-linker) or Bioorg. Med. Chem. Lett., 10, 8, 821-826 (2000), where Q is an S-linker.
    [958]
    [959] Reagent: (a) POCl 3 ; (b) EtOH, Et 3 N, room temperature; (c) R y -H (R = S, NH or O); (d) oxone; (e) R 1 -QH (Q = S, NH or O) or R 1 -CH 2 -M / catalyst (M is Al, Mg or Sn and the catalyst is Pd 0 or Ni 0 ).
    [960] Scheme IV sets forth a general route for the preparation of compounds of the invention wherein R y is a group attached to the pyrimidine core via nitrogen, oxygen or sulfur heteroatoms. Starting material 4,6-dihydroxy-2-methylsulfanylpyrimidine 10 is described in J. Med. Chem., 27, 12, 1621-1629 (1984). The chloro group of intermediate (11) is translocated to aminopyrazole (or aminoindazole) (2) and then sequentially transposed to another amine (or alcohol or thiol), followed by US Pat. No. 2,585,906 (ICI, A procedure similar to that reported in 1949 is performed. The methylsulfanyl group of (13) may then be oxidized to provide methylsulfon (14). This methylsulfonyl group of (14) is transposed to give the desired product II.
    [961]
    [962] Scheme V shows a general route for preparing compounds of Formulas IVa, IVb, IVc and IVd. Steps (a) and (b) are similar to the corresponding steps described in Scheme I above. See Indian J. Chem., Sect. B, 34, 9, 1995, 778-790; J. Chem. Soc., 1947, 899-905; J. Chem. Soc., 34, 9, 1948, 777-782; Indian J. Chem., 1967, 467-470.
    [963] The synthetic transformations presented in Schemes I-IV above are further illustrated by the following method.
    [964]
    [965] Scheme VI shows a general route for preparing aryl guanidine intermediates used to prepare compounds wherein Q is —C (R 6 ′ ) 2 —. Mono-alkylation and bis-alkylation of (19) in step (a) to prepare compound (20) can be accomplished by using methods substantially similar to those described in the following references: Jeffery, JE, et al, J. Chem Soc, Perkin Trans 1, 1996 (21) 2583-2589; Gnecco, D., et al, Org Prep Proced Int, 1996, 28 (4), 478-480; Fedorynski, M. and Jonczyk, A., Org Prep Proced Int, 1995, 27 (3), 355-359; Suzuki, S, et al, Can J Chem, 1994, 71 (2) 357-361; Prasad, G., et al, J Org Chem, 1991, (25), 7188-7190. The method of step (b) for preparing compound (21) from compound (20) can be achieved by using a method substantially similar to that described in Moss, R., et al, Tetrahedron Lett, 1995, (48), 8761-8764; Garigipati, R., Tetrahedron Lett, 1990, (14), 1969-1972].
    [966] Subsequently, using the aryl guanidine intermediate prepared according to Scheme VI, the compounds of the present invention can be prepared by the methods described in Schemes I-V and by methods known to those skilled in the art.
    [967]
    [968] Scheme VII shows a general method that can be used to prepare compounds of formula II wherein Q is 1,2-cyclopropanediyl. Then, using compound (26), the desired amino-pyrazole compound can be prepared using the process mentioned above in Scheme I step (b).
    [969] Method A: Triethylamine (8.13 ml, 63 mmol) was added to a solution of 2,4-dichloroquinazolin (12.69 g, 63 mmol) and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 ml). And the reaction mixture is stirred at room temperature for 3 hours. The pale yellow precipitate was then collected by filtration, washed with cold ethanol and dried under vacuum to afford (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine. To obtain.
    [970] Prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (155 mg, 0.6 mmol) and 3-chloroaniline (0.316 ml, 2.99 mmol) prepared above. Reflux in tert-butanol (3 ml) over 20 hours. The mixture is concentrated in vacuo and the residue is suspended in EtOH / H 2 O (1 ml / 3 ml). K 2 CO 3 (83 mg, 0.6 mmol) is added and the suspension is stirred at room temperature for 2 hours. The solid formed is collected and dried under vacuum to afford the product [2- (3-chlorophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine. .
    [971] Method B: Sodium hydride (45 mg, 1.12 mmol) in THF (2 ml) was treated with 3-methoxyphenol (0.94 g, 7.6 mmol) and the reaction mixture was stirred until foaming ceased. The THF was removed under vacuum and (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (150 mg, 0.51 mmol) prepared above was added. The reaction mixture is stirred at 100 ° C. for 20 hours, then poured into aqueous K 2 CO 3 and stirred at room temperature for 2 hours. The solid formed is collected and recrystallized from ethanol to give the product [2- (3-methoxyphenoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine To obtain.
    [972] Method C: To a solution of 4-hydroxy-2-phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus oxychloride (10 ml) was added tripropylamine (3.02 ml, 15.8 mmol) and the reaction mixture at 110 ° C. Heat for 30 minutes. Excess phosphorus oxychloride is evaporated in vacuo and the residue is poured into ice-cold aqueous NaHCO 3 phase and extracted with ethyl acetate. The organic layer is washed with brine, dried, filtered and evaporated. The resulting residue is purified by flash chromatography (SiO 2 , hexane / AcOEt gradient) to afford 4-chloro-2-phenoxymethylquinazoline.
    [973] To a solution of 4-chloro-2-phenoxymethylquinazoline (0.5 g, 1.85 mmol) in THF (30 ml) was added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69 mmol) and the reaction mixture was Heat at 65 ° C. for 24 hours. The solvent is evaporated and ethanol is added. A white solid is formed which is collected by filtration and dried under vacuum to afford (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl) -amine do.
    [974] Method D: NiCl in a solution of (2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (123 mg, 0.43 mmol) prepared above in THF (5 ml). 2 (dppp) (12 mg, 2.1.10 -5 mol) is added followed by 1M benzyl magnesium chloride (2.15 ml, 2.15 mmol) in THF. The solution is heated at 50 ° C. for 20 h, then the reaction mixture is quenched with aqueous NH 4 Cl and the product is extracted with ethyl acetate. The solvent is evaporated and the residue is purified by flash chromatography to afford the desired (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl) -amine.
    [975] Method E: (2-Chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) ) Is refluxed in tert-butanol (3 ml) over 20 hours. Diethyl ether (10 ml) is added to the mixture and the solid formed is collected by filtration. This solid is suspended in EtOH / H 2 O (1 ml / 3 ml), then K 2 CO 3 (110 mg, 0.8 mmol) is added and the suspension is stirred at room temperature for 2 hours. The solid that forms is collected and dried under vacuum to yield the product [2- (4-acetamidophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine To obtain.
    [976] Method F: of 2,4-dichloro-5,6,7,8-tetrahydroquinazolin (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 ml) Triethylamine (0.357 ml, 2.56 mmol) was added to the solution, followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture was heated at 90 ° C. for 20 hours. The reaction mixture is partitioned between ethyl acetate and aqueous saturated NaHCO 3 . The organic layer is washed with brine and evaporated in vacuo. The residue was purified by flash chromatography (SiO 2 , hexanes / AcOEt gradient) to afford (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazole 3-yl) -amine is obtained.
    [977] (2-Chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl) -amine prepared above as described in Method L. Reacted with 2-naphthalene mercaptan to give the desired (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -5,6,7,8-tetrahydroquina To obtain zolin-4-yl] -amine.
    [978] Method G: (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxycarbonylphenylsulfanyl) -quinazolin-4 in a mixture of THF / water (1/1, 10 ml) A solution of -yl] -amine (110 mg, 0.26 mmol) is treated with 1 M LiOH (0.75 ml, 0.75 mmol). The mixture is stirred at rt for 20 h and then neutralized with 1M HCl (0.75 ml, 0.75 mmol). The solid formed is collected by filtration to give the desired [2- (3-carboxyphenylsulfanyl) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine. .
    [979] Method H: [2- (4-acetamidophenylsulfanyl) -7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) in dichloroethane (3 ml) A solution of amine (23 mg, 5.54.10 -5 mol) is treated with 1M BBr 3 (222 μl, 2.21.10 -4 mol) in dichloromethane. The mixture is heated at 80 ° C. for 4 h, then 1M BBr 3 (222 μl, 2.21.10 −4 mol) in DCM is added. The reaction mixture is heated further at 80 ° C. for 3 hours. The solvent is evaporated and methanol is added to the residue to quench the residual BBr 3 . The solvent is evaporated in vacuo and this operation is repeated three times. 1M HCl (2 ml) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in mixture water / EtOH (3/1, 8 ml). The mixture is neutralized with NaHCO 3 and stirred at room temperature for 2 hours. The solid was then collected by filtration, washed with water and diethyl ether to afford the desired [2- (4-acetamidophenylsulfanyl) -7-hydroxy-quinazolin-4-yl]-(5-methyl -2H-pyrazol-3-yl) -amine is obtained.
    [980] Method I: [2- (4-acetamidophenylsulfanyl) -7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-in DMF (1 ml) To a solution of amine (32 mg, 7.87.10 -5 mol) is added potassium carbonate (65 mg, 4.72.10 -4 mol) and the reaction mixture is heated to 80 ° C. N- (3-chloropropyl) morpholine (39 mg, 2.36.10 -4 mol) is then added and the mixture is stirred at 80 ° C. for 4 hours, cooled to room temperature and the solvent is evaporated. The residue thus produced is purified by flash chromatography to obtain the desired [2- (4-acetamidophenylsulfanyl) -7- (3-morpholin-4-yl-propoxy) -quinazolin-4-yl] -(5-methyl-2H-pyrazol-3-yl) -amine is obtained.
    [981] Method J: [2- (4-acetamidophenylsulfanyl) -7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine in methanol (5 ml) Pd / C 10% (40 mg) is added to a solution of 147 mg, 3.38.10 -4 mol) and the reaction mixture is treated with hydrogen for 20 hours under a balun pressure of 45 ° C. The catalyst is filtered through a pad of celite and washed with dilute HCl. The combined yellow filtrate was evaporated and the resulting solid residue was crystallized from methanol to give the desired [2- (4-acetamidophenylsulfanyl) -7-hydroxyaminoquinazolin-4-yl]-(5-methyl -2H-pyrazol-3-yl) -amine is obtained.
    [982] Method K: [2- (4-acetamidophenylsulfanyl) -7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (182 mg, 4.18.10 -4 mol) is dissolved in the mixture EtOH / water / AcOH (25/10/1, 36 ml) and the reaction is heated at 90 ° C. Iron powder (93 mg) is added and the mixture is stirred at 90 ° C. for 4 hours, cooled to room temperature and filtered through a pad of celite. The pad is washed with methanol and the combined filtrates are concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 , DCM / MeOH gradient) to afford the desired [2- (4-acetamidophenylsulfanyl) -7-aminoquinazolin-4-yl]-(5-methyl-2H -Pyrazol-3-yl) -amine is obtained.
    [983] Method L: Triethylamine (195) in a solution of 2,4-dichloro-6-phenyl-pyrimidine (300 mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7 ml). Μl, 1.40 mmol) is added followed by sodium iodide (200 mg, 1.33 mmol) and the reaction mixture is heated at 90 ° C. for 15 h. The resulting solution is partitioned between ethyl acetate and water, the organic phase is washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was triturated in methanol and the resulting white solid was collected by filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (236 mg, 62%) is obtained.
    [984] (2-Chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (60 mg, 0.21 mmol) prepared above was tert-butanol (5 ml). In combination with 4-acetamidothiophenol (176 mg, 1.05 mmol), and the mixture is heated to reflux for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO 3 . The organic layer is washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO 2 , DCM / MeOH gradient) to give [2- (4-acetamidophenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl -2H-pyrazol-3-yl) -amine (74 mg, 85%) is obtained.
    [985] Method M: NaOH (2.33 g, 58.3 mmol) was added to a suspension of 4,6-dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture of EtOH / water (1/1, 140 ml), followed by 4-methoxy Benzyl chloride (7.90 ml, 58.3 mmol) is added. The solution is stirred at 60 ° C. for 1.5 hours and then for another 6 hours at room temperature. The resulting white precipitate is collected by filtration to give 4,6-dihydroxy-2- (4-methoxy-benzylsulfanyl) -pyrimidine.
    [986] 4,6-dihydroxy-2- (4-methoxy-benzylsulfanyl) -pyrimidine (2.5 g, 9.46 mmol) prepared above was suspended in POCl 3 (20 ml), tripropylamide (3.60 ml, 18.9 mmol) is added dropwise to the mixture. The reaction is then heated at 110 ° C. for 4 hours. The brown solution is cooled to room temperature and the solvent is evaporated. The residue is poured onto ice-cold NaHCO 3 phase and the product is extracted with ethyl acetate. The organic phase was dried over MgSO 4 , concentrated in vacuo and the residue was purified by flash chromatography (SiO 2 , hexanes / AcOEt gradient) to 4,6-dichloro-2 (4-methoxy-benzylsulfanyl)- Obtain pyrimidine.
    [987] 4,6-dichloro-2- (4-methoxy-benzylsulfanyl) -pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) prepared above in BuOH (20 ml) Diisopropylethylamine (0.56 ml, 3.19 mmol) was added to the solution of) followed by sodium iodide (455 mg, 3.04 mmol). The reaction mixture is stirred at 120 ° C. for 15 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO 2 , hexanes / AcOEt gradient) to [6-chloro-2- (4-methoxy-benzylsulfanyl) -pyrimidin-4-yl]- (5-methyl-2H-pyrazol-3-yl) -amine is obtained.
    [988] [6-Chloro-2- (4-methoxy-benzylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3-, prepared above in 1-methylpiperazine (10 ml) Il) -amine (500 mg, 1.38 mmol) is heated at 130 ° C. for 15 hours. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO 2 , dichloromethane / MeOH gradient) to afford the desired product [2- (4-methoxy-benzylsulfanyl) -6- (4-methylpipepe) Razin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine.
    [989] Method N: [2- (4-Acetamido-phenylsulfanyl) -6- (4-methoxyphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyra in dichloroethane (5 ml) A solution of sol-3-yl) -amine (100 mg, 2.24.10 -4 mol) is treated with 1M BBr 3 (896 μl, 8.96.10 -4 mol) in DCM. The mixture is heated at 80 ° C. for 4 hours, then 1M BBr 3 (896 μl, 8.96.10 −4 mol) in DCM is added. The reaction mixture is heated further at 80 ° C. for 3 hours. The solvent is evaporated and methanol is added to the residue to quench the residual BBr 3 . The solvent is evaporated in vacuo and this evaporation step is repeated three times. 1M HCl (8 ml) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water / EtOH (3/1, 24 ml). The mixture is neutralized with NaHCO 3 and stirred at room temperature for 2 hours. The solid was then collected by filtration and washed with water and diethyl ether to [2- (4-acetamidophenylsulfanyl) -6- (4-hydroxyphenyl) -pyrimidin-4-yl]-( 5-Methyl-2H-pyrazol-3-yl) -amine is obtained.
    [990] [2- (4-Acetamidophenylsulfanyl) -6- (4-hydroxyphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazole-) prepared above in DMF (3 ml). to a solution of the amine (70mg, 1.62.10 -4 mol) is potassium carbonate (134mg, 9.71.10 -4 mol) - 3- day). The reaction mixture is heated to 80 ° C. and then 1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10 -4 mol) is added. The mixture is stirred at 80 ° C. for 4 hours, cooled to room temperature and the solvent is evaporated. The residue was purified by flash chromatography to give the desired product {2- (4-acetamido-phenylsulfanyl) -6- [4- (3-dimethylaminopropoxy) -phenyl] -pyrimidin-4-yl}- (5-methyl-2H-pyrazol-3-yl) -amine is obtained.
    [991] Method O: [6-methoxycarbonyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3- in THF (100 ml) To a solution of yl) -amine (2 g, 4.85 mmol) lithium borohydride (0.32 g, 14.5 mmol) is added. The reaction mixture is stirred at 50 ° C. for 1.5 h. The reaction is then quenched with dilute HCl and extracted with ethyl acetate. The organic layer is washed successively with aqueous saturated NaHCO 3 and brine, dried over MgSO 4 and then evaporated. The solid residue was triturated in ethyl acetate and the resulting white solid was collected by filtration to give the desired product [6-hydroxymethyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl]- (5-methyl-2H-pyrazol-3-yl) -amine is obtained.
    [992] Method P: Diiso in a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole (2.61 g, 26.9 mmol) in BuOH (60 ml) Propylethylamine (4.69 ml, 26.9 mmol) is added followed by sodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred at 120 ° C. for 15 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO 2 , hexanes / AcOEt gradient) to [6-chloro-2-methylsulfanyl-pyrimidin-4-yl]-(5-methyl-2H- Obtain pyrazol-3-yl) -amine.
    [993] [6-Chloro-2-methylsulfanyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (2.42 g, 9.46 mmol) was prepared at 15 ° C. Heat in morpholine (10 ml) for hours. The solvent is then removed in vacuo, the solid residue is triturated in EtOH and filtered to collect [2-methylsulfanyl-6- (morpholin-4-yl) -pyrimidin-4-yl]-(5-methyl -2H-pyrazol-3-yl) -amine is obtained.
    [994] [2-Methylsulfanyl-6- (morpholin-4-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine prepared above in MeOH (10 ml) To a suspension of (500 mg, 1.63 mmol) is added a solution of oxone (3.0 g) in water (10 ml). The reaction mixture is stirred at room temperature for 15 hours and most of the solvent is evaporated. The residue is partitioned between DCM and aqueous saturated NaHCO 3 . The organic layer is washed with brine, dried, filtered and evaporated. The residue was triturated in MeOH and the resulting white solid was collected by filtration to [2-methylsulfanyl-6- (morpholin-4-yl) -pyrimidin-4-yl]-(5-methyl-2H- Obtain pyrazol-3-yl) -amine.
    [995] [2-Methylsulfanyl-6- (morpholin-4-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (178 mg, 0.52 mmol) ) And 4-acetamidothiophenol (176 mg, 1.05 mmol) are refluxed in tert-butanol (5 ml) for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO 3 . The organic layer is washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography to give the desired product [2- (4-acetamidophenylsulfanyl) -6- (morpholin-4-yl) -pyrimidin-4-yl]-(5-methyl-2H- Obtain pyrazol-3-yl) -amine.
    [996] In order to better understand the invention described herein, the following examples are presented. These examples are for illustrative purposes only, and thus the invention is not limited in any way.
    [997] Synthetic Example
    [998] The following HPLC method is used for the analysis of compounds as specified in the synthetic examples presented below. The term “R t ” as used herein refers to the retention time observed for this compound using the specified HPLC method.
    [999] HPLC-Method A:
    [1000] Column: C18, 3 μm, 2.1 × 50 mm, “Lighting” of Jones Chromatography.
    [1001] Gradient: Elution with 100% water (containing 1% acetonitrile, containing 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 4.0 minutes, hold with 100% acetonitrile for 1.4 minutes, then return to initial conditions. Return Total run time 7.0 minutes. Flow rate: 0.8 ml / min.
    [1002] HPLC-Method B:
    [1003] Column: C18, 5 μm, 4.6 × 150 mm, “Dynamax” from Rainin.
    [1004] Gradient: Elution with 100% water (1% acetonitrile, containing 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 20 minutes, hold with 100% acetonitrile for 7.0 minutes, then return to initial conditions. Return Total run time 31.5 minutes. Flow rate: 1.0 ml / min.
    [1005] HPLC-Method C:
    [1006] Column: Cyano, 5 μm, 4.6 × 150 mm, “Microsorb” by Varian.
    [1007] Gradient: Eluted with 99% water (0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA) over 20 minutes, 8.0 Hold for minutes, then return to initial conditions. Total run time 30 minutes. Flow rate: 1.0 ml / min.
    [1008] HPLC-Method D:
    [1009] Column: Waters (YMC) ODS-AQ 2.0 × 50 mm, S5, 120A.
    [1010] Gradient: Eluted with 90% water (0.2% formic acid), 10% acetonitrile (containing 0.1% formic acid) to 10% water (0.1% formic acid), 90% acetonitrile (containing 0.1% formic acid) over 5.0 minutes, 0.8 Hold for minutes, then return to initial conditions. Total run time 7.0 minutes. Flow rate: 1.0 ml / min.
    [1011] HPLC-Method E:
    [1012] Column: 50 × 2.0 mm Hypersil C18 BDS; 5 μm.
    [1013] Gradient: Elute with 100% water (0.1% TFA) to 5% water (0.1% TFA), 95% acetonitrile (containing 0.1% TFA) over 2.1 minutes and return to initial conditions after 2.3 minutes.
    [1014] Flow rate: 1 ml / min.
