RU2340611C2 - Pyrazole derivatives applied as protein kinase inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II

or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R², R^2', R^x and R^y are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R² and R^2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and R^x and R^y, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Description

This application claims priority for provisional patent application US 60/232795, filed September 15, 2000, provisional patent application US 60/257887, filed December 21, 2000, and provisional patent application US 60/286949, filed 27 April 2001, the contents of which are incorporated herein 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 the protein kinases GSK-3 and Aurora-2. The invention also relates to methods of treatment associated with said protein kinases of diseases such as diabetes, cancer and Alzheimer's disease.

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 cell cycle regulation.

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 malignant tumors in humans, 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 rate-limiting enzyme necessary for glycogen synthesis, the 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 are involved with GSK-3 in many aspects of cell metabolism, proliferation, differentiation, and cell development.

In a GSK-3 mediated pathway suitable for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this path, 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, which can ultimately lead to cardiovascular disease, renal 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 live-bearing 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, interest is now being shown 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 was 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 report that p38 kinase is an integral part of the transmission path of an insulin-induced signal that regulates glycogen synthesis or glucose uptake. Therefore, p38 inhibition, unlike GSK-3, is not expected to improve glycogen synthesis and / or glucose uptake.

The need to search for new drugs for the treatment of human diseases remains. 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, diabetes, Alzheimer's disease and other diseases.

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 as Aurora-2 and GSK-3 protein kinase inhibitors. Compounds having the general formula I are provided:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ -Z ⁴ are as described below;

ring A is selected from the group including:

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from -R ¹ , any substitutable non-ortho position in ring C is independently substituted by -R ⁵ and two adjacent substituents on ring C are optionally combined with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen sulfur or nitrogen, wherein said fused ring is optionally substituted with a halogen, oxo group or —R ⁸ radical;

ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl rings, where the heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur where ring D is substituted on any substituted ring carbon with an oxo group or —R ⁵ group and on any substituted ring nitrogen by —R ⁴ group, provided that when ring D is a six-membered aryl or heteroaryl group a face, —R ⁵ represents hydrogen at each ortho position of the ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, each phenyl, heteroaryl and heterocyclyl ring being indicated optionally substituted with up to three groups selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and a neighboring substituent combined with their intermediate atoms, form the specified ring, condensed noe with ring C;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in said condensed ring formed by R ^x and R ^y radicals is substituted by oxo or T-R ³ and any substituted nitrogen atom in said ring formed by R ^x and R ^y radical is substituted by R ⁴ ;

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

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, where any substitutable carbon atom in said condensed ring formed by R ² and R ^{2 ′} is substituted with halogen, oxo, —CN, NO ₂ , —R ⁷ or VR ⁶ , and any substitutable nitrogen in said ring formed by the radicals R ² and R ^{2 ′} , is 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 (optionally substituted 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 (C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ^7, or two R ⁴ radicals ^on the same atom nitrogen, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are combined with a 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;

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ ; and

R ^{9 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 should be used, unless otherwise indicated, the following definitions of the terms used. The phrase “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 or 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, whether 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-containing ring. The term “heterocycle”, “heterocyclyl” or “heterocyclic”, whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term “heteroaryl”, used alone or as part of 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, 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, indolyl, quinolinyl, benzotriazolyl, benzothiazazol Ben zimidazolyl, 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 by Ph, -O (Ph) substituted

—O (Ph), —CH ₂ (Ph) substituted with —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 ^o CO ₂ R ^o , -NR ° NR ° C (O) R °, -NR ° NR ° C (O) N (R °) ₂ , -NR ° NR ° CO ₂ R ^o ,

-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 ^o , -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 R ° represents hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph) substituted by Ph, -O ( Ph) substituted with —O (Ph), —CH ₂ (Ph), or substituted with —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 R ⁺ represents hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph) substituted by Ph, —O (Ph) substituted by —O (Ph), —CH ₂ (Ph) substituted with —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 “linker” means an organic moiety that joins two parts of a compound. Linkers usually consist of an atom, such as an oxygen atom or a sulfur atom, a link 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 linker is usually in the range of about 14-200, preferably 14-96, with a length of up to about six atoms. Examples of linking groups 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 are as 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, single stereochemical isomers, as well as enantiomeric and distereomeric 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.

Compounds of the formula I or their salts can be formulated. A pharmaceutical composition is preferred. In one embodiment, the composition comprises an amount of a protein kinase inhibitor effective to inhibit a protein kinase, in particular GSK-3, in a biological sample or in a patient. In another embodiment, the compounds of the present invention and their pharmaceutical compositions that contain an amount of a protein kinase inhibitor effective for treating or preventing a GSK-3-mediated condition, and a pharmaceutically acceptable carrier, excipient or excipient, may be formulated for administration to a patient .

The term “GSK-3-mediated condition” or “disease” 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 object of the present invention is a method of enhancing glycogen synthesis and / or lowering blood glucose in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. This method is especially useful for 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 object of the present invention is a method of inhibiting the activity of GSK-3 in a biological sample, which comprises contacting the biological sample with a GSK-3 inhibitor of formula I.

Another object of the present invention is a method of inhibiting the activity of Aurora-2 in a patient, which comprises administering to the patient a compound of formula I or a composition containing said compound.

Another object of the present invention is a method of treating or preventing Aurora-2-mediated disease with an Aurora-2 inhibitor, which 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 condition” or “disease” 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 condition" or "disease" also means those diseases or conditions that facilitate treatment with an Aurora-2 inhibitor. Such conditions include, but are not limited to, cancer. The term "cancer" covers, but is not limited to, the following types of cancer: colon cancer and ovarian cancer.

Another object of the present invention is a method of inhibiting the activity of Aurora-2 in a biological sample, which comprises contacting the biological sample with an Aurora-2 inhibitor of formula I or a composition containing it. Another object of the present invention is a method of treating or preventing CDK-2-mediated disease with a CDK-2 inhibitor, which 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 "CDK-2-mediated condition" or "disease" 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 condition" or "disease" 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. Qpin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, M.D., Current Opinion in Qncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-59 (2000).

Another object of the present invention is a method of inhibiting the activity of CDK-2 in a biological sample or in a patient, which comprises administering to the patient a compound of formula I or a composition containing said compound.

Another object of the present invention is a method of treating or preventing ERK-2-mediated diseases by an ERK-2 inhibitor, which 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 "ERK-2-mediated condition" when used in this description means any painful condition or other worsened condition, in which, as you know, plays the role of ERK-2. The term "ERK-2-mediated condition" or "disease" 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 throat (mouth), 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 object of the present invention is a method of inhibiting the activity of ERK-2 in a biological sample or in a patient, which comprises administering to the patient a compound of formula I or a composition containing said compound.

Another object of the present invention is a method of treating or preventing AKT-mediated disease with an AKT inhibitor, which 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 "ACT-mediated condition" when used in this description means any painful condition or other worsened condition in which, as you know, plays the role of ACT. The term "ACT-mediated condition" or "disease" 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 object of the present invention is a method of inhibiting AKT activity in a biological sample or in a patient, which comprises administering to a patient a compound of formula I or a composition containing said compound.

