RU2332415C2 - Pyrazole derivatives, useful as inhibitors of protein kinase - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyrazole derivatives of formula (IIa)

or their pharmaceutically acceptable salts, where: R^x and R^y banded with intervening atoms while deriving benzol or cyclohexylene rings, optionally substituted by R³; R¹ represents T-(ring D); ring D represents phenyl, optionally substituted by 1-2 groups R⁵, or naphtyl or imidazolyl or benzymidazolyl, optionally substituted by C₁-C₆alkyl group; T represents the linking; R² represents hydrogen, C₁-C₆alkyl or C₃-C₆cycloalkyl; R^2' represents hydrogen, or R² and R^2' is banded with their intervening atoms while deriving phenyl ring; R³ is selected from C₁-C₆alkyl, hydrogen, halogen, -OH, -NH₂, -NHOH, -NO₂, C₁-C₆alkoxy, optionally substituted -N(R⁴)₂; each R⁴ independently selected from C₁-C₆alkyl, -CO₂C₁-C₆alkyl or two R⁴ at the same nitrogen atom joined with nitrogen atom while deriving morpholine ring; each R⁵ represents one or two substitutes, independently selected from C₁-C₆alkyl, halogen, OH, -NH₂, -CF₃, C₁-C₆alkoxy, -COOH, -CO₂C₁-C₆alkyl, -NHCO-C₁-C₆aliphatic group, NHCO(C₁-C₆alkyl)N(R⁴)₂, -CONHC₁-C₆alkyl, -CONH(C₁-C₆alkyl)N(R⁴)₂, and -NHSO₂C₁-C₆alkyl. The compounds are useful as inhibitors of protein kinase, in particular as inhibitors Aurora-2 and GSK-3 for the treatment of cancer, diabetes and Alzheimer's disease. The subjects matter is also pharmaceutical composition on basis of their compounds and methods of the treatment of diseases mediated by the protein kinase.

EFFECT: production of new pyrazole derivatives - inhibitors of protein kinase.

25 cl, 12 tbl, 292 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority over the initial application for US patent 60/257887, filed December 21, 2000, and the initial application for US patent 60/286949, filed April 27, 2001, the contents of which are incorporated into this description by reference.

FIELD OF THE INVENTION

The present invention relates to the field of medical chemistry and relates to compounds that are inhibitors of protein kinase, compositions containing such compounds, and methods for their use. In particular, the present invention relates to compounds that are inhibitors of Aurora-2 protein kinase. The invention also relates to methods of treating diseases associated with said protein kinases, in particular diseases related to Aurora-2, such as cancer.

BACKGROUND OF THE INVENTION

Recently, the search for new therapeutic agents has been greatly facilitated by a better understanding of the structure of enzymes and other biomolecules associated with certain diseases. An important class of enzymes that are the subject of extensive research are protein kinases.

Protein kinases mediate intracellular signal conversion. They do this by transferring phosphoryl from nucleoside triphosphate to the protein acceptor, which is part of the signaling pathway. There are many kinases and pathways through which extracellular and other stimuli elicit a variety of cellular responses that take place in the cell. Examples of such irritants include environmental and chemical stress signals (e.g., osmotic shock, heat stroke, ultraviolet radiation, bacterial endotoxin, H ₂ O ₂ ), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor α (TNF (α)) and growth factors (e.g., granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can cause one or more cellular responses related to cell growth, migration and differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of the cell cycle.

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 hormonal diseases. Therefore, considerable efforts have been made in medical chemistry to find protein kinase inhibitors effective as drugs.

Aurora-2 is a serine / threonine protein kinase involved in the occurrence of a malignant tumor in a person, such as colon cancer, breast cancer and other solid tumors. It is believed that said kinase is involved in protein phosphorylation regulating the cell cycle. In particular, Aurora-2 may play a role in controlling the proper cleavage of chromosomes during mitosis. Dysregulation of the cell cycle can lead to cell proliferation and other disorders. It was found that in the tissue of a malignant tumor of the human colon, Aurora-2 protein is overly expressed. See Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a serine / threonine protein kinase composed of α and β isoforms, each of which is encoded by different genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 is involved in various diseases, including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiac muscle hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases can be caused by the abnormal work of some cellular signaling pathways, where GSK-3 plays a role, or lead to it. As already established, GSK-3 phosphorylates a number of regulatory proteins and modulates their activity. These proteins include glycogen synthase, which is a speed-limiting enzyme necessary for glycogen synthesis, Tau microtubule concomitant protein, β-catenin gene transcription factor, translation initiation factor e1F2B, as well as ATP-citrate lyase, axin, heat-shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and SERVα. Various of these target proteins involve GSK-3 in many aspects of cell metabolism, proliferation, differentiation, and cell development.

In the GSK-3 mediated metabolic pathway suitable for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. According to this metabolism, GSK-3 is a negative regulator of the insulin-induced signal. Typically, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and glycogen synthase deactivation. Inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem. J. 299, 123-128 (1994)]. But in a patient with diabetes, when the response to insulin is weakened, glycogen synthesis and glucose uptake are not able to increase despite the relatively high level of insulin in the blood. This leads to an abnormally high blood glucose with acute and long-term effects that can ultimately lead to cardiovascular disease, kidney failure, and blindness. In such patients, there is no normal inhibition of insulin-induced GSK-3. Already there has been a report that in patients with type II diabetes there is an excessive severity of GSK-3 [WO 00/38675]. Thus, therapeutic GSK-3 inhibitors may be useful in treating diabetic patients with a weakened response to insulin.

GSK-3 activity is also associated with Alzheimer's disease. This disease is characterized by the well-known β-amyloid peptide and the formation of intracellular neurofibrillary plexuses. Neurofibrillary plexuses contain hyperphosphorylated Tau protein, where Tau is phosphorylated in abnormal areas. It has already been shown that GSK-3 phosphorylates these abnormal regions in cell and animal models. In addition, inhibition of GSK-3 has been shown to prevent Tau hyperphosphorylation in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Thus, apparently, the activity of GSK-3 can contribute to the formation of neurofibrillary plexuses and the development of Alzheimer's disease.

Another substrate for GSK-3 is β-catenin, which decomposes after phosphorylation by GSK-3. It has already been reported that patients with schizophrenia have a reduced level of β-catenin, which is also accompanied by other diseases associated with 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)].

Due to the biological importance of GSK-3, there is currently an interest in therapeutically effective GSK-3 inhibitors. There are recent reports [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)] about small molecules that inhibit GSK-3.

For many of the above diseases associated with the pathological activity of GSK-3, other protein kinases are also targeted for their treatment. However, different protein kinases often act on different biological pathways. For example, as was recently reported (WO 00/12497 (Scios)), some quinazoline derivatives are p38 kinase inhibitors. It has been reported that these compounds can be used to treat conditions characterized by increased p38-α activity and / or increased TGF-β activity. Although p38 activity is accompanied by a wide variety of diseases, including diabetes, there is no evidence that p38 kinase is an integral part of the transmission of an insulin-induced signal that regulates glycogen synthesis or glucose uptake. Therefore, inhibition of p38, unlike GSK-3, is not expected to improve glycogen synthesis and / or glucose uptake.

The need to develop new drugs for the treatment of human diseases continues to be relevant. The Aurora-2 and GSK-3 protein kinases are particularly attractive for the discovery of new drugs because of their important role in the onset and development of cancer and diabetes, respectively.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that the compounds of the present invention and pharmaceutical compositions containing them can be used as protein kinase inhibitors, in particular Aurora-2 protein kinase inhibitors. Compounds having the general formula I are provided:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen or C — R ⁸ , and Z ² represents nitrogen or CH, wherein at least one of Z ¹ and Z ² represents nitrogen;

R ^x and R ^{y are} independently selected from T-R ³ or LZR ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, wherein each substituted carbon in said condensed ring formed by R ^x and R ^y is independently substituted by oxo, T-R ³ or LZR ³ and each replaced nitrogen in said ring formed by R ^x and R ^y independently substituted by R ⁴ ;

Q is selected from —N (R ⁴ ) -, —O—, —S—, —C (R ^{6 ′} ) ₂ -, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl or 1,3-cyclobutanediyl;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain, wherein when Q represents —C (R ^{6 ′} ) ₂ -, the methylene unit of said C _1-4 alkylidene chain is an optionally substituted group —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 -;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two R ⁶ groups ^on the same nitrogen atom can be combined with a nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{6 ′ is} independently selected from hydrogen or a C _1-4 aliphatic group, or two R ^{6 ′} groups at the same carbon atom are combined with each other to form a 3-6 membered carbocyclic ring;

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R ^{8 is} selected from —R, halogen, —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 group), -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 .

In this description, unless otherwise indicated, the following definitions of terms. The expression “optionally substituted” is used interchangeably with the expression “substituted or unsubstituted” or with the term “(un) substituted”. Unless otherwise indicated, an optionally substituted group may have a substituent at each substituted position of the group, and each substitution is independent of the other.

The term "aliphatic" as used herein means unbranched, branched or cyclic C _{1 -C 12} hydrocarbons that are fully saturated or that contain one or more units of unsaturation, but are not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted unbranched, branched or cyclic alkyl, alkenyl, alkynyl groups and their hybrids, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl” and “alkoxycarbonyl”, used as such or as part of a larger fragment, encompass both unbranched and branched chains containing one to twelve carbon atoms. The terms “alkenyl” and “alkynyl”, used as such or as part of a larger fragment, encompass both unbranched and branched chains containing two to twelve carbon atoms. The term “cycloalkyl”, used as such or as part of a larger fragment, includes cyclic C ₃ -C ₁₂ hydrocarbons that are fully saturated or that contain one or more units of unsaturation, but are not aromatic.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” mean respectively alkyl, alkenyl or alkoxy substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br or I.

The term “heteroatom” means nitrogen, oxygen or sulfur and encompasses any oxidized form of nitrogen and sulfur and a quaternized form of any nitrogenous base. The term "nitrogen" also includes substituted nitrogen in the heterocyclic ring. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be in the form of N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl).

The terms carbocyclic, carbocyclic, carbocyclic, or carbocyclic, as used herein, mean an aliphatic ring system having from three to fourteen members. The terms carbocyclic, carbocyclic, carbocyclic or carbocyclic, saturated or partially unsaturated, also refer to rings that are optionally substituted. The terms carbocyclic, carbocyclic, carbocyclic or carbocyclic also encompass aliphatic rings fused to one or more aromatic or non-aromatic rings, such as in decahydronaphthyl or tetrahydronaphthyl, where the radical or attachment point is in the aliphatic ring.

The term “aryl,” as used herein individually or as part of a larger fragment, as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to aromatic ring groups having from five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl” also refers to rings that are optionally substituted. The term “aryl” can be used interchangeably with the term “aryl ring”. Aryl also encompasses fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl” as used herein also includes a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phenanthridinyl or tetrahydronaphthyl, where the radical or the attachment point is on the aromatic ring.

The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used herein includes non-aromatic ring systems having from five to fourteen members, preferably from five to ten, in which one or more ring carbon atoms, preferably from one to four, each replaced with a heteroatom such as N, O or S. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one, (1-substituted) -2-oxobenzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropy wounded, 4-tetrahydropyranyl, [1,3] -dioxalanyl, [1,3] -dithiolanyl, [1,3] -dioxanyl, 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-piperidinyl, 4-piperidinyl thiazolidinyl, diazolonyl, N-substituted diazolonyl, l-phthalimidinyl, benzoxanil, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl and benzothianyl. The term “heterocyclyl” or “heterocyclic” as used herein also includes a group in which a non-aromatic ring containing a heteroatom is fused to one or more aromatic or non-aromatic rings, such as indolinyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, where the radical or the attachment point is in a non-aromatic heteroatom ring. The term “heterocycle”, “heterocyclic” or “heterocyclic”, saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term “heteroaryl”, used alone or as part of a larger fragment, as in “heteroaralkyl” or “heteroarylalkoxy,” refers to heteroaromatic ring groups having from five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, 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, benzimidazolyl, benzothienyl, benzofuranyl, indazolyl, quinolinyl, benzotriasis lil, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. The term “heteroaryl” as used herein also includes a group in which the heterocyclic ring is fused to one or more aromatic or non-aromatic rings, where the radical or attachment point is in the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [3,4-d] pyrimidinyl. The term “heteroaryl” also refers to rings that are optionally substituted. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl or heteroalkyl group include halogen, —R ^o , —OR ^o , SR ^o , 1,2-methylenedioxy, 1,2-ethylenedioxy, protected OH (such as 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 °) ₂ , -NR ° C (O) R °, -NR ° C (O) N (R °) ₂ , -NR ^о CO ₂ R ^о , -NR ° NR ° C (O) R °, -NR ° NR ° C (O) N (R °) ₂ , -NR ° NR ° CO ₂ R ^о , -C (O) C (O) R ° , -C (O) CH ₂ C (O) R °, -CO ₂ R °, -C (O) R °, -C (O) N (R °) ₂ , -OC (O) N (R ° ) ₂ , -S (O) ₂ R ^о , -SO ₂ N (R °) ₂ , -S (O) R °, -NR ° SO ₂ N (R °) ₂ , -NR ^о SO ₂ R ^о , -C (= S) N (R °) ₂ , -C (= NH) -N (R °) ₂ , - (CH ₂ ) _y NHC (O) R °, - (CH ₂ ) _y NHC (O) CH (VR ^o ) (R °), where each R ° is independently selected from hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -O (Ph), substituted - O (Ph), —CH ₂ (Ph), or substituted —CH ₂ (Ph), y represents 0-6 and V represents a linking group. Examples of substituents on the aliphatic group or the phenyl ring of the radical R ^a include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkilaminokarboniloksi, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

An aliphatic group or non-aromatic heterocyclic ring may contain one or more substituents. Examples of suitable substituents on a saturated carbon atom of an aliphatic group or a non-aromatic heterocyclic ring include those listed above for an unsaturated carbon atom 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 each R * is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents in the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylalkylalkylalkylcarbonyl.

Suitable substituents on the nitrogen atom 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 each R ^{+ is} independently selected from hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -O (Ph), substituted -O (Ph), - CH ₂ (Ph), substituted —CH ₂ (Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examples of substituents on the aliphatic group or phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxyalkylcarbonyl.

The term “linking group” or “binder” means an organic moiety that connects two parts of a compound. Binders usually consist of an atom, such as an oxygen atom or a sulfur atom, a unit, such as —NH—, —CH ₂ -, —C (O) -, —C (O) NH—, or a chain of atoms, such as an alkylidene chain . The molecular weight of the binder is usually in the range of about 14-200, preferably 14-96, with a length of up to about six atoms. Examples of binders include a saturated or unsaturated C _1-6 alkylidene chain, which is optionally substituted and in which one or two saturated carbon are optionally substituted with the group -C (O) -, -C (O) C (O) -, -CONH-, -CONHNH-, -CO ₂ -, -OC (O) -, -NHCO ₂ -, -O-, -NHCONH-, -OC (O) NH-, -NHNH-, -NHCO-, -S-, - SO-, -SO ₂ -, -NH-, -SO ₂ NH- or -NHSO ₂ -.

The term “alkylidene chain” refers to an optionally substituted straight or branched carbon chain, which may be fully saturated or may have one or more units of unsaturation. Optional substituents such as those described above for the aliphatic group.

A combination of substituents or variables is permissible only if such a combination gives a stable or chemically possible compound. A stable or chemically feasible compound is a compound whose chemical structure does not substantially change when kept at a temperature of 40 ° C or lower in the absence of moisture or other chemically active compounds for at least a week.

Unless otherwise indicated, it is intended that the structures shown herein include all their stereochemical forms, i.e. R and S configurations for each asymmetric center. Therefore, individual stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of the present invention. Unless otherwise indicated, it is intended that the structures shown herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the proposed structures, if we exclude the replacement of hydrogen with deuterium or tritium or the replacement of carbon with ¹³ C- or ¹⁴ C-enriched carbon, are within the scope of the present invention.

Compositions can be made from compounds of formula I or their salts. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an effective protein kinase inhibitor amount of a protein kinase inhibitor, in particular Aurora-2, in a biological sample or in a patient. The compounds of the present invention and their pharmaceutical compositions that contain an effective amount of a protein kinase inhibitor for the treatment or prevention of the Aurora-2-mediated condition, and a pharmaceutically acceptable carrier, excipient or excipient, may be in the form of a preparation suitable for administration to a patient.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a composition containing it.

The term “Aurora-2-mediated disease” or “Aurora-2-mediated condition” as used herein means any disease or other worsened condition in which Aurora-2 is known to play a role. The term "Aurora-2-mediated disease" or "Aurora-2-mediated condition" also means those diseases or conditions that facilitate treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, colon cancer, breast cancer, stomach cancer, and ovarian cancer.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 in a biological sample, and comprises contacting the biological sample with an Aurora-2 inhibitor of formula I or a composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, and includes administering to the patient a compound of formula I or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a composition containing it.

The term “GSK-3-mediated disease” or “GSK-3-mediated condition” as used herein means any disease or other worsened condition in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington’s disease, Parkinson’s disease, AIDS-related dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiac muscle hypertrophy, ischemia reperfusion, and baldness .

One aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, and comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin, which is useful for the treatment of schizophrenia. Another aspect of the present invention relates to a method for inhibiting the activity of GSK-3 in a biological sample and comprises contacting the biological sample with a GSK-3 inhibitor of formula I.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, and includes administering to the patient a compound of formula I or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a CDK-2-mediated disease with a CDK-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a composition containing it.

The term “CDK-2-mediated disease” or “CDK-2-mediated condition” as used herein means any disease or other worsened condition in which CDK-2 is known to play a role. The term "CDK-2-mediated disease" or "CDK-2-mediated condition" also means those diseases or conditions that facilitate 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. See Fischer, P.M. and Lane, D.P., Current Medicinal Chemistry, 1, 1213-1245 (2000); Mani, S., Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, M.D., Current Opinion in Oncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-59 (2000).

Another aspect of the present invention relates to a method for inhibiting the activity of CDK-2 in a biological sample or in a patient, and includes administering to a patient a compound of formula I or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing ERK-2-mediated diseases by an ERK-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a composition containing it.

The term “ERK-2-mediated disease” or “ERK-2-mediated condition” as used herein means any disease state or other worsened condition in which ERK-2 is known to play a role. The term "ERK-2-mediated disease" or "ERK-2-mediated condition" also means those diseases or conditions that facilitate treatment with an ERK-2 inhibitor. Such conditions include, but are not limited to, cancer, shock, diabetes, hepatomegaly, cardiovascular disease, including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, including asthma, inflammation, neurological disorders and hormonal diseases. The term “cancer” includes, but is not limited to, the following types of cancer: breast, ovary, cervical, prostate, testis, genitourinary, esophagus, larynx, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer , epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma noma, seminoma, melanoma, sarcoma, cancer of the bladder, cancer of the liver and bile ducts, cancer of the kidney, myeloid disorders, lymphoid disorders, Hodgkin hair cells, cancer of the vestibule of the mouth and pharynx (oral part), cancer of the lip, tongue, oral cavity, pharynx , small intestine, colon and rectum, colon, rectum, brain and central nervous system and leukemia. The protein kinase ERK-2 and its role in various diseases have already been described [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589].

Another aspect of the present invention relates to a method for inhibiting the activity of ERK-2 in a biological sample or in a patient, and includes administering to the patient a compound of formula I or a composition containing said compound. Another aspect of the present invention relates to a method for treating or preventing AKT-mediated disease with an AKT inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition containing it.

The term “ACT-mediated disease” or “ACT-mediated condition,” as used herein, means any disease or other deteriorated condition in which ACT is known to play a role. The term "ACT-mediated disease" or "ACT-mediated condition" also means those diseases or conditions that facilitate treatment with an ACT inhibitor. ACT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of ACT, also known as protein kinase B, with various diseases has already been described [Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y., et al, Oncogene, 19 2000; Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000].

Another aspect of the present invention relates to a method for inhibiting AKT activity in a biological sample or in a patient, and includes administering to a patient a compound of formula I or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing an Src-mediated disease with an Src inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition containing it. The term “Scr-mediated disease” or “Scr-mediated condition” as used herein means any disease or other deteriorated condition in which Src is known to play a role. The term “Src-mediated disease” or “Src-mediated condition” also means those diseases or conditions that facilitate treatment with an Src inhibitor. Such conditions include, but are not limited to, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease. Protein kinase Src and its role in various diseases have already been described [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)].

Another aspect of the present invention relates to a method for inhibiting Src activity in a biological sample or in a patient, and includes administering to the patient a compound of formula I or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing an Lck-mediated disease with an Lck inhibitor and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition containing it.

The term “Lck-mediated disease” or “Lck-mediated condition” as used herein means any disease state or other worsened condition in which Lck is known to play a role. The term "Lck-mediated disease" or "Lck-mediated condition" also means those diseases or conditions that facilitate 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. The association of Lck with various diseases has already been described [Molina et al., Nature, 357, 161 (1992)].

Another aspect of the present invention relates to a method for inhibiting Lck activity in a biological sample or in a patient, and includes administering to a patient a compound of formula I or a composition containing said compound.

The term "pharmaceutically acceptable carrier, excipient or excipient" refers to a non-toxic carrier, excipient or excipient that can be administered to a patient together with the compound of the present invention and which do not impair the pharmacological activity of the compound.

The term “patient” includes humans and veterinary subjects.

The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof, preparations of an enzyme suitable for in vitro testing, a biobtat taken from a mammal, or extracts thereof and blood, saliva, urine, feces, semen, tears and other body fluids or their extracts.

An amount effective to inhibit a protein kinase, for example Aurora-2 and GSK-3, is an amount that significantly inhibits kinase activity compared to enzyme activity in the absence of an inhibitor. Any method can be used to determine inhibition, such as, for example, in the biological test examples described below.

Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions are well known in the art. These include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride, mixtures of saturated vegetable fatty acids , water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glyco v, sodium carboxymethylcellulose, polyacrylates, waxes, polietilenpolioksipropilenovye block polymers, polyethylene glycol and wool fat.

The compositions of the present invention can be administered orally, parenterally, with an aerosol for inhalation, topically, rectally, nasally, buccally, vaginally or through an implanted reservoir. The term “parenteral” includes subcutaneous, intravenous, intramuscular, intraarticular, intrasinovial, intrathoracic, intrathecal, intrahepatic, intralesional and intracranial methods of injection or infusion. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of the present invention may be an aqueous or oily suspension. These suspensions can be prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable excipients and solvents that can be used, water, Ringer's solution and isotonic sodium chloride solution can be mentioned. In addition, sterile fixed oils are conveniently used as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically acceptable oils, such as olive or castor oil, in particular polyoxyethylated versions thereof, are suitable for the manufacture of injectable dosage forms. Said oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose, or similar dispersing agents, which are commonly used for the manufacture of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Twins, Spans, and other emulsifying agents or bioavailability enhancers that are commonly used to make pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used to formulate dosage forms.

The pharmaceutical compositions of the present invention can be administered orally in the form of any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are needed for oral use, the active ingredient is mixed with emulsifying and suspending agents. If necessary, any sweetening, flavoring or coloring agents may also be added.

The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration. Suppositories can be made by mixing the active ingredient with a suitable non-irritating, indifferent substance that is solid at room temperature but liquid at a temperature in the rectum and therefore will melt in the rectum to release the drug substance. Such materials include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutical compositions of the present invention can also be administered topically, in particular when the aim of the treatment is places or organs readily available for topical application, for example, for diseases of the eyes, skin or lower intestinal tract. Suitable topical dosage forms are readily prepared for each of these sites or organs.