    [1015] Example 1 (5-Methyl-2H-pyrazol-3-yl)-(2-methylsulfanyl-quinazolin-4-yl) -amine (IIa-1): Prepared in a similar manner to Method E mentioned above To give a pale yellow solid. mp> 300 ° C. (decomposition); 1 H NMR (DMSO) δ 2.07 (3H, s), 5.54 (1H, s), 7.38 (1H, m), 7.56-7.45 (4H, m), 7.65 (2H, m), 7.73 (1H, m) 8.55 (1 H, d), 10.43 (1 H, s), 12.05 (1 H, br s); IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525, 1476; MS 334.0 (M + H) +
    [1016] Example 2 [2- (4-Chlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-2): Method E mentioned above Prepared in a similar manner to yield a pale yellow solid. mp 259-260 ° C; 1 H NMR (DMSO) δ 2.12 (3H, s), 5.40 (1H, s), 7.60 (1H, t), 7.64 (2H, d), 7.76 (3H, d), 7.92 (1H, t), 8.70 (1 H, d) 11.50 (1 H, br s); IR (solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339, 1286, 1219; MS 368.0 (M + H) +
    [1017] Example 3 [2- (2,4-Dichlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-3): mentioned above Prepared in a similar manner to Method E, to obtain a pale yellow solid. mp 258-259 ° C; 1 H NMR (DMSO) δ 2.12 (3H, s), 5.40 (1H, s), 7.54 (1H, t), 7.63 (1H, m), 7.68 (1H, d), 7.86 (1H, t), 7.92 (1H, d), 7.96 (1H, d), 8.66 (1H, d) 11.20 (1H, broad singlet); IR (solid) 1623, 1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 (M + H) +
    [1018] Example 4 [2- (4-methoxyphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-4): the above-mentioned method Prepared in a similar manner to E to give a pale yellow solid. mp 264-268 ° C; 1 H NMR (DMSO) δ 2.04 (3H, s), 3.85 (3H, s), 5.43 (1H, s), 7.12 (2H, d), 7.53 (1H, t), 7.61 (3H, d), 7.84 (3H, t), 8.63 (1H, d), 11.09 (1H, br s), 12.30 (1H, br s); IR (solid) 1622, 1598, 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171, 1161; MS 364.1 (M + H) +
    [1019] Example 5 [2- (2-ethylphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-5): Method E mentioned above Prepared in a similar manner to yield a pale yellow solid. mp 205-208 ° C; 1 H NMR (DMSO) δ 2.05 (3H, s), 5.19 (1H, s), 7.38 (1H, t), 7.52-7.64 (3H, m), 7.68 (2H, d), 7.90 (1H, t) , 8.68 (1 H, d); IR (solid) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344, 1294, 1224, 1162; MS 362.1 (M + H) +
    [1020] Example 6 {2- [2,4-bis (trifluoromethyl) phenylsulfanyl] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine (IIa- 6): Prepared in a similar manner to above-mentioned method E, to obtain a pale yellow solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 1.98 (3H, s), 5.37 (1H, s), 7.50 (1H, t), 7.59 (2H, d), 7.84 (1H, d), 8.32 (1H, s), 8.40 (2H, s), 8.66 (1H, d), 10.73 (1H, br s); IR (solid) 1628, 1603, 1577, 1548, 1512, 1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470.1 (M + H) +
    [1021] Example 7 [2- (2-Chlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-7): Method E mentioned above Prepared in a similar manner to yield a pale yellow solid. mp 262-263 ° C; 1 H NMR (DMSO) δ 2.05 (3H, s), 5.35 (1H, s), 7.52 (2H, t), 7.65 (2H, m), 7.74 (1H, d), 7.83 (1H, t), 7.88 (1H, d), 8.62 (1H, d), 10.97 (1H, br s); IR (solid) 1621, 1603, 1569, 1544, 1491, 1448, 1400, 1376, 1336, 1288, 1208; MS 368.0 (M + H) +
    [1022] Example 8 [2- (2,3-Dichlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-8): mentioned above Prepared in a similar manner to Method E, to obtain a pale yellow solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 2.05 (3H, s), 5.34 (1H, s), 7.50 (2H, m), 7.60 (1H, d), 7.75 (1H, t), 7.88 (2H, m), 8.62 (1 H, d), 10.72 (1 H, br s); IR (solid) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M + H) +
    [1023] Example 9 [2- (3-Chlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-9): Method E mentioned above Prepared in a similar manner to yield a pale yellow solid. mp 248-249 ° C .; 1 H NMR (DMSO) δ 2.05 (3H, s), 5.42 (1H, s), 7.55 (2H, m), 7.66 (3H, m), 7.81 (1H, s), 7.85 (1H, t), 8.62 (1H, d), 11.10 (1H, broad singlet); IR (solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292, 1217, 1165; MS 368.0 (M + H) +
    [1024] Example 10 [2- (1-Methylimidazol-2-ylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-10) : Prepared in a similar manner to Method E mentioned above to give an off-white solid. mp 255-256 ° C .; 1 H NMR (DMSO) δ 2.19 (3H, s), 3.59 (1H, s), 5.51 (1H, s), 7.18 (1H, s), 7.45 (1H, t), 7.57 (1H, s), 7.59 (1H, d), 7.77 (1H, t), 8.57 (1H, d), 10.57 (1H, s), 12.13 (1H, br s); IR (solid) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, 1278, 1211; MS 338.2 (M + H) +
    [1025] Example 11 [2- (2-hydroxyphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-11): the above-mentioned method Prepared in a similar manner to E to give a pale yellow solid. mp 273-275 ° C .; 1 H NMR (DMSO) δ 2.06 (3H, s), 5.41 (1H, s), 6.99 (1H, t), 7.07 (1H, d), 7.50 (1H, t), 7.57-7.62 (2H, m) , 7.73 (1 H, d), 7.94 (1 H, t), 8.71 (1 H, d), 10.29 (1 H, br s), 11.66 (1 H, br s); IR (solid) 1623, 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165; MS 350.1 (M + H) +
    [1026] Example 12 [2- (2,4-Difluorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-12): Prepared in a similar manner to Method E mentioned, to give a pale yellow solid. mp 256-258 ° C .; 1 H NMR (DMSO) 2.10 (3H, s), 5.41 (1H, s), 7.33 (1H, t), 7.51-7.58 (2H, m), 7.65 (1H, d), 7.82-7.91 (2H, m ), 8.63 (1 H, d), 11.06 (1 H, br s); IR (solid) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219,1162, 1140; MS 370.1 (M + H) +
    [1027] Example 13 [2- (3,4-Dimethoxyphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-13): alluded to above Prepared in a similar manner to Process E, whereby a pale yellow solid is obtained. mp 229-232 ° C; 1 H NMR (DMSO) δ 2.05 (3H, s), 3.70 (3H, s), 3.85 (3H, s), 5.39 (1H, s), 6.95 (1H, d), 7.30 (2H, d), 7.60 (1H, t), 7.77 (1H, d), 7.94 (1H, t), 8.72 (1H, d), 11.66 (1H, br s); IR (solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 1237, 1218, 1161, 1137; MS 394.1 (M + H) +
    [1028] Example 14 [2- (3-Methylphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-14): Prepared in a similar manner to yield a pale yellow solid. mp 249-250 ° C .; 1 H NMR (DMSO) δ 2.06 (3H, s), 2.36 (3H, s), 5.31 (1H, s), 7.45 (2H, d), 7.48-7.58 (3H, m), 7.61 (1H, d) , 7.88 (1 H, t), 8.68 (1 H, d), 11.66 (1 H, br s); IR (solid) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M + H) +
    [1029] Example 15 [2- (2-methoxyphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-15): the above-mentioned method Prepared in a similar manner to E to give a pale yellow solid. mp 237-239 ° C; 1 H NMR (DMSO) δ 2.07 (3H, s), 3.71 (3H, s), 5.35 (1H, s), 7.12 (1H, t), 7.23 (1H, d), 7.55 (1H, t), 7.60 -7.67 (3H, m), 7.87 (1H, t), 8.66 (1H, d), 11.20 (1H, br s); IR (solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS 364.1 (M + H) +
    [1030] Example 16 [2- (2-naphthalenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-16): the above-mentioned method Prepared in a similar manner to E to give a pale yellow solid. mp 267-270 ° C .; 1 H NMR (DMSO) δ 2.05 (3H, s), 5.09 (1H, s), 7.57 (1H, t), 7.62-7.75 (4H, m), 7.90 (1H, t), 8.07 (3H, t) , 8.40 (1 H, s), 8.66 (1 H, d), 11.28 (1 H, br s); IR (solid) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M + H) +
    [1031] Example 17 [2- (2,6-Dichlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-17): mentioned above Prepared in a similar manner to Method E to obtain a light brown solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 2.11 (3H, s), 5.49 (1H, s), 7.49 (1H, t), 7.59-7.67 (2H, m), 7.76 (2H, d), 7.81 (1H, d) , 8.60 (1 H, d), 10.60 (1 H, s); IR (solid) 1618, 1599, 1565, 1533, 1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M + H) +
    [1032] Example 18 [2- (3,4-Dichlorophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-18): mentioned above Prepared in a similar manner to Method E, to obtain a pale yellow solid. mp 268-272 ° C; 1 H NMR (DMSO) δ 2.11 (3H, s), 5.47 (1H, s), 7.56 (1H, t), 7.68-7.72 (2H, m), 7.83 (2H, d), 7.88 (1H, t) , 8.05 (1 H, d), 8.66 (1 H, d); IR (solid) 1628, 1607, 1556, 1488, 1436, 14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402.0 (M + H) +
    [1033] Example 19 [2- (benzimidazol-2-ylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-19): alluded to above Prepared in a similar manner to Process E, whereby a light gray solid is obtained. mp 192-196 ° C; 1 H NMR (DMSO) δ 1.60 (3H, s), 5.48 (1H, s), 7.44 (2H, m), 7.53 (1H, t), 7.69 (2H, d), 7.76 (2H, m), 7.85 (1H, t), 8.64 (1H, d), 10.79 (1H, s); IR (solid) 1618, 1606, 1569, 1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 (M + H) +
    [1034] Example 20 [2- (2-Aminophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-20): Method E mentioned above Prepared in a similar manner to yield a pale yellow solid. mp 257-259 ° C; 1 H NMR (DMSO) δ 2.11-2.30 (3H, 2xbr s), 6.10 (1H, br s), 7.10-7.80 (7H, m), 8.60 (1H, br s), 9.80 (1H, br s), 10.80 (1H, broad singlet); IR (solid) 1623, 1591, 1567, 1538, 1496, 1483, 1410, 1351
    [1035] Example 21 (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl) -amine (IIa-21): in a similar manner to Method E mentioned above To give a yellow solid. mp 233-236 ° C; 1 H NMR (DMSO) δ 0.89 (2H, d), 0.98 (2H, d), 1.67 (1H, m), 5.48 (1H, s), 7.54-7.73 (7H, m), 7.89 (1H, t) , 8.68 (1 H, d), 11.60 (1 H, br s); IR (solid) 1629, 1606, 1577, 1546, 1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360.3 (M + H) +
    [1036] Example 22 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxycarbonylphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-22): Preparation is carried out in a similar manner to the method E mentioned to obtain a white solid. mp 224-225 ° C .; 1 H NMR (DMSO) δ 0.52 (2H, m), 0.86 (2H, m), 1.67 (1H, m), 3.86 (3H, s), 5.60 (1H, s), 7.45 (1H, t), 7.56 (1H, d), 7.66 (1H, t), 7.76 (1H, t), 7.93 (1H, d), 8.10 (1H, d), 8.18 (1H, s), 8.57 (1H, d), 10.48 ( 1 H, br s), 12.07 (1 H, br s); IR (solid) 1724, 1617, 1593, 1567,1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS 418.3 (M + H) +
    [1037] Example 23 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methylphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-23): Method E mentioned above Prepared in a similar manner to yield a white solid. mp 241-243 ° C .; 1 H NMR (DMSO) δ 0.55-0.63 (2H, m), 1.87-1.97 (1H, m), 1.67-1.79 (1H, m), 2.35 (3H, s), 5.72 (1H, s), 7.30- 7.60 (6H, m), 7.68-7.78 (1H, m), 8.50-8.60 (1H, d), 10.38 (1H, s), 12.02 (1H, s); IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, 1344, 1287, 1176, 758, 665, 656; MS (M + H) +
    [1038] Example 24 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxyphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-24): mentioned above Prepared in a similar manner to Method E, to obtain a white solid. mp 232-234 ° C .; 1 H NMR (DMSO) δ 0.55-0.62 (2H, m), 0.88-0.97 (2H, m), 1.70-1.80 (1H, m), 3.79 (3H, s), 5.79 (1H, s), 7.08 ( 1H, d), 7.22-7.29 (2H, m), 7.40-7.50 (2H, m), 7.60 (1H, d), 7.79 (1H, t), 8.57 (1H, d), 10.40 (1H, s) , 12.04 (1 H, s); IR (solid) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1001, 969, 826, 761, 692, 667; MS (M + H) +
    [1039] Example 25 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3,4-dimethoxyphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-25): Preparation is carried out in a similar manner to the method E mentioned to obtain a white solid. mp 250-252 ° C .; 1 H NMR (DMSO) δ 0.54-0.60 (2H, m), 0.83-0.91 (2H, m), 1.68-1.77 (1H, m), 3.79 (3H, s), 3.85 (3H, s), 5.79 ( 1H, s), 7.10 (1H, d), 7.20-7.26 (2H, m), 7.45 (1H, t), 7.57 (1H, d), 7.77 (1H, t), 8.55 (1H, d), 10.45 (1 H, s), 12.04 (1 H, m); IR (solid) 1617, 1593, 1567, 1530, 1504, 1479, 1457, 1439, 1398, 1364, 1347, 1288, 1269, 1250, 1232, 1181, 1169, 1138, 1037, 1020, 997, 972, 882, 846, 804, 764, 750; MS (M + H) +
    [1040] Example 26 [2- (3-carboxyphenylsulfanyl) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-26): according to method G Prepared from IIa-22 to give a yellow solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 0.53 (2H, d), 0.86 (2H, d), 1.65 (1H, m), 5.37 (1H, s), 7.55 (1H, t), 7.68 (1H, t), 7.81 (1H, d), 7.88 (1H, t), 7.95 (1H, d), 8.15 (1H, d), 8.15 (1H, s), 8.71 (1H, d), 11.32 (1H, br s); IR (solid) 1702, 1626, 1609, 1559, 1490, 1412, 1355, 1293, 1222, 1170; MS 404.7 (M + H) +
    [1041] Example 27 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -quinazolin-4-yl] -amine (IIa-27): mentioned above Prepared in a similar manner to Method E to yield an off-white solid. mp 285-288 ° C; 1 H NMR (DMSO) δ 0.25 (2H, br s), 0.52 (2H, br s), 0.87 (1H, m), 5.54 (1H, br s), 7.42-7.77 (4H, m), 8.00 (3H , m), 8.30 (1 H, br s), 8.56 (1 H, br d), 10.42 and 11.88 (1 H, 2 x br s); IR (solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287, 1240, 1216, 1167, 1158, 1142, 1128, 996, 965; MS 410.7 (M + H) +
    [1042] Example 28 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (2,4-difluorophenylsulfanyl) -quinazolin-4-yl] -amine (IIa-28): Prepared in a similar manner to Method E mentioned above to give an off-white solid. mp 250-253 ° C .; 1 H NMR (DMSO) δ 0.61 (2H, m), 0.91 (2H, m), 1.74 (1H, m), 5.67 (1H, m), 7.24-7.28 (1H, m), 7.44-7.48 (3H, m), 7.53-7.81 (2H, brm), 8.55 (1H, m), 10.47 and 12.10 (1H, 2 x br s); IR (solid) 1614, 1598, 1565, 1525, 1479, 1423, 1398, 1366, 1345, 1285, 1267, 1243, 1213, 1168, 1143, 1114, 1026, 995, 968; MS 396.6 (M + H) +
    [1043] Example 29 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -5,6,7,8-tetrahydroquinazolin-4-yl]- Amine (IIa-29): Prepared in a similar manner to Method F mentioned above to give a white solid. mp 244 ° C .; 1 H NMR (DMSO) δ 0.13 (2H, s), 0.45 (2H, s), 0.79 (1H, s), 1.73 (4H, s), 2.42 (2H, s), 2.58 (2H, s), 5.28 (1H, s), 7.58 (2H, d), 7.61 (2H, d), 7.97 (3H, d), 8.23 (1H, s), 8.56 (1H, s), 11.63 (1H, s); IR (solid) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657, 651; MS 414.7 (M + H) +
    [1044] Example 30 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (2,3-dichlorophenylsulfanyl) -quinazolin-4-yl] -amine (IIa-30): alluded to above Prepared in a similar manner to Process E, whereby an off-white solid is obtained. mp 250-252 ° C .; 1 H NMR (DMSO) δ 0.60 (2H, d), 0.93 (2H, d), 1.70 (1H, m), 5.54 (1H, s), 7.47 (2H, m), 7.57 (1H, d), 7.76 (1H, t), 7.86 (2H, d), 8.57 (1H, d), 10.48 (1H, s), 12.04 (1H, s); IR (solid) 1616, 1601, 1570, 1528, 1486, 1432, 1400, 1367, 1335, 1285, 1246, 1210, 1159, 1146, 1051, 1033, 1021, 997; MS 428.6 (M + H) +
    [1045] Example 31 [2- (3-Chlorophenylsulfanyl) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-31): the above-mentioned method Prepared in a similar manner to E to give an off-white solid. mp 235-238 ° C; 1 H NMR (DMSO) δ 0.58 (2H, d), 0.92 (2H, d), 1.75 (1H, m), 5.71 (1H, s), 7.44 (1H, t), 7.50-7.63 (4H, m) , 7.73 (1 H, s), 7.75 (1 H, t), 8.57 (1 H, d), 10.46 (1 H, s), 12.08 (1 H, s); IR (solid) 1616, 1593, 1562, 1528, 1479, 1456, 1406, 1367, 1343, 1286, 1244, 1216, 1176, 1067, 1051, 997; MS 394.7 (M + H) +
    [1046] Example 32 [2- (2-Chlorophenylsulfanyl) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-32): the above-mentioned method Prepared in a similar manner to E to give an off-white solid. mp 255-257 ° C; 1 H NMR (DMSO) δ 0.59 (2H, d), 0.91 (2H, d), 1.71 (1H, m), 5.62 (1H, s), 7.45 (2H, m), 7.57 (1H, m), 7.69 (1H, d), 7.75 (1H, t), 7.85 (1H, d), 8.56 (1H, d), 10.43 (1H, s), 12.03 (1H, s); IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398, 1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, 1030, 997; MS 394.7 (M + H) +
    [1047] Example 33 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3,4-dimethylphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-33): alluded to above Prepared in a similar manner to Process E, whereby an off-white solid is obtained. mp 255-256 ° C .; 1 H NMR (DMSO) δ 0.56 (2H, m), 0.90 (2H, m), 1.67 (1H, m), 2.26 and 2.29 (6H, 2 xs), 5.75 (1H, br s), 7.26 (1H, m), 7.35-7.55 (4H, m), 7.74 (1H, m), 8.54 (1H, br s), 10.44 and 12.06 (2H, 2 x br s); IR (solid) 1617, 1596, 1569, 1526, 1479, 1459, 1404, 1366, 1343, 1287, 1243, 1218, 1167, 1145, 1017, 996, 966; MS 388.3 (M + H) +
    [1048] Example 34 [2- (benzimidazol-2-ylsulfanyl) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-34): Prepared in a similar manner to Method E mentioned, to give an off-white solid. mp 201-203 ° C; 1 H NMR (DMSO) δ 0.44 (2H, m), 0.71 (2H, m), 1.17 (1H, m), 5.72 (1H, m), 7.23 (2H, m), 7.51-7.81 (5H, m) , 8.59 (1H, m), 10.59, 12.06 and 13.17 (3H, 3 x br s); IR (solid) 1617, 1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024, 1010, 965; MS 400.2 (M + H) +
    [1049] Example 35 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (4-methoxycarbonylphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-35): Prepared in a similar manner to Method E mentioned, to give an off-white solid. mp 245-246 ° C .; 1 H NMR (DMSO) δ 0.47 (2H, br s), 0.80 (2H, br s), 1.62 (1H, m), 3.85 (3H, s), 5.69 (1H, br s), 7.46 (1H, m ), 7.58 (1H, m), 7.76-7.81 (3H, m), 8.02-8.05 (2H, m), 8.57 (1H, m), 10.48 and 12.11 (2H, 2 x br s); IR (solid) 1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435, 1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS 418.2 (M + H) +
    [1050] Example 36 [2- (4-acetamido-phenylsulfanyl) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-36): Prepared in a similar manner to Method E mentioned, to give an off-white solid. mp 239-241 ° C .; 1 H NMR (DMSO) δ 0.57 (2H, m), 0.83 (2H, m), 1.69 (1H, m), 2.02 (3H, s), 5.73 (1H, br s), 7.41 (1H, m), 7.53-7.57 (3H, m), 7.73-7.75 (3H, m), 8.54 (1H, m), 10.18, 10.39 and 11.98 (3H, 3 x br s); IR (solid) 1665, 1618, 1607, 1586, 1572, 1564, 1529, 1482, 1387, 1343, 1320, 1287, 1243, 1221, 1162, 1005, 968; MS 417.2 (M + H) +
    [1051] Example 37 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-1-ylsulfanyl) -quinazolin-4-yl] -amine (IIa-37): mentioned above Prepared in a similar manner to Method E to yield an off-white solid. mp 271-273 ° C .; 1 H NMR (DMSO) δ 0.46-0.47 (2H, m), 0.87-0.89 (2H, m), 1.57 (1H, m), 5.01 (1H, m), 7.42 (1H, m), 7.52-7.54 ( 3H, m), 7.64 (1H, m), 7.75 (1H, m), 7.98 (1H, m), 8.06 (1H, m), 8.17 (1H, m), 8.28 (1H, m), 8.50 (1H , m), 10.29 (1H, broad singlet), 11.84 (1H, broad singlet); IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362, 1343, 1285, 1242, 1219, 1173, 998, 963; MS 410.2 (M + H) +
    [1052] Example 38 [2- (4-acetamidophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-38): mentioned above Prepared in a similar manner to Method E, to obtain a white solid. mp 268-271 ° C; 1 H NMR (DMSO) δ 2.02 (3H, s), 2.09 (3H, s), 5.56 (1H, s), 7.40 (1H, t), 7.55 (3H, m), 7.75 (3H, d), 8.55 (1H, d), 10.21 (1H, s), 10.40 (1H, s), 12.03 (1H, s); IR (solid) 1662, 1620, 1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, 1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391.2 (M + H) +
    [1053] Example 39 [2- (4-Methanesulfonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-39): Prepared in a similar manner to Method E mentioned, to give an off-white solid. mp 219-222 ° C .; 1 H NMR (DMSO) δ 2.15 (3H, s), 2.61 (3H, s), 5.84 (1H, s), 6.91 (2H, d), 7.22 (2H, d), 7.36 (1H, s), 7.52 (1H, d), 7.69 (1H, s), 8.53 (1H, d), 10.31 (1H, s), 11.96 (1H, s); IR (solid) 1621, 1602, 1584, 1567, 1528, 1486, 1351, 1287, 1253, 1207, 1179, 1102, 1091, 983; MS 427.0 (M + H) +
    [1054] Example 40 [2- (4-acetamidophenylsulfanyl) -7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-40 ): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 291-293 ° C .; 1 H NMR (DMSO) δ 2.01 (3H, s), 2.09 (3H, s), 3.87 (3H, s), 5.55 (1H, s), 6.96 (1H, s), 6.99 (1H, d), 7.55 (2H, d), 7.73 (2H, d), 8.45 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.99 (1H, s); IR (solid); MS 421.2 (M + H) +
    [1055] Example 41 [2- (4-acetamidophenylsulfanyl) -8- (3-morpholin-4-yl-propoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazole 3-yl) -amine (IIa-41): Prepared in a similar manner to the above-mentioned method E to give a white solid. mp 262-264 ° C; 1 H NMR (DMSO) δ 1.94 (2H, quintet), 2.03 (3H, s), 2.09 (3H, s), 2.38 (4H, s), 2.45 (2H, t), 3.58 (4H, s), 4.11 (2H, t), 5.60 (1H, s), 7.24 (1H, d), 7.30 (1H, t), 7.57 (2H, d), 7.73 (2H, d), 8.07 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, br s); IR (solid) 3245, 3045, 2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468, 1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823; MS 534.4 (M + H) +
    [1056] Example 42 [2- (4-methoxycarbonylphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-42): alluded to above Prepared in a similar manner to Process E, whereby an off-white solid is obtained. mp 257-260 ° C; 1 H NMR (DMSO) δ 1.95 (3H, s), 3.89 (3H, s), 5.51 (1H, br s), 7.39 (1H, br s), 7.51 (1H, br s), 7.70 (1H, br s), 7.81 (2H, d), 8.04 (2H, d), 8.51 (1H, br s), 10.48 (1H, br s), 12.03 (1H, br s); IR (solid) 1718, 1618, 1599, 1568, 1531, 1481, 1434, 1395, 1362, 1342, 1286, 1247, 1216, 1156, 1116, 1018, 1003, 968; MS 392.2 (M + H) +
    [1057] Example 43 [2- (4-carboxyphenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-43): Method E mentioned above Prepared in a similar manner to yield an off-white solid. mp 263-265 ° C; 1 H NMR (DMSO) δ 1.98 (3H, s), 5.50 (1H, s), 7.46 (1H, t), 7.60 (1H, d), 7.78 (3H, m), 8.02 (2H, d), 8.58 (1H, d), 10.58 (1H, s), 12.50 (1H, br s); IR (solid) 1623, 1605, 1574, 1560, 1533, 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088, 1018; MS 378.2 (M + H) +