Another object of the present invention is a method of treating or preventing Src-mediated disease with an Src inhibitor, which 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 “Scr-mediated condition,” as used herein, means any disease state or other worsened condition in which Src is known to play a role. The term "Src-mediated condition" or "disease" also means those diseases or conditions that facilitate treatment with an Src inhibitor. Such conditions include, but are not limited to, hypercalcemia, osteoporosis, osteoarthritis, 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 object of the present invention is a method of inhibiting Src activity in a biological sample or in a patient, which comprises administering to the 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 (s) can be administered to a patient together with a compound of the present invention and which (s) does not interfere with the pharmacological activity of said compound.

The term “patient” encompasses human and veterinary subjects.

The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof, preparations of an enzyme suitable for in vitro 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 protein kinase, for example, GSK-3 and Aurora-2, 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 include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffers 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, colloid nd silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The compositions of the present invention 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 fillers and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. 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 prepared by mixing the active ingredient with a suitable non-irritant excipient 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. 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 may be prepared 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 benzalkonium 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 treating and preventing 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 sites (e.g., brain or lymphatic system) relative to other starting species of the 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 and sulfonate esters.

Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, 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 derived from 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 so 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 understood that the specific dose and treatment regimen of 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 the assessment of the attending 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 diabetes with the GSK-3 inhibitors of the present invention for treating diabetes, other antidiabetic agents may be combined. Such agents include, but are not limited to, insulin or insulin analogues in the form for injection or for inhalation, glitazones, alpha glucosidase inhibitors, biguanides, insulin and sulfonylureas sensitizers.

Other examples of agents with which the inhibitors of the present invention can also be combined include, but are not limited to, chemotherapeutic agents or other antiproliferative agents such as adrimycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons and platinum derivatives; 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, as in tautomers 1 and 2 shown below. Unless otherwise indicated, the presentation of one tautomer implies the inclusion of another.

R ^x and R ^y (at positions Z ³ and Z ^4, respectively) 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 5-, 6-, 7- or an 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R ^x —R ^y ring is optionally substituted. Examples of ring A systems in compounds IA - I-DD are shown below, where Z ¹ is nitrogen or C (R ⁹ ) and Z ² is nitrogen or C (H).

Preferred ring A bicyclic systems include IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL and IM, more preferably IA, IB, IC, IF and IH and most preferably IA, IB and IH.

In a ring A monocyclic system, preferred R ^x groups, when present, include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred R ^y groups when present include TR ³ , where T is a bond or methylene, and R ³ is —R, —N (R ⁴ ) _2, or —OR. Examples of a preferred R ^y group include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen substituted phenyl, and methoxymethyl.

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, —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 , 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, or —N (R ⁴ ) ₂ , where R is 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, R ² groups include hydrogen, C _1-4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl 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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-l-yl). Preferred R ^{2 ′} is hydrogen.

An option that is especially useful for the treatment of GSK-3-mediated diseases relates to compounds of formula II:

or their pharmaceutically acceptable derivatives or prodrugs, where:

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from —R ¹ , any substitutable non-aorto position in the ring C independently substituted with -R ^5, and two adjacent substituents on the ring C optionally combined together with their intervening atoms to form a fused saturated, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen , Sulfur or nitrogen, said fused ring is optionally substituted by halogen, oxo, or -R ⁸ radical;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, wherein said phenyl, heteroaryl and heterocyclyl rings are optionally each substituted with up to three groups each selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and adjacent Deputy, combined with their intermediate a ohms, form said ring fused to Ring C;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in said condensed ring formed by R ^x and R ^y radicals is substituted by oxo or T-R ³ and any substituted nitrogen atom in said ring formed by R ^x and R ^y radical is substituted by R ⁴ ;

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

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, where any substitutable carbon atom in said condensed ring formed by R ² and R ^{2 ′} is substituted with halogen, oxo, —CN, NO ₂ , —R ⁷ or VR ⁶ , and any substitutable nitrogen in said ring formed by the radicals R ² and R ^{2 ′} , is 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 (optionally substituted 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, or two R ⁴ radicals ^on the same the nitrogen atoms, taken together with each other, form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are combined with a 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

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ .

When the R ^x and R ^y groups in Formula II, taken together to form a fused ring, preferred R ^x —R ^y rings include a 5-, 6-, 7-, or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R ^x —R ^y ring is optionally substituted. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula II are mono- or bicyclic systems shown below.

More preferred pyrimidine ring systems of formula II include II-A, II-B, II-C, II-F and II-H, most preferably II-A, II-B and II-H.

In the monocyclic pyrimidine ring system of formula II, preferred R ^x groups include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred R ^y groups include TR ³ , where T is a bond or methylene, and R ³ is —R,

-N (R ⁴ ) ₂ or -OR. When R ³ is —R or —OR, a preferred R is an optionally substituted group selected from a C _1-6 aliphatic group, phenyl or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of a preferred R ^y group include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula II, the ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —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 , 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, or —N (R ⁴ ) ₂ , where R is optional substituted C _1-6 aliphatic group.

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

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula II 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), wherein (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 II is monocyclic, preferred R ² groups include hydrogen, a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include methyl, tert-butyl, —CH ₂ OCH ₃ , cyclopropyl, furanyl, thienyl and phenyl. A preferred R ^{2 ′} group is hydrogen.

More preferred ring systems of formula II are the following systems, which may be substituted as described above, where R ² and R ^{2 ′} taken together with the pyrazole ring form an indazole ring, and R ^x and R ^y represent each methyl, or R ^x and R ^y taken together with the pyrimidine ring form a quinazoline or tetrahydroquinazoline ring:

Particularly preferred are those compounds of formula II-Aa, II-Ba or II-Ha in which ring C is a phenyl ring and R ¹ is halogen, methyl or trifluoromethyl.

Preferred groups for ring C in formula II are phenyl and pyridinyl. When two adjacent substituents in ring C are taken together to form a fused ring, ring C is a bicyclic ring system. Preferred fused rings include a benzene or pyridine ring. Such rings are preferably fused at the ortho and meta positions of ring C. Examples of preferred bicyclic systems for ring C include naphthyl, quinolinyl and isoquinolinyl.

An important feature of the compounds of formula II is the ortho substituent R ¹ in ring C. The ortho position in ring C or ring D is relative to the position where ring A is attached. Preferred groups include halogen, an optionally substituted C _1-6 aliphatic group, phenyl COR ⁶ , -OR ⁶ , -CN,

—SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , —CONH ₂ , —NHCOR ⁶ , —OC (O) NH _2, or

-NHSO ₂ R ⁶ . When R ¹ is optionally substituted

C _1-6 aliphatic group, most preferred optional substituents are halogens. Examples of preferred R ¹ groups include —CF ₃ , —Cl, —F, —CN, COCH ₃ , —OCH ₃ , —OH, —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₃ , —CF ₂ CH ₃ , cyclohexyl, tert-butyl, isopropyl, cyclopropyl, —C≡, —C≡CH ₃ , —SO ₂ CH ₃ , —SO ₂ NH ₂ , —N (CH ₃ ) ₂ , —CO ₂ CH ₃ , —CONH ₂ , -NHCOCH ₃ , -OC (O) NH ₂ , -NHSO ₂ CH ₃ and -OCF ₃ .