Topical application for the lower intestinal tract can be carried out by means of a rectal dosage form in the form of a suppository (see above) or by means of a suitable enema formulation. Patches for topical transdermal administration may also be used.

For topical use, the pharmaceutical compositions may be formulated as a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. In another embodiment, the pharmaceutical compositions may be formulated in a suitable form of a lotion or cream containing active ingredients 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.

For ophthalmic use, the pharmaceutical compositions can be made in the form of finest suspensions in isotonic sterile saline with a pH adjusted or, preferably, in the form of solutions in isotonic sterile saline with a pH adjusted with or without a preservative, such as benzylalkonium chloride. In another embodiment, the pharmaceutical compositions for ophthalmic administration can be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions of the present invention may also be administered by aerosol spraying into the nose or by inhalation. Such compositions are prepared according to a technique well known in the art of dosage forms, and they can be formulated in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing substances.

In addition to the compounds of the present invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of the present invention can also be used in the compositions for the treatment and prevention of the above diseases and disorders.

“Pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable derivative in the form of a salt, ester, ester salt or other derivative of a compound of the present invention which, when administered to a recipient, is capable of producing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or its remainder. Particularly suitable derivatives or prodrugs are those that increase the bioavailability of the compounds of the present invention when administered to a patient (for example, by allowing an orally administered compound to be more easily absorbed into the blood) or improve the delivery of the parent compound to biological targets (e.g., brain or lymphatic system) relative to other parent species of compound.

Pharmaceutically acceptable prodrugs of the compounds of the present invention include, but are not limited to, esters, amino acid esters, phosphate esters, metal salts, sulfonate esters, carbamates and amides.

Pharmaceutically acceptable salts of the compounds of the present invention include salts prepared with pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, glycohexanoate, glycohexanoate heptoacetate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, for example oxalic, although not pharmaceutically acceptable themselves, can be used to prepare salts useful as intermediates for preparing the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

Salts prepared with suitable bases include alkali metal salts (e.g. sodium and potassium), alkaline earth metal salts (e.g. magnesium), ammonium salts and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also provides for the quaternization of basic nitrogen-containing groups of the compounds of the present invention. By such a quaternization, water or oil soluble or dispersible products can be obtained.

The amount of a protein kinase inhibitor that can be mixed with a carrier to form a unit dosage form can vary depending on the patient being treated and on the particular route of administration. Preferably, the compositions should be formulated in such a way that a dose of an inhibitor in the range of 0.01-100 mg / kg body weight / day can be administered to a patient taking said compositions. It should also be taken into account that the specific dose and the prescribed treatment regimen for a particular patient will depend on many factors, including the activity of the particular compound used, age, body weight, general health, gender, diet, time of administration, excretion rate, combination of drugs and assessment of the patient physician and the severity of the particular disease to be treated. The amount of inhibitor will also depend on the particular compound in the composition.

Depending on the particular protein kinase-mediated condition that needs to be treated or prevented, additional drugs may be administered with the inhibitors of the present invention, which are usually administered to treat or prevent this condition. For example, in the treatment of cancer, other chemotherapeutic agents or other antiproliferative agents may be combined with the cancer compounds of the invention. Such agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents with which the inhibitors of the present invention can also be combined include, but are not limited to diabetes agents, such as insulin or insulin analogues, in a form suitable for injection or inhalation, glitazones, alpha glucosidase inhibitors, biguanides, insulin and sulfonylureas sensitizers; anti-inflammatory drugs such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulating and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mucofenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's drugs; agents for treating cardiovascular disease, such as beta-blockers, ACE inhibitors (ACEs), diuretics, nitrates, calcium channel blockers and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for treating a blood disease, such as corticosteroids, anti-leukemia agents and growth factors, and agents for treating immunodeficiency disorders, such as gammaglobulin.

These additional agents may be administered separately from the composition containing the protein kinase inhibitor, as part of a multi-drug regimen. In another embodiment, these agents may be part of a unit dosage form mixed with the protein kinase inhibitor of the present invention in one composition.

The compounds of the present invention may exist in alternative tautomeric forms, such as tautomers i and ii shown below. Unless otherwise indicated, the presentation of one tautomer implies the inclusion of another.

R ^x and R ^y can be taken together to form a fused ring to give a bicyclic ring system containing ring A. Preferred R ^x / R ^y rings include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0- 2 heteroatoms, wherein said R ^x / R ^y ring is optionally substituted. The following are examples of bicyclic systems containing ring A, in the form of compounds IA - I-BB, where Z ¹ represents nitrogen or C (R ⁸ ) and Z ² represents nitrogen or C (H).

Preferred ring A bicyclic 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 and most preferably IA, IB, ID, IE and IJ.

In the monocyclic ring system A, preferred R ^x groups, when present, include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl. Preferred R ^y groups when present include TR ³ or LZR ³ , where T is a bond or methylene, 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, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl; A C _1-6 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-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 halogen-substituted phenyl.

In a ring A bicyclic system, the ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

R ² and R ^{2 '} can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido and a partially unsaturated 6-membered carbocyclic ring, said fused ring being optionally substituted. Examples of these fused rings are presented in the following compounds of formula I having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′} include one or more of the following substituents: halogen, —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 preferred represents methyl.

When the pyrazole ring system is monocyclic, preferred R ² groups include hydrogen, a C _1-4 aliphatic group, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenyl (phenyl) β-heterocyclyl) carbonyl. Examples of such preferred R ² substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, tert-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 (n-C ₃ H ₇ ), CON (Et ) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (n-C 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 (piperidin-l-yl). A preferred R ^{2 ′} group is hydrogen.

An option that is particularly useful for the treatment of Aurora-2-mediated diseases relates to compounds of formula IIa:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted carbon in said fused ring formed the radicals R ^x and R ^y are independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted nitrogen in said ring formed by the radicals R ^x and R ^y is independently substituted by a radical R ⁴ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ⁶ , or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms, selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted with halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by R ² and R ^{2 ′} , is independently substituted by R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 group), -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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred rings formed by the radicals R ^x and R ^y include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, said R ^x / R ^y ring being optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IIa are shown below.

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.

The ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 ′} in formula IIa can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIa having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R ² / R ^{2 ′} fused ring of formula IIa include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl or ethyl.

When the pyrazole ring system of formula IIa is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or C _1-6 aliphatic. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When the D ring of formula IIa is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring of formula IIa is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIa, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred compounds of formula IIa have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted ring carbon in said fused the ring formed by the radicals R ^x and R ^y is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by the radicals R ^x and R ^y is independently substituted by a radical R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(d) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring; and

(e) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ .

More preferred compounds of formula IIa have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(c) R ² is —R, and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ³ is selected from -R, halo, -OR, or -N (R ⁴⁾ _2, wherein R is selected from hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIa have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, piperidine or cyclohexyl ring;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring;

(c) R ² represents hydrogen or a C _1-4 aliphatic group, and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IIa are shown below in table 1.

Table 1

In another aspect, the present invention relates to a composition comprising a compound of formula IIa and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIa or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a compound of formula IIa or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes.

Another aspect of the present invention relates to a method of inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease.

Another aspect of the present invention relates to a method for inhibiting β-catenin phosphorylation and is useful in the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating or preventing a CDK-2-mediated disease with a CDK-2 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting CDK-2 activity in a patient, comprising administering to the patient a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating or preventing an Src-mediated disease with an Src inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Src activity in a patient, comprising administering to the patient a compound of formula IIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2, GSK-3, CDK-2 or Src in a biological sample, comprising contacting the biological sample with an Aurora-2, GSK-3, CDK-2 or Src inhibitor of formula IIa or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora-2, GSK-3, CDK-2 or Src.

Each of the above methods aimed at inhibiting Aurora-2, GSK-3, CDK-2 or Src or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIa, such as the compounds described above.

Another aspect of the present invention relates to compounds of formula IIb:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted carbon in said fused ring formed the radicals R ^x and R ^y are independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted nitrogen in said ring formed by the radicals R ^x and R ^y is independently substituted by a radical R ⁴ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 group), -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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two R ⁶ groups ^on the same nitrogen atom can be combined with a nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred rings formed by the radicals R ^x and R ^y, include 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said ring R ^x / R ^y is optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IIb are shown below.

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.

The ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 ′} in formula IIb can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIb having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula IIb include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl or ethyl.

When the pyrazole ring system of formula IIb is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IIb is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When ring D of formula IIb is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIb, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred compounds of formula IIb have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted ring carbon in said fused the ring formed by the radicals R ^x and R ^y is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by the radicals R ^x and R ^y is independently substituted by a radical R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(d) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring; and

(e) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ .

More preferred compounds of formula IIb have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(c) R ² is —R, and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ³ is selected from -R, halo, -OR, or -N (R ⁴⁾ _2, wherein R is selected from hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIb have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, piperidine or cyclohexyl ring;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring;

(c) R ² represents hydrogen or a C _1-4 aliphatic group and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IIb are shown below in table 2.

table 2

In another aspect, the present invention relates to a composition comprising a compound of formula IIb and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIb or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes.

Another aspect of the present invention relates to a method of inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease.

Another aspect of the present invention relates to a method for inhibiting β-catenin phosphorylation and is useful in the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IIb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IIb or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIb, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IIc:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted carbon in said fused ring formed radicals R ^x and R ^y, independently substituted by oxo, T-R ^3, or LZR ^3, and each substitutable nitrogen in said ring formed by the radicals R ^x and R ^y, independently substituted with R ^4;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain; Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R ⁴ independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (optionally substituted C _1-6 aliphatic), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred rings formed by the radicals R ^x and R ^y, include 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said ring R ^x / R ^y is optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IIc are shown below.

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.

The ring formed by R ^x and R ^y taken together of formula IIc may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 ′} in formula IIc can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIc having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R ² / R ^{2 ′} fused ring of formula IIc include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIc is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IIc is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIc, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred compounds of formula IIc have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted ring carbon in said fused the ring formed by the radicals R ^x and R ^y is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by the radicals R ^x and R ^y is independently substituted by a radical R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(d) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring; and

(e) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ .

More preferred compounds of formula IIc have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(c) R ² is —R, and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ³ is selected from -R, halo, -OR, or -N (R ⁴⁾ _2, wherein R is selected from hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIc have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, piperidine or cyclohexyl ring;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring;

(c) R ² represents hydrogen or a C _1-4 aliphatic group and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Preferred compounds of formula IIc include compounds of formula IIc ':

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^{y are} combined together with their intermediate atoms to form a fused benzene ring, wherein each substituted carbon in said fused ring formed by R ^x and R ^y is independently substituted with T-R ³ or 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 or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

The ring formed together of R ^x and R ^{y of} formula IIc 'may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 '} in the formula IIc' can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIc 'having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R ² / R ^{2 ′} fused ring of formula IIc ′ include one or more of the following substituents: halogen, —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 ) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIc ′ is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IIc ′ is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinyl azolazole , quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIc ', preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred compounds of formula IIc 'have one or more, and more preferably all, features selected from the following:

(a) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(b) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(c) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring; and

(d) R ^{3 is} selected from —R, halogen, —OR or —N (R ⁴ ) ₂ .

More preferred compounds of formula IIc 'have one or more, and more preferably all, features selected from the following:

(a) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(b) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(c) R ^{3 is} selected from —R, halogen, —OR or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIc 'have one or more, and more preferably all, features selected from the following:

(a) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring;

(b) R ² represents hydrogen or a C _1-4 aliphatic group and R ^{2 '} represents hydrogen;

(c) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(d) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Other preferred compounds of formula IIc include compounds of formula IIc ″:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted carbon in said condensed ring formed the radicals R ^x and R ^y are optionally substituted by an oxo group, T-R ³ or LZR ^3, and each substituted nitrogen in said ring formed by the radicals R ^x and R ^y is optionally substituted by a radical R ⁴ ; with the proviso that said condensed ring formed by the radicals R ^x and R ^y is different from the benzene ring;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred rings formed by the radicals R ^x and R ^{y of} formula IIc ″ include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms, or a partially unsaturated carbocyclic ring, said ring R ^x / R ^y is optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IIc are shown below.

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.

The ring formed together of R ^x and R ^{y of} formula IIc ″ may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), -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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 '} in formula IIc "can be taken together to form a fused ring to give a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are represented in the following compounds of formula IIc "having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² / R ^{2 ′ of} formula IIc ″ include one or more of the following substituents: halogen, —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 ) represents an unbranched, branched or cyclic alkyl group, preferably a C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIc ″ is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IIc is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

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, benzothinyl azolazole , quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIc, “preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 , -NHC OCH 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 (tert-butyl), —NH (C _1-4 aliphatic group) such as —NHMe, N (C _1-4 aliphatic group) ₂ such as —NMe ₂ , OH, —O (C _{1- 4} aliphatic group) such as —OMe, a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl, and —CO ₂ (C _1-4 aliphatic group).

Preferred compounds of formula IIc "have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, or a partially unsaturated 6 membered carbocyclic ring , wherein each substitutable ring carbon in said fused ring formed by the radicals R ^x and R ^y, independently substituted by oxo, T-R ^3, or LZR ^3, and each substitutable ring nitrogen in said ring formed by the radicals R ^x and R ^y, independently substituted Radick scrap R ^4;

(b) R ¹ represents T- (ring D), where T represents a bond or methylene unit and ring D represents a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;

(c) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring; and

(d) R ^{3 is} selected from —R, halogen, —OR or —N (R ⁴ ) ₂ .

More preferred compounds of formula IIc "have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings, each substituted ring carbon in said condensed ring formed by the radicals R ^x and R ^y , independently substituted by oxo, T-R ³ or LZR ³ and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(c) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ³ is selected from -R, halo, -OR, or -N (R ⁴⁾ _2, wherein R is selected from hydrogen, C _1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIc "have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a pyridine, piperidine or cyclohexyl ring, wherein each substituted ring carbon in said condensed ring formed by R ^x and R ^y is independently substituted by an oxo group, T-R ³ or LZR ³ and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring;

(c) R ² represents hydrogen or a C _1-4 aliphatic group and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IIc are shown in Table 3 below.

Table 3

In yet another embodiment, the present invention relates to a composition comprising a compound of formula IIc, IIc 'or IIc' 'and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method of inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIc, IIc 'or IIc' 'or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes.

Another aspect of the present invention relates to a method of inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease.

Another aspect of the present invention relates to a method for inhibiting β-catenin phosphorylation and is useful in the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating or preventing an Src-mediated disease with an Src inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Src activity in a patient, comprising administering to the patient a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating or preventing an ERK-2-mediated disease with an ERK-2 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting ERK-2 activity in a patient, comprising administering to the patient a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating or preventing AKT-mediated disease with an AKT inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting AKT protein kinase activity in a patient, comprising administering to the patient a compound of formula IIc, IIc 'or IIc' 'or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2, GSK-3, Src, ERK-2 or ACT in a biological sample, comprising contacting the biological sample with an inhibitor of Aurora-2, GSK-3, Src, ERK-2 or ACT of formula IIc, IIc 'or IIc' 'or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora-2, GSK-3, Src, ERK-2 or ACT.

Each of the above methods aimed at inhibiting Aurora-2, GSK-3, Src, ERK-2, or ACT or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIc, IIc ′ or IIc ’, such as the compounds described above.

Another embodiment of the present invention, particularly useful for the treatment of Aurora-2-mediated diseases, relates to compounds of formula IId:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Q 'is selected from -C (R ^6' ) ₂ -, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl or 1,3-cyclobutanediyl;

R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted carbon in said fused ring formed radicals R ^x and R ^y, independently substituted by oxo, T-R ^3, or LZR ^3, and each substitutable nitrogen in said ring formed by the radicals R ^x and R ^y, independently substituted with R ^4;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T is a bond or a C _1-4 alkylidene chain, wherein when Q ′ is —C (R ^{6 ′} ) ₂ -, the methylene group of said C _1-4 alkylidene chain is optionally substituted with —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 -;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{6 ′ is} independently selected from hydrogen or a C _1-4 aliphatic group or two R ^{6 ′} at the same carbon atom are combined with each other to form a 3-6 membered carbocyclic ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred rings formed by the radicals R ^x and R ^y, include 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said ring R ^x / R ^y is optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IId are shown below.

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.

The ring formed by R ^x and R ^y taken together of formula IId may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 ′} in formula IId can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IId having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R ² / R ^{2 ′} fused ring of formula IId include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IId is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IId is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring of formula IId is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IId, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred Q ′ groups of formula IId include —C (R ^{6 ′} ) ₂ - or 1,2-cyclopropanediyl, wherein each R ^{6 ′ is} independently selected from hydrogen or methyl. A more preferred group Q 'is —CH ₂ -.

Preferred compounds of formula IId have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur or nitrogen, with each substituted ring carbon in said fused the ring formed by the radicals R ^x and R ^y is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by the radicals R ^x and R ^y is independently substituted by a radical R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond or a methylene unit, and wherein said methylene unit is optionally substituted with the substituent —O—, —NH— or —S—;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

(d) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring; and

(e) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ .

More preferred compounds of formula IId have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit, wherein said methylene unit is optionally substituted with -O-, and ring D is a 5-6 membered monocyclic ring or 8-10 a membered bicyclic ring selected from an aryl or heteroaryl ring;

(c) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;

(d) R ^{3 is} selected from —R, halogen, —OR or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -; and

(e) Q ′ is —C (R ^{6 ′} ) ₂ - or 1,2-cyclopropanediyl, wherein each R ^{6 ′ is} independently selected from hydrogen or methyl.

Even more preferred compounds of formula IId have one or more, and more preferably all, features selected from the following:

(a) R ^x and R ^y are taken together with each other to form a benzene, pyridine, piperidine or cyclohexyl ring;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring;

(c) R ² represents hydrogen or a C _1-4 aliphatic group and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—;

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(f) Q ′ is —CH ₂ -.

Representative compounds of formula IId are shown below in table 4.

Table 4

In yet another embodiment, the present invention relates to a composition comprising a compound of formula IId and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IId or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IId or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IId or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a compound of formula IId or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IId or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IId or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IId, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IIIa:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^y are independently selected from T-R ³ or LZR ³ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred R ^x groups of formula IIIa include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IIIa include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The groups R ² and R ^{2 '} in formula IIIa can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIIa having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula IIIa include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIIa is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When the D ring of formula IIIa is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIIa, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), -NH (C _1-4 aliphatic group), such as -NHMe, - N (C _1-4 aliphatic group) ₂ such as —NMe ₂ , OH, —O (C _1-4 aliphatic group) such as —OMe, C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-b scrap, and -CO ₂ (C _1-4 aliphatic group).

Preferred compounds of formula IIIa have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group; (b) R ^y represents T-R ³ or LZR ³ , where T represents a bond or methylene and R ³ represents -R, -N (R ⁴ ) ₂ or -OR;

(c) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring; and

(e) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IIIa have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ , where R is selected from hydrogen, C _{1- 6} aliphatic groups or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

(b) R ¹ represents T- (ring D), where T represents a 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, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIIa have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetymido;

(b) R ^{u is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl or dialkylamino, alkyl or dialkylamino optionally substituted phenyl or methoxymethyl;

(c) R ¹ represents T- (ring D), where T represents a bond and ring D represents a 5-6 membered aryl or heteroaryl ring, wherein ring D is optionally substituted with one or two groups selected from halogen, - 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, —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 ,; and

(d) R ² represents hydrogen or a substituted or unsubstituted C _1-6 aliphatic group and L represents —O—, —S— or —NH—.

Representative compounds of formula IIIa are shown below in table 5.

Table 5

In yet another embodiment, the present invention relates to a composition comprising a compound of formula IIIa and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIIa or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula IIIa or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a compound of formula IIIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for treating or preventing an Src-mediated disease with an Src inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Src activity in a patient, comprising administering to the patient a compound of formula IIIa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2, GSK-3 or Src in a biological sample, comprising contacting the biological sample with an Aurora-2, GSK-3 or Src inhibitor of formula IIIa or with a pharmaceutical composition containing it in an amount effective for inhibiting Aurora-2, GSK-3 or Src.

Each of the above methods aimed at inhibiting Aurora-2, GSK-3 or Src or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIIa, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IIIb:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^y are independently selected from T-R ³ or LZR ³ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred R ^x groups of formula IIIb include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IIIb include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The groups R ² and R ^{2 '} in formula IIIb can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIIb having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula IIIb include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIIb is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IIIb is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIIb, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred compounds of formula IIIb have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group;

(b) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ or —OR;

(c) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring; and

(e) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IIIb have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ , where R is selected from hydrogen, C _{1- 6} aliphatic groups or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

(b) R ¹ represents T- (ring D), where T represents a 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, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(e) L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIIb have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetymido;

(b) R ^{u is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl or dialkylamino, alkyl or dialkylamino optionally substituted phenyl or methoxymethyl;

(c) R ¹ represents T- (ring D), where T represents a bond and ring D represents a 5-6 membered aryl or heteroaryl ring, wherein ring D is optionally substituted with one or two groups selected from halogen, - 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, —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 ,; and

(d) R ² represents hydrogen or a substituted or unsubstituted C _1-6 aliphatic group and L represents —O—, —S— or —NH—.

Representative compounds of formula IIIb are shown below in table 6.

Table 6

In yet another embodiment, the present invention relates to a composition comprising a compound of formula IIIb and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIIb or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a compound of formula IIIb or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IIIb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IIIb or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIIb, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IIIc:

or their pharmaceutically acceptable derivatives or prodrugs, where:

R ^x and R ^y are independently selected from T-R ³ or LZR ³ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred R ^x groups of formula IIIc include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IIIc include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The groups R ² and R ^{2 ′} in formula IIIc can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIIc having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula IIIc include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIIc is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When the D ring of formula IIIc is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIIc, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred compounds of formula IIIc have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group;

(b) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ or —OR;

(c) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring; and

(e) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IIIc have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ , where R is selected from C _1-6 aliphatic a group or a 5-6 membered heterocyclyl, phenyl or a 5-6 membered heteroaryl;

(b) R ¹ represents T- (ring D), where T represents a 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, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(e) L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IIIc have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetymido;

(b) R ^{u is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl or dialkylamino, alkyl or dialkylamino optionally substituted phenyl or methoxymethyl;

(c) R ¹ represents T- (ring D), where T represents a bond and ring D represents a 5-6 membered aryl or heteroaryl ring, wherein ring D is optionally substituted with one or two groups selected from halogen, - 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, —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 ,; and

(d) R ² represents hydrogen or a substituted or unsubstituted C _1-6 aliphatic group and L represents —O—, —S— or —NH—.

Representative compounds of formula IIIc are shown in Table 7 below.

Table 7

In yet another embodiment, the present invention relates to a composition comprising a compound of formula IIIc and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method of inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIIc or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IIIc or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing an Src-mediated disease with an Src inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Src activity in a patient, comprising administering to the patient a compound of formula IIIc or a composition containing said compound.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2, GSK-3 or Src in a biological sample, comprising contacting the biological sample with an Aurora-2, GSK-3 or Src inhibitor of formula IIIc or with a pharmaceutical composition containing it in an amount effective for inhibiting Aurora-2, GSK-3 or Src.

Each of the above methods aimed at inhibiting Aurora-2, GSK-3 or Src or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIIc, such as the above compounds.