    [1058] Example 44 [2- (4-acetamidophenylsulfanyl) -8-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-44 ): Prepared in a similar manner to Method E mentioned above to give an off-white solid. mp 247-249 ° C .; 1 H NMR (DMSO) 1.99 (3H, s), 2.10 (3H, s), 3.93 (3H, s), 5.40 (1H, s), 7.31 (1H, d), 7.38 (1H, t), 7.57 ( 2H, d), 7.76 (2H, d), 8.11 (1H, d), 10.28 (1H, s), 10.61 (1H, s), 12.11 (1H, br s); IR (solid) 3234, 3052, 2938, 1673, 1618, 1591, 1536, 1481, 1459, 1390, 1372, 1345, 1317, 1267, 1249, 1158, 1058, 985, 830; MS 421.2 (M + H) +
    [1059] Example 45 [2- (4-acetamidophenylsulfanyl) -7- (3-morpholin-4-yl-propoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazole 3-yl) -amine (IIa-45): Prepared from IIa-74 according to Method I to give an off-white solid. mp 153 ° C. (decomposition); 1 H NMR (DMSO) δ 2.02 (3H, s), 2.09 (3H, s), 2.29 (2H, quintet), 3.16 (2H, m), 3.36 (4H, m), 3.57 (4H, m), 4.11 (2H, m), 5.58 (1H, s), 7.22-7.29 (2H, m), 7.55 (2H, d), 7.76 (2H, d), 8.07 (1H, d), 10.26 (1H, br s ), 10.35 (1H, s), 12.06 (1H, br s); IR (solid) 1673, 1614, 1591, 1532, 1486, 1391, 1336, 1254, 1109, 1063, 995; MS 534.2 (M + H) +
    [1060] Example 46 [2- (4-Bromophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-46): the above-mentioned method Prepared in a similar manner to E to give an off-white solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 2.15 (3H, s), 5.63 (1H, br s), 7.44 (1H, m), 7.55-7.62 (3H, m), 7.69-7.77 (3H, m), 8.56 (1H , m), 10.47 and 12.12 (2H, 2 x br s); IR (solid) 1615, 1597, 1565, 1525, 1478, 1396, 1362, 1339, 1285, 1218, 1158, 1034, 1009, 967; MS 412.1 / 414.1 (M + H) +
    [1061] Example 47 [2- (3-Bromophenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-47): the above-mentioned method Prepared in a similar manner to E to give an off-white solid. mp 280-281 ° C; 1 H NMR (DMSO) δ 2.12 (3H, s), 5.54 (1H, br s), 7.46 (1H, m), 7.55-7.68 (3H, m), 7.75-7.88 (3H, m), 8.81 (1H , m), 10.49 and 12.11 (2H, 2 x br s); IR (solid) 1617, 1600, 1567, 1530, 1483, 1399, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005, 967; MS 412.2 / 414.2 (M + H) +
    [1062] Example 48 [2- (4-Isopropanesulfonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-48): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 294-297 ° C .; 1 H NMR (DMSO) δ 1.26 (6H, d), 2.13 (3H, s), 5.75 (1H, s), 7.34 (2H, d), 7.41 (1H, t), 7.54 (1H, d), 7.59 (2H, d), 7.73 (1H, t), 8.53 (1H, d), 10.16 (1H, s), 10.42 (1H, s), 12.07 (1H, br s); IR (solid) 1613, 1593, 1560, 1530, 1482, 1384, 1364, 1346, 1320, 1290, 1265, 1243, 1216, 1169, 1141, 1084, 1056, 1019, 999, 969, 916; MS 455.2 (M + H) +
    [1063] Example 49 [2- (4-Isobutyrylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-49): supra Prepared in a similar manner to Method E mentioned, to give an off-white solid. mp 285-287 ° C .; 1 H NMR (DMSO) δ 1.12-1.13 (6H, m), 1.99 (3H, s), 2.64 (1H, m), 5.52 (1H, br s), 7.41 (1H, m), 7.54-7.57 (3H , m), 7.72-7.77 (3H, m), 8.54 (1H, m), 10.12, 10.41 and 12.04 (3H, 3 x br s); IR (solid) 1704, 1680,1617, 1590, 1566, 1516, 1481, 1395, 1358, 1341, 1286, 1247, 1214, 1155, 1052, 1032, 1006, 969; MS 419.3 (M + H) +
    [1064] Example 50 (5-Methyl-2H-pyrazol-3-yl)-[2- (4-propionylamino-phenylsulfanyl) -quinazolin-4-yl] -amine (IIa-50): Mentioned above Prepared in a similar manner to Process E, whereby an off-white solid is obtained. mp 281-282 ° C; 1 H NMR (DMSO) δ 1.11-1.13 (3H, m), 1.98 (3H, s), 2.33 (2H, m), 5.51 (1H, br s), 7.41 (1H, m), 7.55-7.57 (3H , m), 7.71-7.78 (3H, m), 8.54 (1H, m), 10.11, 10.41 and 12.04 (3H, 3 x br s); IR (solid) 1654, 1621, 1599, 1571, 1527, 1476, 1398, 1358, 1341, 1286, 1244, 1216, 1155, 1006, 969; MS 405.3 (M + H) +
    [1065] Example 51 [2- (4-Cyclopropanecarbonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-51): Prepared in a similar manner to Method E mentioned above to give an off-white solid. mp 300-303 ° C .; 1 H NMR (DMSO) δ 0.82-0.84 (4H, m), 1.83 (1H, m), 2.01 (3H, s), 5.55 (1H, br s), 7.39-7.41 (2H, m), 7.53-7.57 (2H, m), 7.72-7.77 (2H, m), 8.53-8.55 (2H, m), 10.40, 10.46 and 12.03 (3H, 3 x br s); IR (solid) 1664, 1614, 1591, 1560, 1526, 1480, 1432, 1390, 1344, 1288, 1240, 1194, 1177, 1152, 997; MS 417.2 (M + H) +
    [1066] Example 52 [2- (4-acetamido-phenylsulfanyl) -8-hydroxyquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-52 ): Brown solid, mp 258-259 ° C; 1 H NMR (DMSO) δ 1.99 (3H, s), 2.09 (3H, s), 5.45 (1H, s), 7.10 (1H, d), 7.22 (1H, t), 7.57 (2H, d), 7.75 (2H, d), 7.95 (1H, d), 9.35 (1H, s), 10.22 (1H, s), 10.26 (1H, s), 12.00 (1H, br s); IR (solid) 3295, 3272, 3181, 3109, 1654, 1591, 1527, 1482, 1459, 1386, 1368, 1314, 1268, 1141, 1077, 991, 814; MS 407.2 (M + H) +
    [1067] Example 53 [2- (4-acetamido-phenylsulfanyl) -7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-53) : Prepared in a similar manner to Method E mentioned above to give a yellow solid; 1 H NMR (DMSO) δ 2.02 (3H, s), 2.09 (3H, s), 5.54 (1H, s), 7.58 (2H, d), 7.75 (2H, d), 8.08 (1H, d), 8.22 (1H, s), 8.80 (1H, d), 10.24 (1H, s), 10.85 (1H, s), 12.15 (1H, s); IR (solid); MS 436.2 (M + H) +
    [1068] Example 54 (5-Methyl-2H-pyrazol-3-yl)-{2- [4- (propane-1-sulfonylamino) -phenylsulfanyl] -quinazolin-4-yl} -amine (IIa -54): Prepared in a similar manner to Method E mentioned above, to obtain a white solid. mp 272-273 ° C; 1 H NMR (DMSO) δ 0.95 (3H, t), 1.71 (2H, m), 2.13 (3H, s), 3.18 (2H, t), 5.70 (1H, s), 7.31 (2H, d), 7.41 (1H, t), 7.52 (1H, d), 7.58 (1H, d), 7.73 (1H, t), 8.55 (1H, d), 10.16 (1H, s), 10.42 (1H, s), 12.07 ( 1H, s); IR (solid) 1615, 1594, 1563, 1530, 1481, 1389, 1362, 1346, 1325, 1291, 1245, 1147, 969; MS 455.2 (M + H) +
    [1069] Example 55 [2- (4-ethylsulfonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-55): Prepared in a similar manner to Method E mentioned, to give an off-white solid. mp 279-280 ° C .; 1 H NMR (DMSO) δ 1.28 (3H, t), 2.19 (3H, s), 3.25 (2H, m), 5.76 (1H, s), 7.36 (2H, d), 7.48 (1H, t), 7.53 (1H, d), 7.65 (1H, d), 7.80 (1H, t), 8.61 (1H, d), 10.23 (1H, s), 10.49 (1H, s), 12.13 (1H, s); IR (solid) 1615, 1597, 1564, 1532, 1506, 1485, 1455, 1388, 1361, 1347, 1323, 1294, 1218, 1150, 1033, 1016, 998, 968, 918; MS 441.2 (M + H) +
    [1070] Example 56 [2- (4-acetamido-phenylsulfanyl) -7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa- 56): A yellow solid is obtained from IIa-53 according to Method J; 1 H NMR (DMSO) δ 1.97 (3H, s), 2.11 (3H, s), 5.19 (1H, s), 6.88-6.91 (2H, m), 7.65 (2H, d), 7.85 (2H, d) , 8.44 (1 H, d), 9.27 (1 H, br s), 10.49 (1 H, s), 11.38 (1 H, s), 14.58 (1 H, br s); IR (solid); MS 422.2 (M + H) +
    [1071] Example 57 [2- (4-Isobutanecarbonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-57): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 281-282 ° C; 1 H NMR (DMSO) δ 0.95-0.97 (6H, m), 2.00 (3H, s), 2.12 (1H, m), 2.23-2.25 (2H, m), 5.56 (1H, s), 7.41 (1H, m), 7.54-7.57 (3H, m), 7.72-7.78 (3H, m), 8.54 (1H, m), 10.14, 10.41 and 12.03 (3H, 3 x br s); IR (solid) 1737, 1658, 1618, 1599, 1566, 1530, 1483, 1432, 1394, 1364, 1343, 1313, 1287, 1242, 1216, 1167, 1151, 1003, 967; MS 433.2 (M + H) +
    [1072] Example 58 [2- (4-tert-Butoxycarbonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa- 58): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 243-246 ° C .; 1 H NMR (DMSO) δ 1.50 (9H, s), 1.97 (3H, s), 5.40 (1H, s), 7.07 (2H, br s), 7.36 (1H, br s), 7.47 (2H, d) , 7.58 (2H, d), 8.12 (1 H, br s), 9.58 (1 H, s), 11.24 (1 H, br s); IR (solid) 1701, 1593, 1559, 1515, 1482, 1396, 1365, 1346, 1308, 1288, 1237, 1154, 1051, 1020, 969; MS 449.2 (M + H) +
    [1073] Example 59 [2- (4-acetamido-phenylsulfanyl) -7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-59) : According to Method K, an off-white solid is obtained from IIa-53. mp 264-265 ° C; 1 H NMR (DMSO) δ 1.99 (3H, s), 2.09 (1H, s), 5.53 (1H, s), 5.97 (2H, s), 6.47 (1H, s), 6.68 (1H, d), 7.52 (2H, d), 7.71 (2H, d), 8.15 (1H, d), 9.83 (1H, br s), 10.19 (1H, s), 10.87 (1H, br s); IR (solid); MS 406.2 (M + H) +
    [1074] Example 60 (5-Methyl-2H-pyrazol-3-yl)-{2- [4- (2-morpholin-4-yl-acetylamino) -phenylsulfanyl] -quinazolin-4-yl} -Amine (IIa-60): Prepared in a similar manner to the above-mentioned method E to give an off-white solid. mp 266-267 ° C; 1 H NMR (DMSO) δ 2.03 (3H, s), 2.57 (4H, m), 3.23 (2H, s), 3.69 (4H, m), 5.58 (1H, s), 7.40 (1H, t), 7.55 -7.62 (3H, m), 7.75 (1H, t), 7.80 (2H, d), 8.54 (1H, d), 10.02 (1H, s), 10.41 (1H, s), 12.03 (1H, s); IR (solid) 1686, 1598, 1564, 1533, 1515, 1484, 1387, 1362, 1348, 1291, 1113, 868, 801, 773; MS 476.4 (M + H) +
    [1075] Example 61 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (4-methylsulfonylamino-phenylsulfanyl) -quinazolin-4-yl] -amine (IIa-61): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 235-238 ° C; 1 H NMR (DMSO) δ 0.61 (2H, s), 0.92 (2H, d), 1.82 (1H, br s), 2.98 (3H, s), 5.90 (1H, s), 7.23 (2H, d), 7.41 (1 H, t), 7.54 (3 H, m), 7.72 (1 H, t), 8.55 (1 H, d), 10.16 (1 H, br s), 10.38 (1 H, s), 11.99 (1 H, s); IR (solid) 1621, 1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290, 1232, 1143, 1113, 985, 972; MS 453.3 (M + H) +
    [1076] Example 62 [2- (4-Amino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-62): the above-mentioned method Prepared in a similar manner to E to give an off-white solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 2.16 (3H, s), 5.58 (1H, s), 6.78 (2H, d), 7.36 (2H, d), 7.64 (2H, m), 7.94 (1H, t), 8.74 (1H, d), 11.82 (1H, broad singlet); IR (solid) 1615, 1591, 1561, 1532, 1495, 1480, 1387, 1363, 1344, 1288, 1244, 1148, 966; MS 349.2 (M + H) +
    [1077] Example 63 [2- (4-acetamido-phenylsulfanyl) -quinazolin-4-yl]-(2H-pyrazol-3-yl) -amine (IIa-63): Prepared in a similar manner to yield a white solid. 1 H NMR (DMSO) δ 2.11 (3H, s), 5.93 (1H, s), 7.31-7.68 (8H, m), 8.54 (1H, s), 10.17 (1H, s), 10.54 (1H, s) , 12.38 (1 H, s); IR (solid); MS 377.4 (M + H) +
    [1078] Example 64 (5-Methyl-2H-pyrazol-3-yl)-{2- [4- (4-morpholin-4-yl-butyrylamino) -phenylsulfanyl] -quinazolin-4-yl } -Amines (IIa-64): Prepared in a similar manner to the above-mentioned method E to give a white solid. mp 240-243 ° C .; 1 H NMR (DMSO) δ 1.77 (2H, m), 2.00 (3H, s), 2.31-2.38 (8H, m), 3.57 (4H, m), 5.54 (1H, s), 7.39-7.76 (7H, m), 8.53 (1 H, br m), 10.15 (1 H, s), 10.41 (1 H, s), 12.00 (1 H, br s); IR (solid); MS 504.3 (M + H) +
    [1079] Example 65 (5-Methyl-2H-pyrazol-3-yl)-{2- [4- (2-morpholin-4-yl-ethylcarbamoyl) -phenylsulfanyl] -quinazolin-4-yl } -Amines (IIa-65): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 246-248 ° C; 1 H NMR (DMSO) δ 1.97 (3H, s), 2.43 (4H, br s), 3.30 (2H, s), 3.42 (2H, m), 3.58 (4H, br s), 5.52 (1H, s) , 7.43 (1H, t), 7.55 (1H, d), 7.76 (3H, m), 7.97 (2H, d), 8.56 (2H, m), 10.45 (1H, s), 12.05 (1H, br s) ; IR (solid) 1637, 1618, 1596, 1568, 1530, 1484, 1396, 1362, 1343, 1286, 1247, 1216, 1159, 1116, 1006, 967; MS 490.3 (M + H) +
    [1080] Example 66 [8-methoxy-2- (4-methylsulfonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa -66): Prepared in a similar manner to Method E mentioned above to give an off-white solid. mp 275-277 ° C; 1 H NMR (DMSO) δ 2.10 (3H, s), 3.07 (3H, s), 3.89 (3H, s), 5.58 (1H, s), 7.24 (1H, d), 7.26-7.36 (3H, m) , 7.60 (2H, d), 8.07 (1H, d), 10.13 (1H, s), 11.26 (1H, s), 12.03 (1H, s); IR (solid) 3379, 1622, 1595, 1531, 1481, 1467, 1344, 1326, 1271, 1248, 1143, 1061, 993, 975, 924, 829; MS 457.2 (M + H) +
    [1081] Example 67 {2- [4- (2-Dimethylamino-ethylcarbamoyl) -phenylsulfanyl] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine ( IIa-67): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 192-193 ° C; 1 H NMR (DMSO) δ 1.99 (3H, s), 2.20 (6H, s), 2.42 (2H, t), 3.40 (2H, q), 5.56 (1H, s), 7.43 (1H, t), 7.57 (1H, d), 7.77 (3H, m), 7.92 (2H, d), 8.56 (2H, m), 10.44 (1H, s), 12.04 (1H, br s); IR (solid) 1650, 1618, 1593, 1561, 1525, 1481, 1419, 1395, 1361, 1337, 1287, 1247, 1214, 1165, 1004, 969; MS 448.3 (M + H) +
    [1082] Example 68 {2- [4- (2-Dimethylamino-acetylamino) -phenylsulfanyl] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine (IIa -68): Prepared in a similar manner to Method E mentioned above, to obtain a white solid. mp 241-243 ° C .; 1 H NMR (DMSO) δ 2.00 (3H, s), 2.33 (6H, s), 3.14 (2H, s), 5.60 (1H, s), 7.40 (1H, t), 7.58 (3H, m), 7.77 (1H, t), 7.76 (2H, d), 8.58 (1H, d), 10.04 (1H, s), 10.42 (1H, s), 11.99 (1H, s) .; IR (solid) 1707, 1617, 1601, 1571, 1509, 1485, 1420, 1397, 1365, 1304, 1290, 1243, 1215, 1161, 970, 847, 813, 765, 716, 683, 656; MS 434.3 (M + H) +
    [1083] Example 69 [8-hydroxy-2- (4-methylsulfonylamino-phenylsulfanyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa -69): pale green solid, mp 291-293 ° C .; 1 H NMR (DMSO) δ 2.10 (3H, s), 3.09 (3H, s), 5.57 (1H, s), 7.11 (1H, d), 7.24 (1H, t), 7.31 (2H, d), 7.62 (2H, d), 7.96 (1H, d), 9.32 (1H, s), 10.16 (1H, s), 11.28 (1H, s), 12.02 (1H, s); IR (solid) 3256, 1596, 1531, 1460, 1392, 1317, 1334, 1296, 1267, 1146, 993, 968, 931, 824; MS 443.2 (M + H) +
    [1084] Example 70 {2- [4- (3-Dimethylamino-propylcarbamoyl) -phenylsulfanyl] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine ( IIa-70): Prepared in a similar manner to Method E mentioned above to give a pink solid. mp 210-213 ° C .; 1 H NMR (DMSO) δ 1.48 (2H, m), 2.01 (3H, s), 2.24 (6H, s), 2.38 (2H, br s), 2.93 (2H, s), 5.57 (1H, s), 7.48 (1H, t), 7.62 (1H, d), 7.80 (3H, m), 8.02 (2H, d), 8.61 (1H, d) 8.74 (1H, s), 10.50 (1H, s), 12.15 ( 1H, br s); IR (solid) 1682, 1618, 1595, 1567, 1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006, 969; MS 462.3 (M + H) + .
    [1085] Example 71 {2- [4- (3-Dimethylamino-propionylamino) -phenylsulfanyl] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine ( IIa-71): Prepared in a similar manner to the above-mentioned method E to obtain an off-white solid. mp 280 ° C. (decomposition); 1 H NMR (DMSO) δ 2.09 (3H, s), 2.60 (6H, s), 2.93 (2H, m), 3.10 (2H, m), 5.64 (1H, s), 7.47 (1H, t), 7.59 -7.70 (3H, m), 7.80-7.87 (3H, m), 8.61 (1H, d), 10.47 (1H, s), 10.48 (1H, s), 12.15 (1H, s) .; IR (solid) 1670, 1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364, 1348, 1286, 1178, 1162, 764; MS 448.4 (M + H) +
    [1086] Example 72 [2- (4-acetamido-phenylsulfanyl) -8-methoxy-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa -72): Prepared in a similar manner to the above-mentioned method E to obtain an off-white solid. mp 265-268 ° C; 1 H NMR (DMSO) δ 0.49-0.56 (2H, m), 0.79-0.83 (2H, m), 1.55-1.70 (1H, m), 2.06 (3H, s), 3.89 (3H, s), 5.61 ( 1H, s), 7.25 (1H, d), 7.33 (1H, t), 7.56 (2H, d), 7.74 (2H, d), 8.07 (1H, d), 10.17 (1H, s), 10.26 (1H , s), 11.94 (1H, broad singlet); IR (solid) 3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160, 1131, 1071, 1011, 984, 869, 815; MS 447.4 (M + H) +
    [1087] Example 73 [2- (4-acetamidophenylsulfanyl) -8- (3-dimethylamino-propoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl ) -Amine (IIa-73): Prepared in a similar manner to above-mentioned method E, to give an off-white solid. mp 170-172 ° C .; 1 H NMR (DMSO) δ 1.91 (2H, quint.), 2.03 (3H, s), 2.09 (3H, s), 2.17 (6H, s), 2.40 (2H, t), 4.10 (2H, t), 5.59 (1H, s), 7.23 (1H, d), 7.30 (1H, t), 7.57 (2H, d), 7.73 (2H, d), 8.06 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, broad singlet); IR (solid) 3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371, 1338, 1316, 1253, 1161, 1137, 1062, 1038, 994, 958, 823; MS 492.4 (M + H) +
    [1088] Example 74 [2- (4-acetamidophenylsulfanyl) -7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-74 ): An off-white solid is obtained from IIa-40 according to Method H. mp 246-248 ° C; 1 H NMR (DMSO) δ 2.00 (3H, s), 2.08 (3H, s), 5.52 (1H, s), 6.78 (1H, s), 6.87 (1H, d), 7.54 (2H, d), 7.72 (2H, d), 8.37 (1H, d), 10.06 (1H, s), 10.17 (1H, s), 10.37 (H, s), 11.95 (1H, br s); IR (solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420, 1389, 1359, 1298, 1223, 1176, 1148, 1087, 1026, 1010, 965; MS 407.4 (M + H) +
    [1089] Example 75 [2- (4-acetamidophenylsulfanyl) -7- (3-dimethylamino-propoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl ) -Amine (IIa-75): Prepared in a similar manner to the above-mentioned method I to obtain an off-white solid. mp 249-250 ° C .; 1 H NMR (DMSO) δ 1.90 (2H, quint.), 2.01 (3H, s), 2.09 (3H, s), 2.19 (6H, s), 2.42 (2H, m), 4.12 (2H, t), 5.55 (1H, s), 6.93 (1H, s), 6.98 (1H, d), 7.55 (2H, d), 7.73 (2H, d), 8.43 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.98 (1H, broad singlet); IR (solid) 3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420, 1394, 1344, 1320, 1292, 1263, 1222, 1168, 1048, 1034, 1005, 967, 864, 844; MS 492.4 (M + H) +
    [1090] Example 76 (2- {4- [2- (tert-butoxycarbonyl-methyl-amino) -acetylamino] -phenylsulfanyl} -quinazolin-4-yl)-(5-methyl-2H- Pyrazol-3-yl) -amine (IIa-76): Prepared in a similar manner to the above-mentioned method E to give a white solid. mp 228-229 ° C. (decomposition); 1 H NMR (DMSO) δ 1.37 (3H, s), 1.40 (3H, s), 2.02 + 2.03 (3H, 2xs), 2.88 + 2.90 (3H, 2xs), 4.01 +4.02 (2H, 2xs), 5.52 + 5.57 (1H, 2xs), 7.47 (1H, t), 7.55-7.63 (3H, m), 7.75-7.80 (3H, m), 8.60 (1H, d), 10.28 + 10.30 (1H, 2xs), 10.45 ( 1H, s), 12.08 (1H, s) .; IR (solid) 1698, 1683, 1653, 1617, 1594, 1559, 1538, 1532, 1507, 1488, 1457, 1418, 1397, 1364, 1346, 1307, 1287, 1246, 1151, 842, 827, 759; MS 520.4 (M + H) +
    [1091] Example 77 {2- [4- (2-Methylamino-acetylamino) -phenylsulfanyl] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine (IIa -77): Prepared in a similar manner to Method E mentioned above, to obtain a white solid. mp 242-244 ° C .; 1 H NMR (DMSO) δ 2.01 (3H, s), 2.34 (3H, s), 3.32 (2H, s), 5.58 (1H, s), 7.45 (1H, t), 7.50-7.60 (3H, m) , 7.75 (1H, t), 7.80 (2H, d), 8.55 (1H, d), 10.10 (1H, br s), 10.42 (1H, s), 12.02 (1H, s); IR (solid) 1674, 1619, 1598, 1570, 1525, 1483, 1417, 1363, 1345, 1298, 1285, 1247, 1160, 966, 827, 804, 784, 763, 712, 670, 653; MS 420.4 (M + H) +
    [1092] Example 78 [2- (4-acetamidophenylsulfanyl) -8-fluoro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIa-78 ): Prepared in a similar manner to Method E mentioned above to give a white solid. mp 257-259 ° C; 1 H NMR (DMSO) δ 2.01 (3H, s), 2.09 (3H, s), 5.49 (1H, s), 7.42 (1H, t), 7.57-7.68 (3H, m), 7.75 (2H, d) , 8.40 (1 H, d), 10.28 (1 H, s), 10.75 (1 H, s); 19 F NMR (DMSO) d -127.3; IR (solid) 1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456, 1434, 1395, 1366, 1332, 1315, 1289, 1254, 1242, 1032, 838, 829, 808, 744; MS 409.4 (M + H) +
    [1093] Example 79 (1H-indazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl) -amine (IIa-79): Prepared in a similar manner to above-mentioned Method E to obtain a white solid To obtain. 1 H NMR (DMSO) δ 7.07 (m, 3H), 7.19 (t, 1H), 7.37 (d, 2H), 7.39 (t, 1H), 7.52 (dd, 1H), 7.54 (t, 1H), 7.55 (d, 1H), 7.56 (t, 1H), 7.83 (t, 1H), 8.53 (d, 1H), 10.71 (s, 1H), 12.85 (s, 1H); MS 370.1 (M + H) +
    [1094] Example 80 {2-[(2-hydroxyethyl) phenylamino] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-1): aforesaid Prepared in a similar manner to Process A, to give a brown solid. mp 217 ° C .; 1 H NMR (DMSO) δ 1.99 (3H, s), 3.69 (2H, t), 4.05 (2H, t), 5.00 (1H, br s), 5.53 (1H, br s), 7.09 (1H, m) , 7.25-7.40 (4H, m), 7.40-7.48 (2H, m), 7.54 (1H, m), 8.34 (1H, m), 10.07 (1H, s), 11.67 (1H, br s); IR (solid) 3395, 3155, 3052, 2934, 1623, 1598, 1577, 1475, 1434, 1393; MS 361.2 (M + H) +
    [1095] Example 81 [2- (methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-2): in a manner analogous to method A mentioned above To give a white solid. mp 154-156 ° C; 1 H NMR (DMSO) δ 2.03 (3H, s), 3.51 (3H, s), 5.70 (1H, s), 7.13 (1H, m), 7.36-7.25 (3H, m), 7.48-7.37 (3H, m), 7.58 (1 H, m), 8.38 (1 H, d), 9.98 (1 H, s), 11.91 (1 H s); IR (solid) 1621, 1598, 1578, 1540, 1494, 1473, 1398, 1374; MS 331.0 (M + H) +
    [1096] Example 82 (5-Methyl-2H-pyrazol-3-yl)-{2- [N-methyl-N- (pyridin-3-ylmethyl) amino] -quinazolin-4-yl} -amine (IIc -3): Prepared in a similar manner to Method A mentioned above to give a yellow solid. mp 177 ° C .; 1 H NMR (DMSO) δ 0.45 (2H, s), 0.84 (2H, s), 1.80 (1H, s), 3.16 (3H, s), 4.93 (2H, s), 6.18 (1H, br s), 7.10 (1H, t), 7.34 (2H, s), 7.55 (1H, t), 7.64 (1H, s), 8.36 (1H, d), 8.45 (1H, s), 8.52 (1H, s), 10.03 (1H, s), 12.17 (1H, s); IR (solid) 3104, 2995, 2936, 1618, 1591, 1559, 1541, 1518, 1477, 1409, 1386, 1350, 1300, 1018, 991, 873, 827; MS 372.3 (M + H) +
    [1097] Example 83 (5-methyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl) -amine (IIc-4): Prepared in a similar manner to Method A mentioned above A white solid is obtained; 1 H NMR (DMSO @ 60 ° C.) δ 2.27 (3H, s), 6.47 (1H, br s), 6.92 (1H, m), 7.31 (3H, m), 7.53 (1H, m), 7.70 (1H, m), 7.91 (2H, m), 8.37 (2H, d), 9.16 (1H, br s), 10.05 (1H, br s), 12.15 (1H, br s); IR (solid) 1623, 1601, 1573, 1541, 1478; MS 317.0 (M + H) +
    [1098] Example 84 (2-benzylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-5): Prepared in a similar manner to Method A mentioned above Obtain a white solid. mp 225-227 ° C; 1 H NMR (DMSO) δ 2.20 (3H, s), 4.62 (2H, d), 7.18 (1H, s), 7.43-7.60 (8H, m), 8.22 (1H, s), 9.99 (1H, br s ), 12.05 (1H, broad singlet); IR (solid) 1630, 1609, 1578, 1538, 1511; MS 331.0 (M + H) +
    [1099] Example 85 (2-cyclohexylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-6): prepared in a similar manner to Method A mentioned above To give an off-white solid. mp 280 ° C. (decomposition); 1 H NMR (DMSO) δ 1.11-1.44 (5H, m), 1.56 (1H, m), 1.71 (2H, m), 1.92 (2H, m), 2.26 (3H, s), 3.75 (1H, s) , 6.63 (1 H, br s), 7.04 (1 H, s), 7.28 (1 H, s), 7.51 (1 H, m), 8.26 (1 H, s), 9.97 (1 H, br s), 12.08 (1 H, br) s), 12.75 (1 H, broad singlet); IR (solid) 2927, 2853, 1619, 1596, 1569, 1522, 1482; MS 323.0 (M + H) +