In ring C of formula II, preferred R ⁵ substituents, when present, 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, —SO ₂ N (R ⁴ ) _2, and —N (R ⁴ ) SO ₂ R. More preferred R ⁵ substituents include —Cl, -F, -CN, -CF ₃ , -NH ₂ , NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _{1- 4 an} aliphatic group and —CO ₂ (C _1-4 aliphatic group). Examples of such preferred substituents include —Cl, —F, —CN, —CF ₃ , —NH ₂ , —NHMe, —NMe ₂ , —OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, and —CO ₂ Et.

Preferred compounds of formula II have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring;

(b) R ^x represents hydrogen or a C _1-4 aliphatic group and R ^y represents T-R ³ , or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated a ring having 0-2 ring nitrogen atoms;

(c) R ¹ is halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , -CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; and

(d) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula II have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with —R ⁵ , wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R ^x represents hydrogen or methyl and R ^y represents —R, N (R ⁴ ) ₂ or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a 5-7 membered unsaturated or partially an unsaturated carbocyclic ring optionally substituted with —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 ;

(c) R ¹ represents a halogen, C _1-6 halogen-aliphatic group, C _1-6 aliphatic group, phenyl or —CN;

(d) R ^{2 '} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group, or R ² and R ^2' are taken together with their intermediate atoms to form substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(e) each R ^{5 is} independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula II have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl ring optionally substituted with —R ⁵ ;

(b) R ^x is hydrogen or methyl, and R ^y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl , or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted benzene ring or a partially unsaturated 6-membered carbocyclic ring;

(c) R ¹ is halogen, a C _1-4 aliphatic group optionally substituted with halogen, or —CN;

(d) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or —CO (C _1-4 alkyl), wherein (C _1-4 alkyl) represents an unbranched, branched or cyclic alkyl group; and

(e) each R ^{5 is} independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ ,

-O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group).

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

Table 1

In another embodiment, the present invention provides a composition comprising a compound of formula II and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula II.

Another object of the present invention is a method of treating a disease that facilitates treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula II.

Another object of the present invention is 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 composition containing a compound of formula II. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula II. This method is especially useful for stopping or slowing down the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula II. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of Aurora protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula II.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula II. This method is especially useful for treating cancer, such as colon cancer, ovarian cancer, and lung cancer.

One object of the present invention is a method of inhibiting the activity of CDK-2 protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula II.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula II. This method is especially useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising contacting the biological sample with a GSK-3, Aurora or CDK-2 inhibitor of formula II or with a pharmaceutical composition containing it in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

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

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur, where ring D is substituted on any substituted ring carbon with an oxo group or group

—R ⁵ and for any substitutable ring nitrogen with a —R ⁴ group, provided that when ring D is a six-membered aryl or heteroaryl ring, —R ⁵ is hydrogen at each ortho position of ring D;

R ^x and R ^y taken together with their intermediate atoms form a fused benzene ring or a 5-8 membered carbocyclic ring, where any substituted carbon atom in said fused ring formed by R ^x and R ^y radicals is substituted by an oxo group or a T- group R ³ ;

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

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, where any substituted carbon atom in said condensed ring formed by the radicals R ² and R ^{2 ′} is substituted with halogen, oxo group, —CN, —NO ₂ ,

—R ⁷ or —VR ⁶ and any substitutable nitrogen atom in said ring formed by R ² and R ^{2 ′} is substituted with R ⁴ ;

R ^{3 is} selected from —R, halogen, = O, —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 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 ;

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 (optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ^7, or two R ⁴ at the same nitrogen atoms taken together with each other form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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-O-, -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 are 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 monocyclic rings for ring D in formula III include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. When two adjacent substituents in ring D are taken together to form a fused ring, ring system D is bicyclic. Preferred bicyclic rings for ring D in formula III include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic ring D systems include naphthyl and isoquinolinyl.

Preferred R ⁵ substituents ^on ring D of formula III include halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or a C _1-6 aliphatic group. More preferred R ⁵ substituents include halogen, —CN,

-oxo, -SR, -OR, -N (R ⁴ ) ₂ , -C (O) R or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic group . Examples of substituents on ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

Preferred rings formed when R ^x and R ^y taken together form a fused ring include a 5-, 6- or 7-membered unsaturated or partially unsaturated carbocyclic ring, wherein any substitutable carbon atom in a given fused ring is substituted with an oxo group or T group -R ³ . Examples of preferred bicyclic ring systems are shown below:

Preferred substituents on the fused ring R ^x —R ^y in formula III include —R, oxo, 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 , where R and R ⁴ are as defined above. More preferred substituents on the fused ring R ^x —R ^y include halogen, —CN, oxo, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mono or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy or 5-6 membered heteroaryl. Examples of such preferred substituents include methoxy, methyl, isopropyl, methylsulfonyl, cyano, chloro, pyrrolyl, methoxy, ethoxy, ethylamino, acetyl and acetamido.

Preferred R ² substituents in formula III include hydrogen, a C _1-4 aliphatic group, an alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylalkyl and (N) . 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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-l-yl).

When the R ² and R ^{2 ′} groups taken together in Formula III form a ring, preferred R ² -R ^{2 ′} ring systems containing a pyrazole ring include benzo, pyrido, pyrimido, 3-oxo-2H-pyridazino and partially unsaturated 6 membered carbocyclic ring. Examples of these preferred R ² -R ^{2 ′} ring systems containing a pyrazole ring include:

Preferred substituents on the fused ring R ² —R ^{2 ′} in formula III 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), wherein (C _1-4 alkyl) represents an unbranched, branched or cyclic alkyl group. Preferably, the C _1-4 alkyl group is methyl.

Preferred compounds of formula III have one or more, and more preferably, all features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2 , 3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x and R ^y taken together with their intermediate atoms form an optionally substituted benzene ring or a 5-7 membered carbocyclic ring; and

(c) R ^{2 ′} is hydrogen or methyl and R ² is T-WR ⁶ or R, where W is —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ N (R ⁶ ) - , -CO-, -CO ₂ -, -C (R ⁶ ) ОС (О) -, -С (R ⁶ ) ₂ N (R ⁶ ) СО-, -С (R ⁶ ) ₂ N (R ⁶ ) С (O) O- or —CON (R ⁶ ) - and R is an optionally substituted group selected from a C _1-6 aliphatic group or phenyl, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula III have one or more, and more preferably, all features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro -1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x and R ^y taken together with their intermediate atoms form a benzene ring or a 5-7 membered carbocyclic ring optionally substituted with a group —R, oxo, 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 ; and

(c) each R ^{5 is} independently selected from halogen, oxo, CN, NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups.