Another embodiment of the present invention relates to compounds of formula IIId:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Q 'is selected from -C (R ^6' ) ₂ -, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl or 1,3-cyclobutanediyl;

R ^x and R ^y are independently selected from T-R ³ or LZR ³ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T is a bond or a C _1-4 alkylidene chain, wherein when Q 'is —C (R ^{6 ′} ) ₂ -, the methylene group of said C _1-4 alkylidene chain is optionally substituted with —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 -;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{6 ′ is} independently selected from hydrogen or a C _1-4 aliphatic group or two R ^{6 ′} at the same carbon atom are combined with each other to form a 3-6 membered carbocyclic ring; and

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred R ^x groups of formula IIId include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IIId include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The groups R ² and R ^{2 '} in formula IIId can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IIId having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² / R ^{2 ′ of} formula IIId include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IIId is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen. When the D ring of formula IIId is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IIId, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), -NH (C _1-4 aliphatic group), such as -NHMe, - N (C _1-4 aliphatic group) ₂ such as —NMe ₂ , OH, —O (C _1-4 aliphatic group) such as —OMe, C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-b scrap, and -CO ₂ (C _1-4 aliphatic group).

Preferred Q ′ groups of formula IIId include —C (R ^{6 ′} ) ₂ - or 1,2-cyclopropanediyl, wherein each R ^{6 ′ is} independently selected from hydrogen or methyl. A more preferred group Q 'is —CH ₂ -.

Preferred compounds of formula IIId have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group;

(b) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ or —OR;

(c) R ¹ represents T- (ring D), where T represents a bond or a methylene unit, said methylene unit being an optionally substituted group —O—, —NH— or —S—;

(d) Ring D is a 5-7 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring; and

(e) R ² is —R or —TWR ⁶ , and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IIId have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ , where R is selected from hydrogen, C _{1- 6} aliphatic groups or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

(b) R ¹ represents T- (ring D), where T represents a 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, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;

(e) L is —O—, —S— or —N (R ⁴ ) -; and

(f) Q ′ is —C (R ^{6 ′} ) ₂ - or 1,2-cyclopropanediyl, wherein each R ^{6 ′ is} independently selected from hydrogen or methyl.

Even more preferred compounds of formula IIId have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetymido;

(b) R ^{u is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl or dialkylamino, alkyl or dialkylamino optionally substituted phenyl or methoxymethyl;

(c) R ¹ represents T- (ring D), where T represents a bond and ring D represents a 5-6 membered aryl or heteroaryl ring, wherein ring D is optionally substituted with one or two groups selected from halogen, - 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, —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 ,;

(d) R ² represents hydrogen or a substituted or unsubstituted C _1-6 aliphatic group and L represents —O—, —S— or —NH—; and

(e) Q 'is —CH ₂ -.

Representative compounds of formula IIId are shown in Table 8 below.

Table 8

In yet another embodiment, the present invention relates to a composition comprising a compound of formula IIId and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIId or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IIId or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIId or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula IIId or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IIId or a composition containing said compound.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IIId or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IIId, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IVa:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen or C — R ⁸ and Z ² represents nitrogen or CH, wherein one of Z ¹ and Z ² represents nitrogen;

R ^x and R ^{y are} independently selected from T-R ³ or LZR ³ or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, wherein each substituted carbon in said condensed ring formed by R ^x and R ^y is independently substituted by oxo, T-R ³ or LZR ³ and each replaced nitrogen in said ring formed by R ^x and R ^y , independently substituted by R ⁴ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R ^{8 is} selected from —R, halogen, —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 group), -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 .

Preferred rings formed by the radicals R ^x and R ^{y of} formula IVa include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, said R ^x / R ^y ring being optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred pyridine ring systems of formula IVa are shown below.

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 systems described above in which Z ¹ represents nitrogen and Z ² represents CH.

Preferred R ^x groups of formula IVa include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IVa include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The ring formed by the R ^x and R ^y groups of formula IVa taken together may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 ′} in formula IVa can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IVa having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R ² / R ^{2 ′} fused ring of formula IVa include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IVa is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IVa is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IVa, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred R ⁸ groups of formula IVa, when present, include R, OR and N (R ⁴ ) ₂ . Examples of preferred R ⁸ groups 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, (piperidin-1- sludge) CH ₂ CH ₂ O and NH ₂ CH ₂ CH ₂ O.

Preferred compounds of formula IVa have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group and R ^y represents T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ - or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic aryl or heteroaryl ring; and

(d) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IVa have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ -, where R is selected from hydrogen, C _{1 -6} aliphatic group or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, or R ^x and R ^y are taken together with their intermediate atoms to form benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y is not is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;

(c) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, or a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IVa have one or more, and more preferably all, features selected from the following:

(a) R ^x represents methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido, and R ^{y is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert -butyl, alkoxyalkylamine, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl, or R ^x and R ^y are taken together with their intervening atoms to form a benzene, pyridine, piperidine or cyclohexyl ring, and AUC annoe ring is optionally substituted by halogen, -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 , where R is hydrogen or an optionally substituted C _1-6 aliphatic group;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from halogen, —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 ;

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IVa are shown below in table 9.

Table 9

In another aspect, the present invention relates to a composition comprising a compound of formula IVa and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IVa or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IVa or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IVa or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IVa, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IVb:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen or C — R ⁸ and Z ² represents nitrogen or CH, wherein one of Z ¹ and Z ² represents nitrogen;

R ^x and R ^{y are} independently selected from T-R ³ or LZR ³ or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, wherein each substituted carbon in said condensed ring formed by R ^x and R ^y is independently substituted by oxo, T-R ³ or LZR ³ and each replaced nitrogen in said ring formed by R ^x and R ^y , independently substituted by R ⁴ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R ^{8 is} selected from —R, halogen, —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 group), -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 .

Preferred rings formed by the radicals R ^x and R ^{y of} formula IVb include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, said R ^x / R ^y ring being optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IVb are shown below.

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 systems described above in which Z ¹ represents nitrogen and Z ² represents CH.

Preferred R ^x groups of formula IVb include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IVb include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The ring formed by the R ^x and R ^y groups of formula IVb taken together may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 '} in formula IVb can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IVb having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² / R ^{2 ′ of} formula IVb include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IVb is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IVb is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IVb, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred R ⁸ groups of formula IVb, when present, include R, OR and N (R ⁴ ) ₂ . Examples of preferred R ⁸ groups 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, (piperidin-1- sludge) CH ₂ CH ₂ O and NH ₂ CH ₂ CH ₂ O.

Preferred compounds of formula IVb have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group and R ^y represents T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ - or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic aryl or heteroaryl ring; and

(d) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IVb have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ -, where R is selected from hydrogen, C _{1 -6} aliphatic group or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, or R ^x and R ^y are taken together with their intermediate atoms to form benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y is not is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;

(c) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, or a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IVb have one or more, and more preferably all, features selected from the following:

(a) R ^x represents methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido, and R ^{y is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert -butyl, alkoxyalkylamine, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl, or R ^x and R ^y are taken together with their intervening atoms to form a benzene, pyridine, piperidine or cyclohexyl ring, and AUC annoe ring is optionally substituted by halogen, -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 , where R is hydrogen or an optionally substituted C _1-6 aliphatic group;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from halogen, —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 ;

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IVb are shown below in table 10.

Table 10

In another aspect, the present invention relates to a composition comprising a compound of formula IVb and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and includes administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 in a patient, comprising administering to the patient a compound of formula IVb or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVb or a composition containing said compound.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a compound of formula IVb or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IVb or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IVb or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IVb, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IVc:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen or C — R ⁸ and Z ² represents nitrogen or CH, wherein one of Z ¹ and Z ² represents nitrogen;

R ^x and R ^{y are} independently selected from T-R ³ or LZR ³ or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, wherein each substituted carbon in said condensed ring formed by R ^x and R ^y is independently substituted by oxo, T-R ³ or LZR ³ and each replaced nitrogen in said ring formed by R ^x and R ^y , independently substituted by R ⁴ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T represents a bond or a C _1-4 alkylidene chain;

Z represents 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 ) = N-О-, -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, - TWR ⁶ or R ² and R ^{2 'are} combined together with their intervening atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen ode or sulfur, wherein each substitutable carbon in said fused ring formed by the radicals R ² and R ^{2 'is} independently substituted by halo, oxo, -CN, -NO _2, -R ^7, or -VR ^6, and each substitutable nitrogen in said ring, formed by the radicals R ² and R ^{2 '} , independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R ^{8 is} selected from —R, halogen, —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 group), -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 .

Preferred rings formed by the radicals R ^x and R ^{y of} formula IVc include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, said R ^x / R ^y ring being optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred pyridine ring systems of formula IVc are shown below.

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 systems described above in which Z ¹ represents nitrogen and Z ² represents CH.

Preferred R ^x groups of formula IVc include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IVc include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The ring formed by the combined groups R ^x and R ^{y of the} formula IVc may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), —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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 '} in formula IVc can be taken together to form a fused ring, which gives a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IVc having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula IVc include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IVc is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IVc is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When ring D of formula IVc is bicyclic, preferred bicyclic ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IVc, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), —NH (C _1-4 aliphatic group), such as —NHMe, N (C _1-4 aliphatic group) ₂ , such as -NMe ₂ , OH, -O (C _1-4 aliphatic group), such as -OMe, C _1-4 aliphatic group, such as methyl, ethyl, cyclopropyl, isopropyl or t-b Teal, and -CO ₂ (C _1-4 aliphatic).

Preferred R ⁸ groups of formula IVc, when present, include R, OR and N (R ⁴ ) ₂ . Examples of preferred R ⁸ groups 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, (piperidin-1- sludge) CH ₂ CH ₂ O and NH ₂ CH ₂ CH ₂ O.

Preferred compounds of formula IVc have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group and R ^y represents T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ - or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic aryl or heteroaryl ring; and

(d) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IVc have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ -, where R is selected from hydrogen, C _{1 -6} aliphatic group or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, or R ^x and R ^y are taken together with their intermediate atoms to form benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y is not is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;

(c) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(d) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, or a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -.

Even more preferred compounds of formula IVc have one or more, and more preferably all, features selected from the following:

(a) R ^x represents methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido, and R ^{y is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert -butyl, alkoxyalkylamine, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl, or R ^x and R ^y are taken together with their intervening atoms to form a benzene, pyridine, piperidine or cyclohexyl ring, and AUC annoe ring is optionally substituted by halogen, -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 , where R is hydrogen or an optionally substituted C _1-6 aliphatic group;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from halogen, —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 ;

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—; and

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IVc are shown below in table 11.

Table 11

In another aspect, the present invention relates to a composition comprising a compound of formula IVc and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVc or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method of inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IVc or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVc or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula IVc or a pharmaceutical composition containing it. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 activity in a patient, comprising administering to the patient a compound of formula IVc or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IVc or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IVc, such as the compounds described above.

Another embodiment of the present invention relates to compounds of formula IVd:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen or C — R ⁸ and Z ² represents nitrogen or CH, wherein one of Z ¹ or Z ² represents nitrogen;

Q 'is selected from -C (R ^6' ) ₂ -, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl or 1,3-cyclobutanediyl;

R ^x and R ^{y are} independently selected from T-R ³ or LZR ³ or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, wherein each substituted carbon in said condensed ring formed by R ^x and R ^y is independently substituted by oxo, T-R ³ or LZR ³ and each replaced nitrogen in said ring formed by R ^x and R ^y , independently substituted by R ⁴ ;

R ¹ represents T- (ring D);

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, of which the heteroaryl or heterocyclyl ring contains 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon of ring D is independently substituted by oxo, T-R ⁵ or VZR ^5, and each substituted nitrogen of ring D is independently substituted by —R ⁴ ;

T is a bond or a C _1-4 alkylidene chain, wherein when Q 'is —C (R ^{6 ′} ) ₂ -, the methylene group of said C _1-4 alkylidene chain is optionally substituted with —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 -;

Z represents 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 ) = N-О-, -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, -TWR ^6, or R ² and R ^{2' are} combined together with their intermediate atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substituted carbon in said condensed ring formed by the radicals R ² and R ^{2 ′} is independently substituted by halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ and each replaced nitrogen in said ring formed by the radicals R ² and R ^{2 ′} is independently substituted by the radical R ⁴ ;

R ^{3 is} selected from —R, halogen, —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 group), -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 or —OC (= O) N (R ⁷ ) ₂ ;

each R is independently selected from hydrogen or an optionally substituted group selected from a C _1-6 aliphatic group, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R ^{4 is} independently selected from —R ⁷ , —COR ⁷ , —CO ₂ (an optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ⁷ ;

each R ^{5 is} independently selected from —R, halogen, —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 ;

V represents —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 ) = N-О-, -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 represents —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 ) = N-O-, -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 or an optionally substituted C _1-4 aliphatic group, or two groups R ⁶ have the same nitrogen atom may be combined together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R ^{6 ′ is} independently selected from hydrogen or a C _1-4 aliphatic group or two R ^{6 ′} at the same carbon atom are combined with each other to form a 3-6 membered carbocyclic ring;

each R ^{7 is} independently selected from hydrogen or an optionally substituted C _1-6 aliphatic group or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R ^{8 is} selected from —R, halogen, —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 group), -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 .

Preferred rings formed by the radicals R ^x and R ^{y of} formula IVd include a 5-, 6- or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, said R ^x / R ^y ring being optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred pyridine ring systems of formula IVd are shown below.

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 systems described above in which Z ¹ represents nitrogen and Z ² represents CH.

Preferred R ^x groups of formula IVd include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl or isopropyl.

Preferred R groups ^of formula IVd include T-R ³ or LZR ³ , where T is a bond or methylene, L is —O—, —S— or —N (R ⁴ ) -, —C (R ⁶ ) ₂ O -, —CO— and R ³ represents —R, —N (R ⁴ ) ₂ - or —OR. Examples of preferred R ^y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl or dialkylamino, such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy, such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The ring formed by the R ^x and R ^y groups of formula IVd taken together may be substituted or unsubstituted. Suitable substituents include —R, halogen, —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 group), -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 , where R and R ⁴ are as defined above. Preferred substituents on the R ^x / R ^y ring include halogen, —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 represents hydrogen or an optionally substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 '} in the formula IVd can be taken together to form a fused ring to give a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzene, pyridine, pyrimidine and partially unsaturated 6-membered carbocyclic rings. Examples of these fused rings are presented in the following compounds of formula IVd having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R ² / R ^{2 ′} fused ring of formula IVd include one or more of the following substituents: halogen, —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) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

When the pyrazole ring system of formula IVd is monocyclic, preferred R ² groups include hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include H, methyl, ethyl, propyl, cyclopropyl, isopropyl, cyclopentyl, hydroxypropyl, methoxypropyl and benzyloxypropyl. A preferred R ^{2 ′} group is hydrogen.

When ring D of formula IVd is monocyclic, preferred ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

When the D ring 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, benzothinylazolazole quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

In ring D of formula IVd, preferred substituents T — R ⁵ or VZR ⁵ include halogen, —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 ₂ (R ⁴ ) ₂ , where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or 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 (tert-butyl), -NH (C _1-4 aliphatic group), such as -NHMe, - N (C _1-4 aliphatic group) ₂ such as —NMe ₂ , OH, —O (C _1-4 aliphatic group) such as —OMe, C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-b scrap, and -CO ₂ (C _1-4 aliphatic group).

Preferred R ⁸ groups of formula IVd, when present, include R, OR and N (R ⁴ ) ₂ . Examples of preferred R ⁸ groups 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, (piperidin-1- sludge) CH ₂ CH ₂ O and NH ₂ CH ₂ CH ₂ O.

Preferred Q ′ groups of formula IVd include —C (R ^{6 ′} ) ₂ - or 1,2-cyclopropanediyl, wherein each R ^{6 ′ is} independently selected from hydrogen or methyl. A more preferred group Q 'is —CH ₂ -.

Preferred compounds of formula IVd have one or more, and more preferably all, features selected from the following:

(a) R ^x represents hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group and R ^y represents T-R ³ or LZR ³ , where T is a bond or methylene and R ³ is —R, —N (R ⁴ ) ₂ - or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ represents T- (ring D), where T represents a bond or a methylene unit, said methylene unit being an optionally substituted group —O—, —NH— or —S—;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic aryl or heteroaryl ring; and

(d) R ² is —R or —TWR ⁶ and R ^{2 ′} is hydrogen; or R ² and R ^{2 ′} are taken together with each other to form an optionally substituted benzene ring.

More preferred compounds of formula IVd have one or more, and more preferably all, features selected from the following:

(a) R ^y is T-R ³ or LZR ³ , where T is a bond or methylene and R ^{3 is} selected from —R, —OR or —N (R ⁴ ) ₂ -, where R is selected from hydrogen, C _{1 -6} aliphatic group or 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, or R ^x and R ^y are taken together with their intermediate atoms to form benzene, pyridine, cyclopentyl, cyclohexyl, cycloheptyl, thienyl, piperidine or imidazole rings, and each substituted ring carbon in the specified condensed ring formed by the radicals R ^x and R ^y is not is independently substituted by an oxo group, T-R ³ or LZR ^3, and each substituted ring nitrogen in said ring formed by R ^x and R ^y is independently substituted by R ⁴ ;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered monocyclic or 8-10 membered bicyclic aryl or heteroaryl ring;

(c) R ² is —R and R ^{2 ′} is hydrogen, wherein R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;

(d) R ^{3 is} selected from —R, halogen, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, or a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl and L is —O—, —S— or —N (R ⁴ ) -; and

(e) Q ′ is —C (R ^{6 ′} ) ₂ - or 1,2-cyclopropanediyl, wherein each R ^{6 ′ is} independently selected from hydrogen or methyl.

Even more preferred compounds of formula IVd have one or more, and more preferably all, features selected from the following:

(a) R ^x represents methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido, and R ^{y is} selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, tert -butyl, alkoxyalkylamine, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl, or R ^x and R ^y are taken together with their intervening atoms to form a benzene, pyridine, piperidine or cyclohexyl ring, and AUC annoe ring is optionally substituted by halogen, -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 , where R is hydrogen or an optionally substituted C _1-6 aliphatic group;

(b) R ¹ is T- (ring D), where T is a bond and ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from halogen, —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 ;

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, and R ^{2 '} represents hydrogen;

(d) R ^{3 is} selected from —R, —OR, or —N (R ⁴ ) ₂ , wherein R is selected from hydrogen, a C _1-6 aliphatic group, a 5-6 membered heterocyclyl, phenyl, or a 5-6 membered heteroaryl; and L represents —O—, —S— or —NH—;

(e) ring D is substituted with up to three substituents selected from halogen, —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 ₂ (R ⁴ ) ₂ where R is selected from hydrogen, a C _1-6 aliphatic group, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

(f) Q ′ is —CH ₂ -.

Representative compounds of formula IVd are shown in Table 12 below.

Table 12

In another aspect, the present invention relates to a composition comprising a compound of formula IVd and a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to a method for treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, and comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition containing it.

Another aspect of the present invention relates to a method of inhibiting Aurora-2 activity in a patient, comprising administering to the patient a compound of formula IVd or a composition containing said compound.

Another aspect of the present invention relates to a method for treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition containing it. Another aspect of the present invention relates to a method of enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount va compound of formula IVd or a pharmaceutical composition. This method is especially useful for patients with diabetes. Another method relates to inhibiting the production of hyperphosphorylated Tau protein and is useful for stopping or slowing down the development of Alzheimer's disease. Another method relates to the inhibition of phosphorylation of β-catenin and is useful for the treatment of schizophrenia.

Another aspect of the present invention relates to a method for inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a compound of formula IVd or a composition comprising said compound.

Another aspect of the present invention relates to a method for inhibiting the activity of Aurora-2 or GSK-3 in a biological sample, comprising contacting the biological sample with an Aurora-2 or GSK-3 inhibitor of formula IVd or with a pharmaceutical composition containing it in an amount effective to inhibit Aurora -2 or GSK-3.

Each of the above methods aimed at inhibiting Aurora-2 or GSK-3 or treating a disease alleviated by said inhibition is preferably carried out using a preferred compound of formula IVd, such as the compounds described above.

Compounds of the present invention can be obtained by conventional methods known to those skilled in the art for the preparation of similar compounds, as illustrated below by General Schemes I-VII, by the general methods following, and then by preparation examples.

Scheme I

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 or Mg or Sn, catalyst = Pd ° or Ni °).

Scheme I shows a general route for preparing the compounds of the present invention. Dichlorinated starting material 1 can be prepared by methods similar to those described in J. Indian. Chem. Soc., 61, 690-693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994). The implementation of the interaction of compound 1 with aminopyrazole (or aminoindazole) 2 in a manner similar to that described in Bioorg. Med. Chem. lett, 10, 11, 1175-1180, (2000) or in J. Het. Chem, 21, 1161-1167, (1984) provides monochloride intermediate 3. The substitution conditions for the chlorine in compound 3 with R ¹ -Q depends on the nature of the Q-link and is commonly known in the art. See, for example, J. Med. Chem, 38, 14, 2763-2773, (1995) (where Q is an N-bond), or Chem. Pharm. Bull., 40, 1, 227-229, (1992) (S-bond), or J. Het. Chem., 21, 1161-1167, (1984) (O-bond) or Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998) (C-bond).

Scheme II

Reagents: (a) POCl ₃ , Pr ₃ N, 110 ° C; (b) EtOH, Et ₃ N, room temperature.

Scheme II shows an alternative way to obtain the proposed compounds. Starting material 4 can be obtained by a method similar to that described for similar compounds. See Chem. Heterocycl. Compd., 35, 7, 818-820 (1999) (where Q is an N-bond), Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-bond), Pestic. Sci, 47, 2, 103-114 (1996) (O-bond), J. Med. Chem., 23, 8, 913-918 (1980) (S-bond), or Pharmazie, 43, 7, 475-476 (1988) (C-bond). Chlorination of compound 4 gives intermediate compound 5. See J. Med. Chem., 43, 22, 4288-4312 (2000) (Q is an N-bond), Pestic. Sci, 47, 2, 103-114 (1996) (O-bond), J. Med. Chem., 41, 20, 3793-3803 (1998) (S-bond) or J. Med. Chem., 43, 22, 4288-4312 (2000) (C-bond). Substitution of the 4-Cl group in intermediate 5 with aminopyrazole (or aminoindazole) 2 to obtain the compounds of the present invention can be carried out by known methods for the preparation of similar compounds. See J. Med. Chem., 38, 14, 2763-2773 (1995) (where Q is an N-bond), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (O-bond), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-bond) or J. Med. Chem., 41, 21, 4021-4035 (1998) (C-bond).

Scheme III

Reagents: (a) POCl ₃ ; (b) EtOH, Et ₃ N, room temperature; (c) oxon; (d) R ¹ —QH (Q = S, NH or O) or R ¹ —CH ₂ —M / catalyst (M is Al or Mg or Sn, catalyst = Pd ° or Ni °).

Scheme III shows an alternative way to obtain the proposed compounds. Starting material 6 can be chlorinated to give intermediate 7. Substitution of the 4-chloro group in intermediate 7 with aminopyrazole (or aminoindazole) 2 gives intermediate 8, which, when the methylsulfanyl group is oxidized, gives methylsulfone 9. The methylsulfonyl group of compound 9 can be easily replaced by R ¹ -QH to obtain the desired product II. See J. Am. Chem. Soc., 81, 5997-6006 (1959) (where Q is an N-bond) or Bioorg. Med. Chem. Lett., 10, 8, 821-826 (2000) (S-bond).