    [1100] Example 86 [2- (2,3-Dihydrobenzo [1,4] dioxin-6-ylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) Amine (IIc-7): Prepared in a similar manner to Method A mentioned above, to give an yellowish green solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 2.23 (3H, s), 4.15 (4H, m), 6.32 (1H, br s), 6.76 (1H, d), 7.16 (1H, t), 7.22 (1H, dd), 7.39 (1H, d), 7.57 (1H, t), 7.66 (1H, s), 8.34 (1H, d), 9.07 (1H, br s), 10.20 (1H, br s), 12.15 (1H, br s ); IR (solid) 3445, 3045, 2968, 2927, 2868, 1618, 1595, 1577, 1559, 1509, 1441, 1377, 1073; MS 375.1 (M + H) +
    [1101] Example 87 (2-cyclohexylmethylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-8): in a similar manner to Method A mentioned above To give a white solid. mp 211 ° C .; 1 H NMR (DMSO) δ 0.85-1.30 (5H, m), 1.50-1.85 (6H, m), 2.22 (3H, s), 3.19 (2H, s), 6.50-7.00 (1H, br s), 7.06 (1H, br s), 7.29 (1 H, br s), 7.51 (1 H, t), 8.26 (1 H, br s), 9.97 (1 H, br s), 12.04 (1 H, br s), 12.75 (1 H, br s); IR (solid) 3333, 2927, 2850, 2831, 1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 988; MS 337.4 (M + H) +
    [1102] Example 88 [2- (1H-indazol-6-ylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-9): mentioned above Prepared in a similar manner to Process A, to give an off-white solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 2.24 (3H, s), 5.93 and 6.89 (1H, 2xbr s), 7.05-8.15 (6H, m), 8.25-8.90 (2H, m), 9.25 and 9.97 (1H, 2xbr s ), 10.11 and 10.57 (1H, 2xbr s), 12.15 and 12.80 (2H, 2xbr s); IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1 (M + H) +
    [1103] Example 89 (5-methyl-2H-pyrazol-3-yl)-[2- (pyridin-3-ylmethylamino) -quinazolin-4-yl] -amine (IIc-10): the above-mentioned method Prepared in a similar manner to A to yield an off-white solid. mp 218 ° C .; 1 H NMR (DMSO) δ 2.20 (3H, s), 4.59 (2H, s), 6.30 (1H, br s), 7.10 (1H, s), 7.33 (2H, s), 7.54 (1H, s), 7.78 (1 H, s), 8.31 (1 H, s), 8.43 (1 H, s), 8.61 (1 H, s), 10.0 (1 H, br s), 12.15 (1 H, br s); IR (solid) 3308, 2945, 2919, 2858, 1623, 1593, 1577, 1552, 1501, 1475, 1449, 1383; MS 332.1 (M + H) +
    [1104] Example 90 [2- (3-Chlorophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-11): with Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp> 250 ° C., 1 H NMR (DMSO) δ 2.29 (3H, s), 5.30-6.98 (1H, m), 6.96 (1H, s), 7.28 (2H, s), 7.51 (1H, s), 7.67 (1H, s), 7.77 (1H, s), 8.23 (1H, s), 8.46 (1H, s), 9.35 and 10.00 (1H, 2xbr s), 10.14 and 10.64 (1H, 2xbr s), 12.20 and 12.82 (1H, 2xbr s); IR (solid) 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, 1472, 1440, 1403, 1372; MS 351.1 (M + H) +
    [1105] Example 91 [2- (4-Chlorophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-12): with Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 2.27 (3H, s), 5.20-6.80 (1H, m), 7.26 (1H, s), 7.33 (2H, s), 7.51 (1H, s), 7.66 (1H, s) , 7.99 (2H, d), 8.42 (1H, s), 9.29 and 9.93 (1H, 2xbr s), 10.13 and 10.55 (1H, 2xbr s), 12.19 and 12.81 (1H, 2xbr s); IR (solid) 3439, 3057, 2957, 1618, 1600, 1586, 1572, 1550, 1504, 1486, 1431, 1413, 1367; MS 351.1 (M + H) +
    [1106] Example 92 [2- (4-Fluorobenzylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-13): Method A mentioned above Prepared in a similar manner to yield a white solid. mp 216 ° C .; 1 H NMR (DMSO) δ 2.20 (3H, s), 4.56 (2H, d), 6.30 (1H, br s), 7.05-7.20 (3H, m), 7.31 (1H, d), 7.42 (2H, s ), 7.54 (1H, t), 8.32 (1H, s), 10.01 and 10.34 (1H, 2xbr s), 12.09 and 12.75 (1H, 2xbr s); IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367; MS 349.3 (M + H) +
    [1107] Example 93 {2- [2- (2-hydroxyethyl) phenylamino] -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-14): Prepared in a similar manner to Method A mentioned above to give a white solid. mp 222 ° C .; 1 H NMR (DMSO) δ 2.09 (3H, s), 2.80 (2H, t), 3.61 (2H, t), 4.87 (1H, br s), 5.85 (1H, br s), 7.30-7.53 (5H, m), 7.63 (1H, d), 7.86 (1H, t), 8.68 (1H, d), 10.11 (1H, br s), 11.55 (1H, br s), 12.49 (1H, brs), 13.50 (1H , br s); IR (solid) 3193, 3171, 3111, 3084, 1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3 (M + H) +
    [1108] Example 94 [2- (4-Cyanomethylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-15): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp> 250 ° C .; 1 H NMR (DMSO) 2.23 (3H, s), 4.09 (2H, s), 6.28 (1H, br s), 7.41 (2H, d), 7.48 (1H, t), 7.57-7.63 (3H, m) , 7.87 (1 H, t), 10.70 (1 H, s), 11.56 (1 H, s), 12.63 (1 H, br s), 13.25 (1 H, br s); IR (solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513, 1481, 1413, 1336, 1158, 999; MS 356.2 (M + H) +
    [1109] Example 95 [2- (3-hydroxymethylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-16): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 2.20 (3H, s), 4.53 (2H, s), 5.22 (1H, br s), 6.31 (1H, br s), 7.24 (1H, d), 7.33-7.53 (4H, m), 7.61 (1H, d), 7.86 (1H, t), 8.67 (1H, d), 10.61 (1H, br s), 11.52 (1H, br s), 12.59 (1H, br s), 13.10 ( 1H, br s); IR (solid) 3401, 3209, 3108, 3071, 2975, 2916, 1632, 1609, 1595, 1554, 1485, 1421, 1371, 1348, 1046, 1005, 813; MS 347.3 (M + H) +
    [1110] Example 96 [2- (3-hydroxyphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-17): Method A mentioned above Prepared in a similar manner to yield a white solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 2.22 (3H, s), 6.42 (1H, br s), 6.72 (1H, d), 6.97 (2H, s), 7.21 (1H, t), 7.47 (1H, t), 7.60 (1H, d), 7.85 (1H, t), 8.67 (1H, d), 9.76 (1H, s), 10.53 (1H, s), 11.53 (1H, s), 12.58 (1H, br s), 12.99 (1H, broad singlet); IR (solid) 3354, 3027, 2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332, 1154, 1004; MS 333.2 (M + H) +
    [1111] Example 97 (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl) -amine (IIc-18): prepared in a similar manner to Method A mentioned above To give an off-white solid. mp 234 ° C .; 1 H NMR (DMSO) δ 0.74 (2H, s), 0.92 (2H, s), 1.91 (1H, s), 5.83 and 6.54 (1H, 2xbr s), 6.94 (1H, t), 7.30 (3H, m ), 7.50 (1H, s), 7.65 (1H, s), 7.91 (2H, d), 8.27 (1H, s), 9.13 and 9.77 (1H, 2xbr s), 10.07 and 10.52 (1H, 2xbr s), 12.19 and 12.82 (1H, 2xbr s); IR (solid) 3443, 1622, 1595, 1577, 1554, 1486, 1449, 1413, 1376, 1340, 1235, 1171, 988, 806; MS 343.2 (M + H) +
    [1112] Example 98 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methylphenylamino) -quinazolin-4-yl] -amine (IIc-19): with method A mentioned above Prepared in a similar manner to yield an off-white solid. mp 117 ° C .; 1 H NMR (DMSO) δ 0.72 (2H, s), 0.92 (2H, s), 1.90 (1H, m), 2.32 (3H, s), 6.20 (1H, br s), 6.80 (1H, d), 7.20 (1H, t), 7.27 (1H, br s), 7.51 (1H, br s), 7.55-7.85 (3H, m), 8.43 (1H, br s), 9.50 (1H, br s), 10.44 ( 1 H, s), 12.55 (1 H, br s); IR (solid) 3303, 1618, 1581, 1554, 1536, 1495, 1472, 1436, 1413, 1372, 1336, 1240, 990; MS 357.4 (M + H) +
    [1113] Example 99 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (6-methoxypyridin-3-ylamino) -quinazolin-4-yl] -amine (IIc-20): Prepared in a similar manner to Method A mentioned above to give a pink solid. mp 120 ° C .; 1 H NMR (DMSO) δ 0.72 (2H, s), 0.91 (2H, s), 1.89 (1H, m), 3.85 (3H, s), 6.20 (1H, br s), 6.82 (1H, d), 7.25 (1H, s), 7.48 (1H, m), 7.66 (1H, t), 8.13 (1H, br s), 8.42 (1H, br s), 8.61 (1H, br s), 9.50 (1H, br s), 10.48 (1H, broad singlet), 12.55 (1H, broad singlet); IR (solid) 3457, 3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363, 1272, 1235, 1035, 985, 821; MS 374.2 (M + H) +
    [1114] Example 100 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (indan-5-ylamino) -quinazolin-4-yl] -amine (IIc-21): The above-mentioned method Prepared in a similar manner to A to give a pale brown solid. mp 199-204 ° C; 1 H NMR (DMSO) δ 0.69 (2H, br s), 0.91 (2H, br s), 1.90 (1H, m), 2.02 (2H, m), 2.68 (1H, m), 2.83 (3H, m) , 6.46 (1H, br s), 7.18 (1H, d), 7.26 (1H, br s), 7.50 (1H, d), 7.67 (1H, t), 7.75 (1H, br s), 8.45 (1H, br s), 9.70 (1 H, br s), 10.60 (1 H, br s), 12.30 and 12.80 (1 H, 2xbr s); IR (solid) 1621, 1601, 1572, 1552, 1495, 1474, 1439, 1425, 1408, 1382, 1363, 1319, 1267; MS 383.3 (M + H) +
    [1115] Example 101 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (1H-indol-6-ylamino) -quinazolin-4-yl] -amine (IIc-22): Mentioned above Prepared in a similar manner to Process A, to give a dark brown solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 0.69 (2H, br s), 0.89 (2H, br s), 1.88 (1H, m), 5.77 and 6.74 (1H, 2xbr s), 6.35 (1H, s), 7.22 (3H , br s), 7.45 (2H, d), 7.65 (1H, s), 8.35 (2H, br s), 8.86, 9.70 and 10.01 (1H, 3xbr s), 10.49, 12.12 and 12.84 (1H, 3xbr s) , 10.94 (s, 1 H); IR (solid) 1623, 1603, 1571, 1549, 1495, 1477, 1460, 1419, 1383, 1336, 1264, 1250, 1238; MS 382.4 (M + H) +
    [1116] Example 102 [2- (4-acetamido-3-methylphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-23): Prepared in a similar manner to Method A above, giving an off-white solid. mp> 188 ° C. (decomposition); 1 H NMR (DMSO) δ 0.72 (2H, br s), 0.94 (2H, br s), 1.92 (1H, m), 2.03 (3H, s), 2.19 (3H, s), 5.80 and 6.69 (1H, 2xbr s), 7.22 (2H, br s), 7.49 (1H, br s), 7.70 (3H, m), 8.35 (1H, br s), 9.01, 9.59 and 10.01 (1H, 3xbr s), 9.19 (1H , s), 10.53, 12.16 and 12.81 (1H, 3xbr s); IR (solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428, 1403, 1343, 1320, 1307, 1250; MS 414.4 (M + H) +
    [1117] Example 103 [2- (4-Chloro-3-methylphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-24): Mentioned above Prepared in a similar manner to Process A, to give a pale brown solid. mp 244-246 ° C .; 1 H NMR (DMSO) δ 0.69 (2H, br s), 0.94 (2H, br s), 1.91 (1H, m), 2.32 (3H, s), 5.89 and 6.63 (1H, 2xbr s), 7.28 (2H , m), 7.49 (1H, m), 7.65 (1H, m), 7.80 (1H, br s), 7.86 (1H, s), 8.40 (1H, br s), 9.17, 9.81 and 10.06 (1H, 3xbr s), 10.58, 12.19 and 12.78 (1H, 3xbr s); IR (solid) 1615, 1578, 1549, 1475, 1419, 1397, 1365, 1331, 1296, 1261, 1238, 1187, 1139; MS 391.4 (M + H) +
    [1118] Example 104 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (4-ethylphenylamino) -quinazolin-4-yl] -amine (IIc-25): Method A mentioned above Prepared in a similar manner to yield a pale brown solid. mp 250-251 ° C .; 1 H NMR (DMSO) δ 0.72 (2H, br s), 0.91 (2H, br s), 1.19 (3H, t), 1.91 (1H, m), 2.58 (2H, q), 5.81 and 6.64 (1H, 2xbr s), 7.15 (2H, d), 7.22 (1H, s), 7.47 (1H, s), 7.64 (1H, s), 7.78 (2H, s), 8.36 (1H, br s), 9.03, 9.66 And 10.05 (1H, 3xbr s), 10.49, 12.20 and 12.80 (1H, 3xbr s); IR (solid) 1603, 1574, 1546, 1509, 1497, 1474, 1439, 1417, 1386; MS 371.5 (M + H) +
    [1119] Example 105 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (4-propylphenylamino) -quinazolin-4-yl] -amine (IIc-26): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp 255-256 ° C .; 1 H NMR (DMSO) δ 0.72 (2H, br s), 0.91 (5H, t), 1.60 (2H, m), 1.90 (1H, m), 2.58 (2H, q), 5.81 and 6.63 (1H, 2xbr s), 7.12 (2H, d), 7.21 (1H, s), 7.47 (1H, s), 7.63 (1H, s), 7.77 (2H, s), 8.36 (1H, br s), 9.01, 9.70 and 10.11 (1H, 3x br s), 10.51, 12.17 and 12.80 (1H, 3x br s); IR (solid) 1595, 1571, 1545, 1499, 1477, 1442, 1413, 1388; MS 385.6 (M + H) +
    [1120] Example 106 (5-cyclopropyl-2H-pyrazol-3-yl)-{2- [4- (2-hydroxyethyl) phenylamino] -quinazolin-4-yl} -amine (IIc-27) : Prepared in a similar manner to Method A mentioned above to give a pale brown solid. mp 255-256 ° C .; 1 H NMR (DMSO) δ 0.73 (2H, br s), 0.91 (5H, t), 1.90 (1H, m), 2.69 (2H, t), 3.60 (2H, q), 4.62 (1H, t), 5.81 and 6.65 (1H, 2xbr s), 7.15 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.63 (1H, s), 7.77 (2H, s), 8.36 (1H, br s), 9.05, 9.69 and 10.02 (1H, 3xbr s), 10.52, 12.17 and 12.79 (1H, 3xbr s); IR (solid) 1632, 1569, 1546, 1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 (M + H) +
    [1121] Example 107 (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenethylamino-quinazolin-4-yl) -amine (IIc-28): in a similar manner to Method A mentioned above To give a white solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 0.66 (2H, m), 0.84 (2H, m), 1.83 (1H, m), 2.90 (2H, t), 3.56 (2H, m), 6.29 (1H, br s), 7.01 (1H, t), 7.12-7.38 (6H, m), 7.48 (1H, t), 8.42 (1H, s), 10.91 (1H, br s), 13.11 (1H, br s); IR (solid) 2922, 1650, 1627, 1577, 1550, 1500, 1482, 1395, 1368, 1004, 832; MS 371.3 (M + H) +
    [1122] Example 108 [2- (2-cyclohexylethylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-29): the above-mentioned method Prepared in a similar manner to A to give a white solid. mp> 250 ° C .; 1 H NMR (DMSO) δ 0.70 (2H, s), 0.80-1.00 (4H, m), 1.05-1.30 (4H, m), 1.30-1.50 (3H, m), 1.55-1.80 (5H, m), 1.87 (1H, s), 5.50-6.70 (2H, br s), 7.04 (1H, s), 7.25 (1H, s), 7.49 (1H, s), 8.25 (1H, s), 10.06 (1H, br s), 11.93 (1 H, broad singlet); IR (solid) 3448, 2920, 2852, 1618, 1600, 1568, 1550, 1486, 1418, 1395, 1367, 1258, 1008, 985; MS 377.4 (M + H) +
    [1123] Example 109 [2- (4-carboxymethoxyphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-30): mentioned above Prepared in a similar manner to Method A to give a yellow solid. mp> 250 ° C .; 1 H NMR (DMSO) 0.72 (2H, m), 0.91 (2H, m), 1.90 (1H, m), 4.62 (2H, s), 6.24 (1H, s), 6.88 (2H, s), 7.21 ( 1H, m), 7.45 (1H, m), 7.62 (1H, m), 7.78 (2H, m), 8.35 (1H, m), 9.31 (1H, s), 10.25 (1H, s), 11.70 (1H , br s); IR (solid) 1663, 1595, 1563, 1509, 1422, 1331, 1240, 1176, 1053, 999; MS 417.3 (M + H) +
    [1124] Example 110 [2- (4-cyanomethylphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-31): the above-mentioned method Prepared in a similar manner to A to give a white solid. mp 222 ° C .; 1 H NMR (DMSO) δ 0.74 (2H, m), 0.93 (2H, m), 1.92 (1H, m), 3.97 (2H, s), 5.82 and 6.65 (1H, 2xbr s), 7.29 (3H, m ), 7.50 (1H, m), 7.66 (1H, m), 7.92 (2H, m), 8.39 (1H, m), 9.21 and 9.85 (1H, 2xbr s), 9.90 and 10.56 (1H, 2xs), 12.19 And 12.80 (1H, 2xbr s); IR (solid) 1641, 1622, 1595,1581, 1554, 1513, 1486, 1463, 1408, 1372, 985, 821; MS 382.3 (M + H) +
    [1125] Example 111 [2- (benzothiazol-6-ylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-32): mentioned above Prepared in a similar manner to Process A, to give an off-white solid. mp 255-256 ° C .; 1 H NMR (DMSO) δ 0.73 (2H, m), 0.92 (2H, m), 1.92 (1H, m), 5.83 and 6.63 (1H, 2xbr s), 7.27 (1H, br s), 7.59 (1H, 7.68 (1H, br s), 7.79 (1H, br s), 7.98 (1H, br s), 8.41 (1H, br s), 8.97 (1H, br s), 9.19 (1H, s) , 9.58 and 10.10 (1H, 2xbr s), 10.57, 12.21 and 12.85 (1H, 3xbr s); IR (solid) 1624, 1592, 1575, 1512, 1472, 1411, 1377, 1333, 1244; MS 400.3 (M + H) +
    [1126] Example 112 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3,4-dimethylphenylamino) -quinazolin-4-yl] -amine (IIc-33): Prepared in a similar manner to Method A, to obtain a white solid. mp 245-246 ° C .; 1 H NMR (DMSO) δ 0.72 (2H, br s), 0.90 (2H, br s), 1.90 (1H, m), 2.18 (3H, s), 2.23 (3H, s), 5.77 and 6.63 (1H, 2xbr s), 7.09 (1H, d), 7.23 (1H, br s), 7.47 (1H, br s), 7.59 (1H, br s), 7.64 (1H, br s), 8.36 (1H, br s) , 9.02, 9.55 and 10.07 (1H, 3xbr s), 10.49, 12.31 and 12.80 (1H, 3xbr s); IR (solid) 1620, 1600, 1574, 1552, 1497, 1474, 1436, 1416, 1385, 1262; MS 371.5 (M + H) +
    [1127] Example 113 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (2-phenoxyethylamino) -quinazolin-4-yl] -amine (IIc-34): the above-mentioned method Prepared in a similar manner to A to give a white solid. mp 203 ° C .; 1 H NMR (DMSO) δ 0.70 (2H, m), 0.88 (2H, m), 1.87 (1H, m), 3.73 (2H, d), 4.16 (2H, s), 5.75 and 6.70 (1H, 2xbr s ), 6.93 (1H, t), 6.90-7.20 (3H, m), 7.20-7.45 (3H, m), 7.55 (1H, s), 7.76 (1H, br s), 8.32 (1H, s), 9.95 And 10.35 (1H, 2xs), 12.13 and 12.75 (1H, 2xbr s); IR (solid) 3434, 1622, 1600, 1572, 1554, 1499, 1476, 1422, 1399, 1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M + H) +
    [1128] Example 114 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (thiophen-2-methylamino) -quinazolin-4-yl] -amine (IIc-35): Prepared in a similar manner to Method A, to obtain a white solid. mp 212 ° C .; 1 H NMR (DMSO) δ 0.67 (2H, m), 0.90 (2H, m), 1.86 (1H, m), 4.74 (2H, d), 5.76 and 6.66 (1H, 2xbr s), 6.95 (1H, s ), 6.90-7.20 (2H, m), 7.20-8.45 (5H, m), 9.94 and 10.40 (1H, 2xs), 12.13 and 12.71 (1H, 2xbr s); IR (solid) 3444, 2948, 2847, 1622, 1600, 1559, 1500, 1481, 1418, 1390, 1358, 1336, 1313, 1263, 1217, 1185, 1149, 990, 821; MS 363.4 (M + H) +
    [1129] Example 115 [2- (4-carboxymethylphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-36): Method A mentioned above Prepared in a similar manner to yield a brown solid. mp> 210 ° C. (decomposition); 1 H NMR (DMSO) δ 0.64 (2H, br s), 0.92 (2H, m), 1.92 (1H, m), 3.50 (2H, s), 5.76 and 6.54 (1H, 2xs), 7.19 (1H, s ), 7.24 (1H, m), 7.49 (1H, d), 7.64 (1H, t), 7.84 (2H, d), 8.37 (1H, m), 10.27 and 12.25 (1H, 2xbr s); IR (solid) 1648, 1591, 1555, 1512, 1489, 1428, 1411, 1374; MS 401.4 (M + H) +
    [1130] Example 116 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (1H-indazol-5-ylamino) -quinazolin-4-yl] -amine (IIc-37): Prepared in a similar manner to Method A mentioned, to give a purple solid. mp 268-271 ° C; 1 H NMR (DMSO) δ 0.69 (2H, br s), 0.90 (2H, m), 1.88 (1H.m), 5.86 and 6.58 (1H, 2xs), 7.22 (1H, s), 7.61 (1H, s ), 7.71 (2H, m), 8.01 (1H, s), 8.37 (2H, s), 8.58, 9.05 and 9.58 (1H, 3xbr s), 10.01, 10.68 and 12.38 (1H, 3xbr s), 12.90 (1H , s); IR (solid) 1626, 1605, 1576, 1546, 1512, 1495, 1476, 1447, 1431, 1416, 1393, 1261, 1224; MS 383.3 (M + H) +
    [1131] Example 117 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (pyridin-3-ylmethylamino) -quinazolin-4-yl] -amine (IIc-38): mentioned above Prepared in a similar manner to Method A to give a yellow solid. mp 193 ° C; 1 H NMR (DMSO) δ 0.69 (2H, m), 0.89 (2H, m), 1.86 (1H, m), 4.60 (2H, s), 5.76, 6.22 and 6.66 (1H, 3xbr s), 7.10 (1H , s), 7.33 (2H, s), 7.54 (1H, s), 7.78 (1H, s), 8.31 (1H, s), 8.44 (1H, s), 8.61 (1H, s), 10.00 and 10.32 ( 1H, 2xs), 12.15 and 12.63 (1H, 2xbr s); IR (solid) 2927, 2850, 1623, 1600, 1577, 1536, 1477, 1418, 1332, 1254, 814; MS 358.3 (M + H) +
    [1132] Example 118 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxycarbonylphenylamino) -quinazolin-4-yl] -amine (IIc-39): mentioned above Prepared in a similar manner to Process A, to obtain a white solid. mp 228-231 ° C; 1 H NMR (DMSO) δ 0.73 (2H, br s), 0.91 (2H, m), 1.92 (1H, m), 3.88 (3H, s), 5.99 and 6.79 (1H, 2xs), 7.27 (1H, s ), 7.46 (3H, m), 7.68 (1H, s), 8.36 (1H, d), 8.48 (2H, s), 9.36, 9.84 and 10.00 (1H, 3xbr s), 10.63, 12.17 and 12.79 (1H, 3xbr s); IR (solid) 1716, 1615, 1591, 1579, 1557, 1473, 1432, 1416, 1379, 1334, 1298, 1276, 1226, 1191, 1142, 1110, 1020, 985; MS 401.3 (M + H) +
    [1133] Example 119 [2- (3-carboxyphenylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-40): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp 298-302 ° C .; 1 H NMR (DMSO) δ 0.73 (2H, br s), 0.91 (2H, m), 1.90 (1H, m), 7.26 (1H, s), 7.35 (1H, t), 7.50 (2H, d), 7.66 (1 H, t), 8.31 (2 H, m), 8.41 (1 H, d); IR (solid) 1661, 1597, 1578, 1558, 1517, 1486, 1424, 1385; MS 387.3 (M + H) +
    [1134] Example 120 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-ethylphenylamino) -quinazolin-4-yl] -amine (IIc-41): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp 186-188 ° C; 1 H NMR (DMSO) δ 0.73 (2H, br s), 0.91 (2H, br s), 1.22 (3H, t), 1.90 (1H, m), 2.62 (2H, d), 5.81 and 6.70 (1H, 2 x br s), 6.78 (1H, d), 7.20 (2H, s), 7.48 (1H, s), 7.65 (1H, s), 7.69 (1H, s), 7.81 (1H, s), 8.38 ( 1H, br s), 9.03, 9.74 and 10.03 (1H, 3 x br s), 10.55, 12.16 and 12.82 (1H, 3 x br s); IR (solid) 1614, 1580, 1549, 1534, 1493, 1471, 1433, 1409, 1374, 1340, 1240, 1182, 1165, 1138; MS 371.3 (M + H) +
    [1135] Example 121 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (2,3-dimethylphenylamino) -quinazolin-4-yl] -amine (IIc-42): mentioned above Prepared in a similar manner to Method A to yield an off-white solid. mp 241-242 ° C .; 1 H NMR (DMSO) δ 0.58 (2H, br s), 0.86 (2H, d), 1.77 (1H, br s), 2.11 (3H, br s), 2.28 (3H, s), 5.77 and 6.14 (1H , 2 x br s), 7.01 (1H, s), 7.11 (1H, t), 7.22 (1H, br s), 7.29 (1H, d), 7.56 (1H, s), 8.36 (1H, br s ), 8.49, 8.98 and 9.98 (1H, 3 x br s), 10.48, 12.04 and 12.68 (1H, 3 x br s); IR (solid) 1622, 1603, 1573, 1552, 1495, 1471, 1440, 1428, 1412, 1384, 1268; MS 371.4 (M + H) +
    [1136] Example 122 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3,4-dimethoxyphenylamino) -quinazolin-4-yl] -amine (IIc-43): Mentioned above Prepared in a similar manner to Process A, to give an off-white solid. mp 144 ° C .; 1 H NMR (DMSO) δ 0.69 (2H, s), 0.86 (2H, d), 1.89 (1H, m), 3.61 (3H, s), 3.67 (3H, s), 5.76 (1H, br s), 6.12 (1H, d), 6.31 (1H, s), 6.66 (1H, d), 6.94 (1H, d), 7.27 (1H, t), 7.50 (1H, d), 7.68 (1H, t), 8.45 And 9.36 (1H, br s, rotamers), 9.42 and 10.54 (1H, s, rotamers), 12.29 and 12.82 (1H, br s, rotamers); IR (solid) 3331, 3000, 2959, 2931, 2836, 1627, 1604, 1577, 1536, 1509, 1463, 1441, 1418, 1336, 1259, 1232, 1200, 1027; MS 403.8 (M + H) +
    [1137] Example 123 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxyphenylamino) -quinazolin-4-yl] -amine (IIc-44): the above-mentioned method Prepared in a similar manner to A to yield an off-white solid. mp 207-211 ° C; 1 H NMR (DMSO) δ 0.73 (2H, br s), 0.91 (2H, br s), 1.91 (1H, m), 3.77 (3H, s), 5.81 and 6.71 (1H, 2 x br s), 6.53 (1H, d), 7.19-7.85 (7H, m), 8.34 (1H, s), 9.08, 9.79 and 10.06 (1H, 3 x br s), 10.56, 12.16 and 12.82 (1H, 3 x br s); IR (solid) 1611, 1580, 1549, 1533, 1498, 1477, 1430, 1409, 1374, 1337, 1253, 1204, 1180, 1157, 1141, 1041, 1030, 992; MS 373.7 (M + H) +
    [1138] Example 124 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8-tetrahydroquinazolin-4-yl) -amine (IIc-45): It is prepared in a similar manner to the method C mentioned.