Even more preferred compounds of formula III have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^x and R ^y taken together with their intermediate atoms to form a benzene or 6-membered partially unsaturated carbocyclic ring optionally substituted with halogen, CN, oxo, C _1-6 alkyl, C _1-6 alkoxy, (C _{1- 6} alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy or 5-6 membered heteroaryl;

(b) each R ^{5 is} independently selected from halogen, —CN, oxo, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl C _6-10 aryl or C _1-6 aliphatic groups; and

(c) R ^{2 ′} is hydrogen or methyl and R ² is T-WR ⁶ or R, where W is —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ N (R ⁶ ) - , —CO—, —CO ₂ -, —C (R ⁶ ) OC (O) -, —C (R ⁶ ) ₂ N (R ⁶ ) CO— or —CON (R ⁶ ) -, and R is optional a substituted group selected from a C _1-6 aliphatic group or phenyl, or R ² and R ^{2 ′} , taken together with their intermediate atoms, form a benzene, pyridine or partially unsaturated 6-membered carbocyclic ring, optionally substituted with 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 or -CO (C _1-4 alkyl ), where (C _1-4 alkyl) is an unbranched, branched or cyclic alkyl group.

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

table 2

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

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another object of the present invention is a method of treating a disease that facilitates treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula III.

Another object of the present invention is 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 composition containing a compound of formula III. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula III. This method is especially useful for stopping or slowing down the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula III. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting Aurora protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for the treatment of cancer, such as colon cancer, and breast cancer.

One object of the present invention is a method of inhibiting CDK-2 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

One object of the present invention is a method of inhibiting Src activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Src protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for the treatment of hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis and Paget's disease.

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

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

Compounds of formula III wherein R ^{2 ′} is hydrogen and R ^x and R ^y taken together with the pyrimidine ring form an optionally substituted quinazoline ring system, are also ERK-2 and AKT protein kinase inhibitors.

Thus, another object of the present invention is a method of inhibiting the activity of ERK-2 protein kinase or ACT in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula III, where R ^{2 '} is hydrogen and R ^x and R ^y taken together with a pyrimidine ring form an optionally substituted quinazoline ring system.

Another object of the present invention is a method of treating a disease facilitated by treatment with an ERK-2 protein kinase inhibitor or ACT, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula III, where R ^{2 '} is hydrogen and R ^x and R ^y taken together with the pyrimidine ring form an optionally substituted quinazoline ring system. This method is especially useful for the treatment of cancer, shock, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, restenosis, psoriasis, allergic disorders, including asthma, inflammation and neurological disorders.

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where ring D is substituted on any substituted ring carbon with an oxo group or group

—R ⁵ and for any substitutable ring nitrogen with a —R ⁴ group, provided that when ring D is a six-membered aryl or heteroaryl ring, —R ⁵ is hydrogen at each ortho position of ring D;

R ^x and R ^{y are} independently selected from T-R ³ or R ^x and R ^y taken together with their intermediate atoms form a fused unsaturated or partially unsaturated 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in said condensed ring is optionally and independently substituted by a T-R ³ group, and any substituted nitrogen atom in said ring is substituted by R ⁴ ;

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

R ² and R ^{2 ′ are} independently selected from —R, -TWR ^6, or R ² and R ^{2 ′} taken together with their intermediate atoms form a fused 5-8 membered unsaturated or partially unsaturated ring having 0-3 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein said condensed ring is optionally substituted with up to three groups independently selected from halogen, oxo, —CN, —NO ₂ , —R ⁷ or —VR ⁶ ;

R ^{3 is} selected from —R, halogen, = O, —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 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 ;

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 (optionally substituted C _1-6 aliphatic group), —CON (R ⁷ ) _2, or —SO ₂ R ^7, or two R ⁴ at the same nitrogen atoms taken together with each other form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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-O-, -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 are 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 monocyclic rings for ring D in formula IV include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. Preferred bicyclic rings for ring D in formula IV include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic rings for ring D include naphthyl and isoquinolinyl.

Preferred substituents on ring D of formula IV include halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ),

—N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from 5- 6-membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. More preferred R ⁵ substituents include halogen, —CN,

-oxo, -SR, -OR, -N (R ⁴ ) ₂ , -C (O) R or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic group . Examples of substituents on ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

When the R ^x and R ^y groups in Formula IV taken together form a fused ring, preferred R ^x —R ^y rings include a 5-, 6-, 7-, or 8-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms. This gives a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula IV are mono- or bicyclic systems shown below.

More preferred pyrimidine ring systems of formula IV include IV-E, IV-G, IV-H, IV-J, IV-K, IV-L, IV-M, IV-T, and IV-U.

In the monocyclic pyrimidine ring system of formula IV, preferred R ^x groups include hydrogen, amino, nitro, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred R ^y groups include TR ³ , where T is a bond or methylene, and R ³ is —R, —N (R ⁴ ) _2, or —OR. When R ³ is —R or —OR, a preferred R is an optionally substituted group selected from a C _1-6 aliphatic group, phenyl or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of a preferred R ^y group include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl, methoxyphenyl, trimethoxyphenyl or halogen substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula IV, the ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —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 , where R and R ⁴ are as defined above for compounds of formula IV. Preferred substituents on the R ^x —R ^y ring include halogen, —R, —OR, —COR, —CO ₂ R, —CON (R ⁴ ) ₂ ,

—CN or —N (R ⁴ ) ₂ , where R is a substituted or unsubstituted C _1-6 aliphatic group.

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

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula IV 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), wherein (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 IV is monocyclic, preferred R ² groups include hydrogen, a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group. Examples of such preferred R ² groups include methyl, tert-butyl, —CH ₂ OCH ₃ , cyclopropyl, furanyl, thienyl and phenyl. A preferred R ^{2 ′} group is hydrogen.

Preferred compounds of formula IV have one or more, and more preferably all, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2 , 3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x represents hydrogen or a C _1-4 aliphatic group and R ^y represents T-R ³ or R ^x and R ^y taken together with their intermediate atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 heteroatoms; and

(c) R ^{2 ′} represents hydrogen or methyl, and R ² represents T-WR ⁶ or R, where W represents

-C (R ⁶ ) ₂ O-, -C (R ⁶ ) ₂ N (R ⁶ ) -, -CO-, -CO ₂ -, -C (R ⁶ ) OC (O) -, -C (R ⁶ ) ₂ N (R ⁶ ) CO—, —C (R ⁶ ) ₂ N (R ⁶ ) C (O) O— or —CON (R ⁶ ) -, and R is an optionally substituted group selected from C _{1- 6 of the} aliphatic group or phenyl, or R ² and R ^{2 '} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula IV have one or more, and more preferably all, features selected from the group consisting of: (a) ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1, 2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x is hydrogen or methyl and R ^y is —R, —N (R ⁴ ) ₂ or —OR or R ^x and R ^y are taken together with their intermediate atoms to form a 5-7 membered unsaturated or partially an unsaturated ring having 1-2 ring nitrogen atoms, said ring being an optionally substituted group —R, halogen, oxo, —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 ; and

(c) each R ^{5 is} independently selected from halogen, oxo, CN, NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , -N (R ⁴ ) SO ₂ R, -SR,

-OR, -C (O) R or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic group.