Scheme IV

Reagents: (a) POCl ₃ ; (b) EtOH, Et ₃ N, room temperature; (c) R ^y —H (Q = S, NH or O); (d) oxon; (e) R ¹ -QH (Q = S, NH or O) or R ¹ -CH ₂ -M / catalyst (M is Al or Mg or Sn, catalyst = Pd ° or Ni °)

Scheme IV shows a general route to the preparation of the compounds of the present invention in which R ^y represents a group attached to the pyrimidine nucleus through a nitrogen, oxygen or sulfur heteroatom. The starting 4,6-dihydroxy-2-methylsulfanylpyrimidine 10 can be prepared as described in J. Med. Chem., 27, 12, 1621-1629 (1984). The chlorine atoms in intermediate 11 can be substituted sequentially with aminopyrazole (or aminoindazole) 2 and then with another amine (or alcohol or thiol), followed by procedures similar to those described in US Pat. No. 2,585,906 (ICI, 1949). The methylsulfanyl group of compound 13 can then be oxidized to give methylsulfone 14. Substitution of the methylsulfonyl group of compound 14 gives the desired product II.

Scheme V

Scheme V shows a general route to the preparation of compounds of formulas IVa, IVb, IVc and IVd. Steps (a) and (b) are similar to the corresponding steps described above for Scheme I. 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; and Indian. J. Chem., 1967, 467-470.

The synthetic transformations shown in Schemes I-IV are further illustrated by the following methods.

Scheme VI

Scheme VI shows a general route to the preparation of the arylguanidine intermediate used to prepare compounds in which Q is —C (R ^{6 ′} ) ₂ -. The mono- or dialkylation of compound 19 in step (a) to give compound 20 can be carried out by methods essentially similar to those described by 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; and Prasad, G., et al, J Org Chem, 1991, (25), 7188-7190. The preparation of compound 21 from compound 20 in step (b) can be carried out by methods essentially analogous to those described by Moss, R., et al, Tetrahedron Lett, 1995, (48), 8761-8764 and Garigipati, R., Tetrahedron Lett, 1990, (14), 1969-1972.

The arylguanidine intermediates prepared according to Scheme VI can then be used to prepare the compounds of the present invention by the methods described above shown in Schemes I-V and by methods known to those skilled in the art of chemistry.

Scheme VII

Scheme VII shows a general process that can be used to prepare compounds of formula II, wherein Q is 1,2-cyclopropanediyl. Compound 26 can then be used to prepare the desired aminopyrazole derivatives as described above, shown in Scheme I, step (b).

Method A. To a solution of 2,4-dichloroquinazoline (12.69 g, 63 mmol) and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 ml), triethylamine (8.13 ml, 63 mmol) and the reaction mixture was stirred for 3 hours at room temperature. The resulting pale yellow precipitate was collected by filtration, washed with cold ethanol and dried in vacuo to give (2-chloroquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine.

The resulting (2-chloroquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (155 mg, 0.6 mmol) and 3-chloraniline (0.316 ml, 2.99 mmol) are refluxed refrigerator in tert-butanol (3 ml) for 20 hours. The mixture was concentrated in vacuo and the residue was suspended in EtOH / H ₂ O (1 ml / 3 ml). K ₂ CO ₃ (83 mg, 0.6 mmol) was added and the suspension was stirred for 2 hours at room temperature. The resulting solid was collected and dried in vacuo to give the product [2- (3-chlorophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine.

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 the gas evolution ceased. THF was removed in vacuo and the above (2-chloroquinazinin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (150 mg, 0.51 mmol) was added. The reaction mixture was stirred at 100 ° C for 20 hours, after which it was poured into aqueous K ₂ CO ₃ and stirred for 2 hours at room temperature. The resulting solid was collected and recrystallized from ethanol to give [2- (3-methoxyphenoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine.

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 was heated for 30 minutes at 110 ° FROM. The excess phosphorus oxychloride was evaporated in vacuo, the residue was poured into ice-cold aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried, filtered and evaporated. The resulting residue was purified by flash chromatography (SiO ₂ , hexane / AcOEt gradient) to give 4-chloro-2-phenoxymethylquinazoline.

To a solution of the above 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 heated at 65 ° C for 24 hours. The solvent was evaporated and ethanol was added. The resulting white solid was collected by filtration and dried in vacuo to give (5-cyclopropyl-2H-pyrazol-3-yl) - (2-phenoxymethylquinazolin-4-yl) amine.

Method D. To a solution of the above (2-chloroquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (123 mg, 0.43 mmol) in THF (5 ml) was added NiCl ₂ ( dppp) (12 mg, 2.1 · 10 ^-5 mol), and then 1 M benzylmagnesium chloride in THF (2.15 ml, 2.15 mmol). The solution was heated at 50 ° C. for 20 hours and then the reaction mixture was quenched with aqueous NH ₄ Cl and the product was extracted with ethyl acetate. The solvent was evaporated and the residue was purified by flash chromatography to give the desired (2-benzylquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine.

Method E. Solution (2-chloroquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) refluxed in tert-butanol (3 ml) for 20 hours. Diethyl ether (10 ml) was added to the mixture, and the resulting solid was collected by filtration. The resulting solid was suspended in EtOH / H ₂ O (1 ml / 3 ml), then K ₂ CO ₃ (110 mg, 0.8 mmol) was added and the suspension was stirred for 2 hours at room temperature. The resulting solid was collected and dried in vacuo to give the product [2- (4-acetamidophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine.

Method F. To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 ml) add triethylamine (0.357 ml, 2.56 mmol) and then sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is heated at 90 ° C for 20 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ . The organic layer was washed with brine and evaporated in vacuo. The residue was purified by flash chromatography (SiO ₂ , hexane / AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine .

The (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine obtained above is reacted with 2-naphthalene mercaptan as described in method L, and the result is the desired (5-cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylsulfanyl) -5,6,7,8-tetrahydroquinazolin-4-yl] amine.

Method G. Solution of (5-cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxycarbonylphenylsulfanyl) quinazolin-4-yl] amine (110 mg, 0.26 mmol) in a THF / water mixture (1 / 1, 10 ml) is treated with 1 M LiOH (0.75 ml, 0.75 mmol). The mixture was stirred for 20 hours at room temperature and then neutralized by adding 1 M HCl (0.75 ml, 0.75 mmol). The resulting solid was collected by filtration to obtain the desired [2- (3-carboxyphenylsulfanyl) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine.

Method N. A solution of [2- (4-acetamidophenylsulfanyl) -7-methoxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (23 mg, 5.54 · 10 ^-5 mol) in dichloroethane (3 ml) was treated with 1 M BBr ₃ in dichloromethane (222 μl, 2.21 · 10 ^-4 mol). The mixture was heated at 80 ° C. for 4 hours and then 1 M BBr ₃ in DCM (222 μl, 2.21 · 10 ⁻⁴ mol) was added. The reaction mixture is heated at 80 ° C for another 3 hours. The solvent was evaporated and methanol was added to the residue to quench the residual BBr ₃ . The solvent is evaporated in vacuo and the above operation is repeated 3 times. To the solid residue was added 1 M HCl (2 ml) and the suspension was stirred at room temperature for 15 hours. The solid was collected by filtration and suspended in a mixture of water / EtOH (3/1, 8 ml). The mixture was neutralized by the addition of NaHCO ₃ and stirred for 2 hours at room temperature. The resulting solid was collected by filtration, washed with water and diethyl ether to obtain the desired [2- (4-acetamidophenylsulfanyl) -7-hydroxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine.

Method I. To a solution of [2- (4-acetamidophenylsulfanyl) -7-hydroxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (32 mg, 7.87 · 10 ^-5 mol) in DMF (1 ml) potassium carbonate (65 mg, 4.72 · 10 ^-4 mol) was added and the reaction mixture was heated to 80 ° C. Then N- (3-chloropropyl) morpholine (39 mg, 2.36 · 10 ^-4 mol) was added and the mixture was stirred at 80 ° C for 4 hours, cooled to room temperature and the solvent was evaporated. The resulting residue was purified by flash chromatography to give the desired [2- (4-acetamidophenylsulfanyl) -7- (3-morpholin-4-ylpropoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine .

Method J. To a solution of [2- (4-acetamidophenylsulfanyl) -7-nitroquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (147 mg, 3.38 · 10 ^-4 mol) in methanol (5 ml), 10% Pd / C (40 mg) was added and the reaction mixture was treated with hydrogen at a cylinder pressure at 45 ° C for 20 hours. The catalyst is filtered off through a celite pad, which is then washed with dilute HCl. The combined yellow filtrate was evaporated and the resulting solid was crystallized from methanol to give the desired [2- (4-acetamidophenylsulfanyl) -7-hydroxyaminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine.

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 EtOH / water / AcOH mixtures (25/10/1, 36 ml) and the reaction mixture was heated at 90 ° C. Iron powder (93 mg) was added and the mixture was stirred at 90 ° C for 4 hours, cooled to room temperature and filtered through a pad of celite. The pad was washed with methanol and the combined filtrate was concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ , DCM / MeOH gradient) to give the desired [2- (4-acetamidophenylsulfanyl) -7-aminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine .

Method L. To a solution of 2,4-dichloro-6-phenylpyrimidine (300 mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7 ml) is added triethylamine (195 μl, 1.33 mmol) and then sodium iodide (200 mg, 1.33 mmol) and the reaction mixture was stirred for 15 hours at 90 ° C. The resulting solution was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over MgSO _4, and then concentrated in vacuo. The residue was triturated in methanol and the resulting white solid was collected by filtration to obtain (2-chloro-6-phenylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (236 mg, 62%) .

The above (2-chloro-6-phenylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (60 mg, 0.21 mmol) is mixed with 4-acetamidothiophenol (176 mg, 1, 05 mmol) in tert-butanol (5 ml) and the mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO ₃ . The organic layer was 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-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (74 mg, 85%).

Method M. To a suspension of 4,6-dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture of EtOH / water (1/1, 140 ml) add NaOH (2.33 g, 58.3 mmol) and then 4-methoxybenzyl chloride (7 90 ml, 58.3 mmol). The solution was stirred for 1.5 hours at 60 ° C and then another 6 hours at room temperature. The resulting white precipitate was collected by filtration to obtain 4,6-dihydroxy-2- (4-methoxybenzylsulfanyl) pyrimidine.

The above 4,6-dihydroxy-2- (4-methoxybenzylsulfanyl) pyrimidine (2.5 g, 9.46 mmol) was suspended in POCl ₃ (20 ml) and tripropylamine (3.60 ml, 18, 9 mmol). Then the reaction mixture is heated at 110 ° C for 4 hours. The brown solution was cooled to room temperature and the solvent was evaporated. The residue was poured onto ice-cooled NaHCO ₃ and then the product was extracted with ethyl acetate. The organic phase is dried over MgSO ₄ , concentrated in vacuo and the residue purified by flash chromatography (SiO ₂ , hexane / AcOEt gradient) to give 4,6-dichloro-2- (4-methoxybenzylsulfanyl) pyrimidine.

To a solution of the obtained 4,6-dichloro-2- (4-methoxybenzylsulfanyl) pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH (20 ml) diisopropylethylamine (0.56 ml, 3.19 mmol) and then sodium iodide (455 mg, 3.04 mmol). The reaction mixture was stirred for 15 hours at 120 ° C. The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO ₂ , hexane / AcOEt gradient) to give [6-chloro-2- (4-methoxybenzylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3 -yl) amine.

The above [6-chloro-2- (4-methoxybenzylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10 ml) is heated at 130 ° C for 15 hours. Then the solvent was removed in vacuo and the residue was purified by flash chromatography (SiO ₂ , dichloromethane / MeOH gradient) to give the desired product [2- (4-methoxybenzylsulfanyl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine.

Method N. Solution of [2- (4-acetamidophenylsulfanyl) -6- (4-methoxyphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (100 mg, 2.24 · 10 ^-4 mol) in dichloroethane (5 ml) was treated with 1 M BBr ₃ in DCM (896 μl, 8.96 · 10 ^-4 mol). The mixture was then heated at 80 ° C for 4 hours, after which 1 M BBr ₃ in DCM was added thereto (896 μl, 8.96 · 10 ^-4 mol). The reaction mixture is then heated at 80 ° C for another 3 hours. The solvent was evaporated and methanol was added to the residue to quench the residual BBr ₃ . The solvent is evaporated in vacuo and the indicated evaporation step is repeated 3 times. To the solid residue was added 1 M HCl (8 ml) and the suspension was stirred at room temperature for 15 hours. The solid was collected by filtration and suspended in a mixture of water / EtOH (3/1, 24 ml). The mixture was neutralized by the addition of NaHCO ₃ and stirred for 2 hours at room temperature. The resulting solid was collected by filtration, washed with water and diethyl ether to obtain the desired [2- (4-acetamidophenylsulfanyl) -6- (4-hydroxyphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3- il) amine.

To a solution of the above [2- (4-acetamidophenylsulfanyl) -6- (4-hydroxyphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (70 mg, 1.62 · 10 ^-4 mol) in DMF (3 ml) potassium carbonate (134 mg, 9.71 · 10 ^-4 mol) is added. The reaction mixture was heated to 80 ° C and then 1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86 · 10 ^-4 mol) was added. The mixture was stirred at 80 ° C. for 4 hours, cooled to room temperature and the solvent was evaporated. The residue was purified by flash chromatography to give the desired product {2- (4-acetamidophenylsulfanyl) -6- [4- (3-dimethylaminopropoxy) phenyl] pyrimidin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine.

Method O. To a solution of [6-methoxycarbonyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (2 g, 4.85 mmol) in THF (100 ml) add lithium borohydride (0.32 g, 14.5 mmol). The reaction mixture was stirred at 50 ° C for 1.5 hours. Then the reaction mixture was quenched with diluted HCl and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated. The solid residue was triturated in ethyl acetate and the resulting white solid was collected by filtration to obtain the desired [6-hydroxymethyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine .

Method R. To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole (2.61 g, 26.9 mmol) in BuOH (60 ml) was added diisopropylethylamine (4.69 ml, 26.9 mmol) and then sodium iodide (3.84 g, 25.6 mmol). The reaction mixture was stirred for 15 hours at 120 ° C. The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO ₂ , hexane / AcOEt gradient) to give (6-chloro-2-methylsulfanylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine.

The above (6-chloro-2-methylsulfanylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (2.42 g, 9.46 mmol) is heated in morpholine (10 ml) at 130 ° C for 15 hours. The solvent was then removed in vacuo and the residue was triturated with EtOH and collected by filtration to obtain [2-methylsulfanyl-6- (morpholin-4-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl )amine.

To a suspension of the above [2-methylsulfanyl-6- (morpholin-4-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (500 mg, 1.63 mmol) in MeOH (10 ml) add a solution of oxone (3.0 g) in water (10 ml). The reaction mixture was stirred at room temperature for 15 hours and most of the solvent was evaporated. The residue was partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was washed with brine, dried, filtered and evaporated. The residue was triturated with MeOH and the resulting white solid was collected by filtration to obtain [2-methylsulfonyl-6- (morpholin-4-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine .

The above [2-methylsulfonyl-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 was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO ₃ . The organic layer was 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-pyrazol-3-yl) amine.

For a more complete understanding of the present invention, the following examples are described. It should be understood that these examples are for illustrative purposes only and should not be construed as in any way limiting the present invention.

SYNTHESIS EXAMPLES

The following HPLC methods were used to analyze the specific compounds indicated in the synthesis examples described below. As used herein, the term “R _t ” refers to retention time for a compound analyzed using a specific HPLC method.

HPLC method A:

Column: C18, 3 μm, 2.1 × 50 mm, “Lighting” f. Jones Chromatography.

Gradient: from 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) in 4.0 minutes, holding at 100% acetonitrile for 1.4 minutes and return to baseline conditions. Total working time is 7.0 minutes. Flow rate: 0.8 ml / min.

HPLC method B:

Column: C18, 5 μm, 4.6 × 150 mm, Dynamax f. Rainin Gradient: from 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) in 20 minutes, holding at 100% acetonitrile for 7.0 minutes and return to baseline conditions. Total working time is 31.5 minutes. Flow rate: 1.0 ml / min.

HPLC method C:

Column: Cyano, 5 μm, 4.6 × 150 mm, Microsorb f. Varian.

Gradient: from 99% water (0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA) for 20 minutes, exposure for 8.0 minutes and return to baseline. Total working time is 30 minutes. Flow rate: 1.0 ml / min.

HPLC method D:

Column: Waters (YMC) ODS-AQ 2.0 × 50 mm, S5, 120A.

Gradient: from 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) in 5.0 minutes, holding for 0.8 minutes and returning to the initial conditions. Total working time is 7.0 minutes. Flow rate: 1.0 ml / min.

HPLC Method E:

Column: 50 × 2.0 mm, Hypersil C18 BDS; 5 microns.

Gradient: elution from 100% water (0.1% TFA) to 5% water (0.1% TFA), 95% acetonitrile (containing 0.1% TFA) in 2.1 minutes, return to baseline after 2, 3 minutes. Flow rate: 1.0 ml / min.

Example 1 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylsulfanylquinazolin-4-yl) amine (IIa-1): Obtained by a method similar to the method described above, as a pale yellow solid, t mp> 300 ° C (decomp.); 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 (1H, d), 10.43 (1H, s), 12.05 (1H, br s); IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525, 1476; MS 334.0 (M + H) ⁺ .

Example 2 [2- (4-Chlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-2): Obtained by a method similar to the method described above, in the form of 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 (1H, d), 11.50 (1H, br s); IR (solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339, 1286, 1219; MS 368.0 (M + H) ⁺ .

Example 3 [2- (2,4-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-3): Obtained by a method similar to the method described above, in the form 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, d), 7.92 (1H, d), 7.96 (1H, d), 8.66 (1H, d) 11.20 (1H, br s); IR (solid) 1623, 1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 (M + H) ⁺ .

Example 4 [2- (4-Methoxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-4): Obtained by a method similar to the method described above, in the form of 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) ⁺ .

Example 5 [2- (2-Ethylphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-5): Obtained by a method similar to the method described above, in the form of 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 (1H, d); IR (solid) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344, 1294, 1224, 1162; MS 362.1 (M + H) ⁺ .

Example 6 {2- [2,4-Bis (trifluoromethyl) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIa-6): Obtained by a method similar to the above method E, in the form of a pale yellow solid, so pl. > 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) ⁺ .

Example 7 [2- (4-Chlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-7): Obtained by a method similar to the method described above, in the form of 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, d), 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) ⁺ .

Example 8 [2- (2,3-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-8): Obtained by a method similar to the method described above, in the form 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 (1H, d), 10.72 (1H, br s); IR (solid) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M + H) ⁺ .

Example 9 [2- (3-Chlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-9): Obtained by a method similar to the method described above, in the form of 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, br s); IR (solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292, 1217, 1165; MS 368.0 (M + H) ⁺ .

Example 10 [2- (1-Methylimidazol-2-ylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-10): Obtained by a method similar to the method described above, in the form of 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, broad s); IR (solid) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, 1278, 1211; MS 338.2 (M + H) ⁺ .

Example 11 [2- (2-Hydroxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-11): Obtained by a method similar to the method described above, in the form of 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 (1H, d), 7.94 (1H, t), 8.71 (1H, d), 10.29 (1H, br. s) 11.66 (1H, broad s); IR (solid) 1623, 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165; MS 350.1 (M + H) ⁺ .

Example 12 [2- (2,4-Difluorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-12): Obtained by a method similar to the method described above, in the form pale yellow solid, mp 256-258 ° C; ¹ H NMR (DMSO) δ 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 (1H, d), 11.06 (1H, br s); IR (solid) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 (M + H) ⁺ .

Example 13 [2- (3,4-Dimethoxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-13): Obtained by a method similar to the method described above, in the form pale yellow solid, 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, broad s); IR (solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 1237, 1218, 1161, 1137; MS 394.1 (M + H) ⁺ .

Example 14 [2- (3-Methylphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-14): Obtained by a method similar to the method described above, in the form of 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 (1H, t), 8.68 (1H, d), 11.66 (1H, br s); IR (solid) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M + H) ⁺ .

Example 15 [2- (2-Methoxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-15): Obtained by a method similar to the method described above, in the form of 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, broad. from); IR (solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS 364.1 (M + H) ⁺ .

Example 16 [2- (2-Naphthalenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-16): Obtained by a method similar to the method described above, in the form of 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 (1H, s), 8.66 (1H, d), 11.28 (1H, br s); IR (solid) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M + H) ⁺ .

Example 17 [2- (2,6-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-17): Obtained by a method similar to the method described above, in the form pale 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 (1H, d), 10.60 (1H, s); IR (solid) 1618, 1599, 1565, 1533, 1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M + H) ⁺ .

Example 18 [2- (3,4-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-18): Obtained by a method similar to the method described above, in the form 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 (1H, d), 8.66 (1H, d); IR (solid) 1628, 1607, 1556, 1488, 1436, 14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402.0 (M + H) ⁺ .

Example 19 [2- (Benzimidazol-2-ylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-19): Obtained by a method similar to the method described above, in the form pale gray solid, 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) ⁺ .

Example 20 [2- (2-Aminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-20): Obtained by a method similar to the method described above, in the form of a light yellow solid, mp 257-259 ° C; ¹ H NMR (DMSO) δ 2.11-2.30 (3H, 2 x br 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, br s); IR (solid) 1623, 1591, 1567, 1538, 1496, 1483, 1410, 1351.

Example 21 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenylsulfanylquinazolin-4-yl) amine (IIa-21): Obtained by a method similar to the method described above, in the form of a yellow solid, so pl. . 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 (1H, d), 11.60 (1H, br s); IR (solid) 1629, 1606, 1577, 1546, 1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360.3 (M + H) ⁺ .

Example 22 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxycarbonylphenylsulfanyl) quinazolin-4-yl) amine (IIa-22): Obtained by a method similar to the method described above, in the form of a white solid substances, so pl. 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 (1H, br s), 12.07 (1H, br s ); IR (solid) 1724, 1617, 1593, 1567, 1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS 418.3 (M + H) ⁺ .

Example 23 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methylphenylsulfanyl) quinazolin-4-yl) amine (IIa-23): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. 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) ⁺ .

Example 24 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxyphenylsulfanyl) quinazolin-4-yl) amine (IIa-22): Obtained by a method similar to the method described above, in the form of a white solid substances, so pl. 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 (1H, 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) ⁺ .

Example 25 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dimethoxyphenylsulfanyl) quinazolin-4-yl) amine (IIa-25): Obtained by a method similar to the method described above, in the form white solid, mp 250-252 ° C, ¹ N 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 (1H, s), 12.04 ( 1H, 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) ⁺ .

Example 26 [2- (3-Carboxyphenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIa-26): Obtained from IIa-22 by method G as a yellow solid, so pl. > 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) ⁺ .

Example 27 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylsulfanyl) quinazolin-4-yl) amine (IIa-27): Obtained by a method similar to the method described above, in the form 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 (1H, br s), 8.56 (1H, br d), 10.42 and 11.88 (1H, 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) ⁺ .

Example 28 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,4-difluorophenylsulfanyl) quinazolin-4-yl) amine (IIa-28): Obtained by a method similar to the method described above, in the form 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, br.m), 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) ⁺ .

Example 29 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylphenylsulfanyl) -5,6,7,8-tetrahydroquinazolin-4-yl) amine (IIa-29): Obtained by the method similar to the above method F, in the form of a white solid, so pl. 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) ⁺ .