    [1139] Example 125 [2- (biphenyl-3-ylamino) -quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIc-46): Above-mentioned Prepared in a similar manner to Method A, to obtain a light brown solid. mp 153 ° C .; 1 H NMR (DMSO) δ 0.73 (2H, s), 0.90 (2H, d), 1.89 (1H, m), 5.83 and 6.70 (1H, br s, rotamer), 7.25 (2H, d), 7.32 ( 2H, m), 7.50 (3H, t), 7.68 (3H, m), 8.00 (1H, d), 8.22 (1H, br s), 8.40 (1H, br s), 9.20 and 9.89 (1H, br s , Rotamers), 10.06 and 10.46 (1H, s, rotamers), 12.17 and 12.84 (1H, br s, rotamers); IR (solid) 3333, 1627, 1609, 1581, 1540, 1504, 1472, 1449, 1426, 1335, 1248, 1216, 1102, 988, 819; MS 419.3 (M + H) +
    [1140] Example 126 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-phenylprop-1-ylamino) -quinazolin-4-yl] -amine (IIc-47): Prepared in a similar manner to Method A mentioned above to give a white solid. mp 189 ° C .; 1 H NMR (DMSO) δ 0.71 (2H, s), 0.91 (2H, s), 1.89 (3H, s), 2.69 (2H, s), 3.37 (2H, s), 5.76 and 6.66 (1H, br s , Rotamers), 6.95-7.60 (8H, m), 8.10-8.40 (1H, m), 9.89 and 10.30 (1H, br s, rotamers), 12.10 and 12.75 (1H, br s, rotamers); IR (solid) 1622, 1595, 1572, 1545, 1499, 1481, 1417, 1390, 1367, 1048, 997, 829; MS 385.4 (M + H) +
    [1141] Example 127 [2- (4-Acetamido-3-methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-48): Prepared in a similar manner to Method A mentioned, to give a pale brown solid. mp 251 ° C .; 1 H NMR (DMSO) δ 2.04 (3H, s), 2.19 (3H, s), 2.56 (3H, s), 5.92 and 6.80 (1H, br s, rotamer), 7.22 (2H, s), 7.48 ( 1H, s), 7.64 (1H, s), 7.73 (2H, s), 8.40 (1H, s), 9.05 and 9.74 (1H, br s, rotamers), 9.20 (1H, s), 10.05 and 10.54 ( 1H, br s, rotamer), 12.15 and 12.82 (1H, br s, rotamer); IR (solid) 3309, 2972, 2936, 1641, 1604, 1577, 1536, 1504, 1468, 1423, 1409, 1377, 1341, 1304, 1259, 1223, 1100, 1009, 864; MS 388.2 (M + H) +
    [1142] Example 128 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (indan-2-ylamino) -quinazolin-4-yl] -amine (IIc-49): the above-mentioned method Prepared in a similar manner to A to give a brown solid. mp 233-234 ° C; 1 H NMR (DMSO) δ 0.65 (2H, s), 0.84 (2H, s), 1.83 (1H, s), 2.91 (2H, m), 3.33 (2H, s), 4.72 (1H, s), 6.07 (1 H, br s), 7.00-7.60 (8 H, m), 8.29 (1 H, s), 10.30 (1 H, br s), 12.24 (1 H, br s); IR (solid) 3425, 2941, 2836, 1622, 1595, 1572, 1540, 1495, 1476, 1426, 1394, 1248, 1025, 1007, 870, 833; MS 383.3 (M + H) +
    [1143] Example 129 [2- (3-Methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-50): Similar to Method A mentioned above To give an off-white solid. mp 240-242 ° C .; 1 H NMR (DMSO) δ 2.25 (3H, s), 2.30 (3H, s), 5.95 (1H, br s), 6.76 (1H, d), 7.10-7.35 (2H, m), 7.48 (1H, s ), 7.55-7.85 (3H, m), 8.40 (1H, s), 9.05 and 9.74 (1H, br s, rotamer), 10.07 and 10.55 (1H, br s, rotamer), 12.14 and 12.81 (1H, br s, rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549, 1536, 1481, 1445, 1408, 1372, 1330, 1267, 1239, 1184, 1166, 1139, 993, 838, 806; MS 331.3 (M + H) +
    [1144] Example 130 [2- (2-Chloro-5-methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-51): referred to above Prepared in a similar manner to Method A to afford a gray solid. mp 246-247 ° C .; 1 H NMR (DMSO) δ 2.19 (3H, s), 2.31 (3H, s), 6.37 (1H, br s), 6.94 (1H, d), 7.23 (1H, s), 7.37 (1H, d), 7.43 (1H, d), 7.64 (1H, t), 7.97 (1H, s), 8.19 (1H, s), 8.42 (1H, br s), 10.17 (1H, br s), 12.19 (1H, br s ); IR (solid) 3409, 2918, 2850, 1627, 1591, 1573, 1545, 1513, 1486, 1463, 1418, 1386, 1332, 1291, 1259, 1182, 1000, 827; MS 365.2 (M + H) +
    [1145] Example 131 (5-cyclopropyl-2H-pyrazol-3-yl)-{2- [4- (morpholin-1-yl) phenylamino] -quinazolin-4-yl} -amine (IIc-52 ): Prepared in a similar manner to Method A mentioned above to give a gray solid. mp 275-276 ° C .; 1 H NMR (DMSO) δ 0.71, (2H, s), 0.90 (2H, s), 1.89 (1H, s), 3.05 (4H, s), 3.75 (4H, s), 5.78 and 6.61 (1H, br s, rotamer), 6.93 (2H, s), 7.20 (1H, s), 7.43 (1H, s), 7.50-7.90 (3H, m), 8.39 (1H, s), 8.95 and 9.58 (1H, br s, rotamers), 10.07 and 10.47 (1H, br s, rotamers), 12.16 and 12.81 (1H, br s, rotamers); IR (solid) 3245, 2990, 2972, 2959, 2936, 2918, 1618, 1577, 1559, 1509, 1477, 1445, 1413, 1382, 1264, 1223, 1150, 1109, 1050, 923, 882, 823; MS 428.3 (M + H) +
    [1146] Example 132 [2- (benzothiazol-6-ylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-53): mentioned above Prepared in a similar manner to Method A to yield an off-white solid. mp 236-239 ° C; 1 H NMR (DMSO) δ 2.25 (3H, s), 6.35 (1H, br s), 7.22 (1H, t), 7.53 (1H, d), 7.62 (1H, t), 7.76 (1H, d), 7.98 (1H, d), 8.39 (1H, d), 9.05 (1H, s), 9.17 (1H, s), 9.59 (1H, br s), 10.30 (1H, br s), 12.35 (1H, br s ); IR (solid) 1622, 1605, 1567, 1546, 1505, 1473, 1441, 1417, 1385, 1341, 1297, 1273, 1253, 1192, 1130; MS 374.1 (M + H) +
    [1147] Example 133 [2- (3,4-Dimethylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-54): the above-mentioned method Prepared in a similar manner to A to yield an off-white solid. mp 249-251 ° C; 1 H NMR (DMSO) δ 2.18 (3H, br s), 2.21 (3H, br s), 2.24 (3H, br s), 5.92 and 6.80 (1H, 2 x br s), 7.05 (1H, br s) , 7.21 (1H, br s), 7.46 (1H, br s), 7.64 (3H, br s), 8.37 (1H, br s), 9.00, 9.51 and 9.73 (1H, 3 x br s), 10.12, 10.54 And 12.17 (1H, 3 x br s); IR (solid) 1616, 1582, 1547, 1505, 1473, 1452, 1413, 1368, 1334, 1294, 1246, 1210, 1188, 1170, 1139; MS 345.3 (M + H) +
    [1148] Example 134 [2- (3-ethylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-55): Method A as mentioned above Prepared in a similar manner to yield an off-white solid. mp 238-239 ° C; 1 H NMR (DMSO) δ 1.21 (3H, t), 2.25 (3H, br s), 2.61 (2H, q), 5.92 and 6.80 (1H, 2 x br s), 6.78 (1H, d), 7.21 ( 2H, br s, 7.48 (1 H, br s), 7.65 (1 H, s), 7.72 (1 H, s), 7.80 (1 H, s), 8.40 (1 H, br s), 9.09, 9.58 and 10.10 (1 H , 3 x br s), 10.54, 12.26 and 12.81 (1H, 3 x br s); IR (solid) 1619, 1556, 1535, 1471, 1441, 1407, 1377, 1341, 1274, 1246, 1185, 1167, 1139, 995; MS 345.5 (M + H) +
    [1149] Example 135 [2- (3-methoxyphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-56): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp 212-215 ° C; 1 H NMR (DMSO) δ 2.25 (3H, br s), 3.77 (3H, s), 5.92 and 6.84 (1H, 2 x br s), 6.55 (1H, d), 7.13 (2H, m), 7.41- 7.50 (2H, m), 7.65 (1H, s), 7.77 (1H, s), 8.41 (1H, br s), 9.10, 9.79 and 10.10 (1H, 3 x br s), 10.55, 12.13 and 12.82 (1H , 3 x br s); IR (solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277, 1256, 1201, 1159; MS 347.4 (M + H) +
    [1150] Example 136 [2- (4-acetamido-3-cyanophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-57) : Prepared in a similar manner to Method A mentioned above to give an off-white solid. mp 294-296 ° C .; 1 H NMR (DMSO) δ 2.08 (3H, s), 2.28 (3H, s), 6.67 (1H, br s), 7.27 (1H, s), 7.43 (1H, d), 7.53 (1H, s), 7.68 (1H, s), 8.04 (1H, d), 8.45 (2H, s), 9.41, 10.35, and 12.18 (2H, 3 x br s), 10.00 (1H, s); IR (solid) 1620, 1583, 1558, 1237, 1508, 1477, 1446, 1413, 1373, 1341, 1292, 1259, 1241, 1180, 1162, 1142, 1105, 1030, 1000; MS 399.2 (M + H) +
    [1151] Example 137 [2- (2-methoxybiphenyl-5-ylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-58): Prepared in a similar manner to Method A mentioned to give a white solid. mp 222-223 ° C; 1 H NMR (DMSO) δ 2.22 (3H, s), 3.75 (3H, s), 6.82 (1H, br s), 7.05-7.11 (1H, m), 7.15-7.25 (1H, m), 7.30-7.36 (1H, m), 7.40-7.50 (3H, m), 7.49-7.55 (2H, m), 7.55-7.70 (1H, m), 7.70-7.82 (1H, m), 7.90-8.02 (1H, m) , 8.30-8.50 (1H, m); IR (solid) 1625, 1604, 1574, 1556, 1496, 1473, 1444, 1403, 1384, 1258, 1234, 1182, 1018, 824, 806, 755, 698; MS 423.4 (M + H) +
    [1152] Example 138 [2- (4-acetamidophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-59): the above-mentioned method Prepared in a similar manner to A to yield an off-white solid. mp 253-256 ° C; 1 H NMR (DMSO) δ 2.02 (3H, s), 2.25 (3H, br s), 5.92 and 6.77 (1H, 2 x br s), 7.21 (1H, s), 7.49 (3H, s), 7.63 ( 1H, s), 7.83 (2H, d), 8.38 (1H, br s), 9.03 and 10.05 (1H, 2 x br s), 9.81 (1H, s), 12.13 and 12.80 (1H, 2 x br s) ; IR (solid) 1669, 1635, 1617, 1574, 1535, 1512, 1486, 1422, 1394, 1366, 1316, 1268, 1231, 1184, 1119, 1101; MS 374.1 (M + H) +
    [1153] Example 139 [2- (4-tert-Butoxycarbonylamino-phenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-60 ): Prepared in a similar manner to Method A mentioned above to give an off-white solid. mp 238-242 ° C .; 1 H NMR (DMSO) δ 1.48 (9H, s), 2.24 (3H, s), 6.23 (1H, br s), 7.12 (1H, s), 7.36 (3H, s), 7.54 (1H, s), 7.67 (2H, d), 8.30 (1H, d), 9.14 (2H, br s), 10.24 and 12.19 (1H, 2 x br s); IR (solid) 1698, 1620, 1555, 1520, 1475, 1443, 1405, 1371, 1310, 1241, 1167, 1055, 996; MS 432.1 (M + H) +
    [1154] Example 140 [2- (4-cyanophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-61): Method A above-mentioned Prepared in a similar manner to yield an off-white solid. mp 293-298 ° C .; 1 H NMR (DMSO) δ 2.25 (3H, s), 6.50 (1H, br s), 7.27 (1H, s), 7.51 (1H, s), 7.64 (1H, s), 7.71 (2H, d), 8.40 (1 H, s), 9.76 (1 H, br s), 10.34 (1 H, br s), 12.33 (1 H, br s); IR (solid) 1633, 1605, 1571, 1517, 1505,1469, 1418, 1337, 1255, 1174, 1000; MS 342.1 (M + H) +
    [1155] Example 141 (5-Methyl-2H-pyrazol-3-yl)-[2- (6-oxo-6,10b-dihydro-4aH-benzo [c] chromen-2-ylamino) -quinazoline 4-yl] -amine (IIc-62): Prepared in a similar manner to Method A mentioned above to give a pale yellow solid. mp 293-298 ° C .; 1 H NMR (DMSO) δ 1.72 (3H, br s), 6.23 (1H, br s), 7.50 (1H, t), 7.66 (2H, t), 7.75 (1H, t), 7.87 (1H, t) , 7.77 (1H, t), 8.26 (1H, d), 8.33 (1H, d), 8.58-8.72 (2H, m), 10.55 (1H, s), 11.55 (1H, s), 12.40 (1H, s ); IR (solid) 1707, 1629, 1607, 1579, 1540, 1497, 1488, 1471, 1446, 1428, 1417, 1346, 1332, 1298, 1270, 1255, 1207, 1114, 998, 816, 793, 766, 758, 710, 685; MS 435.4 (M + H) +
    [1156] Example 142 [2- (biphenyl-3-ylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-63): the above-mentioned method Prepared in a similar manner to A to give a pale brown solid. mp 206-207 ° C; 1 H NMR (DMSO) δ 2.20 (3H, s), 6.80 (1H, br s), 7.24-7.27 (2H, m), 7.36-7.40 (2H, m), 7.48-7.52 (3H, m), 7.67 -7.69 (3H, m), 7.94 (1H, m), 8.26 (1H, m), 8.42 (1H, m), 9.30 (1H, br s), 10.16 (1H, br s), 12.13 (1H, br s); IR (solid) 1593, 1578, 1544, 1498, 1479, 1414, 1384, 1251, 1209, 1003; MS 393.2 (M + H) +
    [1157] Example 143 [2- (4-methoxycarbonylmethyl-3-methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-64) : Prepared in a similar manner to Method A mentioned above to give a white solid. mp 245-246 ° C .; 1 H NMR (DMSO) δ 2.23 (3H, s), 2.26 (3H, s), 3.63 (3H, s), 3.64 (2H, s), 5.99 (0.5H, br s), 6.80 (0.5 H, br s), 7.10 (1H, m), 7.25 (1H, m), 7.50 (1H, m), 7.61-7.80 (3H, m), 8.44 (1H, m), 9.10 (0.5H, br s), 9.78 (0.5H, br s), 10.11 (0.5H, br s), 10.56 (0.5H, br s), 12.18 (0.5H, br s), 12.90 (0.5H, br s); IR (solid) 1732, 1710, 1622, 1581, 1554, 1538, 1508, 1490, 1446, 1411, 1371, 1336, 1306, 1257, 1244, 1204, 1146, 1016, 998, 797, 754, 692; MS 403.4 (M + H) +
    [1158] Example 144 [2- (4-carboxymethyl-3-methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-65): methanol / [2- (4-methoxycarbonylmethyl-3-methylphenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) in a mixture of water (3/1, 8 ml) Treat a solution of amine (IIc-64, 200 mg, 0.5 mmol) with 1M NaOH (2 ml, 2 mmol). The mixture is heated at 70 ° C. for 2 hours and then neutralized with 1M HCl (2 ml, 2 mmol). The solid formed is collected by filtration to give the title compound (185 mg, 95%) as a pale yellow solid. mp 245 ° C. (decomposition); 1 H NMR (DMSO) δ 2.27 (6H, 2xs), 3.55 (2H, s), 6.49 (1H, s), 7.13 (1H, d), 7.26 (1H, t), 7.50 (1H, d), 7.62 -7.78 (3H, m), 8.42 (1H, d), 9.34 (1H, d), 10.26 (1H, s), 12.36 (1H, s); IR (solid) 1660, 1590, 1562, 1504, 1427, 1385, 810, 776, 751, 693; MS 389.4 (M + H) +
    [1159] Example 145 [2- (4-Aminophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-66): DCM / TFA (5 / [2- (4-tert-Butoxycarbonylamino-phenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc in 1, 12 ml) -60, 100 mg, 0.232 mmol) is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue is triturated in aqueous K 2 CO 3 . The resulting solid is collected by filtration and washed with diethyl ether to give IIc-66 (69 mg, 90%) as off-white solid. mp 164-167 ° C; 1 H NMR (DMSO) δ 2.24 (3H, s), 6.33 (1H, br s), 7.12 (2H, d), 7.48 (3H, m), 7.58 (1H, d), 7.86 (1H, t), 8.64 (1 H, d), 10.86 (1 H, br s), 11.46 (1 H, s); IR (solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M + H) +
    [1160] Example 146 [2- (4-Bromophenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-67): Method A mentioned above Prepared in a similar manner to yield an off-white solid. mp 290-293 ° C; 1 H NMR (DMSO) δ 2.27 (3H, s), 6.71 (1H, br s), 7.22 (1H, m), 7.46-7.50 (3H, m), 7.66 (1H, m), 7.92-7.94 (2H , m), 8.38 (1H, m), 9.28, 10.11 and 12.13 (3H, 3 x br s); IR (solid) 1619, 1572, 1548, 1486, 1436, 1409, 1372, 1238, 1186, 1136, 1071, 997; MS 395.1 / 397.1 (M + H) +
    [1161] Example 147 [2- (4-Isobutyrylamino-phenylamino) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-68): Mentioned above Prepared in a similar manner to Process A, to give a yellow solid. mp 176-179 ° C; 1 H NMR (DMSO) δ 1.11 (6H, d), 2.15 (3H, s), 2.62 (1H, m), 6.25 (1H, br s), 7.41 (1H, d), 7.46 (1H, t), 7.63 (1H, d), 7.71 (2H, d), 7.84 (1H, t), 8.64 (1H, d), 10.00 (1H, s), 10.34 (1H, br s), 11.47 (1H, br s) , 12.47 (1H, broad singlet); IR (solid) 1676, 1653, 1585, 1561, 1512, 1423, 1407, 1312, 1199, 1177, 1128; MS 402.3 (M + H) +
    [1162] Example 148 (5-ethyl-2H-pyrazol-3-yl)-[2- (5-ethyl-2H-pyrazol-3-ylamino) -quinazolin-4-yl] -amine (IIc-69 ): Triethylamine (0.35 ml, 2.51 mmol) in a solution of 2,4-dichloroquinazolin (0.5 g, 2.51 mmol) and 3-amino-5-ethylpyrazole (558 mg, 5.02 mmol) in ethanol (10 ml) Is added and the resulting mixture is stirred at room temperature for 3 hours. The resulting pale yellow precipitate is collected by filtration, washed with cold ethanol and dried in vacuo to give IIc-69 (306 mg, 35%) as off-white solid. mp 248-252 ° C; 1 H NMR (DMSO) δ 1.30 (m, 6H), 2.72 (m, 4H), 6.12 (br.s, 1H), 6.54 and 6.90 (br.s, 1H), 7.58 (t, 1H), 7.74 ( d, 1 H), 7.90 (t, 1 H), 8.78 (d, 1 H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2 (M + H) +
    [1163] Example 149 (1H-indazol-3-yl)-(2-phenylamino-quinazolin-4-yl) -amine (IIc-70): Prepared in a similar manner to Method A mentioned above to give a white solid do; 1 H NMR (DMSO) δ 6.90 (m, 3H), 7.11 (t, 1H), 7.19 (m, 2H), 7.44 (t, 1H), 7.57 (m, 1H), 7.62 (d, 1H), 7.67 (d, 2H), 7.71 (d, 1H), 7.93 (t, 1H), 8.59 (d, 1H), 11.55 (br. s, 1H), 13.15 (s, 1H); MS 353.2 (M + H) +
    [1164] Example 150 (1H-indazol-3-yl)-[2- (3-trifluoromethylphenylamino) -quinazolin-4-yl] -amine (IIc-71): analogous to Method A mentioned above To give a pale yellow solid. 1 H NMR (DMSO) δ 7.00 (t, 1H), 7.02 (d, 1H), 7.22 (d, 1H), 7.37 (td, 1H), 7.56 (m, 3H), 7.61 (d, 1H), 7.66 (d, 2H), 7.92 (t, 1H), 8.60 (d, 1H), 10.61 (br. s, 1H), 11.42 (br. s, 1H), 13.12 (s, 1H); MS 421.2 (M + H) +
    [1165] Example 151 (1H-indazol-3-yl)-[2- (4-trifluoromethylphenylamino) -quinazolin-4-yl] -amine (IIc-72): analogous to Method A mentioned above To give a pale yellow solid. 1 H NMR (DMSO) δ 7.08 (t, 1H), 7.16 (d, 2H), 7.44 (m, 3H), 7.58 (t, 1H), 7.6 (t, 2H), 7.69 (d, 1H), 7.95 (t, 1H), 8.62 (d, 1H), 10.82 (br. s, 1H), 11.50 (br. s, 1H), 12.20 (s, 1H); MS 421.2 (M + H) +
    [1166] Example 152 [2- (Adamantan-2-ylamino) -quinazolin-4-yl]-(1H-indazol-3-yl) -amine (IIc-73): Similar to Method A mentioned above In a manner to yield a white solid. 1 H NMR (DMSO) δ 0.83 (br. S, 1H), 0.85 (br. S, 1H), 1.44 (m, 4H), 1.55 (m, 3H), 1.63 (s, 2H), 1.73 (s, 1H), 1.82 (s, 1H), 1.84 (s, 1H), 3.56 (m, 1H), 7.10 (t, 1H), 7.41 (t, 1H), 7.51 (t, 1H), 7.54 (d, 1H ), 7.57 (d, 1H), 7.69 (d, 1H), 7.90 (t, 1H), 8.45 (d, 1H), 8.58 (d, 1H), 11.60 (s, 1H), 13.10 (s, 1H) ; MS 411.3 (M + H) +
    [1167] Example 153 (1H-indazol-3-yl)-(2-methyl-phenyl-amino-quinazolin-4-yl) -amine (IIc-74): Prepared in a similar manner to Method A above, white To obtain a solid; 1 H NMR (DMSO) δ 3.27 (s, 1H), 6.88 (t, 1H), 6.93 (t, 2H), 7.04 (t, 1H), 7.14 (d, 2H), 7.22 (t, 1H), 7.36 (m, 2H), 7.48 (d, 1H), 7.54 (d, 1H), 7.62 (t, 1H), 8.37 (d, 1H), 10.11 (s, 1H), 12.71 (s, 1H); MS 367.2 (M + H) +
    [1168] Example 154 [2- (2-Chloro-phenyl) -amino-quinazolin-4-yl]-(1H-indazol-3-yl) -amine (IIc-75): analogous to method A mentioned above To give a white solid. 1 H NMR (DMSO) δ 6.81 (t, 1H), 6.87 (td, 1H), 7.07 (t, 1H), 7.34 (dd, 1H), 7.35 (t, 1H), 7.40 (t, 1H), 7.53 (d, 1H), 7.56 (d, 1H), 7.63 (d, 2H), 7.72 (t, 1H), 8.07 (d, 1H), 8.46 (d, 1H), 10.37 (s, 1H), 12.89 ( s, 1 H); MS 387.1 (M + H) +
    [1169] Example 155 (1H-indazol-3-yl)-[2- (2-trifluoromethylphenylamino) -quinazolin-4-yl] -amine (IIc-76): analogous to Method A mentioned above To give a white solid; 1 H NMR (DMSO) δ 7.01 (t, 1H), 7.20 (m, 1H), 7.32 (m, 1H), 7.36 (t, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.61 (t, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.95 (t, 2H), 8.62 (d, 1H), 10.15 (m, 1H), 11.62 ( s, 1 H), 13.03 (s, 1 H); MS 421.2 (M + H) +
    [1170] Example 156 [2- (4-Cyanomethylphenylamino) -quinazolin-4-yl]-(1H-indazol-3-yl) -amine (IIc-77): In a manner analogous to method A mentioned above To give a white solid; 1 H NMR (DMSO) δ 13.16 (s, 1H), 11.49 (br. S, 1H), 10.38 (br. S, 1H), 8.58 (d, 1H), 7.92 (t, 1H), 7.67 (t, 2H), 7.61 (d, 1H), 7.56 (m, 1H), 7.44 (t, 1H), 7.22 (m, 2H), 7.08 (t, 1H), 6.86 (m, 2H), 3.87 (s, 2H ); MS 392.2 (M + H) + .
    [1171] Example 157 [2- (4-Chlorophenylamino) -5,6,7,8-tetrahydroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc -78): prepared in a similar manner to Method C mentioned above; MS 355.5 (M + H) +
    [1172] Example 158 (5-methyl-2H-pyrazol-3-yl)-(2-phenylamino-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl) -amine ( IIc-79): to be prepared in a similar manner to the above-mentioned method C; MS 335.3 (M + H) +
    [1173] Example 159 [2- (benzimidazol-2-ylamino) -7-benzyl-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidin-4-yl]-( 5-Methyl-2H-pyrazol-3-yl) -amine (IIc-80): Prepared in a similar manner to the above-mentioned method C; MS 452.0 (M + H) +
    [1174] Example 160 (7-benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidin-4-yl)-(5-methyl-2H-pyrazole 3-yl) -amine (IIc-81): to be prepared in a similar manner to the above-mentioned method C; MS 412.1 (M + H) +
    [1175] Example 161 [6-benzyl-2- (4-chlorophenylamino) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-4-yl]-(5-methyl -2H-pyrazol-3-yl) -amine (IIc-82): prepared in a similar manner as above-mentioned method C; MS 446.3 (M + H) +
    [1176] Example 162 [2- (benzimidazol-2-ylamino) -6-benzyl-5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-4-yl]-( 5-Methyl-2H-pyrazol-3-yl) -amine (IIc-83): Prepared in a similar manner to Method C mentioned above; MS 452.2 (M + H) +
    [1177] Example 163 (6-benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-4-yl)-(5-methyl-2H-pyrazole 3-yl) -amine (IIc-84): to be prepared in a similar manner to the above-mentioned method C; MS 411.9 (M + H) +
    [1178] Example 164 (5-methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidin-4-yl ) -Amine (IIc-85): prepared in a manner analogous to the above-mentioned method C; MS 322.3 (M + H) +
    [1179] Example 165 [2- (4-cyanomethylphenylamino) -quinazolin-4-yl]-(1H-pyrazolo [3,4-b] pyridin-3-yl) -amine (IIc-86): Prepared in a similar manner to Method A mentioned to obtain an off-white solid; 1 H NMR (DMSO) δ 13.65 (s, 1H), 12.82 (br. S, 1H), 11.69 (br. S, 1H), 8.55 (dd, 2H), 8.12 (d, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 6.94 (m, 2H), 3.89 (s, 2H); MS 393.1 (M + H) + .
    [1180] Example 166 [2- (4-Cyanobenzylamino) -quinazolin-4-yl]-(1H-pyrazolo [3,4-b] pyridin-3-yl) -amine (IIc-87): Prepared in a similar manner to Method A mentioned to obtain an off-white solid; 1 H NMR (DMSO) δ 13.68 (s, 1H), 12.82 (br. S, 1H), 11.70 (br. S, 1H), 8.55 (m, 3H), 8.00 (d, 1H), 7.92 (t, 1H), 7.59 (m, 4H), 6.96 (m, 2H), 6.86 (m, 1H), 4.23 (s, 2H); MS 393.1 (M + H) + .
    [1181] Example 167 [2- (4-Cyanomethylphenylamino) -quinazolin-4-yl]-(4-fluoro-1 H-indazol-3-yl) -amine (IIc-88): The above-mentioned method Prepared in a similar manner to A to give a white solid; 1 H NMR (DMSO) δ 13.49 (s, 1H), 11.61 (br. S, 1H), 10.64 (br. S, 1H), 8.56 (d, 1H), 7.95 (t, 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.46 (t, 1H), 7.43 (dd, 1H), 7.14 (m, 2H), 6.85 (dd, 3H), 3.88 (s, 2H); MS 410.1 (M + H) + .
    [1182] Example 168 [2- (4-cyanophenylamino) -quinazolin-4-yl]-(1H-indazol-3-yl) -amine (IIc-89): in a manner analogous to method A mentioned above To give a white solid; 1 H NMR (DMSO) δ 13.14 (s, 1H), 11.31 (br. S, 1H), 10.51 (br. S, 1H), 8.59 (d, 1H), 7.91 (t, 1H), 7.65 (d, 3H), 7.56 (t, 1H), 7.50 (m, 2H), 7.45 (dd, 1H), 7.26 (d, 2H), 7.08 (t, 1H); MS 378.2 (M + H) + .
    [1183] Example 169 [2- (4-cyanobenzylamino) -quinazolin-4-yl]-(1H-indazol-3-yl) -amine (IIc-90): In a manner analogous to method A mentioned above To give a white solid; 1 H NMR (DMSO) δ 13.12 (s, 1H), 12.91 (br. S, 1H), 11.60 (br. S, 1H), 8.57 (d, 1H), 7.91 (t, 1H), 7.63 (d, 1H), 7.55 (m, 5H), 7.38 (t, 1H), 6.89 (t, 1H), 6.84 (br. D, 2H), 4.19 (s, 2H); MS 392.2 (M + H) + .
    [1184] Example 170 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-yloxy) -quinazolin-4-yl] -amine (IIb-1): the above-mentioned method Prepared in a similar manner to B to give a white solid. mp 327-328 ° C; 1 H NMR (DMSO) δ 0.05-0.07 (2H, m), 0.50-0.68 (2H, m), 1.28-1.40 (1H, m), 5.68 (1H, s), 7.40-7.50 (2H, m), 7.50-7.64 (3H, m), 7.70-7.80 (2H, m), 7.82-8.08 (3H, m), 8.64 (1H, d), 10.58 (1H, s), 12.07 (1H, s); IR ( Solid) 1621, 1595, 1575, 1554, 1508, 1480, 1410, 1385, 1320, 1254, 1240, 1212, 1166, 830, 819, 758; MS 394.4 (M + H) +
    [1185] Example 171 (5-methyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-yloxy) -quinazolin-4-yl] -amine (IIb-2): Method B mentioned above Prepared in a similar manner to yield a pale brown solid. mp> 300 ° C .; 1 H NMR (DMSO) δ 1.62 (3H, s), 5.65 (1H, s), 7.96 (2H, br s), 7.55 (3H, d), 7.76 (2H, m), 7.92 (1H, d), 8.00 (2H, m), 8.58 (1H, d), 10.56 (1H, s), 11.99 (1H, s); IR (solid) 1625, 1601, 1571, 1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159; MS 368.7 (M + H) +
    [1186] Example 172 (5-Methyl-2H-pyrazol-3-yl)-(2-phenoxy-quinazolin-4-yl) -amine (IIb-3): Prepared in a similar manner to Method B mentioned above A brown solid is obtained. mp 287-290 ° C .; 1 H NMR (DMSO) δ 2.10 (3H, s), 5.92 (1H, s), 7.23 (2H, d), 7.29 (1H, t), 7.38 (1H, t), 7.46-7.53 (3H, m) , 7.85 (1 H, t), 8.58 (1 H, d), 10.55 (1 H, s), 12.11 (1 H, s); IR (solid) 1622, 1602, 1572, 1556, 1542, 1477, 1454, 1402, 1373, 1316, 1249, 1200, 1172, 1158; MS 318.3 (M + H) +
    [1187] Example 173 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (5,6,7,8-tetrahydronaphthalen-2-yloxy) -quinazolin-4-yl] -amine (IIb-4): Prepared in a similar manner to Method B mentioned above, to obtain a solid. mp 277-279 ° C .; 1 H NMR (DMSO) δ 0.40-0.50 (2H, m), 0.89-0.96 (2H, m), 1.71-1.87 (5H, m), 2.70-2.83 (4H, m), 5.88 (1H, s), 6.88-6.96 (2H, m), 7.12 (1H, d), 7.39 (1H, t), 7.58 (1H, d), 7.76 (1H, t), 8.58 (1H, d), 10.54 (1H, s) , 12.20 (1 H, s); IR (solid) 1731, 1641, 1614, 1570, 1506, 1495, 1464, 1424, 1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4 (M + H) +
    [1188] Example 174 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methylphenoxy) -quinazolin-4-yl] -amine (IIb-5): Method B mentioned above Prepared in a similar manner to yield an off-white solid. mp 283-284 ° C .; 1 H NMR (DMSO) δ 0.49-0.53 (2H, m), 0.89-0.96 (2H, m), 1.72-1.81 (1H, m), 2.40 (3H, s), 5.82 (1H, s), 7.03 ( 1H, d), 7.08 (1H, s), 7.15 (1H, d), 7.35-7.46 (2H, m), 7.58 (1H, d), 7.78 (1H, t), 8.62 (1H, d), 10.58 (1H, s), 12.25 (1H, s); IR (solid) 1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319, 1253, 1189, 1158, 997, 842, 789, 763; MS 358.4 (M + H) +
    [1189] Example 175 [2- (3-methoxyphenoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIb-6): Method B mentioned above Prepared in a similar manner to yield a white solid. mp 277-278 ° C; 1 H NMR (DMSO) δ 2.15 (3H, s), 3.78 (3H, s), 6.00 (1H, s), 6.77-6.90 (3H, m), 7.30-7.41 (2H, m), 7.52 (1H, d), 7.70 (1 H, t), 8.59 (1 H, d), 10.57 (1 H, s), 12.10 (1 H, s); IR (solid) 1623, 1603, 1575, 1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142, 1046, 1022, 833, 760; MS 348.4 (M + H) +
    [1190] Example 176 [2- (3,4-Dimethoxyphenoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIb-7): mentioned above Prepared in a similar manner to Method B to yield an off-white solid. mp 277-278 ° C; 1 H NMR (DMSO) δ 2.09 (3H, s), 3.70 (3H, s), 3.78 (3H, s), 5.98 (1H, s), 6.73-6.77 (1H, m), 6.90 (1H, s) , 7.00 (1H, d), 7.35-7.45 (1H, m), 7.58 (1H, d), 7.70-7.78 (1H, m), 8.63 (1H, d), 10.55 (1H, s), 12.19 (1H , s) .; IR (solid) 1626, 1603, 1576, 1557, 1509, 1481, 1436, 1409, 1382, 1372, 1318, 1249, 1227, 1195, 1180, 1158, 1120, 1029, 965, 835, 803, 767,753; MS 378.4 (M + H) +
    [1191] Example 177 [2- (benzo [1,3] dioxol-5-yloxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIb-8 ): Prepared in a similar manner to Method B mentioned above to give an off-white solid. mp 296-299 ° C. (decomposition); 1 H NMR (DMSO) δ 2.13 (3H, s), 6.05 (1H, s), 6.09 (2H, s), 6.69 (1H, d), 6.90 (1H, s), 6.98 (1H, d), 7.39 (1H, t), 7.53 (1H, d), 7.70 (1H, t), 8.58 (1H, d), 10.59 (1H, s); IR (solid) 1602, 1577, 1538, 1508, 1499, 1481, 1455, 1401, 1377, 1323, 1251, 1241, 1169, 1121, 1038, 1022, 951, 935, 863, 813, 752; MS 362.4 (M + H) +
    [1192] Example 178 [2- (3-methoxycarbonylphenoxy) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIb-9): mentioned above Prepared in a similar manner to Method B to yield an off-white solid. mp 269-270 ° C .; 1 H NMR (DMSO) δ 2.05 (3H, s), 3.90 (3H, s), 5.88 (1H, s), 7.00-7.90 (7H, m), 8.50-8.65 (1H, m), 10.65 (1H, s); IR (solid) 1722, 1626, 1605, 1578, 1559, 1507, 1429, 1378, 1317, 1282, 1272, 1255, 1204, 1185, 1096, 1021, 990, 869, 841, 758; MS 362.4 (M + H) +
    [1193] Example 179 (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl) -amine (IId-1): in a similar manner to Method C mentioned above To give a pale yellow solid. mp 265-267 ° C .; 1 H NMR (DMSO) δ 0.67 (2H, m), 0.93 (2H, m), 1.87 (1H, m), 5.19 (2H, s), 6.55 (1H, br s), 6.90-7.02 (3H, m ), 7.26-7.30 (2H, m), 7.54 (1H, m), 7.74-7.83 (2H, m), 8.61 (1H, m), 10.45 (1H, br s), 12.18 (1H, br s); MS 358.4 (M + H) +
    [1194] Example 180 (2-benzyloxymethyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IId-2): in a similar manner to Method C mentioned above To give a white solid. mp 211-213 ° C; 1 H NMR (DMSO) δ 0.65 (2H, m), 0.90 (2H, m), 1.86 (1H, m), 4.63 (2H, s), 4.68 (1H, s), 6.71 (1H, s), 7.28 -7.54 (6H, m), 7.76-7.81 (2H, m), 8.61 (1H, m), 10.41 (1H, s), 12.19 (1H, s); MS 372.3 (M + H) +
    [1195] Example 181 (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IId-3): prepared in a similar manner to Method D mentioned above Obtain a white solid. mp 219-221 ° C; 1 H NMR (DMSO) δ 0.66 (2H, m), 0.95 (2H, m), 1.87 (1H, m), 4.11 (2H, s), 6.31 (1H, s), 7.20-7.50 (6H, m) , 7.71-7.79 (2H, m), 8.55 (1H, m), 10.27 (1H, s), 12.15 (1H, s); MS 342.7 (M + H) +
    [1196] Example 182 (5-cyclopropyl-2H-pyrazol-3-yl)-(2-methyl-quinazolin-4-yl) -amine (IId-4): Prepared in a similar manner to Method C mentioned above Obtain a white solid. mp 289-290 ° C .; 1 H NMR (DMSO) δ 2.31 (3H, s), 2.71 (3H, s), 6.73 (1H, s), 7.75 (2H, q), 8.04 (1H, t), 8.82 (1H, s), 11.94 (1 H, s), 12.65 (1 H, s); IR (solid) 3266, 1636, 1607, 1579, 1479, 1407, 769, 668; MS 240.4 (M + H) +
    [1197] Example 183 [2- (4-Chlorophenoxymethyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazole-3 -Yl) -amine (IId-5): prepared in a similar manner to above-mentioned method C, to give a white solid; 1 H NMR (DMSO) δ 1.58 (2H, m), 1.68 (2H, m), 1.85 (2H, m), 2.20 (3H, s), 2.90 (2H, m), 3.00 (2H, m), 5.26 (2H, s), 6.15 (1H, s), 7.15 (2H, d), 7.40 (2H, d), 10.25 (1H, br); MS 384.3 (M + H) + .