Even more preferred compounds of formula IV have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a 6-membered unsaturated or partially unsaturated ring with 1-2 ring nitrogen atoms, optionally substituted with halogen, CN, oxo, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy or 5-6 membered heteroaryl;

(b) each R ^{5 is} independently selected from halogen, —CN, oxo, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl C _6-10 aryl or C _1-6 aliphatic groups; and

(c) R ^{2 ′} is hydrogen and R ² is T-WR ⁶ or R, where W is —C (R ⁶ ) ₂ O—, —C (R ⁶ ) ₂ N (R ⁶ ) -, - CO—, —CO ₂ -, —C (R ⁶ ) OC (O) -, —C (R ⁶ ) ₂ N (R ⁶ ) CO— or —CON (R ⁶ ) -, and R is an optionally substituted group selected from a C _1-6 aliphatic group or phenyl, or R ² and R ^{2 ′} , taken together with their intermediate atoms to form a benzene, pyridine or partially unsaturated 6-membered carbocyclic ring optionally substituted with halogen, oxo, —N (R ⁴ ) ₂ , -C _1-4 alkyl, -C _1-4 halogenated, -NO ₂ , -O (C _1-4 alkyl), -CO ₂ (C _1-4 alkyl), -C N, -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 or —CO (C _1-4 alkyl), wherein (C _1-4 alkyl) represents an unbranched, branched or cyclic alkyl group.

Representative compounds of formula IV are shown in table 3 below.

Table 3

In another embodiment, the present invention provides a composition comprising a compound of formula IV and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula IV.

Another object of the present invention is a method of treating a disease facilitated by treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula IV.

Another object of the present invention is 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 composition containing a compound of formula IV. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula IV. This method is especially useful for stopping or slowing down the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula IV. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of Aurora protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula IV. Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for treating cancer, such as colon cancer, ovarian cancer, and breast cancer.

One object of the present invention is a method of inhibiting the activity of CDK-2 protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula IV.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula IV. This method is especially useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising contacting the biological sample with a GSK-3, Aurora or CDK-2 inhibitor of formula IV or with a pharmaceutical composition containing it in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

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

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents N, CR ^a or CH and Z ² represents N or CH, provided that one of Z ¹ and Z ² represents nitrogen;

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from —R ¹ , any substitutable non-ortho position in the C ring is independently substituted by the radical —R ⁵ , and two adjacent substituents on the C ring are optionally combined with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen a, sulfur or nitrogen, said condensed ring being optionally substituted with a halogen, oxo group or —R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted on any substituted ring carbon with an oxo group or an —R ⁵ group and on any substituted ring nitrogen by an —R ⁴ group, provided that when the D ring is six-membered aryl or heteroaryl nth ring, —R ⁵ represents hydrogen at each ortho position of ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, said phenyl, heteroaryl and heterocyclyl rings being optionally each substituted with up to three groups, independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and a neighboring substituent taken together with their intermediates atoms form the specified col tso condensed with ring C;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in the specified condensed ring formed by the radicals R ^x and R ^y is substituted by an oxo group or T-R ³ , and any substituted nitrogen atom in the specified ring formed by the radicals R ^x and R ^y is substituted by the radical R ⁴ ;

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

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, where any substituted carbon atom in said condensed ring formed by the radicals R ² and R ^{2 ′} is substituted with halogen, oxo group, —CN, NO ₂ , —R ⁷ or VR ^6, and any substituted nitrogen atom in said ring formed by the radicals R ² and R ^{2 ′} is 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 (optionally substituted 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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ ; and

R ^{a is} selected from 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, —OC (= O) N (R ⁴ ) _2, or an optionally substituted group selected from a C _1-6 aliphatic group With a _6-10 aryl group, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

The compounds of formula V can be represented with specific Z ¹ and Z ² as shown below:

When the R ^x and R ^y groups in Formula V are taken together to form a fused ring, preferred R ^x —R ^y rings include a 5-, 6-, 7-, or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said R ^x —R ^y ring is optionally substituted. This gives a bicyclic ring system containing a pyridine ring. Examples of preferred bicyclic ring systems of formula V are shown below.

More preferred bicyclic ring systems of formula V include Va-A, Vb-A, Vc-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, Va-E, Vb- E, Vc-E, Va-J, Vb-J, Vc-J, Va-K, Vb-K, Vc-K, Va-L, Vb-L, Vc-L, Va-M, Vb-M and Vc-M, most preferably Va-A, Vb-A, Vc-A, Va-B, Vb-B and Vc-B.

In the monocyclic pyridine ring system of formula V, preferred R ^x groups include hydrogen, alkyl or dialkylamino, acetamido or a C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred R ^y groups include TR ³ , where T is a bond or methylene, and R ³ is —R,

-N (R ⁴ ) ₂ or -OR. When R ³ is —R or —OR, a preferred R is an optionally substituted group selected from a C _1-6 aliphatic group, phenyl or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of a preferred R ^y group include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula V, the ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —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 , 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, or —N (R ⁴ ) ₂ , where R is optional substituted C _1-6 aliphatic group.

The groups R ² and R ^{2 ′ of} formula V can be taken together with each other 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. Examples of these fused rings are presented in the following compounds of formula V having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′ of} formula V 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), wherein (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 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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-l-yl). Preferred R ^{2 ′} is hydrogen.

More preferred ring systems of Formula V are the following systems, which may be substituted as described above, where R ² and R ^{2 ′} taken together with the pyrazole ring form an optionally substituted indazole ring, and R ^x and R ^y represent each methyl or R ^x and R ^y taken together with the pyridine ring form an optionally substituted quinoline, isoquinoline, tetrahydroquinoline or tetrahydroisoquinoline ring:

When G is ring C, phenyl and pyridinyl are preferred groups for ring C in formula V. When two adjacent substituents in ring C are taken together to form a fused ring, ring C is a bicyclic ring system. Preferred fused rings include a benzene or pyridine ring.

Such rings are preferably fused at the ortho and meta positions of ring C. Examples of preferred bicyclic systems for ring C include naphthyl and isoquinolinyl. Preferred R ¹ groups include halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN,

—SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , —CONH ₂ , —NHCOR ⁶ , —OC (O) NH _2, or

-NHSO ₂ R ⁶ .