Example 30 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,3-dichlorophenylsulfanyl) quinazolin-4-yl) amine (IIa-30): Obtained by a method similar to the method described above, in the form off-white solid, 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) ⁺ .

Example 31 [2- (3-Chlorophenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIa-31): Obtained by a method similar to the method described above, in the form not quite 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 (1H, s), 7.75 (1H, t), 8.57 (1H, d), 10.46 (1H, s) 12.08 (1H, s); IR (solid) 1616, 1593, 1562,, 1528, 1479, 1456, 1406, 1367, 1343, 1286, 1244, 1216, 1176, 1067, 1051, 997; MS 394.7 (M + H) ⁺ .

Example 32 [2- (2-Chlorophenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIa-32): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 33 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dimethylphenylsulfanyl) quinazolin-4-yl) amine (IIa-33): Obtained by a method similar to the method described above, in the form off-white solid, 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 x s), 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) ⁺ .

Example 34 [2- (Benzimidazol-2-ylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIa-34): Obtained by a method similar to the method described above, in the form 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) ⁺ .

Example 35 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methoxycarbonylphenylsulfanyl) quinazolin-4-yl) amine (IIa-35): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 36 [2- (4-Acetamidophenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIa-36): Obtained by a method similar to the method described above, in the form not quite 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, broad .c), 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) ⁺ .

Example 37 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-1-ylsulfanyl) quinazolin-4-yl) amine (IIa-37): Obtained by a method similar to the method described above, in the form 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, br s), 11.84 (1H, broad s); IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362, 1343, 1285, 1242, 1219, 1173, 998, 963; MS 410.2 (M + H) ⁺ .

Example 38 [2- (4-Acetamidophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-38): Obtained by the method similar to the method described above, in the form of a white solid substances, e.g. 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) ⁺ .

Example 39 [2- (4-Methanesulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-39): Obtained by a method similar to the method described above, in the form not quite 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, s), 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) ⁺ .

Example 40 [2- (4-Acetamidophenylsulfanyl) -7-methoxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-40): Obtained by a method similar to the method described above, in as 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) ⁺ .

Example 41 [2- (4-Acetamidophenylsulfanyl) -8- (3-morpholin-4-ylpropoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-41): Received in a manner similar to the above method E, in the form of a white solid, so pl. 262-264 ° C; ¹ H NMR (DMSO) δ 1.94 (2H, quint.), 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, broad .from); 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) ⁺ .

Example 42 [2- (4-Methoxycarbonylphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-42): Obtained by a method similar to the method described above, in the form not quite white solid, 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, s); 12.03 (1H, 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) ⁺ .

Example 43 [2- (4-Carboxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-43): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 44 [2- (4-Acetamidophenylsulfanyl) -8-methoxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-44): Obtained by a method similar to the method described above, in as an off-white solid, mp. 247-249 ° C; ¹ H NMR (DMSO) δ 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) ⁺ .

Example 45 [2- (4-Acetamidophenylsulfanyl) -7- (3-morpholin-4-ylpropoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-45): Received from IIa-74 by method I in the form of an off-white solid, mp. 153 ° C (decomp.); ¹ H NMR (DMSO) δ 2.02 (3H, s), 2.09 (3H, s), 2.29 (2H, quint.), 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, s), 10.35 (1H, s), 12.06 (1H, s) ; IR (solid) 1673, 1614, 1591, 1532, 1486, 1391, 1336, 1254, 1109, 1063, 995; MS 534.2 (M + H) ⁺ .

Example 46 [2- (4-Bromophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-46): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 47 [2- (3-Bromophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-47): Obtained by a method similar to the method described above, in the form not quite white solid, mp 280-28l ° 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 × 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) ⁺ .

Example 48 [2- (4-Isopropanesulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-48): Obtained by a method similar to the method described above, in the form of a white solid substances, so pl. 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) ⁺ .

Example 49 [2- (4-Isobutyrylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-49): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 50 (5-Methyl-2H-pyrazol-3-yl) - [2- (4-propionylaminophenylsulfanyl) quinazolin-4-yl] amine (IIa-50): Obtained by a method similar to the method described above, in the form not quite white solid, 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; MC 405.3 (M + H) ⁺ .

Example 51 [2- (4-Cyclopropanecarbonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-51): Obtained by a method similar to the method described above, in the form not quite 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; MC 417.2 (M + H) ⁺ .

Example 52 [2- (4-Acetamidophenylsulfanyl) -8-hydroxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-52): tan 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; MC 407.2 (M + H) ⁺ .

Example 53 [2- (4-Acetamidophenylsulfanyl) -7-nitroquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-53): Obtained by a method similar to the method described above, in as 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) ⁺ .

Example 54 (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (propan-1-sulfonylamino) phenylsulfanyl] quinazolin-4-yl} amine (IIa-54): Obtained by a method similar to that described above method E, in the form of a white solid, so pl. 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) ⁺ .

Example 55 [2- (4-Ethylsulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-55): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 56 [2- (4-Acetamidophenylsulfanyl) -7-hydroxyaminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-56): Obtained from IIa-53 by method J as yellow solid, 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 (1H, d), 9.27 (1H, broad s), 10.49 (1H, s), 11.38 (1H, s), 14.58 (1H, br s), IR (solid); MS 422.2 (M + H) ⁺ .

Example 57 [2- (4-Isobutanecarbonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-57): Obtained by a method similar to the method described above, in the form of a white solid substances, so pl. 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 × 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) ⁺ .

Example 58 [2- (4-tert-Butoxycarbonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-58): Obtained by a method similar to the method described above, in the form 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 broad s), 7.47 (2H, d), 7.58 (2H, d), 8.12 (1H, broad s), 9.58 (1H, s), 11.24 (1H, s); IR (solid) 1701, 1593, 1559, 1515, 1482, 1396, 1365, 1346, 1308, 1288, 1237, 1154, 1051, 1020, 969; MS 449.2 (M + H) ⁺ .

Example 59 [2- (4-Acetamidophenylsulfanyl) -7-aminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-59): Obtained from IIa-53 by method K as non a completely white solid, so pl. 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, broad s); IR (solid); MS 406.2 (M + H) ⁺ .

Example 60 (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (2-morpholin-4-yl-acetylamino) phenylsulfanyl] quinazolin-4-yl} amine (IIa-60): Obtained by a method similar to method E described above, in the form of 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) ⁺ .

Example 61 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methylsulfonylaminophenylsulfanyl) quinazolin-4-yl) amine (IIa-61): Obtained in the manner similar to the method described above, in the form of a white solid substances, 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 (1H, t), 7.54 (3H, m), 7.72 (1H, t), 8.55 (1H, d), 10 16 (1H, br s), 10.38 (1H, s), 11.99 (1H, s); IR (solid) 1621, 1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290, 1232, 1143, 1113, 985, 972; MS 453.3 (M + H) ⁺ .

Example 62 [2- (4-Aminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-62): Obtained by a method similar to the method described above, in the form not quite 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, br s); IR (solid) 1615, 1591, 1561, 1532, 1495, 1480, 1387, 1363, 1344, 1288, 1244, 1148, 966; MS 349.2 (M + H) ⁺ .

Example 63 [2- (4-Acetamidophenylsulfanyl) quinazolin-4-yl] - (2H-pyrazol-3-yl) amine (IIa-63): Obtained by the method similar to the method described above, in the form of a white solid, ¹ N NMR (DMSO) δ 2.11 (3H, s), 5.93 (1H, s), 7.31-7.68 (8H, m), 8.54 (1H, s), 10.17 (1H c), 10.54 (1H, s), 12.38 (1H, s); IR (solid); MS 377.4 (M + H) ⁺ .

Example 64 (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (4-morpholin-4-yl-butyrylamino) phenylsulfanyl] quinazolin-4-yl} amine (IIa-64): Obtained by the method similar to the method described above, in the form of a white solid, so pl. 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 (1H, br.m), 10.15 (1H, s), 10.41 (1H, s), 12, 00 (1H, br s); IR (solid); MS 504.3 (M + H) ⁺ .

Example 65 (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (2-morpholin-4-yl-ethylcarbamoyl) phenylsulfanyl] quinazolin-4-yl} amine (IIa-65): Obtained by the method similar to the method described above, in the form of a white solid, so pl. 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 broad 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) ⁺ .

Example 66 [8-Methoxy-2- (4-methylsulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-66): Obtained by a method similar to the method described above, in the form of 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, C) 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) ⁺ .

Example 67 {2- [4- (2-Dimethylaminoethylcarbamoyl) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIa-67): Obtained by a method similar to the above method E in the form of a white solid, so pl. 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) ⁺ .

Example 68 {2- [4- (2-Dimethylaminoacetylamino) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIa-68): Obtained by a method similar to the method described above in the form of a white solid, so pl. 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) ⁺ .

Example 69 [8-Hydroxy-2- (4-methylsulfonylaminophenylsulfanyl) 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) ⁺ .

Example 70 {2- [4- (3-Dimethylaminopropylcarbamoyl) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIa-67): Obtained by a method similar to the above method E , in the form of a pink solid, so pl. 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) ⁺ .

Example 71 {2- [4- (3-Dimethylaminopropionylamino) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIa-71): Obtained by a method similar to the above method E , in the form of an off-white solid, mp. 280 ° C (decomp.); 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, C); IR (solid) 1670, 1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364, 1348, 1286, 1178, 1162, 764; MS 448.4 (M + H) ⁺ .

Example 72 [2- (4-Acetamidophenylsulfanyl) -8-methoxyquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIa-72): Obtained by a method similar to the method described above, in as 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, br s); 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) ⁺ .

Example 73 [2- (4-Acetamidophenylsulfanyl) -8- (3-dimethylaminopropoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-73): Obtained by a method similar to that described above method E, in the form of 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, br s); 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) ⁺ .

Example 74 [2- (4-Acetamidophenylsulfanyl) -7-hydroxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-73): Obtained from IIa-40 by Method H as non- a completely white solid, so pl. 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) ⁺ .

Example 75 [2- (4-Acetamidophenylsulfanyl) -7- (3-dimethylaminopropoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIa-75): Obtained by a method similar to that described above method I, in the form of 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, br s); 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) ⁺ .

Example 76 (2- {4- [2- (tert-Butoxycarbonylmethylamino) acetylamino] phenylsulfanyl} quinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIa-76): Obtained by the method, similar to the above method E, in the form of a white solid, so pl. 228-229 ° C (decomp.); ¹ H NMR (DMSO) δ 1.37 (3H, s), 1.40 (3H, s), 2.02 + 2.03 (3H, 2 x s), 2.88 + 2.90 (3H, 2 x s), 4.01 + 4.02 (2H, 2 x s), 5.52 + 5.57 (1H, 2 x s), 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, 2 x s), 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) ⁺ .

Example 77 {2- [4- (2-Methylaminoacetylamino) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIa-77): Obtained by a method similar to the above method E in the form of a white solid, so pl. 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) ⁺ .

Example 78 [2- (4-Acetamidophenylsulfanyl) -8-fluoroquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIa-78): Obtained by a method similar to the method described above, in as 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 (1H, d), 10.28 (1H, s), 10.75 (1H, s); ¹⁹ F NMR (DMSO) δ -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) ⁺ .

Example 79 (1H-Indazol-3-yl) - (2-phenylsulfanylquinazolin-4-yl) amine (IIa-79): Obtained by a method similar to the method described above, as a white solid, 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) ⁺ .

Example 80 {2 - [(2-Hydroxyethyl) phenylamino] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIc-1): Obtained by a method similar to the method described above, in as 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 broad 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) ⁺ .

Example 81 [2- (Methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-2): Obtained by a method similar to the method described above, in the form of a white solid, so pl. 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 (1H, m), 8.38 (1H, d), 9.98 (1H, s ), 11.91 (1H s); IR (solid) 1621, 1598, 1578, 1540, 1494, 1473, 1398, 1374; MS 331.0 (M + H) ⁺ .

Example 82 (5-methyl-2H-pyrazol-3-yl) - {2- [N-methyl-N- (pyridin-3-ylmethyl) amino] quinazolin-4-yl} amine (IIc-3): Obtained by the method similar to the method described above, in the form of a yellow solid, so pl. 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) ⁺ .

Example 83 (5-methyl-2H-pyrazol-3-yl) - (2-phenylaminoquinazolin-4-yl) amine (IIc-4): Obtained by a method similar to the method described above, in the form of a white solid, 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, broad s); IR (solid) 1623, 1601, 1573, 1541, 1478; MS 317.0 (M + H) ⁺ .

Example 84 (2-Benzylaminoquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIc-5): Obtained by a method similar to the method described above, in the form of a white solid, so pl. . 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, br s); IR (solid) 1630, 1609, 1578, 1538, 1511; MS 331.0 (M + H) ⁺ .

Example 85 (2-Cyclohexylaminoquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIc-6): Obtained by a method similar to the method described above, in the form of an off-white solid, t .pl. 280 ° C (decomp.); 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 (1H, br s), 7.04 (1H, s), 7.28 (1H, s), 7.51 (1H, m), 8.26 (1H, s), 12.95 (1H, s); 12.75 (1H, s); IR (solid) 2927, 2853, 1619, 1596, 1569, 1522, 1482; MS 323.0 (M + H) ⁺ .

Example 86 [2- (2,3-Dihydrobenzo [1,4] dioxin-6-ylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-7): Received in a manner similar to method A described above, in the form of an off-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, d), 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) ⁺ .

Example 87 (2-Cyclohexylmethylaminoquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIc-8): Obtained by a method similar to the method described above, in the form of a white solid, so pl. . 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 (1H, br s), 7.51 (1H, t), 8.26 (1H, br s), 9.97 (1H, br s), 12.04 (1H, br s), 12.75 (1H, br s); IR (solid) 3333, 2927, 2850, 2831, 1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 988; MS 337.4 (M + H) ⁺ .

Example 88 [2- (1H-Indazol-6-ylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-9): Obtained by a method similar to the method described above, in the form of an off-white solid, mp. > 250 ° C; ¹ H NMR (DMSO) δ 2.24 (3H, s), 5.93 and 6.89 (1H, 2 x br s), 7.05-8.15 (6H, m), 8.25- 8.90 (2H, m), 9.25 and 9.97 (1H, 2 x br s), 10.11 and 10.57 (1H, 2 x br s), 12.15 and 12.80 (2H, 2 x br s); IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1 (M + H) ⁺ .

Example 89 (5-methyl-2H-pyrazol-3-yl) - [2- (pyridin-3-ylmethylamino) quinazolin-4-yl] amine (IIc-10): Obtained by the method similar to the method described above, in the form 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 (1H, s), 8.31 (1H, s), 8.43 (1H, s), 8.61 (1H, s), 10 0 (1H, broad s); 12.15 (1H, broad s); IR (solid) 3308, 2945, 2919, 2858, 1623, 1593, 1577, 1552, 1501, 1475, 1449, 1383; MS 332.1 (M + H) ⁺ .

Example 90 [2- (3-Chlorophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-11): Obtained by a method similar to the method described above, in the form not quite 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, 2 x br s), 10.14 and 10.64 (1H, 2 x br s), 12.20 and 12.82 (1H, 2 x br s); IR (solid) 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, 1472, 1440, 1403, 1372; MS 351.1 (M + H) ⁺ .

Example 91 [2- (4-Chlorophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-12): Obtained by a method similar to the method described above, in the form not quite 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, 2 x br s), 10.13 and 10.55 (1H, 2 x br s), 12.19 and 12.81 (1H, 2 x br s), IR (solid) 3439, 3057, 2957, 1618, 1600, 1586 , 1572, 1550, 1504, 1486, 1431, 1413, 1367; MS 351.1 (M + H) ⁺ .

Example 92 [2- (4-Fluorobenzylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-13): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. 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, 2 x br s ), 12.09 and 12.75 (1H, 2 x broad s); IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367; MS 349.3 (M + H) ⁺ .

Example 93 {2- [2- (2-Hydroxyethyl) phenylamino] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIc-14): Obtained by a method similar to the method described above in the form of a white solid, so pl. 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 broad 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, br s), 13.50 (1H, br s); IR (solid) 3193, 3171, 3111, 3084, 1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3 (M + H) ⁺ .

Example 94 [2- (4-Cyanmethylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-15): Obtained by a method similar to the method described above, in the form not quite white solid, mp > 250 ° C; ¹ H NMR (DMSO) δ 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 (1H, t), 10.70 (1H, s), 11.56 (1H, s), 12.63 (1H, broad s), 13.25 (1H, broad s); IR (solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513, 1481, 1413, 1336, 1158, 999; MS 356.2 (M + H) ⁺ .

Example 95 [2- (3-Hydroxymethylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-16): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 96 [2- (3-Hydroxyphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-17): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. > 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, br s); IR (solid) 3354, 3027, 2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332, 1154, 1004; MS 333.2 (M + H) ⁺ .

Example 97 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenylaminoquinazolin-4-yl) amine (IIc-18): Obtained by a method similar to the method described above, as an off-white solid, t .pl. 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, 2 x br s), 6.94 (1H, s), 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, 2 x br s), 10.07 and 10.52 (1H, 2 x br s), 12.19 and 12.82 (1H, 2 x br s); IR (solid) 3443, 1622, 1595, 1577, 1554, 1486, 1449, 1413, 1376, 1340, 1235, 1171, 988, 806; MS 343.2 (M + H) ⁺ .

Example 98 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methylphenylamino) quinazolin-4-yl] amine (IIc-19): Obtained by a method similar to the method described above, in the form not quite 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, broad 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 (1H, s), 12.55 (1H, br s); IR (solid) 3303, 1618, 1581, 1554, 1536, 1495, 1472, 1436, 1413, 1372, 1336, 1240, 990; MS 357.4 (M + H) ⁺ .

Example 99 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (6-methoxypyridin-3-ylamino) quinazolin-4-yl] amine (IIc-20): Obtained by a method similar to the method described above, in the form of a pink solid, so pl. 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, broad 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, broad s), 8.61 (1H, broad s), 9.50 (1H, broad s), 10.48 (1H, broad s), 12.55 (1H , s); IR (solid) 3457, 3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363, 1272, 1235, 1035, 985, 821; MS 374.2 (M + H) ⁺ .

Example 100 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (indan-5-yl-amino) quinazolin-4-yl] amine (IIc-21): Obtained by a method similar to the method described above, in the form of 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, broad s), 7.75 (1H, broad s), 8.45 (1H, broad s), 9.70 (1H, broad s), 10.60 (1H, broad s), 12.30 and 12.80 (1H, 2 x broad s); IR (solid) 1621, 1601, 1572, 1552, 1495, 1474, 1439, 1425, 1408, 1382, 1363, 1319, 1267; MS 383.3 (M + H) ⁺ .

Example 101 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (1H-indol-6-ylamino) quinazolin-4-yl] amine (IIc-22): Obtained by a method similar to the method described above, as 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, 2 x br 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, 3 × br s), 10.49, 12.12 and l 2.84 (1H, 3 x br s), 10.94 ( s, 1H); IR (solid) 1623, 1603, 1571, 1549, 1495, 1477, 1460, 1419, 1383, 1336, 1264, 1250, 1238; MS 382.4 (M + H) ⁺ .

Example 102 [2- (4-Acetamido-3-methylphenylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-23): Obtained by a method similar to the method described above, in the form of an off-white solid, mp. > 188 ° C (decomp.); 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, 2 x br 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, 3 x br s), 9.19 (1H, s), 10.53, 12 16 and 12.81 (1H, 3 x br s); IR (solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428, 1403, 1343, 1320, 1307, 1250; MS 414.4 (M + H) ⁺ .

Example 103 [2- (4-Chloro-3-methylphenylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-24): Obtained by a method similar to the method described above, in the form of 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, 2 x br 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, 3 x br s), 10.58, 12.19 and 12.78 (1H, 3 x br s); IR (solid) 1615, 1578, 1549, 1475, 1419, 1397, 1365, 1331, 1296, 1261, 1238, 1187, 1139; MS 391.4 (M + H) ⁺ .

Example 104 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-ethylphenylamino) quinazolin-4-yl] amine (IIc-25): Obtained by a method similar to the method described above, in the form of 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, 2 x br 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, 3 x br s), 10.49, 12.20 and 12.80 (1H, 3 x br s); IR (solid) 1603, 1574, 1546, 1509, 1497, 1474, 1439, 1417, 1386; MS 371.5 (M + H) ⁺ .

Example 105 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-propylphenylamino) quinazolin-4-yl] amine (IIc-26): Obtained by a method similar to the method described above, in the form not quite 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 qq), 5.81 and 6.63 (1H, 2 x br 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, 3 x br s); IR (solid) 1595, 1571, 1545, 1499, 1477, 1442, 1413, 1388; MS 385.6 (M + H) ⁺ .

Example 106 (5-Cyclopropyl-2H-pyrazol-3-yl) - {2- [4- (2-hydroxyethyl) phenylamino] quinazolin-4-yl} amine (IIc-27): Obtained by a method similar to the method described above , in the form of 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, 2 x br 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, 3 x broad s), 10.52, 12.17 and 12.79 (1H, 3 x broad s); IR (solid) 1632, 1569, 1546, 1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 (M + H) ⁺ .

Example 107 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenethylaminoquinazolin-4-yl) amine (IIc-28): Obtained by a method similar to the method described above, in the form of a white solid, so pl. . > 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) ⁺ .

Example 108 [2- (2-Cyclohexylethylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-29): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. > 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), 5.40-6.70 (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 (1H, br s); IR (solid) 3448, 2920, 2852, 1618, 1600, 1568, 1550, 1486, 1418, 1395, 1367, 1258, 1008, 985; MS 377.4 (M + H) ⁺ .

Example 109 [2- (4-Carboxymethoxyphenylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-30): Obtained by a method similar to the method described above, in the form of a yellow solid substances, so pl. > 250 ° C; ¹ H NMR (DMSO) δ 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) ⁺ .

Example 110 [2- (4-Cyanomethylphenylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-31): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. 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, 2 x br 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, 2 x br s), 9.90 and 10.56 (1H, 2 x s), 12.19 and 12.80 (1H, 2 x br .from); IR (solid) 1641, 1622, 1595, 1581, 1554, 1513, 1486, 1463, 1408, 1372, 985, 821; MS 382.3 (M + H) ⁺ .

Example 111 [2- (Benzothiazol-6-ylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-32): Obtained by a method similar to the method described above, in the form 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, 2 x br s) , 7.27 (1H, br s), 7.59 (1H, br s), 7.68 (1H, br s), 7.79 (1H, br s), 7.98 (1H broad s), 8.41 (1H, broad s), 8.97 (1H, broad s), 9.19 (1H, s), 9.58 and 10.10 (1H, 2 x wide cs), 10.57, 12.21 and 12.85 (1H, 3 x br s); IR (solid) 1624, 1592, 1575, 1512, 1472, 1411, 1377, 1333, 1244; MS 400.3 (M + H) ⁺ .

Example 112 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dimethylphenylamino) quinazolin-4-yl] amine (IIc-33): Obtained by a method similar to the method described above, in the form 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, 2 x br s), 7.09 (1H, d), 7.23 (1H, br s), 7.47 (1H, br s), 7.59 (1H, broad s), 7.64 (1H, broad s), 8.36 (1H, broad s), 9.02, 9.55 and 10.07 (1H 3 x br s), 10.49, 12.31 and 12.80 (1H, 3 x br s); IR (solid) 1620, 1600, 1574, 1552, 1497, 1474, 1436, 1416, 1385, 1262; MS 371.5 (M + H) ⁺ .