    [1198] Example 184 [2- (4-Chlorophenoxymethyl) -5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IId-6): prepared in a similar manner to above-mentioned method C, to give a white solid; 1 H NMR (DMSO) δ 1.80 (4H, m), 2.15 (3H, s), 2.55 (2H, m obscured), 2.75 (2H, m), 5.25 (2H, s), 6.12 (1H, s), 7.08 (2H, d), 7.35 (2H, d), 9.80 (1H, br); MS 370.2 (M + H) + .
    [1199] Example 185 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -6-phenylpyrimidin-4-yl] -amine (IIIa-1): Prepared in a similar manner to Method L mentioned above, to obtain a white solid. mp 233-234 ° C; 1 H NMR (DMSO) δ 0.21 (2H, br s), 0.56 (2H, br s), 1.17 (1H, br m), 5.35 (1H, br s), 7.02 (1H, br s), 7.49 (3H , m), 7.59 (2H, m), 7.73 (1H, d), 7.88 (2H, m), 8.02 (3H, m), 8.30 (1H, m), 10.01 (1H, s), 11.75 (1H, br s); IR (solid); MS 436.7 (M + H) +
    [1200] Example 186 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxycarbonyl-phenylylsulfanyl) -6-phenylpyrimidin-4-yl] -amine (IIIa -2): Prepared in a similar manner to Method L mentioned above, to obtain a white solid. mp 126-129 ° C .; 1 H NMR (DMSO) δ 0.52 (2H, m), 0.87 (2H, m), 1.69 (1H, m), 3.87 (3H, s), 5.47 (1H, s), 7.03 (1H, br s), 7.49 (3H, m), 7.67 (1H, m), 7.87 (2H, m), 7.94 (1H, m), 8.09 (1H, m), 8.23 (1H, m), 10.07 (1H, s), 11.94 (1H, s); IR (solid); MS 444.7 (M + H) +
    [1201] Example 187 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine (IIIa-3): mentioned above Prepared in a similar manner to Method L to afford a white solid. mp 248-250 ° C .; 1 H NMR (DMSO) δ 0.21 (2H, br s), 0.55 (2H, br s), 0.94 (1H, br m), 5.31 (1H, br s), 6.55 (1H, br s), 7.57-7.66 (3H, m), 7.99-8.03 (4H, m), 8.25 (1H, s), 9.94 (1H, s), 11.75 (1H, br s); IR (solid); MS 360.7 (M + H) +
    [1202] Example 188 (5-cyclopropyl-2H-pyrazol-3-yl)-[5,6-dimethyl-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine (IIIa- 4): Prepared in a similar manner to Method L mentioned above to give a white solid. mp> 270 ° C .; 1 H NMR (DMSO) δ 0.14 (2H, d), 0.45 (2H, d), 0.78 (1H, s), 2.05 (3H, s), 2.27 (3H, s), 5.26 (1H, s), 7.60 (3H, d), 7.99 (3H, d), 8.21 (1H, s), 8.66 (1H, s), 11.60 (1H, s); IR (solid) 1560, 1508, 1478, 1288, 1176, 1109, 994, 809, 740, 669; MS 388.7 (M + H) +
    [1203] Example 189 (5-cyclopropyl-2H-pyrazol-3-yl)-[5-methyl-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine (IIIa-5) : Prepared in a similar manner to Method L mentioned above to give a white solid. mp 197 ° C .; 1 H NMR (DMSO) δ 0.21 (2H, d), 0.51 (2H, d), 0.78 (1H, s), 2.08 (3H, s), 5.40 (1H, s), 7.57 (2H, d), 7.62 (1H, d), 7.92 (1H, s), 7.97 (3H, d), 8.22 (1H, s), 8.88 (1H, s), 11.70 (1H, s); IR (solid) 1738, 1583, 1563, 1488, 1460, 1364, 1234,1216, 808, 656; MS 374.2 (M + H) +
    [1204] Example 190 (5-cyclopropyl-2H-pyrazol-3-yl)-[6-methyl-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine (IIIa-6) : Prepared in a similar manner to Method L mentioned above to give a white solid. mp 232 ° C; 1 H NMR (DMSO) δ 0.15 (2H, s), 0.51 (2H, s), 0.92 (1H, s), 2.20 (3H, s), 5.22 (1H, s), 7.60 (2H, s), 7.67 (1H, d), 7.98 (3H, s), 8.24 (1H, s), 9.79 (1H, s), 11.60 (1H, s); IR (solid) 1586, 1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666; MS 374.2 (M + H) +
    [1205] Example 191 (5-cyclopropyl-2H-pyrazol-3-yl)-[6- (morpholin-4-yl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -Amine (IIIa-7): Tri in a solution of 2,4,6-trichloropyrimidine (600 mg, 3.27 mmol) and 3-amino-5-cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 ml) Ethylamine (456 μl, 3.27 mmol) is added and the resulting mixture is stirred at room temperature for 15 hours. The solvent was evaporated and the residue was purified by flash chromatography (SiO 2 , hexanes / AcOEt gradient) to give (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl ) -Amine (705 mg, 80%) is obtained.
    [1206] (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl) -amine (211 mg, 0.781 mmol) and 2-naphthalenethiol in tert-butanol (5 ml) Triethylamine (174 μl, 1.25 mmol) is added to a solution of (125 mg, 0.781 mmol), and the resulting mixture is heated under reflux for 15 h. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO 3 . The organic layer is washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 , hexanes / AcOEt gradient) to give [6-chloro-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl]-(5-cyclopropyl-2H- Obtain pyrazol-3-yl) -amine.
    [1207] [6-Chloro-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (70 mg, 1.78.10 formed above) -4 mol) is dissolved in morpholine (3 ml) and the mixture is heated at 120 ° C for 15 h. The solvent is evaporated and the residue is purified by flash chromatography to give IIIa-7 (50 mg, 63%) as a white solid. mp 118-120 ° C .; 1 H NMR (DMSO) δ 0.34-0.91 (4H, 4xm), 1.28 and 1.78 (1H, 2xm), 3.32 (2H, m), 3.60 (6H, m), 5.38-6.16 (2H, br m), 7.55 -7.66 (3H, m), 7.95-8.02 (3H, m), 8.19 and 8.23 (1H, 2xs), 9.28 and 9.31 (1H, 2xbr s), 11.71 and 11.84 (1H, 2xbr s); IR (solid); MS 445.2 (M + H) +
    [1208] Example 192 (5-cyclopropyl-2H-pyrazol-3-yl)-[6- (1-methylpiperazin-4-yl) -2- (naphthalen-2-ylsulfanyl) -pyrimidine-4 -Yl] -amine (IIIa-8): Prepared in a manner substantially similar to that described above for compound IIIb-7, to yield a white solid. mp 113-115 ° C .; 1 H NMR (DMSO) δ 0.35-0.91 (4H, 4xm), 1.31 and 1.78 (1H, 2xm), 2.17 and 2.19 (3H, 2xs), 2.29 (4H, m), 3.35 (2H, m), 3.61 ( 2H, m), 5.38-6.20 (2H, br m), 7.55-7.66 (3H, m), 7.95-8.02 (3H, m), 8.17 and 8.23 (1H, 2xs), 9.26 and 9.32 (1H, 2xbr s ), 11.71 and 11.85 (1H, 2xbr s); IR (solid); MS 458.3 (M + H) +
    [1209] Example 193 [6- (2,6-dimethylphenyl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amine (IIIa-9): Prepared in a similar manner to Method L mentioned above, to give an off-white solid. mp 148-152 ° C .; 1 H NMR (DMSO) δ 2.10 (6H, s), 2.26 (3H, d), 5.09 and 6.31 (1H, 2x br s), 7.03 (3H, s), 7.22 (1H, s), 7.59 (2H, t), 7.69 (1H, d), 7.99 (3H, d), 8.28 (1H, s), 9.93 (1H, s), 11.67 (1H, br s); IR (solid) 2970, 1739, 1436, 1365, 1229, 1217, 1205; MS 438.3 (M + H) +
    [1210] Example 194 [6- (2-Methylphenyl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -10): Prepared in a similar manner to Method L mentioned above to give a white solid. mp 211-214 ° C; 1 H NMR (DMSO) δ 1.41 (3H, s), 2.30 (3H, s), 5.26 and 6.55 (1H, 2x br s), 7.34 (5H, m), 7.62 (2H, t), 7.70 (1H, d), 7.99 (3H, t), 8.30 (1 H, s), 9.97 (1 H, s), 11.73 (1 H, br s); IR (solid) 2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0 (M + H) +
    [1211] Example 195 [2- (4-acetamido-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-11 ): Prepared in a similar manner to Method L mentioned above to give a white solid. mp 153-155 ° C; 1 H NMR (DMSO) δ 2.01 (3H, s), 2.08 (3H, s), 5.43 (1H, s), 6.96 (1H, br s), 7.49-7.88 (9H, m), 10.00 (1H, br s), 10.23 (1 H, s), 11.86 (1 H, br s); MS 417.2 (M + H) +
    [1212] Example 196 (5-methyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -6-phenyl-pyrimidin-4-yl] -amine (IIIa-12): Prepared in a similar manner to Method L mentioned above, to obtain a white solid. mp 237-239 ° C; 1 H NMR (DMSO) δ 1.39 (3H, br s), 5.12 (1H, br s), 6.98 (1H, br s), 7.50 (3H, m), 7.62-7.63 (2H, m), 7.72 (1H , d), 7.90 (2H, m), 8.03-8.05 (3H, m), 8.31 (1H, s), 10.00 (1H, s), 11.73 (1H, br s); IR (solid); MS 410.2 (M + H) +
    [1213] Example 197 [2- (4-Isobutyrylylamino-phenylsulfanyl) -6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-13 ): Prepared in a similar manner to Method L mentioned above to give an off-white solid. mp 201-202 ° C; 1 H NMR (DMSO) δ 1.05-1.13 (6H, m), 1.97 (3H, s), 2.65 (1H, m), 5.37 (1H, br s), 6.93 (1H, br s), 7.50-7.58 ( 5H, m), 7.78-7.90 (4H, m), 9.99, 10.12 and 11.84 (3H, 3 x br s); IR (solid) 1676, 1614, 1586, 1573, 1514, 1483, 1395, 1299, 1262, 1242, 1214, 1168, 1089, 988; MS 445.3 (M + H) +
    [1214] Example 198 [6- (4-Methylpiperazin-1-yl) -2-methylsulfanyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -14): prepared in a similar manner to method M mentioned above to give an off-white solid; 1 H NMR (DMSO) δ 2.18 (3H, s), 2.20 (3H, s), 2.36 (4H, m), 2.41 (3H, s), 3.46 (4H, m), 5.91 (1H, s), 6.41 (1 H, br s), 9.20 (1 H, s), 11.87 (1 H, s); IR (solid); MS 320.3 (M + H) +
    [1215] Example 199 (5-Methyl-2H-pyrazol-3-yl)-[6-phenyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl] -amine (IIIa-15 ): Prepared in a similar manner to Method L mentioned above to give a pale pink solid. mp 204-206 ° C; 1 H NMR (DMSO) δ 1.09-1.13 (3H, m), 2.00 (3H, s), 2.33-2.37 (2H, m), 5.40 (1H, br s), 6.95 (1H, br s), 7.50 ( 3H, m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.88 (2H, m), 9.99, 10.15 and 11.85 (3H, 3 x br s); IR (solid) 1678, 1623, 1580, 1534, 1496, 1453, 1398, 1307, 1245, 1203, 1119, 1049, 1030, 1004; MS 431.2 (M + H) +
    [1216] Example 200 [2- (4-Cyclopropanecarbonylamino-phenylsulfanyl) -6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa- 16): Prepared in a similar manner to Method L mentioned above to give an off-white solid. mp 253-255 ° C .; 1 H NMR (DMSO) δ 0.82-0.83 (4H, m), 1.83 (1H, m), 2.00 (3H, s), 5.41 (1H, br s), 6.88 (1H, br s), 7.42-7.50 ( 3H, m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.89 (2H, m), 9.99, 10.47 and 11.85 (3H, 3 x br s); IR (solid) 1672, 1621, 1591, 1581, 1573, 1537, 1495, 1448, 1405, 1390, 1312, 1254, 1246, 1202, 1192, 1179, 1119.2, 1005, 959; MS 443.2 (M + H) +
    [1217] Example 201 (5-methyl-2H-pyrazol-3-yl)-{6-phenyl-2- [4- (propane-1-sulfonylamino) -phenylsulfanyl] -pyrimidin-4-yl} -Amine (IIIa-17): Prepared in a similar manner to Method L mentioned above to give an off-white solid. mp 232-235 ° C .; 1 H NMR (DMSO) δ 0.94 (3H, t), 1.71 (2H, m), 2.12 (3H, s), 3.13 (2H, t), 5.59 (1H, s), 7.31 (2H, d), 7.49 (3H, s), 7.59 (2H, d), 7.85 (2H, s), 10.00 (1H, br s), 10.16 (1H, s), 12.05 (1H, br s); IR (solid) 1628, 1587, 1545, 1525, 1496, 1455, 1311, 1255, 1236, 1212, 1186, 1140, 1032, 1001, 934; MS 481.2 (M + H) +
    [1218] Example 202 [2- (4-ethanesulfonylamino-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa- 18): Prepared in a similar manner to Method L mentioned above to give a pale yellow solid. mp 251-254 ° C; 1 H NMR (DMSO) δ 1.21 (3H, t), 2.12 (3H, s), 3.15 (2H, q), 5.59 (1H, s), 7.32 (2H, d), 7.49 (3H, s), 7.57 (2H, d), 7.85 (2H, s), 9.99 (1H, br s), 10.15 (1H, br s), 11.90 (1H, br s); IR (solid) 1621, 1585, 1542, 1523, 1495, 1455, 1315, 1257, 1208, 1142, 1049, 1033, 1002,932; MS 467.2 (M + H) +
    [1219] Example 203 [2- (4-Acetamidophenyl-sulfanyl) -6- (2-methylphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-19): Prepared in a similar manner to Method L mentioned above, to obtain a white solid. mp 212-214 ° C; 1 H NMR (DMSO) δ 2.01 (3H, s), 2.08 (3H, s), 2.24 (3H, s), 5.43 (1H, s), 6.56 (1H, br s), 7.49-7.88 (9H, m ), 10.00 (1H, br s), 10.23 (1H, s), 11.86 (1H, br s); IR (solid) 1701, 1634, 1588, 1555, 1496, 1390, 1307, 1208, 1169, 823, 803; MS 431.4 (M + H) +
    [1220] Example 204 [2- (4-Isobutanecarbonylamino-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -20): Prepared in a similar manner to Method L mentioned above to give an off-white solid. mp 241-243 ° C .; 1 H NMR (DMSO) δ 0.95-0.96 (6H, m), 2.00 (3H, s), 2.11 (1H, m), 2.23-2.25 (2H, m), 5.43 (1H, br s), 6.95 (1H , br s), 7.50-7.58 (5H, m), 7.77-7.89 (4H, m), 10.00, 10.13 and 11.84 (3H, 3 x br s); IR (solid) 1660, 1628, 1589, 1575, 1543, 1525, 1496, 1451, 1398, 1357, 1314, 1301, 1251, 1206, 1108, 995; MS 459.2 (M + H) +
    [1221] Example 205 [2- (4-Acetamido-phenylsulfanyl) -5-methyl-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-21): Prepared in a similar manner to Method L mentioned above, to obtain a pale pink solid. mp 276-277 ° C; 1 H NMR (DMSO) δ 1.98 (3H, s), 2.08 (6H, s), 5.41 (1H, br s), 7.47-7.55 (7H, m), 7.72-7.74 (2H, m), 8.89, 10.20 And 11.87 (3H, 3 x br s); IR (solid) 1676, 1591, 1555, 1540, 1519, 1493, 1393, 1375, 1303, 1260, 1230, 1176, 1148, 1045, 1011, 969; MS 431.2 (M + H) +
    [1222] Example 206 [2- (4-acetamido-phenylsulfanyl) -6- (4-methoxyphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -Amine (IIIa-22): Prepared in a similar manner to the above mentioned method L to give an off-white solid. mp 241-245 ° C .; 1 H NMR (DMSO) δ 1.99 (3H, s), 2.06 (3H, s), 3.82 (3H, s), 5.44 (1H, s), 7.03 (2H, d), 7.53 (2H, d), 7.71 (2H, s), 7.83 (2H, s), 10.12 (1H, s), 10.23 (1H, s), 11.84 (1H, s); IR (solid) 1627, 1606, 1571, 1511, 1313, 1257, 1181, 830; MS 447.2 (M + H) +
    [1223] Example 207 [6- (3-Acetamidophenyl) -2- (4-acetamido-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl ) -Amine (IIIa-23): Prepared in a similar manner to the abovementioned method L to give a brown solid. mp 227-230 ° C .; 1 H NMR (DMSO) δ 2.01 (3H, s), 2.11 (6H, s), 5.34 (1H, s), 6.99 (1H, br s), 7.41 (1H, t), 7.49-7.62 (3H, m ), 3.71-3.76 (3H, m), 8.19 (1H s), 10.09-10.18 (2H, br s), 10.23 (1H, s), 12.20 (1H, br s); IR (solid) 1635, 1573, 1533, 1488, 1372, 1318, 1297, 827, 798; MS 474.3 (M + H) +
    [1224] Example 208 [2- (4-Isopropanesulfonylamino-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -24): Prepared in a similar manner to Method L mentioned above, to obtain a white solid. mp 255-257 ° C; 1 H NMR (DMSO) δ 1.28 (6H, d), 2.14 (3H, s), 3.32 (1H, s), 5.60 (1H, s), 7.36 (2H, d), 7.49 (3H, s), 7.60 (2H, d), 7.85 (2H, s), 10.00 (1H, br s), 10.11 (1H, s), 11.92 (1H, br s); IR (solid) 1625, 1587, 1574, 1545, 1525, 1495, 1313, 1295, 1257, 1234, 1136, 1000, 934; MS 481.2 (M + H) +
    [1225] Example 209 {2- [4- (2-Dimethylamino-acetylamino) -phenylsulfanyl] -6-phenyl-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -Amine (IIIa-25): Prepared in a similar manner to Method L mentioned above to give an off-white solid. mp 213-215 ° C; 1 H NMR (DMSO) δ 2.00 (3H, s), 2.31 (6H, s), 3.15 (2H, s), 5.45 (1H, s), 6.83 (1H, br s), 7.46-7.51 (3H, m ), 7.59 (2H, d), 7.80-7.92 (5H, m), 9.98 (1H, s), 10.05 (1H, s); IR (solid) 1701, 1617, 1587, 1571, 1509, 1480, 1456, 1304, 1284, 1254, 1238, 1213, 1181, 1156, 987, 833, 782, 754, 695; MS 460.3 (M + H) +
    [1226] Example 210 [2- (3-Chloro-benzylsulfanyl) -6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ( IIIa-26): Prepared in a similar manner to Method M mentioned above to give a white solid. mp 224-225 ° C .; 1 H NMR (DMSO) δ 2.17 (3H, s), 3.40-3.50 (4H, m), 3.60-3.71 (4H, m), 4.30 (2H, s), 5.95 (1H, brs), 6.41 (1H, brs), 7.23-7.55 (4H, m), 9.31 (1H, s), 11.89 (1H, brs); IR (solid) 1557, 1476, 1442, 1401, 1314, 1232, 1121, 1018; MS 417.4 (M + H) +
    [1227] Example 211 [2- (3-Chloro-benzylsulfanyl) -6- (2-methoxy-ethylamino) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -Amine (IIIa-27): Prepared in a similar manner to Method M mentioned above to give a white solid. mp 101-102 ° C .; 1 H NMR (DMSO) δ 2.15 (3H, s), 3.21 (3H, s), 3.28-3.41 (4H, m), 4.29 (2H, s), 5.78 (1H, brs), 6.20 (1H, brs) , 7.10 (1 H, brs), 7.21-7.50 (4 H, m), 9.01 (1 H, brs); IR (solid) 1598, 1555, 1527, 1336, 1293, 1117, 1079, 974, 783; MS 405.4 (M + H) +
    [1228] Example 212 [2-benzylsulfanyl-6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -28): prepared in a similar manner to Method M mentioned above to obtain a yellow gum; 1 H NMR (CDCl 3 ) δ 2.23 (3H, s), 2.28 (3H, s), 2.31-2.64 (4H, m), 3.30-3.65 (4H, m), 4.38 (2H, s), 5.83 (1H , s), 6.23 (1H, broad singlet), 7.17-7.49 (5H, m), 7.98-8.18 (1H, m); IR (solid) 1555, 1494, 1371, 1315, 1286, 1233, 999, 977, 801, 774, 709; MS 396.4 (M + H) +
    [1229] Example 213 [2-benzylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-29): Prepared in a similar manner to the method M mentioned to obtain an off-white foam; 1 H NMR (CDCl 3 ) δ 2.31 (3H, s), 3.39-3.80 (8H, m), 4.39 (2H, s), 5.84 (1H, s), 6.25 (1H, brs), 7.20-7.50 (5H m), 8.10 (1 H, s); IR (solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767, 698; MS 383.4 (M + H) +
    [1230] Example 214 [2- (3-Chloro-benzylsulfanyl) -6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3- Il) -amine (IIIa-30): prepared in a similar manner to the above-mentioned method M to give a white foam; 1 H NMR (CDCl 3 ) δ 2.31 (3H, s), 2.35 (3H, s), 2.40-2.51 (4H, m), 3.56-3.69 (4H, m), 4.34 (2H, s), 5.85 (1H , s), 6.29 (1H, brs), 6.89 (1H, s), 7.18-7.50 (4H, m); IR (solid) 1553, 1514, 1484, 1446, 1277, 1228, 999, 799; MS 430.4 (M + H) +
    [1231] Example 215 [2- (4-methoxy-benzylsulfanyl) -6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazole-3 -Yl) -amine (IIIa-31): prepared in a similar manner to method M mentioned above to give a yellow oil; 1 H NMR (CDCl 3 ) δ 2.28 (3H, s), 2.33 (3H, s), 2.44-2.45 (4H, m), 3.62 (4H, m), 3.80 (3H, s), 4.34 (2H, s ), 5.32 (1 H, s), 6.28 (1 H, br s), 6.83-6.85 (2 H, m), 7.34-7.36 (2 H, m); IR (solid) 1659, 1554, 1508, 1485, 1449, 1366, 1318, 1302, 1277, 1230, 1166, 1146, 1030, 999, 973, 948; MS 443.4 (M + H) +
    [1232] Example 216 [2- (4-Acetamido-phenylsulfanyl) -6-tert-butyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ( IIIa-32): Prepared in a similar manner to Method L mentioned above to give a white solid. mp 227-228 ° C; 1 H NMR (DMSO) δ 1.10 (3H, br s), 1.20 (9H, s), 2.00 (3H, s), 2.35 (2H, q), 5.35 (1H, br s), 6.55 (1H, br s ), 7.55 (2H, d), 7.75 (2H, d), 10.1 (1H, br s), 1.15 (1H, s), 12.1 (1H, br s); IR (solid); MS (M + H) +
    [1233] Example 217 (5-cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl] -amine (IIIa- 33): Prepared in a similar manner to Method L mentioned above to give an off-white solid. mp 208-209 ° C; 1 H NMR (DMSO) δ 0.52 (2H, m), 0.80 (2H, m), 1.08-1.10 (3H, m), 1.65 (1H, br s), 2.33-2.37 (2H, m), 5.50 (1H , br s), 7.03 (1H, br s), 7.47 (3H, m), 7.50-7.58 (2H, m), 7.76-7.77 (2H, m), 7.88-7.98 (2H, m), 10.00, 10.11 And 11.86 (3H, 3 x br s); IR (solid) 1676, 1617, 1575, 1539, 1520, 1485, 1459, 1418, 1395, 1304, 1255, 1243, 1215, 1161, 1071, 990; MS 457.4 (M + H) +
    [1234] Example 218 [2- (3-Chloro-benzylsulfanyl) -6- (piperidin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -Amine (IIIa-34): Prepared in a similar manner to Method M mentioned above to give a white solid. mp 234-235 ° C .; 1 H NMR (DMSO) δ 1.40-1.64 (6H, m), 2.13 (3H, s), 3.42-3.51 (4H, m), 4.27 (2H, s), 5.85 (1H, br s), 6.46 (1H , brs), 7.23-7.41 (3H, m), 7.48 (1H, s), 9.18 (1H, s), 11.83 (1H, s); IR (solid) 1598, 1546, 1483, 1398, 1317, 1227, 974, 798, 779; MS 415.4 (M + H) +
    [1235] Example 219 (5-methyl-2H-pyrazol-3-yl)-{2- [4- (morpholinsulfonyl) -benzylsulfanyl] -6-morpholin-4-yl-pyrimidin-4- Il} -amine (IIIa-35): prepared in a similar manner to Method M mentioned above to give a white solid; 1 H NMR (DMSO) δ 2.24 (3H, s), 2.90-3.01 (4H, m), 3.29-3.36 (4H, m), 3.48-3.57 (4H, m), 3.67-3.75 (4H, m), 4.43 (2H, s), 5.82-6.10 (2H, m), 7.50-7.70 (5H, m); IR (solid) 1550, 1483, 1441, 1346, 1308, 1255, 1160, 1112, 941, 726; MS 532.5 (M + H) +
    [1236] Example 220 {6- (2-methoxy-ethylamino) -2- [4- (morpholinesulfonyl) -benzylsulfanyl] -pyrimidin-4-yl}-(5-methyl-2H-pyrazole 3-yl) -amine (IIIa-36): Prepared in a similar manner to the abovementioned method M to give a white solid. mp 193-195 ° C; 1 H NMR (DMSO) δ 2.15 (3H, s), 2.79-2.89 (4H, m), 3.34 (3H, s), 3.40-3.51 (4H, m), 3.59-3.67 (4H, m), 4.41 ( 2H, s), 5.76-5.72 (1H, m), 6.20 (1H, brs), 7.10 (1H, brs), 7.61-7.74 (4H, m), 9.03 (1H, brs), 11.81 (1H, brs) ; IR (solid) 1593, 1555, 1484, 1350, 1298, 1255, 1160, 1107, 936; MS 520.5 (M + H) +