When R ¹ is optionally substituted

C _1-6 aliphatic group, most preferred optional substituents are halogens. Examples of preferred R ¹ groups include —CF ₃ , —Cl, —F, —CN, COCH ₃ , —OCH ₃ , —OH, —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₃ , —CF ₂ CH ₃ , cyclohexyl, tert-butyl, isopropyl, cyclopropyl, —C≡, —C≡CH ₃ , —SO ₂ CH ₃ , —SO ₂ NH ₂ , —N (CH ₃ ) ₂ , —CO ₂ CH ₃ , —CONH ₂ , -NHCOCH ₃ , -OC (O) NH ₂ , -NHSO ₂ CH ₃ and -OCF ₃ .

In ring C, preferred R ⁵ substituents, when present, 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, —SO ₂ N (R ⁴ ) _2, and —N (R ⁴ ) SO ₂ R. More preferred R ⁵ substituents include —Cl, —F , -CN, -CF ₃ ,

-NH ₂ , NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _{1 -4} aliphatic group). Examples of such preferred substituents include —Cl, —F, —CN, —CF ₃ , —NH ₂ , —NHMe, —NMe ₂ ,

—OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl and —CO ₂ Et.

When G is Ring D, preferred monocyclic rings for Ring D in Formula V include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. When two adjacent substituents in ring D are taken together to form a fused ring, ring system D is bicyclic. Preferred bicyclic rings for ring D in Formula V include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on ring D of formula V include one or more of the following substituents: halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. More preferred substituents for ring D include halogen, —CN, —oxy, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. Examples of substituents for ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

Preferred compounds of formula V have one or more, and more preferably all, of the features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents on it form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring, and R ¹ represents a halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3 a dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x represents hydrogen or a C _1-4 aliphatic group and R ^y represents T-R ³ , or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated a ring having 0-2 ring nitrogen atoms; and

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula V have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-6} haloaliphatic group, a C _1-6 aliphatic group, phenyl or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro -1H-iso-indolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x represents hydrogen or methyl and R ^y represents —R, N (R ⁴ ) ₂ or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form partially benzene or 5-7 membered an unsaturated carbocyclic ring optionally substituted with —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 ;

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) _2, or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula V have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{1-4 an} aliphatic group optionally substituted with halogen, or

-CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl or naphthyl ;

(b) R ^x is hydrogen or methyl and R ^y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, or R ^x and R ^y are taken together with their intermediate atoms to form a benzene ring or a 6-membered partially unsaturated carbocyclic ring optionally substituted with halogen, CN, oxo, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylamino carbonyl, mono- or dialkilaminokarboniloksi or 5-6 membered heteroaryl;

(c) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or -CO (C _{1- 4 by} alkyl), where (C _1-4 alkyl) is an unbranched, branched or cyclic alkyl group; and

(d) Ring D is a substituted oxo group or R ⁵ , where each R ^{5 is} independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group).

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

Table 4

In another embodiment, the present invention provides a composition comprising a compound of formula V and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula V.

Another object of the present invention is a method of treating a disease facilitated by treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula V.

Another object of the present invention is 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 composition containing a compound of formula V. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula V. This method is particularly useful for stopping or slowing the progression of Alzheimer's disease.

Another object of the present invention is a method of inhibiting phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula V. This method is particularly useful for treating schizophrenia.

One object of the present invention is a method of inhibiting the activity of Aurora protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula V.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula V. This method is particularly useful for treating cancer, such as colon cancer, cancer ovary and breast cancer. One object of the present invention is a method of inhibiting CDK-2 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula V.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula V. This method is particularly useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising contacting the biological sample with a GSK-3, Aurora or CDK-2 inhibitor of formula V or with a pharmaceutical composition containing it in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

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

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from —R ¹ , any substitutable non-aorto position in the ring C is independently substituted by -R ⁵ and two adjacent substituents on ring C are optionally combined with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said condensed ring being optionally substituted with a halogen, oxo group or —R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur, where ring D is substituted on any substituted ring carbon with an oxo group or group

—R ⁵ and for any substitutable ring nitrogen with a —R ⁴ group, provided that when ring D is a six-membered aryl or heteroaryl ring, —R ⁵ is hydrogen at each ortho position of ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, wherein said phenyl, heteroaryl and heterocyclyl rings are optionally each substituted with up to three groups each independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and neighboring deputy, combined with their prom weft atoms form said ring fused to Ring C;

R ^y represents T-R ^{3 '} ;

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

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, where any substitutable carbon atom in said condensed ring formed by R ² and R ^{2 ′} is substituted with halogen, oxo, —CN, NO ₂ , —R ⁷ or VR ⁶ , and any substitutable nitrogen in said ring formed by the radicals R ² and R ^{2 ′} , is substituted by the radical R ⁴ ; R ^{3 ′} is an optionally substituted group selected from a C _1-6 aliphatic group, a C _3-10 carbocyclyl, a C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms ;

each R is independently selected from hydrogen or an optionally substituted group selected from 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, or two R ⁴ radicals ^on the same the nitrogen atoms, taken together with each other, form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 taken together with a 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ .

Preferred R groups ^of Formula VI include T-R ^{3 ′} , where T is a bond or methylene and R ^{3 ′} is an optionally substituted group selected from a C _1-6 aliphatic group, C _3-10 carbocyclyl, C _6-10 aryl a heteroaryl ring having 5-10 ring atoms; or a heterocyclyl ring having 5-10 ring atoms. A preferred R ^{3 ′} group is an optionally substituted group selected from a C _3-6 carbocyclyl, phenyl or 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R ^y include 2-pyridyl, 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl and optionally substituted phenyl, such as phenyl or halogen-substituted phenyl.

The groups R ² and R ^{2 'of} formula VI can be taken together with each other 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. Examples of these fused rings are presented in the following compounds of formula VI having a pyrazole-containing bicyclic ring system:

Preferred substituents in the fused ring R ² -R ^{2 '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 is monocyclic, preferred R ² groups in Formula VI include hydrogen, C _1-4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkylalkylalkylaminoalkylalkyl and (N-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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-l-yl). Preferred R ^{2 ′} is hydrogen.

When G is ring C, phenyl and pyridinyl are preferred groups for ring C in formula VI. When two adjacent substituents in ring C are taken together to form a fused ring, ring C is a bicyclic ring system. Preferred fused rings include a benzene or pyridine ring. Such rings are preferably fused at the ortho and meta positions of ring C. Examples of preferred bicyclic systems for ring C include naphthyl and isoquinolinyl. Preferred R ¹ groups include halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , - CO ₂ R ⁶ , —CONH ₂ , —NHCOR ⁶ , —OC (O) NH _2, or —NHSO ₂ R ⁶ . When R ¹ is an optionally substituted C _1-6 aliphatic group, halogens are most preferred optional substituents. Examples of preferred R ¹ groups include —CF ₃ , —Cl, —F, —CN, COCH ₃ , —OCH ₃ , —OH, —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₃ , —CF ₂ CH ₃ , cyclohexyl, tert-butyl, isopropyl, cyclopropyl, —C≡, —C≡CH ₃ , —SO ₂ CH ₃ , —SO ₂ NH ₂ , —N (CH ₃ ) ₂ , —CO ₂ CH ₃ , —CONH ₂ , -NHCOCH ₃ , -OC (O) NH ₂ , -NHSO ₂ CH ₃ and -OCF ₃ .