Example 113 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2-phenoxyethylamino) quinazolin-4-yl] amine (IIc-34): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. 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, 2 x br 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, 2 x s), 12, 13 and 12.75 (1H, 2 x br s); IR (solid) 3434, 1622, 1600, 1572, 1554, 1499, 1476, 1422, 1399, 1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M + H) ⁺ .

Example 114 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (thiophen-2-methylamino) quinazolin-4-yl] amine (IIc-35): Obtained by a method similar to the method described above, in the form 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, 2 x br s), 6.95 (1H, s), 6.90-7.20 (2H, m), 7.20-8.45 (5H, m), 9.94 and 10 40 (1H, 2 x s), 12.13 and 12.71 (1H, 2 x br 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) ⁺ .

Example 115 [2- (4-Carboxymethylphenylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-36): Obtained by the method similar to the method described above, in the form of a brown solid substances, so pl. > 210 ° C (decomp.); 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, 2 x s), 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, 2 x br s); IR (solid) 1648, 1591, 1555, 1512, 1489, 1428, 1411, 1374; MS 401.4 (M + H) ⁺ .

Example 116 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (1H-indazol-5-ylamino) quinazolin-4-yl] amine (IIc-37): Obtained by a method similar to the method described above, in the form of a purple solid, so pl. 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, 2 x s) 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, 3 x bs), 10.01, 10.68 and 12.38 (1H, 3 x bs), 12.90 (1H, s); IR (solid) 1626, 1605, 1576, 1546, 1512, 1495, 1476, 1447, 1431, 1416, 1393, 1261, 1224; MS 383.3 (M + H) ⁺ .

Example 117 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (pyridin-3-ylmethylamino) quinazolin-4-yl] amine (IIc-38): Obtained by a method similar to the method described above, in the form 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, 3 x br 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, 2 x s), 12.15 and 12.63 ( 1H, 2 x br s); IR (solid) 2927, 2850, 1623, 1600, 1577, 1536, 1477, 1418, 1332, 1254, 814; MS 358.3 (M + H) ⁺ .

Example 118 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxycarbonylphenylamino) quinazolin-4-yl] amine (IIc-39): Obtained by the method similar to the method described above, in the form of a white solid substances, so pl. 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, 2 x s), 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, 3 x br s), 10.63, 12.17 and 12.79 (1H, 3 x br 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) ⁺ .

Example 119 [2- (3-Carboxyphenylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-40): Obtained by a method similar to the method described above, in the form not quite 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 (1H, t), 8.31 (2H, m), 8.41 (1H, d); IR (solid) 1661, 1597, 1578, 1558, 1517, 1486, 1424, 1385; MS 387.3 (M + H) ⁺ .

Example 120 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-ethylphenylamino) quinazolin-4-yl] amine (IIc-41): Obtained by a method similar to the method described above, in the form not quite white solid, mp 186-l88 ° 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) ⁺ .

Example 121 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,3-dimethylphenylamino) quinazolin-4-yl] amine (IIc-42): Obtained by a method similar to the method described above, in the form 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 broad s), 10.48, 12.04 and 12.68 (1H, 3 x broad s); IR (solid) 1622, 1603, 1573, 1552, 1495, 1471, 1440, 1428, 1412, 1384, 1268; MS 371.4 (M + H) ⁺ .

Example 122 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dimethoxyphenylamino) quinazolin-4-yl] amine (IIc-43): Obtained by a method similar to the method described above, in the form gray 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) ⁺ .

Example 123 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxyphenylamino) quinazolin-4-yl] amine (IIc-44): Obtained by the method similar to the method described above, in the form of a gray solid substances, so pl. 207-21l ° 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 × broad s); 10.56, 12.16 and 12.82 (1H, 3 × broad 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) ⁺ .

Example 124 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino-5,6,7,8-tetrahydroquinazolinin-4-yl] amine (IIc-45): Obtained by a method similar to the method described above. .

Example 125 [2- (Biphenyl-3-ylamino) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIc-46): Obtained by a method similar to the method described above, in the form pale 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, rotamers) 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) ⁺ .

Example 126 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-phenylprop-1-ylamino) quinazolin-4-yl] amine (IIc-47): Obtained by a method similar to the method described above, in the form of a white solid, so pl. 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) ⁺ .

Example 127 [2- (4-Acetamido-3-methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-48): Obtained by a method similar to the method described above, in the form of 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, rotamers) 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, rotamers), 12.15 and 12.82 (1H, br .c, rotamers); 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) ⁺ .

Example 128 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (indan-2-ylamino) quinazolin-4-yl] amine (IIc-49): Obtained by a method similar to the method described above, in the form 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 (1H, br s), 7.00-7.60 (8H, m), 8.29 (1H, s), 10.30 (1H, broad s), 12.24 (1H, broad s); IR (solid) 3425, 2941, 2836, 1622, 1595, 1572, 1540, 1495, 1476, 1426, 1394, 1248, 1025, 1007, 870, 833; MS 383.3 (M + H) ⁺ .

Example 129 [2- (3-Methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-50): Obtained by a method similar to the method described above, in the form not quite 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, broad .s, rotamers), 10.07 and 10.55 (1H, br s, rotamers), 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) ⁺ .

Example 130 [2- (2-Chloro-5-methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-51): Obtained by a method similar to the method described above, in the form of a gray solid, so pl. 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, broad s); 10.17 (1H, broad s); 12.19 (1H, broad 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) ⁺ .

Example 131 (5-Cyclopropyl-2H-pyrazol-3-yl) - {2- [4- (morpholin-1-yl) phenylamino] quinazolin-4-yl} amine (IIc-52): Obtained by a method similar to that described above method A, in the form of a gray solid, so pl. 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, rotamers), 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) ⁺ .

Example 132 [2- (Benzothiazol-6-ylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-53): Obtained by a method similar to the method described above, in the form 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, C), 9.17 (1H, s), 9 59 (1H, broad s); 10.30 (1H, broad s); 12.35 (1H, broad s); IR (solid) 1622, 1605, 1567, 1546, 1505, 1473, 1441, 1417, 1385, 1341, 1297, 1273, 1253, 1192, 1130; MS 374.1 (M + H) ⁺ .

Example 133 [2- (3,4-Dimethylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-54): Obtained by a method similar to the method described above, in the form off-white solid, mp 249-251 ° C; ¹ H NMR (DMSO) δ 2.18 (3H, broad s), 2.21 (3H, broad s), 2.24 (3H, broad 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 .from); IR (solid) 1616, 1582, 1547, 1505, 1473, 1452, 1413, 1368, 1334, 1294, 1246, 1210, 1188, 1170, 1139; MS 345.3 (M + H) ⁺ .

Example 134 [2- (3-Ethylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-55): Obtained by a method similar to the method described above, in the form not quite 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 × br. s), 6.78 (1H, s), 7.21 (2H, s), 7.48 (1H, s), 7.65 (1H, s), 7.72 (1H, s) ), 7.80 (1H, s), 8.40 (1H, br s), 9.09, 9.58 and 10.10 (1H, 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) ⁺ .

Example 135 [2- (3-Methoxyphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-56): Obtained by a method similar to the method described above, in the form not quite 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, broad) c), 9.10, 9.79 and 10.10 (1H, 3 × bs), 10.55, 12.13 and 12.82 (1H, 3 x bs); IR (solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277, 1256, 1201, 1159; MS 347.4 (M + H) ⁺ .

Example 136 [2- (4-Acetamido-3-cyanophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-57): Obtained by a method similar to the method described above, in the form of 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) @ ⁺ .

Example 137 [2- (2-Methoxybiphenyl-5-ylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-58): Obtained by a method similar to the method described above, in the form of a white solid, so pl. 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) ⁺ .

Example 138 [2- (4-Acetamidophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-59): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 139 [2- (4-tert-Butoxycarbonylaminophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-60): Obtained by a method similar to the method described above, in the form 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 × br s); IR (solid) 1698, 1620, 1555, 1520, 1475, 1443, 1405, 1371, 1310, 1241, 1167, 1055, 996; MS 432.1 (M + H) ⁺ .

Example 140 [2- (4-Cyanophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-61): Obtained by a method similar to the method described above, in the form not quite 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 (1H, s), 9.76 (1H, s), 10.34 (1H, s), 12.33 (1H, s); IR (solid) 1633, 1605, 1571, 1517, 1505, 1469, 1418, 1337, 1255, 1174, 1000; MS 342.1 (M + H) ⁺ .

Example 141 (5-Methyl-2H-pyrazol-3-yl) - [2- (6-oxo-6,10b-dihydro-4aH-benzo [c] chromen-2-ylamino) quinazolin-4-yl] amine ( IIc-62): Obtained by a method similar to the method described above, in the form of a pale yellow solid, so pl. 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) ⁺ .

Example 142 [2- (Biphenyl-3-ylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-63): Obtained by a method similar to the method described above, in the form 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) ⁺ .

Example 143 [2- (4-Methoxycarbonylmethyl-3-methylphenylamino) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-64): Obtained by a method similar to the method described above in the form of a white solid, so pl. 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 broad s), 6.80 (0.5H, broad 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) ⁺ .

Example 144 [2- (4-Carboxymethyl-3-methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-65): Solution [2- (4-methoxycarbonylmethyl- 3-methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-64, 200 mg, 0.5 mmol) in methanol / water (3/1, 8 ml ) was treated with 1M NaOH (2 ml, 2 mmol). The mixture was heated at 70 ° C. for 2 hours and then neutralized by the addition of 1 M HCl (2 ml, 2 mmol). The resulting solid was collected by filtration to obtain the title compound (185 mg, 95%) as a pale yellow solid, mp. 245 ° C (decomp.); ¹ H NMR (DMSO) δ 2.27 (6H, 2 x s), 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) ⁺ .

Example 145 [2- (4-Aminophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-66): Solution of [2- (4-tert-butoxycarbonylaminophenylamino) quinazolin- 4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-60, 100 mg, 0.232 mmol) in a DCM / TFA mixture (5/1, 12 ml) was stirred for 2 hours at room temperature. The solvents were removed in vacuo and the residue was triturated in aqueous K ₂ CO ₃ . The resulting solid was collected by filtration and washed with diethyl ether to give IIc-66 (69 mg, 90%) as an 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 (1H, d), 10.86 (1H, broad s), 11.46 (1H, s); IR (solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M + H) ⁺ .

Example 146 [2- (4-Bromophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-67): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 147 [2- (4-Isobutyrylaminophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-68): Obtained by a method similar to the method described above, in the form of a yellow solid substances, so pl. 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, br s); IR (solid) 1676, 1653, 1585, 1561, 1512, 1423, 1407, 1312, 1199, 1177, 1128; MS 402.3 (M + H) ⁺ .

Example 148 (5-Ethyl-2H-pyrazol-3-yl) - [2- (5-ethyl-2H-pyrazol-3-ylamino) quinazolin-4-yl] amine (IIc-69): To a solution of 2.4 β-dichloroquinazoline (0.5 g, 2.51 mmol) and 3-amino-5-ethylpyrazole (558 mg, 5.02 mmol) in ethanol (10 ml) were added triethylamine (0.35 ml, 2.51 mmol) and the resulting mixture was stirred for 3 hours at room temperature. The resulting pale yellow precipitate was collected by filtration, washed with cold ethanol and dried in vacuo to give compound IIc-69 (306 mg, 35%) as an 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, 1H); 7.90 (t, 1H); 8.78 (d, 1H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2 (M + H) ⁺ .

Example 149 (1H-Indazol-3-yl) - (2-phenylaminoquinazolin-4-yl) amine (IIc-70): Obtained by a method similar to the method described above, in the form of a white solid, 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) ⁺ .

Example 150 (1H-Indazol-3-yl) - [2- (3-trifluoromethylphenylamino) quinazolin-4-yl] amine (IIc-71): Obtained by a method similar to the method described above, in the form of 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) ⁺ .

Example 151 (1H-Indazol-3-yl) - [2- (4-trifluoromethylphenylamino) quinazolin-4-yl] amine (IIc-72): Obtained by a method similar to the method described above, in the form of 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) ⁺ .

Example 152 [2- (Adamantan-2-ylamino) quinazolin-4-yl] - (1H-indazol-3-yl) amine (IIc-73): Obtained by a method similar to the method described above, in the form of 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) ⁺ .

Example 153 (1H-Indazol-3-yl) - (2-methylphenylaminoquinazolin-4-yl) amine (IIc-74): Obtained by a method similar to the method described above, in the form of a white 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) ⁺ .

Example 154 [2- (2-Chlorophenyl) aminoquinazolin-4-yl] - (1H-indazol-3-yl) amine (IIc-75): Obtained by a method similar to the method described above, in the form of a white solid, ¹ N 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, 1H); MS 387.1 (M + H) ⁺ .

Example 155 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenylamino) quinazolin-4-yl] amine (IIc-76): Obtained by the method similar to the method described above, in the form of a white solid, ¹ N 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, 1H), 13.03 (s, 1H); MS 421.2 (M + H) ⁺ .

Example 156 [2- (4-Cyanomethylphenylamino) quinazolin-4-yl] - (1H-indazol-3-yl) amine (IIc-77): Obtained by the method similar to the method described above, in the form of a white solid, ¹ N 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) ⁺ .

Example 157 [2- (4-Chlorophenylamino) -5,6,7,8-tetrahydroquinazolinin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-78): Obtained by a method similar to method C described above; MS 355.5 (M + H) ⁺ .

Example 158 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl) amine (IIc-79): Obtained by a method similar to method C described above; MS 335.3 (M + H) ⁺ .

Example 159 [2- (Benzimidazol-2-ylamino) -7-benzyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3 -yl) amine (IIc-80): Obtained by a method similar to the method described above; MS 452.0 (M + H) ⁺ .

Example 160 (7-Benzyl-2-phenylamino-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine ( IIc-81): Obtained by a method similar to the method described above; MS 412.1 (M + H) ⁺ .

Example 161 [6-Benzyl-2- (4-chlorophenylamino) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl ) amine (IIc-82): Obtained by a method similar to the method described above; MS 446.3 (M + H) ⁺ .

Example 162 [2- (Benzimidazol-2-ylamino) -6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3 -yl) amine (IIc-83): Obtained by a method similar to the method described above; MS 452.2 (M + H) ⁺ .

Example 163 (6-Benzyl-2-phenylamino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine ( IIc-84): Obtained by a method similar to the above method C; MS 411.9 (M + H) ⁺ .

Example 164 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4-yl) amine (IIc-85): Obtained by a method similar to method C described above; MS 322.3 (M + H) ⁺ .

Example 165 [2- (4-Cyanmethylphenylamino) quinazolin-4-yl] - (1H-pyrazolo [3,4-b] pyridin-3-yl) amine (IIc-86): Obtained by a method similar to the method described above, as 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) ⁺ .

Example 166 [2- (4-Cyanobenzylamino) quinazolin-4-yl] - (1H-pyrazolo- [3,4-b] pyridin-3-yl) amine (IIc-87): Obtained by a method similar to the method described above , as 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) ⁺ .

Example 167 [2- (4-Cyanomethylphenylamino) quinazolin-4-yl] - (4-fluoro-1H-indazol-3-yl) amine (IIc-88): Obtained by a method similar to the method described above, in the form of a white solid substances, 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) ⁺ .

Example 168 [2- (4-Cyanophenylamino) quinazolin-4-yl] - (1H-indazol-3-yl) amine (IIc-89): Obtained by a method similar to the method described above, in the form of a white solid, ¹ N 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) ⁺ .

Example 169 [2- (4-Cyanobenzylamino) quinazolin-4-yl] - (1H-indazol-3-yl) amine (IIc-90): Obtained by the method similar to the method described above, in the form of a white solid, ¹ N 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 (brd, 2H) 4.19 (s, 2H); MS 392.2 (M + H) ⁺ .

Example 170 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-yloxy) quinazolin-4-yl] amine (IIb-1): Obtained by a method similar to the method described above, in the form 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) ⁺ .

Example 171 (5-Methyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-yloxy) quinazolin-4-yl] amine (IIb-2): Obtained by a method similar to the method described above, in the form 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) ⁺ .

Example 172 (5-Methyl-2H-pyrazol-3-yl) - (2-phenoxyquinazolin-4-yl) amine (IIb-3): Obtained by a method similar to the method described above, in the form of a tan solid, t .pl. 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 (1H, t), 8.58 (1H, d), 10.55 (1H, s), 12.11 (1H, s) ; IR (solid) 1622, 1602, 1572, 1556, 1542, 1477, 1454, 1402, 1373, 1316, 1249, 1200, 1172, 1158; MS 318.3 (M + H) ⁺ .

Example 173 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (5,6,7,8-tetrahydronaphthalen-2-yloxy) quinazolin-4-yl] amine (IIb-4): Obtained by the method, similar to the above method B, in the form of a solid substance, so pl. 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 (1H, s); IR (solid) 1731, 1641, 1614, 1570, 1506, 1495, 1464, 1424, 1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4 (M + H) ⁺ .

Example 174 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methylphenoxy) quinazolin-4-yl] amine (IIb-5): Obtained by a method similar to the method described above, in the form of not quite 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) ⁺ .

Example 175 [2- (3-Methoxyphenoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIb-6): Obtained by a method similar to the method described above, in the form of a white solid substances, so pl. 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 (1H, t), 8.59 (1H, d), 10.57 (1H, s ), 12.10 (1H, s); IR (solid) 1623, 1603, 1575, 1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142, 1046, 1022, 833, 760; MS 348.4 (M + H) ⁺ .

Example 176 [2- (3,4-Dimethoxyphenoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIb-7): Obtained by a method similar to the method described above, in the form 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) ⁺ .

Example 177 [2- (Benzo [1,3] dioxol-5-yloxy) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIb-8): Obtained by a method similar to that described above method B, in the form of an off-white solid, mp. 296-299 ° C (decomp.); 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) ⁺ .

Example 178 [2- (3-Methoxycarbonylphenoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIb-9): Obtained by a method similar to the method described above, in the form not quite 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) ⁺ .

Example 179 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenoxymethylquinazolin-4-yl) amine (IId-1): Obtained by a method similar to the method described above, in the form of a pale yellow solid, t .pl. 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, broad .c), 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 s), 10.45 (1H, br s), 12.18 (1H, br s); MS 358.4 (M + H) ⁺ .

Example 180 (2-Benzyloxymethylquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IId-2): Obtained by a method similar to the method described above, in the form of a white solid, so pl. . 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) ⁺ .

Example 181 (2-Benzylquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IId-3): Obtained by a method similar to the method described above, in the form of a white solid, so pl. . 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) ⁺ .

Example 182 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-methylquinazolin-4-yl) amine (IId-4): Obtained by a method similar to the method described above, in the form of a white solid, so pl. . 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 (1H, s), 12.65 (1H, s), IR (solid) 3266, 1636, 1607, 1579, 1479, 1407, 769, 668; MS 240.4 (M + H) ⁺ .

Example 183 [2- (4-Chlorophenoxymethyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IId-5): Obtained by a method similar to the method described above, C, as 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, broad); MS 384.3 (M + H) ⁺ .

Example 184 [2- (4-Chlorophenoxymethyl) -5,6,7,8-tetrahydroquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IId-6): Obtained by a method similar to method C described above, in the form of a white solid, ¹ H NMR (DMSO) δ 1.80 (4H, m), 2.15 (3H, s), 2.55 (2H, m darkened), 2.75 ( 2H, m), 5.25 (2H, s), 6.12 (1H, s), 7.08 (2H, d), 7.35 (2H, d), 9.80 (1H, broad) ; MS 370.2 (M + H) ⁺ .

Example 185 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylsulfanyl) -6-phenylpyrimidin-4-yl] amine (IIIa-1): Obtained by a method similar to the above method L in the form of a white solid, so pl. 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) ⁺ .

Example 186 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxycarbonylphenylsulfanyl) -6-phenylpyrimidin-4-yl] amine (IIIa-2): Obtained by a method similar to the method described above, in as 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) ⁺ .

Example 187 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] amine (IIIa-3): Obtained by a method similar to the method described above, in the form 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) ⁺ .

Example 188 (5-Cyclopropyl-2H-pyrazol-3-yl) - [5,6-dimethyl-2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] amine (IIIa-4): Obtained by a method similar to that described above method L, in the form of a white solid, so pl. > 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) ⁺ .

Example 189 (5-Cyclopropyl-2H-pyrazol-3-yl) - [5-methyl-2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] amine (IIIa-5): Obtained by a method similar to the method described above L, in the form of a white solid, so pl. 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) ⁺ .

Example 190 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-methyl-2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] amine (IIIa-6): Obtained by a method similar to the method described above L, in the form of a white solid, so pl. 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, s), 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) ⁺ .

Example 191 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6- (morpholin-4-yl) -2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] amine (IIIa-7): K 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) was added triethylamine (456 μl, 3.27 mmol ) and the reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (SiO ₂ , hexane / AcOEt gradient) to give (5-cyclopropyl-2H-pyrazol-3-yl) - (2,6-dichloropyrimidin-4-yl) amine (705 mg, 80%).

To a solution of (5-cyclopropyl-2H-pyrazol-3-yl) - (2,6-dichloropyrimidin-4-yl) amine (211 mg, 0.781 mmol) and 2-naphthalentiol (125 mg, 0.781 mmol) in tert-butanol (5 ml) was added triethylamine (174 μl, 1.25 mmol) and the resulting mixture was boiled under reflux for 15 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO ₃ . The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ , gradient hexane / AcOEt) to give [6-chloro-2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl ) amine.

The above [6-chloro-2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (70 mg, 1.78 · 10 ^-4 mol) dissolved in morpholine (3 ml) and the mixture was heated at 120 ° C for 15 hours. The solvent was evaporated and the residue was purified by flash chromatography to give compound IIIa-7 (50 mg, 63%) as a white solid, mp. 118-120 ° C; ¹ H NMR (DMSO) δ 0.34-0.91 (4H, 4 x m), 1.28 and 1.78 (1H, 2 x m), 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, 2 x s), 9.28 and 9.31 (1H, 2 x br s), 11.71 and 11.84 (1H, 2 x br s), IR (solid) ; MS 445.2 (M + H) ⁺ .

Example 192 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6- (1-methylpiperazin-4-yl) -2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] amine (IIIa-8) : Obtained by a method essentially similar to the above method for obtaining compound IIIa-7, in the form of a white solid, so pl. 113-115 ° C; ¹ H NMR (DMSO) δ 0.35-0.91 (4H, 4 x m), 1.31 and 1.78 (1H, 2 x m), 2.17 and 2.19 (3H, 2 x s ), 2.29 (4H, m), 3.35 (2H, m), 3.61 (2H, m), 5.38-6.20 (2H, m), 7.55-7, 66 (3H, m), 7.95-8.02 (3H, m), 8.17 and 8.23 (1H, 2x s), 9.26 and 9.32 (1H, 2 x br s), 11.71 and 11.85 (1H, 2 x br s); IR (solid); MS 458.3 (M + H) ⁺ .

Example 193 [6- (2,6-Dimethylphenyl) -2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-9): Received in a manner similar to method L described above, in the form of 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, 2 x 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) ⁺ .

Example 194 [6- (2-Methylphenyl) -2- (naphthalen-2-ylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-10): Obtained by the method, similar to the above method L, in the form of a white solid, so pl. 211-214 ° C; ¹ H NMR (DMSO) δ 1.41 (3H, s), 2.30 (3H, s), 5.26 and 6.55 (1H, 2 x br s), 7.34 (5H, m) 7.62 (2H, t), 7.70 (1H, d), 7.99 (3H, t), 8.30 (1H, s), 9.97 (1H, s), 11.73 ( 1H, broad s); IR (solid) 2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0 (M + H) ⁺ .