    [1237] Example 221 {6- (4-Methylpiperazin-1-yl) -2- [4- (morpholinsulfonyl) -benzylsulfanyl] -pyrimidin-4-yl}-(5-methyl-2H- Pyrazol-3-yl) -amine (IIIa-37): Prepared in a similar manner to the above-mentioned method M to give a white solid. mp 206-207 ° C; 1 H NMR (DMSO) δ 2.09 (3H, s), 2.20 (3H, s), 2.26-2.40 (4H, m), 2.78-2.88 (4H, m), 3.38-3.49 (4H, m), 3.56- 3.67 (4H, m), 4.41 (2H, s), 5.82 (1H, brs), 6.42 (1H, brs), 7.60-7.74 (4H, m), 9.26 (1H, s), 11.89 (1H, brs) ; IR (solid) 1583, 1558, 1479, 1346, 1231, 1160, 1112, 998, 969, 926; MS 545.5 (M + H) +
    [1238] Example 222 [6-methoxymethyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -38): prepared in a similar manner to Method L mentioned above to give a white solid; 1 H NMR (DMSO) δ 1.03-1.14 (3H, m), 2.00 (3H, s), 2.29-2.40 (2H, m), OMe under DMSO, 4.22 (2H, m), 5.26 (1H, brs), 6.45 (1H, brs), 7.44-7.56 (2H, m), 7.68-7.80 (2H, m), 9.86 (1H, brs), 10.11 (1H, s), 11.79 (1H, brs); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360, 1269, 1174, 1107; MS 399.4 (M + H) +
    [1239] Example 223 [2- (4-methoxycarbonyl-phenylsulfanyl) -6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ( IIIa-39): Prepared in a similar manner to Method L mentioned above to give a white solid. mp 204-205 ° C; 1 H NMR (DMSO) δ 1.89 (3H, brs), 3.85 (3H, s), OMe under DMSO, 4.23 (2H, s), 5.22 (1H, brs), 6.51 (1H, brs), 7.70-7.81 ( 2H, m), 7.96-8.06 (2H, m), 9.99 (1H, brs), 11.85 (1H, brs); IR (solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119, 1109, 997, 841; MS 386.3 (M + H) +
    [1240] Example 224 [2- (3,5-Dimethoxy-benzylsulfanyl) -6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -Amine (IIIa-40): prepared in a similar manner to method M mentioned above to give a white solid; 1 H NMR (DMSO) δ 2.15 (3H, s), 3.40-3.49 (4H, m), 3.60-3.74 (10H, m), 4.25 (2H, s), 5.88 (1H, brs), 6.31-6.61 ( 5H, m), 9.32 (1H, s), 11.86 (1H, s); IR (solid) 1581, 1556, 1470, 1439, 1315, 1232, 1205, 1159, 1144; MS 443.4 (M + H) +
    [1241] Example 225 [2- (3,5-Dimethoxy-benzylsulfanyl) -6-pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl ) -Amine (IIIa-41): prepared in a similar manner to method M mentioned above to give a white solid; 1 H NMR (DMSO) δ 1.80-1.97 (4H, m), 2.15 (3H, s), 3.43-3.45 (4H, m), 3.69 (6H, s), 4.26 (2H, s), 5.85 (1H, brs), 6.18 (1H, brs), 6.35 (1H, brs), 6.60 (2H, s), 9.12 (1H, s), 11.88 (1H, s); IR (solid 1598, 1560, 1474, 1470, 1346, 1303, 1207, 1136, 1050; MS 427.4 (M + H) +
    [1242] Example 226 (5-Methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl-2- (naphthalen-2-ylmethylsulfanyl) -pyrimidin-4-yl] -amine (IIIa-42): Prepared in a similar manner to method M mentioned above to give an off-white solid; 1 H NMR (DMSO) δ 2.15 (3H, s), 3.37-3.50 (4H, m), 3.59-3.70 (4H, m), 4.48 (2H, s), 5.88 (1H, brs), 6.40 (1H, brs), 7.40-7.60 (3H, m), 7.78-7.95 (4H, m), 9.30 (1H, s), 11.89 (1H, brs); IR (solid) 1607,1555, 1484, 1441, 1398, 1365, 1308, 1231, 1179, 1112; MS 433.4 (M + H) +
    [1243] Example 227 {2- (4-acetamido-phenylsulfanyl) -6- [4- (3-dimethylamino-propoxy) -phenyl] -pyrimidin-4-yl}-(5-methyl-2H -Pyrazol-3-yl) -amine (IIIa-43): Prepared in a similar manner to method N mentioned above to give a white solid. mp 219-222 ° C .; 1 H NMR (CDCl 3 ) δ 1.97-2.07 (2H, m), 2.14 (3H, s), 2.18 (3H, s), 2.30 (6H, s), 2.52 (2H, t), 4.09 (2H, t), 5.56 (1H, s), 6.80 (1H, br s), 6.99 (2H, d), 7.60 (2H, d), 7.68-7.78 (3H, m), 7.85 (2H, d); IR (solid) 1606, 1590, 1512, 1482, 1309, 1250, 1238, 1210, 1178, 1151, 1055, 989, 824, 711, 690, 665, 656; MS 518.4 (M + H) +
    [1244] Example 228 [2- (4-acetamidophenylsulfanyl) -6- (morpholin-4-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -Amine (IIIa-44): prepared in a similar manner to method P mentioned above to give a white solid; MS 426.4 (M + H) +
    [1245] Example 229 [6-hydroxymethyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa -45): Prepared from IIIa-48 according to Method O to give a white solid; 1 H NMR (DMSO) δ 1.08-1.18 (3H, m), 1.96 (3H, brs), 2.29-2.40 (2H, m), 4.20-4.40 (3H, m), 5.20-5.46 (2H, m), 6.56 (1H, s), 7.50 (2H, d), 7.79 (2H, d), 9.90 (1H, brs), 10.13 (1H, s), 11.78 (1H, brs); MS 385.4 (M + H) +
    [1246] Example 230 [2- (4-acetamido-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-46): remarked above Prepared in a similar manner to Process L, whereby an off-white solid is obtained. mp 249-250 ° C .; 1 H NMR (DMSO) δ 1.99 (3H, s), 2.08 (3H, s), 5.38 (1H, br s), 6.45 (1H, br s), 7.50 (2H, d), 7.71 (2H, d) , 7.98 (1 H, d), 9.89 (1 H, br s), 10.19 (1 H, br s), 11.83 (1 H, br s); IR (solid) 1657, 1609, 1584, 1515, 1494, 1468, 1395, 1372, 1355, 1330, 1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M + H) +
    [1247] Example 231 [6- (1-Butoxycarbonyl) -2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl ) -Amine (IIIa-47): Prepared in a similar manner to the abovementioned method L to give a yellow solid. 1 H NMR (DMSO) δ 0.90-0.98 (3H, m), 1.03-1.12 (3H, m), 1.31-1.45 (2H, m), 1.60-1.71 (2H, m), 1.94 (3H, brs), 2.29-2.40 (2H, m), 4.20-4.30 (2H, m), 5.25 (1H, brs), 7.08 (1H, brs), 7.49-7.55 (2H, m), 7.72-7.81 (2H, m), 10.15 (1H, brs), 10.32 (1H, brs), 11.89 (1H, brs); IR (solid) 1736, 1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 (M + H) +
    [1248] Example 232 [6-methoxycarbonyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ( IIIa-48): Prepared in a similar manner to Method L mentioned above to give a yellow solid; 1 H NMR (DMSO) δ 1.10 (3H, t), 1.94 (3H, brs), 2.35 (2H, q), 3.84 (3H, s), 5.22 (1H, brs), 7.05 (1H, s), 7.52 (2H, d), 7.79 (2H, d), 10.18 (1H, brs), 10.38 (1H, brs), 11.89 (1H, brs) .; IR (solid) 1741, 1679, 1617, 1589, 1512, 1484, 1374, 1284, 1250; MS 413.4 (M + H) +
    [1249] Example 233 (5-methyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl) -amine (IIIc-1): white solid; MS 343.4 (M + H) +
    [1250] Example 234 (5-cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl) -amine (IIIc-2): white solid, mp 267- 269 ° C .; 1 H NMR (DMSO) δ 0.63 (2H, m), 0.96 (2H, m), 1.87 (1H, m), 6.07 (1H, s), 6.84 (1H, br s), 7.20 (1H, m), 7.33-8.05 (9 H, m), 10.52 (1 H, br s), 11.08 (1 H, br s), 12.53 (1 H, br s); IR (solid); MS 369.7 (M + H) +
    [1251] Example 235 (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methylphenylamino) -6-phenyl-pyrimidin-4-yl] -amine (IIIc-3): white solid , mp 267-270 ° C; 1 H NMR (DMSO) δ 0.63 (2H, m), 0.94 (2H, m), 1.87 (1H, m), 2.36 (3H, s), 6.12 (1H, s), 6.81 (1H, br s), 7.03 (1H, m), 7.29-7.94 (8H, m), 10.43 (1H, br s), 11.12 (1H, br s), 12.47 (1H, br s); IR (solid); MS 383.7 (M + H) +
    [1252] Example 236 [2- (4-cyanomethylphenylamino) -6-phenyl-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIIc-4): Light yellow solid, mp 294-297 ° C .; 1 H NMR (DMSO) δ 0.64 (2H, m), 0.97 (2H, m), 1.89 (1H, m), 4.06 (2H, s), 6.07 (1H, s), 6.87 (1H, br s), 7.40 (2H, m), 7.63-7.90 (5H, m), 7.95 (2H, m), 10.51 (1H, br s), 11.02 (1H, br s), 12.57 (1H, br s); IR (solid); MS 408.8 (M + H) +
    [1253] Example 237 (5-cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2- (pyridin-3-ylmethylamino) -pyrimidin-4-yl] -amine (IIIc-5) : Off-white solid, mp 191-193 ° C .; 1 H NMR (DMSO) δ 0.65 (2H, m), 0.89 (2H, m), 1.83 (1H, m), 4.59 (2H, s), 6.04 (1H, br s), 6.76 (1H, br s) , 7.32-7.56 (5H, m), 7.77 (1H, m), 7.88-7.97 (2H, m), 8.43 (1H, m), 8.61 (1H, s), 9.47 (1H, br s), 11.93 ( 1H, br s); IR (solid); MS 384.8 (M + H) +
    [1254] Example 238 [2- (3-Chlorophenyl) amino-6- (3-nitrophenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc- 6): off-white solid; 1 H NMR (CD 3 OD) δ 5.95 (1H, s), 6.65 (1H, s), 6.90 (1H, d), 7.18 (1H, t), 7.32 (1H, d), 7.58 (1H, t) , 7.82 (1 H, s), 8.18 (1 H, d), 8.25 (1 H, d), 8.65 (1 H, s); MS 422.1 (M + H) +
    [1255] Example 239 [2- (3-chlorophenyl) amino-6- (3,4,5-trimethoxyphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl ) -Amine (IIIc-7): white solid; MS 467.7 (M + H) +
    [1256] Example 240 (5-methyl-2H-pyrazol-3-yl)-[2- (4-sulfamoylphenylamino) -6- (3,4,5-trimethoxyphenyl) -pyrimidine-4- Il] -amine (IIIc-8): white solid; MS 512.6 (M + H) +
    [1257] Example 241 [2- (4-Chlorophenyl) amino-6-methyl-pyrimidin-4-yl]-[5- (furan-2-yl) -2H-pyrazol-3-yl] -amine (IIIc -9): white solid; MS 367.1 (M + H) +
    [1258] Example 242 [2- (benzimidazol-2-ylamino-) 6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-10) : MS 335.5 (M + H) +
    [1259] Example 243 [2- (4-Chlorophenyl) amino-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIIc-11): MS 377.5 (M + H) +
    [1260] Example 244 [2- (4-Chlorophenyl) amino-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-12): MS 329.4 (M + H) +
    [1261] Example 245 (5-tert-butyl-2H-pyrazol-3-yl)-[2- (3-chlorophenyl) amino-6- (3-nitrophenyl) -pyrimidin-4-yl] -amine (IIIc-13): off-white solid; 1 H NMR (CD 3 OD) δ 1.32 (9H, s), 6.18 (1H, s), 7.04 (1H, s), 7.14 (1H, d), 7.35 (1H, t), 7.58 (1H, d) , 7.82 (1 H, t), 7.91 (1 H, s), 8.35 (1 H, d), 8.40 (1 H, d), 8.90 (1 H, s); MS 464.2 (M + H) +
    [1262] Example 246 [2- (3-Chlorophenyl) amino-6- (3-nitrophenyl) -pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIIc- 14): δ off-white solid; 1 H NMR (CD 3 OD) δ 6.66 (1H, s), 7.12 (1H, d), 7.30-7.45 (5H, m), 7.50 (1H, d), 7.62 (2H, d), 7.78 (1H, t), 7.88 (1 H, s), 8.35 (1 H, d), 8.42 (1 H, d), 8.85 (1 H, s); MS 484.1 (M + H) +
    [1263] Example 247 [5- (furan-2-yl) -2H-pyrazol-3-yl]-(6-phenyl-2-phenylamino-pyrimidin-4-yl) -amine (IIIc-15): MS 395.4 (M + H) +
    [1264] Example 248 [2- (benzimidazol-2-ylamino) -6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIIc-16) : MS 383.2 (M + H) +
    [1265] Example 249 [2- (benzimidazol-2-ylamino) -6-methyl-pyrimidin-4-yl]-[5- (furan-2-yl) -2H-pyrazol-3-yl]- Amine (IIIc-17): MS 373.4 (M + H) +
    [1266] Example 250 [2- (4-Chlorophenylamino) -6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-18): MS 315.4 (M + H) +
    [1267] Example 251 [2- (4-Chlorophenyl) amino-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-19): MS 329.4 (M + H) +
    [1268] Example 252 (5,6-dimethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-20): MS 295.5 (M + H) +
    [1269] Example 253 [2- (4-Chlorophenyl) amino-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-21): MS 345.1 (M + H) +
    [1270] Example 254 [2- (benzimidazol-2-ylamino) -6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc- 22): MS 351.2 (M + H) +
    [1271] Example 255 (6-methoxymethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-23): MS 311.2 (M + H) +
    [1272] Example 256 (6-Methyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIIc-24): MS 281.1 (M + H) +
    [1273] Example 257 [2- (2-Chlorophenoxymethyl) -6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIId-1): MS 392.1 (M + H) +
    [1274] Example 258 [2- (2-Chlorophenoxymethyl) -6-methyl-pyrimidin-4-yl]-[5- (furan-2-yl) -2H-pyrazol-3-yl] -amine ( IIId-2): MS 382.1 (M + H) +
    [1275] Example 259 (6-Methyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-phenyl-2H-pyrazol-3-yl) -amine (IIId-3): MS 358.2 (M + H ) +
    [1276] Example 260 [5- (Furan-2-yl) -2H-pyrazol-3-yl]-(6-methyl-2-phenoxymethyl-pyrimidin-4-yl) -amine (IIId-4): MS 348.2 (M + H) +
    [1277] Example 261 [5- (furan-2-yl) -2H-pyrazol-3-yl]-(6-methyl-2-phenylsulfanylmethyl-pyrimidin-4-yl) -amine (IIId-5) : MS 364.1 (M + H) +
    [1278] Example 262 [6-Methyl-2- (4-methyl-phenylsulfanylmethyl) -pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIId-6) : MS 388.1 (M + H) +
    [1279] Example 263 [5- (furan-2-yl) -2H-pyrazol-3-yl]-[6-methyl-2- (4-methyl-phenylsulfanylmethyl) -pyrimidin-4-yl]- Amine (IIId-7): MS 378.1 (M + H) +
    [1280] Example 264 [2- (4-Fluoro-phenoxymethyl) -6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIId-8) : MS 376.2 (M + H) +
    [1281] Example 265 [2- (4-Fluoro-phenoxymethyl) -6-methyl-pyrimidin-4-yl]-[5- (furan-2-yl) -2H-pyrazol-3-yl]- Amine (IIId-9): MS 366.2 (M + H) +
    [1282] Example 266 (6-ethyl-2-phenylsulfanylmethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-10): MS 326.2 (M + H) +
    [1283] Example 267 (6-ethyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-11): MS 310.2 (M + H ) +
    [1284] Example 268 [6-ethyl-2- (4-fluorophenoxymethyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-12): MS 328.2 (M + H) +
    [1285] Example 269 [6-ethyl-2- (1-methyl-1-phenyl-ethyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-13 ): MS 322.2 (M + H) +
    [1286] Example 270 [2- (4-Chlorophenoxymethyl) -6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl) -amine (IIId-14): MS 392.2 (M + H) +
    [1287] Example 271 [2- (4-Chlorophenoxymethyl) -6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-15): MS 330.2 (M + H) +
    [1288] Example 272 [2- (4-Chlorophenoxymethyl) -6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-16) : White solid; 1 H NMR (DMSO) δ 2.20 (3H, s), 3.43 (3H, s), 4.49 (2H, s), 5.20 (2H, s), 6.05 (1H, br), 7.05 (2H, d), 7.33 (2H, d), 10.55 (1H, broad singlet); MS 360.2 (M + H) +
    [1289] Example 273 [2- (4-Chlorophenoxymethyl) -6-methyl-pyrimidin-4-yl]-[5- (furan-2-yl) -2H-pyrazol-3-yl] -amine ( IIId-17): MS 382.2 (M + H) +
    [1290] Example 274 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanylmethyl-5,6,7,8-tetrahydro-quinazolin-4-yl) -amine (IId-7 ): MS 352.5 (M + H) +
    [1291] Example 275 [2- (4-Methylphenylsulfanylmethyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazole-3 -Yl) -amine (IId-8): MS 380.2 (M + H) +
    [1292] Example 276 [2- (1-Methyl-1-phenyl-ethyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyra Zol-3-yl) -amine (IId-9):
    [1293] MS 362.3 (M + H) +
    [1294] Example 277 [2- (2,6-Dichlorobenzyl) -5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IId-10): MS 388.1 (M + H) +
    [1295] Example 278 [7-benzyl-2- (2,6-dichlorobenzyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4-yl]-(5-methyl -2H-pyrazol-3-yl) -amine (IId-11): MS 479.5 (M + H) +
    [1296] Example 279 [6-benzyl-2- (4-chlorophenoxymethyl) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-4-yl]-(5- Methyl-2H-pyrazol-3-yl) -amine (IId-12): MS 461.2 (M + H) +
    [1297] Example 280 [2- (4-Chlorophenoxymethyl) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-4-yl]-(5-methyl-2H- Pyrazol-3-yl) -amine (IId-13): MS 371.3 (M + H) +
    [1298] Example 281 [2- (2,6-dichlorobenzyl) -6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-18): MS 348.1 (M + H) +
    [1299] Example 282 [2- (2,6-Dichlorobenzyl) -5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (IIId-19) : White solid; 1 H NMR (DMSO) 8.50 (1H, s), 7.70 (1H, d), 7.3-7.1 (3H, m), 5.25 (1H, s), 4.10 (1H, s), 2.30 (3H, s), 2.10 (3H, s), 1.80 (3H, s); MS 362.1 (M + H) +
    [1300] Example 283 (1H-indazol-3-yl)-[2- (2-phenyl-cyclopropyl) -quinazolin-4-yl] -amine (IId-16): 1 HNMR (DMSO) 13.2 (1H, s), 12.0 (1H, s), 8.76 (1H, m), 8.10 (1H, m), 7.85 (2H, m), 7.75 (1H, m), 7.61 (1H, m) 7.41 (1H, m) , 7.30 (2H, m), 7.20 (2H, m), 7.12 (2H, m), 2.35 (2H, m), 1.60 (1H, m), 1.35 (1H, m); MS: m / z, 378.1 MH < + >; HPLCR t = 3.21 min.
    [1301] Example 284 (7-Fluoro-1H-indazol-3-yl)-[2- (2-phenyl-cyclopropyl) -quinazolin-4-yl] -amine (IId-17): 1 HNMR (DMSO ) 13.8 (1H, s), 12.05 (1H, s), 8.75 (1H, m), 8.10 (1H, m), 7.85 (2H, m), 7.60 (1H, m), 7.35 (3H, m) 7.25 -7.10 (4H, m), 2.35 (2H, m), 1.60 (1H, m), 1.35 (1H, m); MS: m / z, 396.1 MH < + >; HPLC R t = 3.26 min.
    [1302] Example 285 (5-Fluoro-1H-indazol-3-yl)-[2- (2-phenyl-cyclopropyl) -quinazolin-4-yl] -amine (IId-18): 1 HNMR (DMSO ) 13.3 (1H, s), 12.0 (1H, s), 8.75 (1H, m), 8.10 (1H, m), 7.85 (2H, m), 7.65 (2H, m), 7.35 (3H, m) 7.20 (1H, m), 7.10 (2H, m) 2.40 (2H, m), 1.65 (1H, m), 1.35 (1H, m); MS: m / z, 396.1 MH < + >; HPLC R t = 3.26 min.
    [1303] Example 286 (5-methyl-1H-pyrazol-3-yl)-[2- (2-phenyl-cyclopropyl) -quinazolin-4-yl] -amine (IId-19): 1 HNMR (DMSO) 12.8 (1H, s), 11.90 (1H, s), 8.80 (1H, m), 8.10 (1H, m), 7.85 (2H, m), 7.30-7.20 (5H, m), 6.55 (1H, s) 2.80 (1 H, m), 2.55 (1 H, m), 2.35 (3 H, s) 2.00 (2 H, m); MS: m / z, 342.1 MH < + >; HPLC R t = 3.13 min.
    [1304] Biological test
    [1305] The activity of the compounds as protein kinase inhibitors can be assayed in vitro, in vivo or in cell lines. In vitro assays include assays that determine the inhibition of phosphorylation activity or ATPase activity of activated protein kinases. Another in vitro assay quantifies the ability of the inhibitors of the invention to bind corresponding protein kinases. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, separating the inhibitor / protein kinase complex, and then determining the amount of radiolabel bound. On the other hand, inhibitor binding can be determined by conducting competition experiments in which the new inhibitor is incubated with protein kinases bound to known radioligands.
    [1306] Biological Test Example 1
    [1307] K for the inhibition of GSK-3 idecision
    [1308] Standard coupled enzyme system [Fox et al. (1998) Protein Sci. 7, 2249] for screening for the ability of compounds to inhibit GSK-3β (AA 1-420) activity. The reaction is 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. Final substrate concentrations in this assay were 20 μM ATP [Sigma Chemicals, St. Louis, MO] and 300 μM peptide [HSSPHQS (PO 3 H 2 ) EDEEE, American Peptide, Sunnyvale, CA. Peptide). The reaction is carried out at 30 ° C. and 20 nM GSK-3β. Final concentrations of components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.
    [1309] An assay stock buffer solution containing all of the reagents listed above except for the test compound and ATP of interest is prepared. This assay stock buffer solution (175 μL) is incubated in 96 well plates with 5 μL of test compound of interest at a final concentration over 0.002 μM to 30 μM at 30 ° C. for 10 minutes. Typically, a 12 point titration is performed by preparing a series of dilutions (from 10 mM compound stock) using DMSO in daughter plates. The reaction is initiated by adding 20 μl ATP (final concentration 20 μM). The reaction rate is obtained over 30 minutes at 30 ° C. using a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.). From these response rate data, K i values are determined as a function of inhibitor concentration.
    [1310] The following compounds were found to exhibit K i values of less than 0.1 μM for GSK-3: IIa-2, IIa-3, IIa-8, IIa-9, IIa-11, IIa-12, IIa-17, IIa -18, IIa-21 to IIa-24, IIa-26, IIa-28, IIa-30 to IIa-32, IIa-39, IIa-43, IIa-46, IIa-47, IIa-61, IIc-3 , IIc-6, IIc-8, IIc-10 to IIc-12, IIc-15, IIc-18, IIc-20 to IIc-22, IIc-24, IIc-25, IIc-27, IIc-30 to IIc -32, IIc-35 to IIc-39, IIc-42, IIc-53, IIc-61, IIc-67, IIc-77, IIc-78, IIb-1, IIb-3, IIb-5, IIb-8 , IId-1, IIIa-2, IIIa-3, IIIa-6, IIIa-17, IIIa-18, IIIa-24, IIIa-27, IIIc-2 to IIIc-5, IIIc-9, IIIc-11, IIIc -12, IIIc-15, IIIc-18, IIIc-19, IIIc-21, IIIc-24, IIIb-1 to IIIb-6, IIIb-8 to IIIb-10, IIIb-13, IIIb-14, IIId-20 , IIId-21, IId-14, and IId-19.
    [1311] The following compounds were found to exhibit K i values of 0.1 to 1.0 μM for GSK-3: IIa-1, IIa-4, IIa-5, IIa-7, IIa-14, IIa-15, IIa-20, IIa-29, IIa-34 to IIa-36, IIa-38, IIa-41, IIa-42, IIa-48, IIa-54, IIa-55, IIa-62, IIa-63, IIa-66, IIa- 69, IIa-78, IIc-1, IIc-2, IIc-4, IIc-5, IIc-7, IIc-9, IIc-13, IIc-14, IIc-16, IIc-17, IIc-19, IIc-23, IIc-26, IIc-28, IIc-29, IIc-33, IIc-34, IIc-40, IIc-41, IIc-43 to IIc-45, IIc-47 to IIc-52, IIc- 54 to IIc-57, IIc-59, IIc-63 to IIc-66, IIc-72, IIc-75, IIc-76, IIc-79, IIc-6, IIb-7, IIb-9, IId-2, IId-5, IId-6, IIIa-1, IIIa-4, IIIa-5, IIIa-7, IIIa-8, IIIa-10, IIIa-11, IIIa-19, IIIa-22, IIIa-23, IIIa- 26, IIIa-29, IIIa-30, IIIa-31, IIIa-33, IIIa-34, IIIa-37, IIIa-42, IIIc-1, IIIc-8, IIIc-20, IIIc-23, IIIb-7, IIIb-11, IIIb-12, IIIb-15, IIIb-16, IId-16, IId-17, and IId-18.