In ring C, preferred R ⁵ substituents, when present, 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, —SO ₂ N (R ⁴ ) _2, and —N (R ⁴ ) SO ₂ R. More preferred R ⁵ substituents include —Cl, —F , -CN, -CF ₃ , -NH ₂ , NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic a group and —CO ₂ (C _1-4 aliphatic group). Examples of such preferred substituents include —Cl, —F, —CN, —CF ₃ , —NH ₂ , —NHMe, —NMe ₂ , —OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, and —CO ₂ Et.

When G is D, preferred monocyclic rings for ring D in Formula VI include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. When two adjacent substituents in ring D are taken together to form a fused ring, ring system D is bicyclic. Preferred bicyclic rings for ring D in Formula VI include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on ring D of formula VI include one or more of the following: halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, -SO ₂ N (R ⁴⁾ _2, -N (R ⁴⁾ SO ₂ R, -SR, -OR, -C ( O) R , or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. More preferred substituents for ring D include halogen, —CN, —oxy, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. Examples of substituents for ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

Preferred compounds of formula VI have one or more, and more preferably all, of the features selected from the group consisting of:

(a) ring C is selected from a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring, and R ¹ represents a halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3 a dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^y represents T-R ^{3 '} , where T represents a bond or methylene; and

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VI have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-6} haloaliphatic group, a C _1-6 aliphatic group, phenyl or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H -isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^y is T-R ^{3 ′} , where T is a bond or methylene and R ^{3 ′} is an optionally substituted group selected from a C _1-6 aliphatic group, C _3-6 carbocyclyl, C _6-10 aryl a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) _2, or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula VI have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^y is T-R ^{3 ′} , where T is a bond or methylene and R ^{3 ′} is an optionally substituted group selected from a C _1-4 aliphatic group, C _3-6 carbocyclyl, phenyl, or 5-6 a membered heteroaryl or heterocyclyl ring;

(b) Ring C is a phenyl or pyridinyl ring optionally substituted with a group —R ⁵ , wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-4} aliphatic group optionally substituted with halogen or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl or naphthyl;

(c) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or —CO (C _1-4 alkyl), wherein (C _1-4 alkyl) represents an unbranched, branched or cyclic alkyl group; and

(d) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group).

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from -R ¹ , any substitutable non-aorto position of carbon in ring C is independently substituted by a radical —R ⁵ and two adjacent substituents on ring C are optionally combined with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said condensed ring being optionally substituted with a halogen, oxo group or —R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted on any substituted ring carbon with an oxo group or an —R ⁵ group and on any substituted ring nitrogen by an —R ⁴ group, provided that when the D ring is six-membered aryl or heteroaryl nth ring, —R ⁵ represents hydrogen at each ortho position of ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, wherein said phenyl, heteroaryl and heterocyclyl rings are optionally each substituted with up to three groups each independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and neighboring deputy, combined with their prom weft atoms form said ring fused to Ring C;

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

R ² and R ^{2 '} are taken 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, where any substitutable carbon atom in the specified fused ring formed by the radicals R ² and R ^{2 ′} is substituted with a halogen, oxo group, —CN, NO ₂ , —R ⁷ or VR ^6, and any substitutable nitrogen atom in said ring formed by the radicals R ² and R ^{2 ′} is substituted by the radical R ⁴ ;

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, or two R ⁴ radicals ^on the same the nitrogen atoms, taken together with each other, form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 taken together with a 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ .

Preferred rings formed by the R ² and R ^{2 ′} groups of the Via formula include benzo, pyrido, pyrimido and a partially unsaturated 6-membered carbocyclic ring. Examples of these rings are presented in the following compounds of formula VIa 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 _1-4 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 G is ring C, phenyl and pyridinyl are preferred groups for ring C in formula VIa. When two adjacent substituents in ring C are taken together to form a fused ring, ring C is a bicyclic ring system. Preferred fused rings include a benzene or pyridine ring. Such rings are preferably fused at the ortho and meta positions of ring C. Examples of preferred bicyclic systems for ring C include naphthyl and isoquinolinyl. Preferred R ¹ groups include halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , - CO ₂ R ^6, -CONH _2, -NHCOR ^6, -OC (O) NH _2, or -NHSO ₂ R ^6. When R ¹ is an optionally substituted C _1-6 aliphatic group, halogens are most preferred optional substituents. Examples of preferred R ¹ groups include —CF ₃ , —Cl, —F, —CN, COCH ₃ , —OCH ₃ , —OH, —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₃ , —CF ₂ CH ₃ , cyclohexyl, tert-butyl, isopropyl, cyclopropyl, —C≡, —C≡CH ₃ , —SO ₂ CH ₃ , —SO ₂ NH ₂ , —N (CH ₃ ) ₂ , —CO ₂ CH ₃ , —CONH ₂ , -NHCOCH ₃ , -OC (O) NH ₂ , -NHSO ₂ CH ₃ and -OCF ₃ .

In ring C, preferred R ⁵ substituents, when present, 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, —SO ₂ N (R ⁴ ) _2, and —N (R ⁴ ) SO ₂ R. More preferred R ⁵ substituents include —Cl, —F , -CN, -CF ₃ , -NH ₂ , NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic a group and —CO ₂ (C _1-4 aliphatic group). Examples of such preferred substituents include —Cl, —F, —CN, —CF ₃ , —NH ₂ , —NHMe, —NMe ₂ , —OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, and —CO ₂ Et.

When G is D, preferred monocyclic rings for ring D in formula VIa include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. When two adjacent substituents in ring D are taken together to form a fused ring, ring system D is bicyclic. Preferred bicyclic rings for ring D in formula VIa include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on the D ring of formula Via include one or more of the following substituents: halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic. More preferred substituents for ring D include halogen, —CN, —oxy, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. Examples of substituents for ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

Preferred compounds of formula VIa have one or more, and more preferably all, of the features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents on it form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring, and R ¹ represents a halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3 a dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring; and

(b) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VIa have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-6} haloaliphatic group, a C _1-6 aliphatic group, phenyl or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H -isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or -CO (C _{1- 4 by} alkyl), where (C _1-4 alkyl) is an unbranched, branched or cyclic alkyl group; and

(c) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) _2, or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula VIa have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-4} aliphatic group optionally substituted with halogen or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or -CO (C _1-4 alkyl ), where (C _1-4 alkyl) represents an unbranched, branched or cyclic alkyl group; and

(d) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group). Representative compounds of formulas VI and VIa are shown below in table 5.

Table 5

In yet another embodiment, the present invention provides a composition comprising a compound of formula VI or VIa and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VI or VIa.

Another object of the present invention is a method of treating a disease facilitated by treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula VI or VIa.