Example 195 [2- (4-Acetamidophenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-11): Obtained by a method similar to the method described above, in as 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, s), 10.23 (1H, s), 11.86 (1H, s); MS 417.2 (M + H) ⁺ .

Example 196 (5-Methyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylsulfanyl) -6-phenylpyrimidin-4-yl] amine (IIIa-12): Obtained by a method similar to the above method L in the form of a white solid, so pl. 237-239 ° C; ¹ H NMR (DMSO) δ 1.39 (3H, broad s), 5.12 (1H, broad s), 6.98 (1H, broad 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) ⁺ .

Example 197 [2- (4-Isobutyrylaminophenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-13): Obtained by a method similar to the method described above, in as 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 × wide s); IR (solid) 1676, 1614, 1586, 1573, 1514, 1483, 1395, 1299, 1262, 1242, 1214, 1168, 1089, 988; MS 445.3 (M + H) ⁺ .

Example 198 [6- (4-Methylpiperazin-1-yl) -2-methylsulfanylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-14): Obtained by a method similar to that described above Method M, as 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 (1H, s), 9.20 (1H, s), 11.87 (1H, s) ; IR (solid); MS 320.3 (M + H) ⁺ .

Example 199 (5-Methyl-2H-pyrazol-3-yl) - [6-phenyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] amine (IIIa-15): Obtained by a method similar to the above method L, in the form of 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) ⁺ .

Example 200 [2- (4-Cyclopropanecarbonylaminophenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-16): Obtained by a method similar to the method described above, in as 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) ⁺ .

Example 201 (5-Methyl-2H-pyrazol-3-yl) - {6-phenyl-2- [4- (propan-1-sulfonylamino) phenylsulfanyl] pyrimidin-4-yl} amine (IIIa-17): Obtained by the method , similar to the above method L, in the form of 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, broad s); IR (solid) 1628, 1587, 1545, 1525, 1496, 1455, 1311, 1255, 1236, 1212, 1186, 1140, 1032, 1001, 934; MS 481.2 (M + H) ^+.

Example 202 [2- (4-Ethanesulfonylaminophenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-18): Obtained by a method similar to the method described above, in as 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, s), 7.85 (2H, s), 9.99 (1H, br s), 10.15 (1H, br s) 11.90 (1H, broad s); IR (solid) 1621, 1585, 1542, 1523, 1495, 1455, 1315, 1257, 1208, 1142, 1049, 1033, 1002, 932; MS 467.2 (M + H) ⁺ .

Example 203 [2- (4-Acetamidophenylsulfanyl) -6- (2-methylphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-19): Obtained by a method similar to as described above, method L, in the form of a white solid, so pl. 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, broad s), 7.49-7.88 (9H, m), 10.00 (1H, br s), 10.23 (1H, s), 11.86 (1H, br s); IR (solid) l701, 1634, 1588, 1555, 1496, 1390, 1307, 1208, 1169, 823, 803; MS 431.4 (M + H) ⁺ .

Example 204 [2- (4-Isobutanecarbonylaminophenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-20): Obtained by a method similar to the method described above, in as 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) ⁺ .

Example 205 [2- (4-Acetamidophenylsulfanyl) -5-methyl-6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-21): Obtained by a method similar to that described above method L, in the form of a pale pink solid, so pl. 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) ⁺ .

Example 206 [2- (4-Acetamidophenylsulfanyl) -6- (4-methoxyphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-22): Obtained by a method similar to that described above method L, in the form of 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, s), 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) ⁺ .

Example 207 [6- (3-Acetamidophenyl) -2- (4-acetamidophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-23): Obtained by a method similar to that described above method L, in the form of a brown solid, so pl. 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) ⁺ .

Example 208 [2- (4-Isopropanesulfonylaminophenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-24): Obtained by a method similar to the method described above, in as 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, s), 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) ⁺ .

Example 209 {2- [4- (2-Dimethylaminoacetylamino) phenylsulfanyl] -6-phenylpyrimidin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-25): Obtained by a method similar to that described above method L, in the form of 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, broad .c), 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) ⁺ .

Example 210 [2- (3-Chlorobenzylsulfanyl) -6-morpholin-4-ylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-26): Obtained by a method similar to that described above method M, in the form of a white solid, so pl. 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, br s), 6.41 (1H, br s), 7.23-7.55 (4H, m), 9.31 (1H, s), 11.89 (1H , s); IR (solid) 1557, 1476, 1442, 1401, 1314, 1232, 1121, 1018; MS 417.4 (M + H) ⁺ .

Example 211 [2- (3-Chlorobenzylsulfanyl) -6- (2-methoxyethylamino) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-27): Obtained by a method similar to that described above method M, in the form of 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, br s), 6.20 (1H, br s), 7.10 (1H, br s), 7.21-7.50 (4H, m), 9.01 (1H, br .from); IR (solid) 1598, 1555, 1527, 1336, 1293, 1117, 1079, 974, 783; MS 405.4 (M + H) ⁺ .

Example 212 [2-Benzylsulfanyl-6- (4-methylpiperazin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-28): Obtained by a method similar to the above method M, in the form of 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, br s), 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) ⁺ .

Example 213 [2-Benzylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-29): Obtained by a method similar to the method described above, in not quite 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 c), 6.25 (1H, br s), 7.20-7.50 (5H, m), 8.10 (1H, s); IR (solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767, 698; MS 383.4 (M + H) ⁺ .

Example 214 [2- (3-Chlorobenzylsulfanyl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-30): Obtained by a method similar to the above method M, in the form of 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, br s), 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) ⁺ .

Example 215 [2- (4-Methoxybenzylsulfanyl) -6- (4-methylpiperazin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-31): Received by a method similar to the above method M, in the form of 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, s), 3.80 (3H, s), 4.34 (2H, s), 5.32 (1H, s), 6.28 (1H, br s), 6 83-6.85 (2H, m); 7.34-7.36 (2H, m); IR (solid) 1659, 1554, 1508, 1485, 1449, 1366, 1318, 1302, 1277, 1230, 1166, 1146, 1030, 999, 973, 948; MS 443.4 (M + H) ⁺ .

Example 216 [2- (4-Acetamidophenylsulfanyl) -6-tert-butyl-pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-32): Obtained by a method similar to that described above method L, in the form of a white solid, so pl. 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 broad s), 6.55 (1H, broad s), 7.55 (2H, d), 7.75 (2H, d), 10.1 (1H, broad s), 1.15 ( 1H, s), 12.1 (1H, br s); IR (solid); MS (M + H) ⁺ .

Example 217 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-phenyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] amine (IIIa-33): Obtained by a method similar to the method described above, in the form of 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 s), 5.50 (1H, s), 7.03 (1H, 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. from); IR (solid) 1676, 1617, 1575, 1539, 1520, 1485, 1459, 1418, 1395, 1304, 1255, 1243, 1215, 1161, 1071, 990; MS 457.4 (M + H) ⁺ .

Example 218 [2- (3-Chlorobenzylsulfanyl) -6- (piperidin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-34): Obtained by the method similar to the above method M, in the form of a white solid, so pl. 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, br s), 7.23-7.41 (3H, m), 7.48 (1H, s), 9.18 (1H c), 11.83 (1H, s); IR (solid) 1598, 1546, 1483, 1398, 1317, 1227, 974, 798, 779; MS 415.4 (M + H) ⁺ .

Example 219 (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (morpholinsulfonyl) benzylsulfanyl] -6-morpholin-4-ylpyrimidin-4-yl} amine (IIIa-35): Obtained by the method, similar to the above method M, in the form of 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) ⁺ .

Example 220 {6- (2-Methoxyethylamino) -2- [4- (morpholinsulfonyl) benzylsulfanyl] pyrimidin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-36): Obtained by the method similar to the above method M, in the form of a white solid, so pl. 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, br s), 7.10 (1H, br s), 7.61-7.74 (4H, m), 9.03 (1H, br s), 11.81 (1H, br s); IR (solid) 1593, 1555, 1484, 1350, 1298, 1255, 1160, 1107, 936; MS 520.5 (M + H) ⁺ .

Example 221 {6- (4-methylpiperazin-1-yl) -2- [4- (morpholinsulfonyl) benzylsulfanyl] pyrimidin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-37 ): Obtained by a method similar to the above method M, in the form of a white solid, so pl. 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, br s), 6.42 (1H, br s), 7.60-7.74 (4H, m), 9.26 (1H, s), 11.89 (1H, br s); IR (solid) 1583, 1558, 1479, 1346, 1231, 1160, 1112, 998, 969, 926; MS 545.5 (M + H) ⁺ .

Example 222 [6-Methoxymethyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-38): Obtained by a method similar to the method described above, as 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 s), 5.26 (1H, s), 6.45 (1H, s), 7.44-7.56 (2H, m), 7.68- 7.80 (2H, m), 9.86 (1H, s), 10.11 (1H, s), 11.79 (1H, s); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360, 1269, 1174, 1107; MS 399.4 (M + H) ⁺ .

Example 223 [2- (4-Methoxycarbonylphenylsulfanyl) -6-methoxymethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-39): Obtained by a method similar to the method described above, in as a white solid, mp 204-205 ° C; ¹ H NMR (DMSO) δ 1.89 (3H, br s), 3.85 (3H, s), Ohm under DMSO, 4.23 (2H, s), 5.22 (1H, br s) 6.51 (1H, br s), 7.70-7.81 (2H, m), 7.96-8.06 (2H, m), 9.99 (1H, br s), 11 85 (1H, broad s); IR (solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119, 1109, 997, 841; MS 386.3 (M + H) ⁺ .

Example 224 [2- (3,5-Dimethoxybenzylsulfanyl) -6-morpholin-4-ylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-40): Obtained by a method similar to the above method M, in the form of 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, br s), 6.31-6.61 (5H, m), 9.32 (1H, s), 11.86 (1H , from); IR (solid) 1581, 1556, 1470, 1439, 1315, 1232, 1205, 1159, 1144; MS 443.4 (M + H) ⁺ .

Example 225 [2- (3,5-Dimethoxybenzylsulfanyl) -6-pyrrolidin-4-ylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-41): Obtained by a method similar to the above method M, in the form of 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, br s), 6.18 (1H, br s), 6.35 (1H, br c), 6.60 (2H, s), 9.12 (1H, s), 11.88 (1H, s); IR (solid) l598, 1560, 1474, 1470, 1346, 1303, 1207, 1136, 1050; MS 427.4 (M + H) ⁺ .

Example 226 (5-Methyl-2H-pyrazol-3-yl) - [6-morpholin-4-yl-2- (naphthalen-2-ylmethylsulfanyl) pyrimidin-4-yl] amine (IIIa-42): Obtained by the method, similar to the above method M, in the form of 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, br s), 6.40 (1H, br s), 7.40-7.60 (3H, m), 7.78-7.95 (4H, m), 9.30 (1H, s), 11.89 (1H, br s); IR (solid) 1607, 1555, 1484, 1441, 1398, 1365, 1308, 1231, 1179, 1112; MS 433.4 (M + H) ⁺ .

Example 227 {2- (4-Acetamidophenylsulfanyl) -6- [4- (3-dimethylaminopropoxy) phenyl] pyrimidin-4-yl} - (5-methyl-2H-pyrazol-3-yl) -amine (IIIa-43) : Obtained by a method similar to the above method N, in the form of a white solid, so pl. 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) ⁺ .

Example 228 [2- (4-Acetamidophenylsulfanyl) -6- [morpholin-4-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-44): Obtained by the method, similar to the above method P, in the form of a white solid; MS 426.4 (M + H) ⁺ .

Example 229 [6-Hydroxymethyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-45): Obtained from IIIa-48 by method O, in as a white solid, ¹ H NMR (DMSO) δ 1.08-1.18 (3H, m), 1.96 (3H, br s), 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, br s), 10.13 (1H, s), 11.78 (1H, br s); MS 385.4 (M + H) ⁺ .

Example 230 [2- (4-Acetamidophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-46): Obtained by a method similar to the method described above, in the form not quite white solid, 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 (1H, d), 9.89 (1H, br s), 10.19 (1H, br s), 11.83 ( 1H, broad s); IR (solid) 1657, 1609, 1584, 1515, 1494, 1468, 1395, 1372, 1355, 1330, 1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M + H) ⁺ .

Example 231 [6- (1-Butoxycarbonyl) -2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-47): Obtained by a method similar to that described above method L, in the form of 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, br s), 2.29-2.40 (2H, m), 4.20-4.30 (2H, m), 5.25 (1H, br s), 7.08 (1H, br s), 7.49-7.55 (2H, m), 7.72-7.81 (2H m) 10.15 (1H, broad s); 10.32 (1H, broad s); 11.89 (1H, broad s); IR (solid) 1736, 1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 (M + H) ⁺ .

Example 232 [6- (Methoxycarbonyl-2- (4-propionylaminophenylsulfanyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIa-48): Obtained by a method similar to the above method L , as a yellow solid, ¹ H NMR (DMSO) δ 1.10 (3H, t), 1.94 (3H, br s), 2.35 (2H, q), 3.84 (3H, s ), 5.22 (1H, br s), 7.05 (1H, s), 7.52 (2H, d), 7.79 (2H, d), 10.18 (1H, br s) , 10.38 (1H, br s), 11.89 (1H, br s) ;; IR (solid) 1741, 1679, 1617, 1589, 1512, 1484, 1374, 1284, 1250; MS 413, 4 (M + H) ⁺ .

Example 233 (5-Methyl-2H-pyrazol-3-yl) - (6-phenyl-2-phenylaminopyrimidin-4-yl) amine (IIIc-1): white solid, MS 343.4 (M + H) ⁺ .

Example 234 (5-Cyclopropyl-2H-pyrazol-3-yl) - (6-phenyl-2-phenylaminopyrimidin-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, broad s), 7.20 (1H, m), 7.33-8.05 (9H, m), 10.52 (1H, br s), 11.08 (1H, br s), 12, 53 (1H, broad s); IR (solid); MS 369.7 (M + H) ⁺ .

Example 235 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methylphenylamino) -6-phenylpyrimidin-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, broad s); 12.47 (1H, broad s); IR (solid); MS 383.7 (M + H) ⁺ .

Example 236 [2- (4-Cyanomethylphenylamino) -6-phenylpyrimidin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (IIIc-4): pale 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, broad s), 11.02 (1H, broad s), 12.57 (1H, broad s); IR (solid); MS 408.8 (M + H) ⁺ .

Example 237 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-phenyl-2- (pyridin-3-ylmethylamino) pyrimidin-4-yl] amine (IIIc-5): off-white solid, t .pl. 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, broad c), 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) ⁺ .

Example 238 [2- (3-Chlorophenyl) amino-6- (3-nitrophenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-6): off-white solid substance, 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 (1H, s), 8.18 (1H, d), 8.25 (1H, d), 8.65 (1H, s) ; MS 422.1 (M + H) ⁺ .

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) ⁺ .

Example 240 (5-Methyl-2H-pyrazol-3-yl) - [2- (4-sulfamoylphenylamino-6- (3,4,5-trimethoxyphenyl) pyrimidin-4-yl] amine (IIIc-8): white solid substance, MS 512.6 (M + H) ⁺ .

Example 241 [2- (4-Chlorophenyl) amino-6-methylpyrimidin-4-yl] - (5- (furan-2-yl) -2H-pyrazol-3-yl) amine (IIIc-9): white solid MS 367.1 (M + H) ⁺ .

Example 242 [2- (Benzimidazol-2-ylamino) -6-ethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-10): MS 335.5 (M + H ) ⁺ .

Example 243 [2- (4-Chlorophenyl) amino-6-methylpyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (IIIc-11): MS 377.5 (M + H) ⁺ .

Example 244 [2- (4-Chlorophenyl) amino-6-ethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-12): MS 329.4 (M + H) ⁺ .

Example 245 (5-tert-Butyl-2H-pyrazol-3-yl) - [2- (3-chlorophenyl) amino-6- (3-nitrophenyl) pyrimidin-4-yl] amine (IIIc-13): not quite 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 (1H, t), 7.91 (1H, s), 8.35 (1H, d), 8.40 (1H, d), 8.90 (1H, s); MS 464.2 (M + H) ⁺ .

Example 246 [2- (3-Chlorophenyl) amino-6- (3-nitrophenyl) pyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (IIIc-14): off-white solid substance, 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 (1H, s), 8.35 (1H, d), 8.42 (1H, d), 8.85 ( 1H, s); MS 484.1 (M + H) ⁺ .

Example 247 [5- (Furan-2-yl) -2H-pyrazol-3-yl] - (6-phenyl-2-phenylaminopyrimidin-4-yl) amine (IIIc-15): MS 395.4 (M + H) ) ⁺ .

Example 248 [2- (Benzimidazol-2-ylamino-6-methylpyrimidin-4-yl] -5-phenyl-2H-pyrazol-3-yl) amine (IIIc-16): MS 383.2 (M + H) ⁺ .

Example 249 [2- (Benzimidazol-2-ylamino-6-methylpyrimidin-4-yl] - [5- (furan-2-yl) -2H-pyrazol-3-yl] amine (IIIc-17): MS 373, 4 (M + H) ⁺ .

Example 250 [2- (4-Chlorophenylamino) -6-methylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-18): MS 315.4 (M + H) ⁺ .

Example 251 [2- (4-Chlorophenyl) amino-5,6-dimethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-19): MS 329.4 (M + H) ⁺ .

Example 252 (5,6-Dimethyl-2-phenylaminopyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-20): MS 295.5 (M + H) ⁺ .

Example 253 [2- (4-Chlorophenyl) amino-6-methoxymethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-21): MS 345.1 (M + H) ⁺ .

Example 254 [2- (Benzimidazol-2-ylamino) -6-methoxymethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-22): MS 351.2 (M + H ) ⁺ .

Example 255 (6-Methoxymethyl-2-phenylaminopyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-23): MS 311.2 (M + H) ⁺ .

Example 256 (6-Methyl-2-phenylaminopyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIIc-24): MS 281.1 (M + H) ⁺ .

Example 257 [2- (2-Chlorophenoxymethyl) -6-methylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIId-1): MS 392.1 (M + H) ⁺ .

Example 258 [2- (2-Chlorophenoxymethyl) -6-methylpyrimidin-4-yl] - [5- (furan-2-yl) -2H-pyrazol-3-yl] amine (IIId-2): MS 382.1 (M + H) ⁺ .

Example 259 (6-Methyl-2-phenoxymethylpyrimidin-4-yl) - (5-phenyl-2H-pyrazol-3-yl) amine (IIId-3): MS 358.2 (M + H) ⁺ .

Example 260 [5- (Furan-2-yl) -2H-pyrazol-3-yl] - (6-methyl-2-phenoxymethylpyrimidin-4-yl) amine (IIId-4): MS 348.2 (M + H) ) ⁺ .

Example 261 [5- (Furan-2-yl) -2H-pyrazol-3-yl] - (6-methyl-2-phenylsulfanylmethylpyrimidin-4-yl) amine (IIId-5): MS 364.1 (M + H) ) ⁺ .

Example 262 [6-Methyl-2- (4-methylphenylsulfanylmethyl) pyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (IIId-6): MS 388.1 (M + H) ⁺ .

Example 263 [5- (Furan-2-yl) -2H-pyrazol-3-yl] - [6-methyl-2- (4-methylphenylsulfanylmethyl) pyrimidin-4-yl] amine (IIId-7): MS 378, 1 (M + H) ⁺ .

Example 264 [2- (4-Fluorophenoxymethyl) -6-methylpyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (IIId-8): MS 376.2 (M + H) ⁺ .

Example 265 [2- (4-Fluorophenoxymethyl) -6-methylpyrimidin-4-yl] - [5- (furan-2-yl) -2H-pyrazol-3-yl] amine (IIId-9): MS 366.2 (M + H) ⁺ .

Example 266 (6-Ethyl-2-phenylsulfanylmethylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIId-10): MS 326.2 (M + H) ⁺ .

Example 267 (6-Ethyl-2-phenoxymethylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IIId-11): MS 310.2 (M + H) ⁺ .

Example 268 [6-Ethyl-2- (4-fluorophenoxymethyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIId-12): MS 328.2 (M + H) ⁺ .

Example 269 [6-Ethyl-2- (1-methyl-1-phenylethyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIId-13): MS 322.2 ( M + H) ⁺ .

Example 270 [2- (4-Chlorophenoxymethyl) -6-methylpyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (IIId-14): MS 392.2 (M + H) ⁺ .

Example 271 [2- (4-Chlorophenoxymethyl) -6-methylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIId-15): MS 330.2 (M + H) ⁺ .

Example 272 [2- (4-Chlorophenoxymethyl) -6-methoxymethylpyrimidin-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, broad), 7.05 (2H, d), 7.33 (2H, d), 10.55 (1H, broad), MS 360.2 (M + H) ⁺ .

Example 273 [2- (4-Chlorophenoxymethyl) -6-methylpyrimidin-4-yl] - [5- (furan-2-yl) -2H-pyrazol-3-yl] amine (IIId-17): MS 382.2 (M + H) ⁺ .

Example 274 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylsulfanylmethyl-5,6,7,8-tetrahydroquinazolin-4-yl) amine (IId-7): MS 352.5 (M + H) ) ⁺ .

Example 275 [2- (4-Methylphenylsulfanylmethyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IId-8): MS 380.2 (M + H) ⁺ .

Example 276 [2- (1-Methyl-1-phenylethyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IId -9): MS 362.3 (M + H) ⁺ .

Example 277 [2- (2,6-Dichlorobenzyl) -5,6,7,8-tetrahydroquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IId-10): MS 388 , 1 (M + H) ⁺ .

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) ⁺ .

Example 279 [6-Benzyl-2- (4-chlorophenoxymethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl ) amine (IId-12): MS 461.2 (M + H) ⁺ .

Example 280 [2- (4-Chlorophenoxymethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IId -13): MS 371.3 (M + H) ⁺ .

Example 281 [2- (2,6-Dichlorobenzyl) -6-methylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIId-18): MS 348.1 (M + H) ) ⁺ .

Example 282 [2- (2,6-Dichlorobenzyl) -5,6-dimethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIId-19): white solid, ¹ N NMR (DMSO) δ 8.50 (1H, s), 7.70 (1H, d), 7.3-7.1 (3H, m), 5.25 (1H, s), 4.10 (1H c), 2.30 (3H, s), 2.10 (3H, s), 1.80 (3H, s); MS 362.1 (M + H) ⁺ .

Example 283 (1H-Indazol-3-yl) - [2- (2-phenylcyclopropyl) quinazolin-4-yl] amine (IId-16): ¹ H NMR (DMSO) δ 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 +; HPLC R _t = 3.21 min.

Example 284 (7-Fluoro-1H-indazol-3-yl) - [2- (2-phenylcyclopropyl) quinazolin-4-yl] amine (IId-17): ¹ H NMR (DMSO) δ 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.

Example 285 (5-Fluoro-1H-indazol-3-yl) - [2- (2-phenylcyclopropyl) quinazolin-4-yl] amine (IId-18): ¹ H NMR (DMSO) δ 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.