    [1312] The following compounds were found to exhibit K i values of 1.0 to 7.0 μM for GSK-3: IIa-10, IIa-13, IIa-25, IIa-40, IIa-45, IIa-49, IIa-50 to IIa-52, IIa-64, IIa-65, IIa-67, IIa-68, IIa-71, IIa-72, IIa-74, IIa-76, IIa-77, IIa-81, IIc-58, IIc- 60, IIc-62, IIc-68 to IIc-71, IIc-74, IId-3, IId-4, IIIa-15, IIIa-16, IIIa-21, IIIa-28, IIIa-35, IIIa-36, IIIa-38, IIIa-41, IIIa-43, IIIa-45, IIIa-49, IIIc-10, IIIc-16, IIIc-17, and IIIc-22.
    [1313] Biological Test Example 2
    [1314] K for the inhibition of aurora-2 idecision
    [1315] Standard coupled enzyme assay [Fox et al. (1998) Protein Sci. 7, 2249], the compounds are screened for the ability to inhibit Aurora-2 in the following manner.
    [1316] 0.1 M HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg / ml pyruvate kinase, 10 mg / ml lactate dehydrogenase, 40 mM ATP and To an assay stock buffer solution containing 800 μM peptide (LRRASLE, American peptide) is added a DMSO solution of the compound of the invention at a final concentration of 30 μM. The resulting mixture is incubated at 30 ° C. for 10 minutes. The reaction is initiated by adding 10 μl of Aurora-2 stock solution to a final concentration of 70 nM in this assay. The reaction rate is obtained by monitoring the absorbance at 340 nm over a 5 minute read time at 30 ° C. using a BioRad Ultramark plate reader (Hercules, CA). From these response rate data, K i values are determined as a function of inhibitor concentration.
    [1317] The following compounds were found to exhibit K i values of less than 0.1 μM for Aurora-2: IIa-1 to IIa-18, IIa-21 to IIa-64, IIa-66, IIa-68, IIa-69, IIa -71 to IIa-78, IIa-81, IIc-1 to IIc-13, IIc-15 to IIc-44, IIc-46 to IIc-61, IIc-63 to IIc-65, IIc-67 to IIc-69 , IIb-1 to IIb-9, IId-1 to IId-3, IIIa-1 to IIIa-8, IIIa-10 to IIIa-13, IIIa-15 to IIIa-32, IIIa-36 to IIIa-41, IIIa -44 to IIIa-49, IIIc-1 to IIIc-5, IIIc-12, and IIIc-15.
    [1318] The following compounds were found to exhibit K i values of 0.1 to 1.0 μM for Aurora-2: IIa-20, IIa-65, IIa-67, IIa-70, IIa-80, IIc-14, IIc-66, IId-5, IId-6, IIIa-14, IIIa-33 to IIIa-35, IIIc-9, IIIc-11, IIIb-1, IIIb-2, IIIb-7, IIIb-10 to IIIb-13, IIIb- 15, IIIb-16, and IIId-20.
    [1319] The following compounds were found to exhibit K i values of 1.0-10.0 μM for Aurora-2: IIa-10, IIc-71, IIc-75, IIc-76, IId-4, IIIa-42, IIIa-43, IIIc-10, IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.
    [1320] Biological Test Example 3
    [1321] CDK-2 Inhibition Assay
    [1322] Standard coupled enzyme assay [Fox et al. (1998) Protein Sci. 7, 2249], the compounds are screened for the ability to inhibit CDK-2 in the following manner.
    [1323] 0.1 M HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg / ml pyruvate kinase, 10 mg / ml lactate dehydrogenase, 100 mM ATP and To an assay stock buffer solution containing 100 μM peptide (MAHHHRSPRKRAKKK, American peptide) is added DMSO solution of the compound of the invention to a final concentration of 30 μM. The resulting mixture is incubated at 30 ° C. for 10 minutes.
    [1324] The reaction is initiated by adding 10 [mu] l of CDK-2 / cyclin A stock solution to a final concentration of 25 nM in this assay. The reaction rate is obtained by monitoring the absorbance at 340 nm over a 5 minute reading time at 30 ° C. using a Biorad Ultramark plate reader (Herculus). From these response rate data, K i values are determined as a function of inhibitor concentration.
    [1325] The following compounds were found to exhibit K i values of less than 1 μM for CDK-2: IIa-14, IIa-36, IIc-15, IIc-25, IIc-27, IIc-32, IIc-53, and IIIc -4.
    [1326] The following compounds were found to exhibit K i values of 1.0 to 20.0 μM for CDK-2: IIa-38, IIa-40, IIa-44, IIa-52, and IIa-54.
    [1327] Biological Test Example 4
    [1328] ERK Suppression Assay
    [1329] Spectrophotometric coupled enzyme assay [Fox et al. (1998) Protein Sci. 7, 2249] are used to assay for inhibition of ERK2 against compounds. In this assay, fixed concentrations of activated ERK2 (10 nM) were determined using 10 mM MgCl 2 , 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg / ml pyruvate kinase, 50 μg / ml lactate dehydrogenase and 200 μM Incubate in DMSO (2.5%) in 0.1 M HEPES buffer (pH 7.5) containing erktide peptides with various concentrations of the compound at 30 ° C. for 10 minutes. The reaction is initiated by adding 65 μM ATP. The rate of absorbance reduction at 340 nm is monitored. IC 50 values are assessed from this reduction data as a function of inhibitor concentration.
    [1330] The following compounds were found to exhibit K i values of less than 1 μM for ERK-2: IIc-15, IIc-27, IIc-32, IIc-53, and IIIc-4.
    [1331] The following compounds were found to exhibit K i values of 1.0 to 20.0 μM for ERK-2: IIc-18, IIc-25 and IIa-36.
    [1332] Biological Test Example 5
    [1333] AKT Suppression Assay
    [1334] Standard coupled enzyme assay [Fox et al. (1998) Protein Sci. 7, 2249], for compounds that screen for the ability to inhibit AKT. The assay is performed in a mixture of 100 mM HEPES (pH 7.5), 10 mM MgCl 2 , 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in this assay are 170 μM ATP (Sigma Chemicals) and 200 μM peptide (RPRAATF, American Peptide). The assay is performed at 30 ° C. and 45 nM AKT. Final concentrations of components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.
    [1335] An assay stock buffer solution containing all of the reagents listed above except for the test compound of interest, AKT and DTT, is prepared. This assay stock buffer solution (56 μl) is placed in a 384 well plate and then 1 μl of 2 mM DMSO stock 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 concentration 45 nM) and 1 mM DTT. The reaction rate is obtained over a 5 minute reading time at 30 ° C. using a Biorad Ultramark Plate Reader (Hercules). IC 50 values are determined by titrating compounds that do not contain test compounds and exhibit at least 50% inhibition relative to the assay mixture and standard wells containing DMSO.
    [1336] The following compounds were found to exhibit K i values of 1.0 to 20.0 μM for AKT-3: IIc-18, IIc-22, IIc-25, IIc-27, IIc-31, IIc-32, IIc-37, IIc-39, IIc-42, and IIc-53.
    [1337] Biological Test Example 6
    [1338] Src Suppression Test
    [1339] Using the radio-utilization assay or spectrophotometric assay, the compound was evaluated as an inhibitor of human Src kinase.
    [1340] Src Inhibition Assay A: Radioactivity-Use Assay
    [1341] The compound is assayed as an inhibitor of full length recombinant human Src kinase (Source: Upstate Biotechnology, Cat. Nos. 14-117) expressed and purified from baculovirus cells. Src kinase activity is monitored by incorporating 33 P from ATP into tyrosine of a random poly Glu-Tyr polymer substrate (Sigma, Cat. No. P-0275) of composition Glu: Tyr = 4: 1. Following is the final concentration of assay components: 0.05 M HEPES, pH 7.6, 10 mM MgCl 2 , 2 mM DTT, 0.25 mg / ml BSA, 10 μM ATP (1 to 2 μCi 33 P-ATP per reaction), 5 mg / ml poly Glu-Tyr And 1 to 2 units of recombinant human Src kinase. In a typical assay, all reaction components except ATP are pre-mixed and divided into equal wells for assay plates. Inhibitors dissolved in DMSO are added to the wells to obtain a final DMSO concentration of 2.5%. The assay plate is incubated at 30 ° C. for 10 minutes before the reaction with 33 P-ATP is initiated. After reacting for 20 minutes, the reaction is quenched with 150 μl of 10% trichloroacetic acid (TCA) containing 20 mM Na 3 PO 4 . The quenched sample is then transferred to a 96-well filter plate (Watman, UNI-filter GF / G glass fiber filter, catalog number 7700-3310) installed on a filter plate vacuum assembly. 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 scintillation fluid is then added to each well. The plate is sealed and the amount of radioactivity associated with the filter is quantified on a TopCount scintillation counter. Incorporated radioactivity is plotted as a function of inhibitor concentration. The data is fitted to a competitive inhibition kinetics model to obtain K i for that compound.
    [1342] Src Suppression Assay B: Spectrophotometric Assay
    [1343] Coupled Enzyme Assay [Fox et al. (1998) Protein Sci. 7, 2249], to quantify the ADP generated from ATP by human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate. In this assay, one molecule of NADH is oxidized to NAD for every ADP molecule produced in the kinase reaction. The disappearance of NADH can be conveniently tracked at 340 nm.
    [1344] The following are the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl 2 , 2 mM DTT, 0.25 mg / ml poly Glu-Tyr and 25 nM of recombinant human Src kinase. Final concentrations of components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 200 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.
    [1345] In a typical assay, all reaction components except ATP are pre-mixed and divided into equal wells for assay plates. Inhibitors dissolved in DMSO are added to the wells to obtain a final DMSO concentration of 2.5%. The assay plate is incubated at 30 ° C. for 10 minutes before initiating the reaction with 100 μM ATP. The absorbance change at 340 nm over time, ie the reaction rate, is monitored on a Molecula device plate reader. The reaction rate data as a function of inhibitor concentration is fitted to a competitive inhibition kinetics model to obtain K i for that compound.
    [1346] The following compounds were found to exhibit K i values of less than 100 nM for Src: IIa-8, IIa-21, IIa-23, IIa-24, IIa-27, IIa-28, IIa-30 to IIa-33, IIb-1, IIb-4, IIb-5, IIc-3, IIc-8, IIc-10, IIc-13, IIc-15, IIc-18, IIc-19, IIc-21 to IIc-24, IIc- 31 to IIc-35, IIc-37 to IIc-39, IIc-41 to IIc-44, IIc-51, IId-1, IId-2, IIIa-1, IIIa-6 to IIIa-8, IIIa-26 to IIIa-30, and IIIc-1 to IIIc-5.
    [1347] The following compounds were found to exhibit K i values of 100 nM to 1 μM for Src: IIa-1, IIa-2, IIa-7, IIa-9, IIa-12, IIa-14, IIa-22, IIa-25 , IIa-26, IIa-29, IIa-34 to IIa-42, IIa-46, IIa-47, IIa-49 to IIa-52, IIa-56, IIa-57, IIa-59, IIa-61, IIa -62, IIa-66, IIa-67, IIa-69, IIa-72, IIa-73, IIa-75, IIb-6, IIb-8, IIc-4 to IIc-7, IIc-9, IIc-11 , IIc-12, IIc-14, IIc-16, IIc-17, IIc-20, IIc-25 to IIc-30, IIc-36, IIc-40, IIc-46 to IIc-50, IIc-52 to IIc -61, IIc-63 to IIc-65, IIc-67, IIc-69, IId-3, IIIa-2 to IIIa-5, IIIa-11, IIIa-14 to IIIa-18, IIIa-22 to IIIa-24 , IIIa-31, IIIa-33, IIIa-35, IIIa-38 to IIIa-43, and IIIa-47.
    [1348] The following compounds were found to exhibit K i values of 1-6 μM for SRC: IIa-13, IIa-20, IIa-44, IIa-45, IIa-48, IIa-54, IIa-55, IIa-63 , IIa-65, IIa-68, IIa-70, IIa-71, IIa-74, IIa-77, IIa-78, IIa-81, IIb-3, IIb-9, IIc-1, IIc-2, IIc -66, IIc-68, IIIa-13, IIIa-21, IIIa-25, IIIa-34, IIIa-36, IIIa-37, and IIIa-44.
    [1349] Although the present inventors have presented many aspects of the present invention, it is clear that the basic configuration of the present invention can be modified to provide other embodiments utilizing the compounds and methods of the present invention. It is, therefore, to be understood that the scope of the invention should not be defined by the specific embodiments presented by way of example, but rather by the claims appended hereto.
    权利要求:
    Claims (28)
    [1" claim-type="Currently amended] A compound of Formula IIIa, or a pharmaceutically acceptable derivative or prodrug thereof:
    Formula IIIa

    In the above formula,
    R x and R y are independently selected from TR 3 and LZR 3 ;
    R 1 is T- (ring D);
    Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl and carbocyclyl, wherein the heteroaryl or heterocyclyl ring is selected from nitrogen, oxygen and sulfur Has 1 to 4 ring heteroatoms selected, wherein each substitutable ring carbon of ring D is independently substituted by oxo, TR 5 or VZR 5 , and each substitutable ring nitrogen of ring D is -R Independently substituted by 4 ;
    T is a valence bond or a C 1-4 alkylidene chain;
    Z is a C 1-4 alkylidene chain;
    L is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    R 2 and R 2 ' are independently selected from -R and TWR 6 , or R 2 and R 2' together with their insertion atoms are fused with 0 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur To form an unsaturated or partially unsaturated 5-8 membered ring, wherein each substitutable ring carbon of the fused ring formed by R 2 and R 2 ′ is halo, oxo, —CN, —NO 2 , —R 7 or — Independently substituted by VR 6 , each substitutable ring nitrogen of the ring formed by R 2 and R 2 ′ is independently substituted by R 4 ;
    R 3 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S ( O) 2 R, -SR, -N (R 4 ) 2 , -CON (R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC (= O) R, -N (R 7 ) COR, -N (R 7 ) CO 2 (C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 7 ) CON (R 7 ) 2 , —N (R 7 ) SO 2 N (R 7 ) 2 , —N (R 4 ) SO 2 R and —OC (═O) N (R 7 ) 2 ;
    R is each independently selected from hydrogen and an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5 to 10 ring atoms and a heterocyclyl ring having 5 to 10 ring atoms Independently selected;
    R 4 is each independently selected from -R 7 , -COR 7 , -CO 2 (optionally substituted C 1-6 aliphatic), -CON (R 7 ) 2 and -SO 2 R 7 ;
    R 5 is -R, -halo, -OR, -C (= O) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S (O) R, -SO 2 R,- SR, -N (R 4 ) 2 , -CON (R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC (= O) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1-6 aliphatic), -N (R 4 ) N (R 4 ) 2 , -C = NN (R 4 ) 2 , -C = N-OR, -N (R 4 ) CON (R 4 ) 2 , —N (R 4 ) SO 2 N (R 4 ) 2 , —N (R 4 ) SO 2 R, and —OC (═O) N (R 4 ) 2 ;
    V is -O-, -S-, -SO-, -SO 2- , -N (R 6 ) SO 2- , -SO 2 N (R 6 )-, -N (R 6 )-, -CO- , -CO 2- , -N (R 6 ) -CO-, -N (R 6 ) C (O) O-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R 6 )-, -N (R 6 ) N (R 6 )-, -C (O) N (R 6 )-, -OC (O) N (R 6 )-, -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )- , -C (R 6 ) 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 ) C (O)-, -C (R 6 ) 2 N (R 6 ) C (O) O -, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) — or —C (R 6 ) 2 N (R 6 ) CON (R 6 ) —;
    W is -C (R 6 ) 2 O-, -C (R 6 ) 2 S-, -C (R 6 ) 2 SO-, -C (R 6 ) 2 SO 2- , -C (R 6 ) 2 SO 2 N (R 6 )-, -C (R 6 ) 2 N (R 6 )-, -CO-, -CO 2- , -C (R 6 ) OC (O)-, -C (R 6 ) OC (O) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (O) O-, -C (R 6 ) = NN (R 6 )-, -C (R 6 ) = NO-, -C (R 6 ) 2 N (R 6 ) N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 ) —, —C (R 6 ) 2 N (R 6 ) CON (R 6 ) — or —CON (R 6 ) —;
    Each R 6 is independently selected from hydrogen and an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom together with the nitrogen atom form a 5-6 membered heterocyclyl or heteroaryl ring and;
    R 7 is each independently selected from hydrogen and an optionally substituted C 1-6 aliphatic group, or two R 7 groups on the same nitrogen together with nitrogen form a 5-8 membered heterocyclyl or heteroaryl ring.
    [2" claim-type="Currently amended] The compound of claim 1 having at least one of the features selected from the group consisting of:
    (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group;
    (b) R y is TR 3 or LZR 3 , where T is a valence bond or methylene and R 3 is —R, —N (R 4 ) 2 or —OR;
    (c) R 1 is T- (ring D), wherein T is a valence bond or methylene unit;
    (d) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    (e) R 2 is —R or —TWR 6 and R 2 ′ is hydrogen, or R 2 and R 2 ′ together form an optionally substituted benzo ring.
    [3" claim-type="Currently amended] The method of claim 2,
    (a) R x is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4 aliphatic group;
    (b) R y is TR 3 or LZR 3 , where T is a valence bond or methylene and R 3 is —R, —N (R 4 ) 2 or —OR;
    (c) R 1 is T- (ring D), wherein T is a valence bond or a methylene unit;
    (d) ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    (e) A compound in which R 2 is -R or -TWR 6 and R 2 ' is hydrogen, or R 2 and R 2' together form an optionally substituted benzo ring.
    [4" claim-type="Currently amended] The compound of claim 2 having at least one of the features selected from the group consisting of:
    (a) R y is TR 3 or LZR 3 where T is a valence bond or methylene, R 3 is selected from -R, -OR and -N (R 4 ) 2 , where R is hydrogen, C 1- 6 aliphatic, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl];
    (b) R 1 is T- (ring D), where T is a valence bond;
    (c) ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring and 5-6 membered heterocyclic ring;
    (e) L is -O-, -S- or -N (R 4 )-.
    [5" claim-type="Currently amended] The method of claim 4, wherein
    (a) R y is TR 3 or LZR 3 , wherein T is a valence bond or methylene, R 3 is selected from —R, —OR and —N (R 4 ) 2 , wherein R is hydrogen, C 1- 6 aliphatic, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl];
    (b) R 1 is T- (ring D), where T is a valence bond;
    (c) ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;
    (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic ring;
    (e) A compound wherein L is -O-, -S- or -N (R 4 )-.
    [6" claim-type="Currently amended] A compound according to claim 4 having at least one of the features selected from the group consisting of:
    (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
    (b) R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, Alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, selected from optionally substituted phenyl and methoxymethyl;
    (c) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, wherein ring D is -halo, -CN, -NO 2 ,- N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) SO 2 R, Is optionally substituted by one or two groups selected from -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ]; ;
    (d) R 2 is hydrogen or substituted or unsubstituted C 1-6 aliphatic and L is —O—, —S— or —NH—.
    [7" claim-type="Currently amended] The method of claim 6,
    (a) R x is hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
    (b) R y is 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, Alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido is selected from optionally substituted phenyl and methoxymethyl;
    (c) R 1 is T- (ring D) [where T is a valence bond and ring D is a 5-6 membered aryl or heteroaryl ring, wherein ring D is -halo, -CN, -NO 2 ,- N (R 4 ) 2 , an optionally substituted C 1-6 aliphatic group, -OR, -CO 2 R, -CONH (R 4 ), -N (R 4 ) COR, -N (R 4 ) SO 2 R, Is optionally substituted by one or two groups selected from -N (R 6 ) COCH 2 CH 2 N (R 4 ) 2 and -N (R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 ]; ;
    (d) A compound wherein R 2 is hydrogen or substituted or unsubstituted C 1-6 aliphatic and L is -O-, -S- or -NH-.
    [8" claim-type="Currently amended] Compounds selected from the group consisting of:
    (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -6-phenylpyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (3-methoxycarbonyl-phenylylsulfanyl) -6-phenylpyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[5,6-dimethyl-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl) -5-methyl-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[6-methyl-2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[6- (morpholin-4-yl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[6- (1-methylpiperazin-4-yl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl] Amines;
    6- (2,6-dimethylphenyl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    6- (2-Methylphenyl) -2- (naphthalen-2-ylsulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-acetamido-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    (5-methyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl) -6-phenyl-pyrimidin-4-yl] -amine;
    [2- (4-isobutyrylylamino-phenylsulfanyl) -6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [6- (4-Methylpiperazin-1-yl) -2-methylsulfanyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    (5-methyl-2H-pyrazol-3-yl)-[6-phenyl-2- (4-propionylamino-phenylsulfanyl) -pyrimidin-4-yl] -amine;
    [2- (4-cyclopropanecarbonylamino-phenylsulfanyl) -6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    (5-methyl-2H-pyrazol-3-yl)-{6-phenyl-2- [4- (propane-1-sulfonylamino) -phenylsulfanyl] -pyrimidin-4-yl} -amine;
    [2- (4-ethanesulfonylamino-phenylsulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-acetamidophenyl-sulfanyl) -6- (2-methylphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-Isobutanecarbonylamino-phenyl-sulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-acetamido-phenyl-sulfanyl) -5-methyl-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-Acetamido-phenyl-sulfanyl) -6- (4-methoxyphenyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ;
    [6- (3-acetamidophenyl) -2- (4-acetamido-phenyl-sulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amines;
    [2- (4-Isopropanesulfonylamino-phenyl-sulfanyl) -6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    {2- [4- (2-Dimethylamino-acetylamino) -phenylsulfanyl] -6-phenyl-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (3-Chloro-benzylsulfanyl) -6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (3-Chloro-benzylsulfanyl) -6- (2-methoxy-ethylamino) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2-benzylsulfanyl-6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2-benzylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (3-Chloro-benzylsulfanyl) -6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amines;
    [2- (4-methoxy-benzylsulfanyl) -6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) Amines;
    [2- (4-acetamido-phenyl-sulfanyl) -6-tert-butyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    (5-cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2- (4-propionylamino-phenyl-sulfanyl) -pyrimidin-4-yl] -amine;
    [2- (3-Chloro-benzylsulfanyl) -6- (piperidin-1-yl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    (5-methyl-2H-pyrazol-3-yl)-{2- [4- (morpholinsulfonyl) -benzylsulfanyl] -6-morpholin-4-yl-pyrimidin-4-yl}- Amines;
    {6- (2-Methoxy-ethylamino) -2- [4- (morpholinesulfonyl) -benzylsulfanyl] -pyrimidin-4-yl}-(5-methyl-2H-pyrazole-3- Yl) -amine;
    {6- (4-Methylpiperazin-1-yl) -2- [4- (morpholinsulfonyl) -benzylsulfanyl] -pyrimidin-4-yl}-(5-methyl-2H-pyrazole- 3-yl) -amine;
    [6-methoxymethyl-2- (4-propionylamino-phenyl-sulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-methoxycarbonyl-phenyl-sulfanyl) -6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (3,5-Dimethoxy-benzylsulfanyl) -6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine] ;
    [2- (3,5-Dimethoxy-benzylsulfanyl) -6-pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ;
    (5-methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl-2- (naphthalen-2-ylmethylsulfanyl) -pyrimidin-4-yl] -amine;
    {2- (4-Acetamido-phenyl-sulfanyl) -6- [4- (3-dimethylamino-propoxy) -phenyl] -pyrimidin-4-yl}-(5-methyl-2H-pyra Sol-3-] yl) -amine;
    [2- (4-acetamidophenylsulfanyl) -6- (morpholin-4-yl)-[pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine ;
    [6-hydroxymethyl-2- (4-propionylamino-phenyl-sulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [2- (4-acetamido-phenyl-sulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine;
    [6- (1-Butoxycarbonyl) -2- (4-propionylamino-phenyl-sulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)- Amines and
    [6-methoxycarbonyl-2- (4-propionylamino-phenyl-sulfanyl) -pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine.
    [9" claim-type="Currently amended] A composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.
    [10" claim-type="Currently amended] The composition of claim 9 further comprising an additional therapeutic agent.
    [11" claim-type="Currently amended] The composition of claim 9 formulated for administration to humans.
    [12" claim-type="Currently amended] A method of inhibiting Aurora-2, GSK-3 or Src activity in a biological sample, comprising contacting the biological sample with a compound according to any one of claims 1 to 8.
    [13" claim-type="Currently amended] A method of inhibiting Aurora-2 activity in a patient, comprising administering the composition according to claim 9 to the patient.
    [14" claim-type="Currently amended] A method of inhibiting Aurora-2 activity in a patient, comprising administering to the patient the composition according to claim 10.
    [15" claim-type="Currently amended] A method of treating Aurora-2-mediated disease, comprising administering a therapeutically effective amount of the composition according to claim 9 to a patient in need of treatment of the Aurora-2-mediated disease.
    [16" claim-type="Currently amended] The method of claim 15, wherein the disease is selected from colon cancer, breast cancer, gastric cancer, and ovarian cancer.
    [17" claim-type="Currently amended] The method of claim 16 further comprising administering an additional therapeutic agent.
    [18" claim-type="Currently amended] The method of claim 17, wherein the additional therapeutic agent is a chemotherapeutic agent.
    [19" claim-type="Currently amended] A method of inhibiting GSK-3 activity in a patient, comprising administering the composition of claim 9 to the patient.
    [20" claim-type="Currently amended] A method of inhibiting GSK-3 activity in a patient, comprising administering to the patient the composition according to claim 10.
    [21" claim-type="Currently amended] A method of treating a GSK-3-mediated disease, comprising administering a therapeutically effective amount of a composition according to claim 9 to a patient in need of treatment of a GSK-3-mediated disease.
    [22" claim-type="Currently amended] 21. The method of claim 20, wherein the GSK-3-mediated disease is diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, myocardial hypertrophy, Reperfusion / ischemia and baldness.
    [23" claim-type="Currently amended] The method of claim 21, wherein the GSK-3-mediated disease is diabetes.
    [24" claim-type="Currently amended] A therapeutically effective amount of the composition according to claim 9 is administered to a patient in need of enhancing glycogen synthesis or lowering blood glucose levels, thereby enhancing glycogen synthesis or lowering blood glucose levels in the patient. How to let.
    [25" claim-type="Currently amended] A method of inhibiting the production of hyperphosphorylated Tau protein in a patient, comprising administering a therapeutically effective amount of the composition according to claim 9 to a patient in need thereof.
    [26" claim-type="Currently amended] A method of inhibiting β-catenin phosphorylation, comprising administering a therapeutically effective amount of the composition according to claim 9 to a patient in need thereof.
    [27" claim-type="Currently amended] A method of inhibiting Src activity in a patient, comprising administering the composition according to claim 9 to the patient.
    [28" claim-type="Currently amended] A method of treating Src-mediated disease, comprising administering a therapeutically effective amount of a composition according to claim 9 to a patient in need of treatment of the Src-mediated disease.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-12-21|Priority to US25788700P
    2000-12-21|Priority to US60/257,887
    2001-04-27|Priority to US28694901P
    2001-04-27|Priority to US60/286,949
    2001-12-19|Application filed by 버텍스 파마슈티칼스 인코포레이티드
    2001-12-19|Priority to PCT/US2001/049401
    2003-07-18|Publication of KR20030061466A
    2008-07-02|Application granted
    2008-07-02|Publication of KR100843114B1
    优先权:
    申请号 | 申请日 | 专利标题
    US25788700P| true| 2000-12-21|2000-12-21|
    US60/257,887|2000-12-21|
    US28694901P| true| 2001-04-27|2001-04-27|
    US60/286,949|2001-04-27|
    PCT/US2001/049401|WO2002057259A2|2000-12-21|2001-12-19|Pyrazole compounds useful as protein kinase inhibitors|
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