Example 286 (5-Methyl-1H-pyrazol-3-yl) - [2- (2-phenylcyclopropyl) quinazolin-4-yl] amine (IId-19): ¹ H NMR (DMSO) δ 12.8 (1H, c), 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 (1H, m), 2.55 (1H, m), 2.35 (3H, s), 2.00 (2H, m); MS: m / z, 342.1 MH +; HPLC R _t = 3.13 min.

BIOLOGICAL TESTS

The activity of the compounds as protein kinase inhibitors can be determined in vitro, in vivo and on the cell line. In vitro studies include methods for determining the inhibition of phosphorylating activity or ATPase activity of activated protein kinase. Alternating in vitro assays quantify the ability of an inhibitor to bind to protein kinase. Inhibitor binding can be measured by labeling the inhibitor with radioactive labels before binding, isolating the inhibitor-protein kinase complex and distributing the number of bound radioactive labels. In another embodiment, the binding of an inhibitor can be determined by conducting a comparative experiment in which new inhibitors are incubated with a protein kinase associated with known radioligands.

EXAMPLE 1 BIOLOGICAL TEST

DEFINITION K _i FOR INHIBITING GSK-3

Compounds were tested for their ability to inhibit GSK-3β activity (AA 1-420) using a standard conjugated enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). The reactions were 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 the sample were 20 μM ATP (Sigma Chemicals, St Louis, MO) and 300 μM peptide (HSSPHQS (PO ₃ H ₂ ) EDEEE, American Peptide, Sunnyvale, CA). Reactions were carried out at 30 ° C and 20 nM GSK-3β. Final concentrations of the components of the conjugated enzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.

An initial test buffer solution was prepared containing all of the reagents listed above with the exception of ATP and the test compound of interest. The initial buffer solution (175 μl) was incubated in a 96-well plate with 5 μl of the test compound of interest at final concentrations in the range of 0.002-30 μM at 30 ° C for 10 minutes. Typically, 12-point titration was performed, preparing serial dilutions (from 10 mM solutions of the starting compounds) by DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 20 μl of ATP (final concentration of 20 μM). Using a reader for tablets f. Molecular Devices Spectramax (Sunnyvale, CA) obtained reaction rates in 10 minutes at 30 ° C. According to the speed, the values of K _{i were} determined depending on the concentration of the inhibitor.

The following compounds had Ki 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 - IIa-24, IIa-26, IIa-28, IIa-30 - IIa-32, IIa-39, IIa-43, IIa-46, IIa-47, IIa-61, IIc-3, IIc-6, IIc-8, IIc-10 - IIc-12, IIc-15, IIc-18, IIc-20 - IIc-22, IIc-24, IIc-25, IIc-27, IIc-30 - IIc-32, IIc- 35 - 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 - IIIc-5, IIIc-9, IIIc-11, IIIc-12, IIIc- 15, IIIc-18, IIIc-19, IIIc-21, IIIc-24, IIIb-1 - IIIb-6, IIIb-8 - IIIb-10, IIIb-13, IIIb-14, IIId-20, IIId-21, IId-14 and IId-19.

The following compounds had Ki values between 0.1 and 1.0 μM for GSK-3: IIa-1, IIa-4, IIa-5, IIa-7, IIa-14, IIa-15, IIa-20, IIa-29 , IIa-34 - 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 - IIc-45, IIc-47 - IIc-52, IIc-54 - IIc -57, IIc-59, IIc-63 - 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.

The following compounds had K _i values between 1.0 and 7.0 μM for GSK-3: IIa-10, IIa-13, IIa-25, IIa-40, IIa-45, IIa-49, IIa-50 - 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 - 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.

EXAMPLE 2 BIOLOGICAL TEST

DEFINITION K _i FOR INHIBITING AURORA-2

Compounds were tested as described below for their ability to inhibit AURORA-2 activity using a standard conjugated enzyme system (Fox et al. (1998) Protein Sci. 7, 2249).

To the initial buffer solution for analysis containing 0.1 M HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 mg / ml pyruvate kinase, 10 mg / ml lactate dehydrogenase, 40 mM ATP and 800 μM peptide (LRRASLG, American Peptide, Sunnyvale, CA), a solution of the compound of the present invention in DMSO was added to a final concentration of 30 μM. The resulting mixture was incubated at 30 ° C for 10 minutes. The reaction was initiated by adding 10 μl of AURORA-2 stock solution to give a final concentration of 70 nM in the sample. Using a reader for tablets f. BioRad Ultramark (Hercules, CA) obtained reaction rates by monitoring the absorbance at 340 nm for 5 minutes of reading at 30 ° C. According to the speed, the values of K _{i were} determined depending on the concentration of the inhibitor.

The following compounds had K _i values of less than 0.1 μM for AURORA-2: IIa-1 - IIa-18, IIa-21 - IIa-64, IIa-66, IIa-68, IIa-69, IIa-71 - IIa -78, IIa-81, IIc-1 - IIc-13, IIc-15 - IIc-44, IIc-46 - IIc-61, IIc-63 - IIc-65, IIc-67 - IIc-69, IIb-1 - IIb-9, IId-1 - IId-3, IIIa-1 - IIIa-8, IIIa-10 - IIIa-13, IIIa-15 - IIIa-32, IIIa-36 - IIIa-41, IIIa-44 - IIIa -49, IIIc-1 - IIIc-5, IIIc-12 and IIIc-15.

The following compounds had K _i values between 0.1 and 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 - IIIa-35, IIIc-9, IIIc-11, IIIb-1, IIIb-2, IIIb-7, IIIb-10 - IIIb-13, IIIb-15, IIIb-16 and IIId-20.

The following compounds had K _i values between 1.0 and 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.

EXAMPLE 3 BIOLOGICAL TEST

CDK-2 INHIBITION TEST

Compounds were tested as described below for their ability to inhibit CDK-2 activity using a standard conjugated enzyme system (Fox et al. (1998) Protein Sci. 7, 2249).

To the initial buffer solution for analysis containing 0.1 M HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 mg / ml pyruvate kinase, 10 mg / ml lactate dehydrogenase, 100 mM ATP and 100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA), a solution of the compound of the present invention in DMSO was added to a final concentration of 30 μM. The resulting mixture was incubated at 30 ° C for 10 minutes.

The reaction was initiated by adding 10 μl of a stock solution of CDK-2 / Cyclin A to obtain a final concentration of 25 nM in the sample. Using a reader for tablets f. BioRad Ultramark (Hercules, CA) obtained reaction rates by monitoring the absorbance at 340 nm for 5 minutes of reading at 30 ° C. According to the speed, the values of K _{i were} determined depending on the concentration of the inhibitor.

The following compounds had 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.

The following compounds had K _i values between 1.0 and 20.0 μM for CDK-2: IIa-38, IIa-40, IIa-44, IIa-52 and IIa-54.

EXAMPLE 4 BIOLOGICAL TEST

ERK INHIBITION TEST

Compounds were tested for inhibition of ERK2 by spectrophotometric analysis of the conjugated enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). In this analysis, a fixed concentration of activated ERK2 (10 nm) was incubated with various concentrations of the compound in DMSO (2.5%) for 10 minutes at 30 ° C in 0.1 M HEPES buffer (pH 7.5) containing 10 mM MgCl ₂ , 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg / ml pyruvate kinase, 50 μg / ml lactate dehydrogenase and 200 μM peptide erctid. The reaction was initiated by the addition of 65 μM ATP. The rate of decrease in absorbance at 340 nm was monitored. According to the speed, IC ₅₀ was evaluated depending on the concentration of the inhibitor.

The following compounds had K _i values of less than 1 μM for ERK-2: IIc-15, IIc-27, IIc-32, IIc-53 and IIIc-4.

The following compounds had K _i values between 1.0 and 20.0 μM for ERK-2: IIc-18, IIc-25 and IIa-36.

EXAMPLE 5 BIOLOGICAL TEST

ACT INHIBITION TEST

Compounds were tested for their ability to inhibit AKT using a standard conjugated enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). The tests were carried out in a mixture of 100 mm HEPES (pH 7.5), 10 mm MgCl ₂ , 25 mm NaCl, 1 mm DTT and 1.5% DMSO. The final substrate concentrations in the sample were 170 μM ATP (Sigma Chemicals) and 200 μM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Tests were performed at 30 ° C and 45 nM ACT. Final concentrations of the components of the conjugated enzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.

An initial test buffer solution was prepared containing all of the reagents listed above with the exception of ACT, DTT, and the test compound of interest. A stock buffer solution (56 μl) was placed in a 384-well plate, after which 1 μl of a 2 mM stock solution in DMSO containing the test compound (final compound concentration 30 μM) was added. The plate was preincubated for approximately 10 minutes at 30 ° C and then the reaction was initiated by adding 10 μl of the enzyme (final concentration 45 nM) and 1 mM DTT. Using a reader for tablets f. BioRad Ultramark (Hercules, CA) obtained reaction rates in 5 minutes of reading at 30 ° C. Compounds showing more than 50% inhibition compared to standard wells containing the assay mixture and DMSO without the test compound were titrated to determine IC ₅₀ values.

The following compounds had K _i values between 1.0 and 20.0 μM for ACT-3: IIc-18, IIc-22, IIc-25, IIc-27, IIc-31, IIc-32, IIc-37, IIc- 39, IIc-42 and IIc-53.

EXAMPLE 6 BIOLOGICAL TEST

SRC INHIBITION TEST

Compounds were evaluated as human Src kinase inhibitors using a radioactive assay or spectrophotometric method.

Src Inhibition Test A: Radioactive Assay

The compounds were tested as full length recombinant human Src kinase inhibitors (F. Upstate Biotechnology, Cat. No. 14-117), expressed and purified from rod-shaped viral cells. Src kinase activity was checked after incorporation of ³³ P from ATP into tyrosine of an arbitrary poly Glu-Tyr polymer substrate composition, Glu: Tyr = 4: 1 (Sigma, Cat. No. P-0275). The final concentrations of the components for analysis were as follows: 0.05 M HEPES (pH 7.6), 10 mM MgCl ₂ , 2 mM DTT, 0.25 mg / ml BSA (BSA), 10 μM ATP (1-2 μCi ³³ P -ATP per reaction), 5 mg / ml poly Glu-Tyr and 1-2 units of recombinant human Src kinase. In a routine test, all components of the reaction mixture with the exception of ATP were pre-mixed and aliquoted into the wells of the test plate. Inhibitors dissolved in DMSO were added to the wells until a final DMSO concentration of 2.5% was obtained. The plate was incubated at 30 ° C for 10 minutes, after which the reaction was initiated by the addition of ³³ P-ATP. After 20 minutes, the reaction was quenched by the addition of 150 μl of 10% trichloroacetic acid (TCA) containing 20 mM Na ₃ PO ₄ . The quenched samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF / F fiberglass filter, Cat. No. 7700-3310) mounted on a vacuum manifold for the filter plate. The filter plates were washed 4 times with 10% TCA containing 20 mM Na ₃ PO ₄ and then 4 times with methanol. Then, 200 μl of scintillation fluid was added to each well. The plates were hermetically sealed and the radioactivity associated with the filters was determined on a TopCount scintillation counter. The incorporated radioactivity was plotted against the concentration of inhibitor. The data were consistent with a comparative model of the kinetics of inhibition to obtain K _i values for the compound.

Src Inhibition Test B: Spectrophotometric Method

The amount of ADP obtained from ATP was determined by catalyzing recombinant human Src kinase phosphorylation of poly Glu-Tyr substrate using the conjugated enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). In this method, one NADH molecule is oxidized to NAD for each ADP molecule obtained in the kinase reaction. The disappearance of NADH can be conveniently traced at 340 nm.

The final concentrations of the components for analysis were as follows: 0.025 M HEPES (pH 7.6), 10 mM MgCl ₂ , 2 mM DTT, 0.25 mg / ml poly Glu-Tyr, and 25 nM recombinant human Src kinase. The final concentrations of the components of the conjugated enzyme system were as follows: 2.5 mM phosphoenolpyruvate, 200 μM NADH, 30 μg / ml pyruvate kinase and 10 μg / ml lactate dehydrogenase.

In a routine test, all components of the reaction mixture with the exception of ATP were pre-mixed and aliquoted into the wells of the test plate. Inhibitors dissolved in DMSO were added to the wells until a final DMSO concentration of 2.5% was obtained. The plate was incubated at 30 ° C for 10 minutes, after which the reaction was initiated by the addition of 100 μM ATP. On a tablet reader, a temporal change in absorbance at 340 nm was recorded, i.e. speed reaction. The obtained velocity data as a function of inhibitor concentration were consistent with a comparative model of the kinetics of inhibition to obtain Ki values for the compound.

The following compounds had Ki values <100 nM for Src: IIa-8, IIa-21, IIa-23, IIa-24, IIa-27, IIa-28, IIa-30 - IIa-33, IIb-1, IIb-4 IIb-5, IIc-3, IIc-8, IIc-10, IIc-13, IIc-15, IIc-18, IIc-19, IIc-21 - IIc-24, IIc-31 - IIc-35, IIc -37 - IIc-39, IIc-41 - IIc-44, IIc-51, IId-1, IId-2, IIIa-1, IIIa-6 - IIIa-8, IIIa-26 - IIIa-30 and IIIc-1 - IIIc-5.

The following compounds had K _i values between 100 nM and 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 - IIa-42, IIa-46, IIa- 47, IIa-49 - 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 - IIc-7, IIc-9, IIc-11, IIc-12, IIc-14, IIc-16, IIc-17, IIc-20, IIc- 25 - IIc-30, IIc-36, IIc-40, IIc-46 - IIc-50, IIc-52 - IIc-61, IIc-63 - IIc-65, IIc-67, IIc-69, IId-3, IIIa-2 - IIIa-5, IIIa-11, IIIa-14 - IIIa-18, IIIa-22 - IIIa-24, IIIa-31, IIIa-33, IIIa-35, IIIa-38 - IIIa-43 and IIIa- 47.

The following compounds had K _i values between 1 μM and 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.

A number of embodiments of the present invention have been presented above, but it is obvious that the basic structure can be modified to give other options that use the compounds and methods of the present invention. Therefore, it is understood that the scope of the present invention is determined by the appended claims, and not by the specific variations that are presented by way of example.

Claims (25)

1. The compound of formula IIa

or a pharmaceutically acceptable salt thereof, where R ^x and R ^{y are} combined together with their intermediate atoms to form a benzene or cyclohexyl ring optionally substituted with R ³ ; R ¹ represents T- (ring D); ring D is phenyl optionally substituted with 1-2 R ⁵ groups, or naphthyl, or imidazolyl, or benzimidazolyl optionally substituted with a C ₁ -C ₆ alkyl group; T is a bond; R ² represents hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; R ^{2 ′} represents hydrogen; or R ² and R ^{2 ′ are} combined together with their intermediate atoms to form a phenyl ring; R ^{3 is} selected from C ₁ -C ₆ alkyl, hydrogen, halogen, —OH, —NH ₂ , —NHOH, —NO ₂ , C ₁ -C ₆ alkoxy, optionally substituted with —N (R ⁴ ) ₂ ; each R ^{4 is} independently selected from C ₁ -C ₆ alkyl, —CO ₂ C ₁ -C ₆ alkyl, or two R ⁴ at the same nitrogen atom are joined together by a nitrogen atom to form a morpholine ring; each R ⁵ represents one or two substituents independently selected from C ₁ -C ₆ alkyl, halogen, —OH, —NH ₂ , —CF ₃ , C ₁ —C ₆ alkoxy, —COOH, —CO ₂ C ₁ —C ₆ alkyl, -NHCO-C ₁ -C ₆ aliphatic group, -NHCO (C ₁ -C ₆ alkyl) N (R ⁴ ) ₂ , -CONHC ₁ -C ₆ alkyl, -CONH (C ₁ -C ₆ alkyl) N (R ⁴ ) ₂ and —NHSO ₂ C ₁ -C ₆ alkyl. 2. The compound according to claim 1, where the specified connection has one or more characteristics selected from the following: (a) R ^x and R ^{y are} combined together with their intermediate atoms to form a benzene or cyclohexyl ring optionally substituted with R ³ ; (b) R ¹ represents T- (ring D); (c) Ring D is phenyl optionally substituted with 1-2 R ⁵ groups, or naphthyl, or imidazolyl, or benzimidazolyl optionally substituted with a C ₁ -C ₆ alkyl group; (d) R ² represents hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; (e) R ^{3 is} selected from C ₁ -C ₆ alkyl, halogen, —OH or C ₁ -C ₆ alkoxy optionally substituted with —N (R) ₂ . 3. The compound according to claim 2, where (a) R ^x and R ^{y are} combined together with their intermediate atoms to form a benzene or cyclohexyl ring optionally substituted with R ³ ; (b) R ¹ represents T- (ring D); (c) Ring D is phenyl optionally substituted with 1-2 R ⁵ groups, or naphthyl, or imidazolyl, or benzimidazolyl optionally substituted with a C ₁ -C ₆ alkyl group; (d) R ² represents C ₁ -C ₆ alkyl; (e) R ^{3 is} selected from C ₁ -C ₆ alkyl, halogen, —OH or C ₁ -C ₆ alkoxy optionally substituted with —N (R ⁴ ) ₂ . 4. The compound according to claim 2, where the specified connection has one or more characteristics selected from the following: (a) R ^x and R ^y are taken together with each other to form a benzene ring; (b) R ¹ represents T- (ring D); (c) Ring D is phenyl optionally substituted with 1-2 R ⁵ groups, or naphthyl, or imidazolyl, or benzimidazolyl optionally substituted with a C ₁ -C ₆ alkyl group; (d) R ² represents hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; 5. The compound according to claim 4, where (a) R ^x and R ^y are taken together with each other to form a benzene ring; (b) R ¹ represents T- (ring D); (c) Ring D is phenyl optionally substituted with 1-2 R ⁵ groups, or naphthyl, or imidazolyl, or benzimidazolyl optionally substituted with a C ₁ -C ₆ alkyl group; (d) R is C ₁ -C ₆ alkyl. 6. A compound selected from the group including (5-Methyl-2H-pyrazol-3-yl) - (2-phenylsulfanylquinazolin-4-yl) amine; [2- (4-Chlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2,4-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Methoxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2-Ethylphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; {2- [2,4-Bis (trifluoromethyl) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2-Chlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2,3-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (3-Chlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (1-Methylimidazol-2-ylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2-Hydroxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2,4-Difluorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (3,4-Dimethoxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (3-Methylphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2-Methoxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2-Naphthalenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2,6-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (3,4-Dichlorophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (Benzimidazol-2-ylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (2-Aminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenylsulfanylquinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxycarbonylphenylsulfanyl) quinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methylphenylsulfanyl) quinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-methoxyphenylsulfanyl) quinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dimethoxyphenylsulfanyl) quinazolin-4-yl) amine; [2- (3-Carboxyphenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalene-2-ylsulfanyl) quinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,4-difluorophenylsulfanyl) quinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-ylsulfanyl) -5,6,7,8-tetrahydroquinazolin-4-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,3-dichlorophenylsulfanyl) quinazolin-4-yl) amine; [2- (3-Chlorophenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine; [2- (2-Chlorophenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dimethylphenylsulfanyl) quinazolin-4-yl) amine; [2- (Benzimidazol-2-ylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methoxycarbonylphenylsulfanyl) quinazolin-4-yl) amine; [2- (4-Acetamidophenylsulfanyl) quinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalen-1-ylsulfanyl) quinazolin-4-yl) amine; [2- (4-Acetamidophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Methanesulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7-methoxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -8- (3-morpholin-4-yl-propoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Methoxycarbonylphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Carboxyphenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -8-methoxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7- (3-morpholin-4-ylpropoxy) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Bromophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (3-Bromophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Isopropanesulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Isobutyrylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; (5-Methyl-2H-pyrazol-3-yl) - [2- (4-propionylaminophenylsulfanyl) quinazolin-4-yl] amine; [2- (4-Cyclopropanecarbonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -8-hydroxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7-nitroquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (propan-1-sulfonylamino) phenylsulfanyl] quinazolin-4-yl} amine; [2- (4-Ethylsulfonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7-hydroxyaminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Isobutanecarbonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-tert-Butoxycarbonylaminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7-aminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (2-morpholin-4-ylacetylamino) phenylsulfanyl] quinazolin-4-yl} amine; (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methylsulfonylaminophenylsulfanyl) quinazolin-4-yl) amine; [2- (4-Aminophenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) quinazolin-4-yl] - (2H-pyrazol-3-yl) amine; (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (4-morpholin-4-yl-butyrylamino) phenylsulfanyl] quinazolin-4-yl} amine; (5-Methyl-2H-pyrazol-3-yl) - {2- [4- (2-morpholin-4-yl-ethylcarbamoyl) phenylsulfanyl] quinazolin-4-yl} amine; [8-Methoxy-2- (4-methylsulfonylaminophenylsulfanyl) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; {2- [4- (2-Dimethylaminoethylcarbamoyl) phenylsulfanyl] -quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine; {2- [4- (2-Dimethylaminoacetylamino) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine; [8-Hydroxy-2- (4-methylsulfonylaminophenylsulfanyl) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; {2- [4- (3-Dimethylaminopropylcarbamoyl) phenylsulfanyl] -quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine; {2- [4- (3-Dimethylaminopropionylamino) phenylsulfanyl] -quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -8-methoxyquinazolin-4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -8- (3-dimethylaminopropoxy) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7-hydroxyquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -7- (3-dimethylaminopropoxy) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine; (2- {4- [2- (tert-Butoxycarbonylmethylamino) acetylamino] phenylsulfanyl} quinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine; {2- [4- (2-Methylaminoacetylamino) phenylsulfanyl] quinazolin-4-yl} - (5-methyl-2H-pyrazol-3-yl) amine; [2- (4-Acetamidophenylsulfanyl) -8-fluoroquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine; (1H-Indazol-3-yl) - (2-phenylsulfanylquinazolin-4-yl) amine. 7. The compound according to claims 1-6 to obtain a pharmaceutical composition for inhibiting the activity of a protein kinase selected from AURORA-2, GSK-3, CDK-2 and Src. 8. A pharmaceutical composition for inhibiting the activity of a protein kinase selected from AURORA-2, GSK-3, CDK-2 and Src, containing the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 9. A method of inhibiting the activity of a protein kinase, such as AURORA-2, GSK-3, CDK-2 or Src, in a biological sample, comprising contacting said biological sample with a compound according to any one of claims 1 to 6, taken in free form or in the composition according to claim 8. 10. The method according to claim 9, inhibition of the activity of AURORA-2. 11. The method according to claim 9, inhibition of GSK-3 activity. 12. The method according to claim 9, inhibition of the activity of CDK-2. 13. The method according to claim 9, inhibition of Src activity. 14. A method of treating Aurora-2-mediated disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a composition of claim 8. 15. The method according to 14, in which the specified disease is selected from cancer of the colon, breast, stomach or ovary. 16. The method according to clause 15, which also includes the introduction of an additional drug. 17. The method according to clause 16, in which the specified additional drug is a chemotherapeutic agent. 18. A method of treating a GSK-3-mediated disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a composition of claim 8. 19. The method of claim 18, wherein said GSK-3-mediated disease is selected from diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia hypertrophy of the heart muscle; reperfusion with ischemia and alopecia. 20. The method of claim 19, wherein said GSK-3-mediated disease is diabetes. 21. A method of enhancing glycogen synthesis or lowering blood glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition of claim 8. 22. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 8. 23. A method of inhibiting β-catenin phosphorylation, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 8. 24. A method of treating a CDK-2-mediated disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a composition of claim 8. 25. A method of treating an Src-mediated disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a composition of claim 8.