Another object of the present invention is 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 composition containing a compound of formula VI or VIa. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula VI or VIa. This method is especially useful for stopping or slowing the progression of Alzheimer's disease.

Another object of the present invention is a method of inhibiting phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula VI or VIa. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting Aurora protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula VI or VIa.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula VI or VIa. This method is especially useful for treating cancer, such as colon cancer, ovarian cancer, and breast cancer.

One object of the present invention is a method of inhibiting CDK-2 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VI or VIa.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula VI or VIa. This method is especially useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising contacting the biological sample with a GSK-3, Aurora or CDK-2 inhibitor of formula VI or VIa or with a pharmaceutical composition containing it effective for inhibiting GSK-3, Aurora or CDK-2.

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

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from —R ¹ , any substitutable non-aorto position in the ring C independently substituted with -R ^5, and two adjacent substituents on the ring C optionally combined together with their intervening atoms to form a fused saturated, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen , Sulfur or nitrogen, said fused ring is optionally substituted by halogen, oxo, or -R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted on any substituted ring carbon with an oxo group or an —R ⁵ group and on any substituted ring nitrogen by an —R ⁴ group, provided that when the D ring is six-membered aryl or heteroaryl nth ring, —R ⁵ represents hydrogen at each ortho position of ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, said phenyl, heteroaryl and heterocyclyl rings being optionally substituted with each group in an amount of up to three independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and a neighboring substituent combined with their intermediates atoms form the specified e ring fused to ring C;

R ^y represents hydrogen or T-R ^{3 ″} ;

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

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 any substitutable carbon atom in said fused ring formed by the radicals R ² and R ^{2 'is} substituted by halo, oxo, -CN, NO _2, -R ^7, or VR ⁶ and any substitutable nitrogen atom in said the ring formed by the radicals R ² and R ^{2 ′} is substituted by the radical R ⁴ ;

R ^{3 ″} is an optionally substituted group selected from C _3-10 carbocyclyl, C _6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R is independently selected from hydrogen or an optionally substituted group selected from 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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ ; and

R ^{9 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), -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 R groups ^of formula VII include T-R ^{3 ″} , where T is a bond or methylene. Preferred R ^{3 ″} groups include an optionally substituted group selected from C _3-6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R ^y include 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl and optionally substituted phenyl, such as phenyl or halogen-substituted phenyl. The groups R ² and R ^{2 ′ of} formula VII can be taken together with each other 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. Examples of these fused rings are presented in the following compounds of formula VII 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 _1-4 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 in Formula VII is monocyclic, preferred R ² groups include hydrogen, C _1-4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkylalkylalkylaminoalkylalkyl and (N-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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-l-yl). Preferred R ^{2 ′} is hydrogen.

When G is ring C, phenyl and pyridinyl are preferred groups for ring C in formula VII. When two adjacent substituents in ring C are taken together to form a fused ring, ring C is a bicyclic ring system. Preferred fused rings include a benzene or pyridine ring. Such rings are preferably fused at the ortho and meta positions of ring C. Examples of preferred bicyclic systems for ring C include naphthyl and isoquinolinyl. Preferred R ¹ groups include halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , - CO ₂ R ⁶ , —CONH ₂ , —NHCOR ⁶ , —OC (O) NH _2, or —NHSO ₂ R ⁶ . When R ¹ is an optionally substituted C _1-6 aliphatic group, halogens are most preferred optional substituents. Examples of preferred R ¹ groups include —CF ₃ , —Cl, —F, —CN, COCH ₃ , —OCH ₃ , —OH, —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₃ , —CF ₂ CH ₃ , cyclohexyl, tert-butyl, isopropyl, cyclopropyl, —C≡, —C≡CH ₃ , —SO ₂ CH ₃ , —SO ₂ NH ₂ , —N (CH ₃ ) ₂ , —CO ₂ CH ₃ , —CONH ₂ , -NHCOCH ₃ , -OC (O) NH ₂ , -NHSO ₂ CH ₃ and -OCF ₃ .

In ring C, preferred R ⁵ substituents, when present, 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, —SO ₂ N (R ⁴ ) _2, and —N (R ⁴ ) SO ₂ R. More preferred R ⁵ substituents include —Cl, —F , -CN, -CF ₃ , -NH ₂ , NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic a group and —CO ₂ (C _1-4 aliphatic group). Examples of such preferred substituents include —Cl, —F, —CN, —CF ₃ , —NH ₂ , —NHMe, —NMe ₂ , —OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, and —CO ₂ Et.

When G is D, preferred monocyclic rings for ring D in Formula VII include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. When two adjacent substituents in ring D are taken together to form a fused ring, ring system D is bicyclic. Preferred bicyclic rings for ring D in Formula VI include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on ring D include one or more of the following substituents: halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR , —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _{6 -10} aryl or C _1-6 aliphatic groups. More preferred substituents for ring D include halogen, —CN, —oxy, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. Examples of substituents for ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

Preferred compounds of formula VII have one or more, and more preferably all, of the features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents on it form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring, and R ¹ represents a halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3 a dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^y represents T-R ^{3 ″} , where T represents a bond or methylene; and

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VII have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-6} haloaliphatic group, a C _1-6 aliphatic group, phenyl or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H -isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^y is T-R ^{3 ″} , where T is a bond or methylene and R ^{3 ″} is an optionally substituted group selected from a C _3-6 carbocyclyl, phenyl or heteroaryl heterocyclyl ring;

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) _2, or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula VII have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^y is T-R ^{3 ″} , where T is a bond or methylene and R ^{3 ″} is an optionally substituted group selected from phenyl or a 5-6 membered heteroaryl or heterocyclyl ring;

(b) Ring C is a phenyl or pyridinyl ring optionally substituted with a group —R ⁵ , wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-4} aliphatic group optionally substituted with halogen or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl or naphthyl;

(c) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or —CO (C _1-4 alkyl), wherein (C _1-4 alkyl) represents an unbranched, branched or cyclic alkyl group; and

(d) Ring D is a substituted oxo group or R ⁵ , each R ⁵ independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group).

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

Table 6

In yet another embodiment, the present invention provides a composition comprising a compound of formula VII and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

Another object of the present invention is a method of treating a disease facilitated by treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula VII.

Another object of the present invention is 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 composition containing a compound of formula VII. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula VII. This method is especially useful for stopping or slowing down the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting the phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula VII. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of Aurora protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII. Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula VII. This method is especially useful for treating cancer, such as colon cancer, ovarian cancer, and breast cancer.

One object of the present invention is a method of inhibiting the activity of CDK-2 protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula VII. This method is especially useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising contacting the biological sample with a GSK-3, Aurora or CDK-2 inhibitor of formula VII or with a pharmaceutical composition containing it in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

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

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents N or CR ⁹ , Z ² represents N or CH, and Z ³ represents N or CR ^x , with the proviso that one of Z ¹ and Z ³ represents nitrogen;

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from —R ¹ , any substitutable non-aorto position in the ring C is independently substituted by -R ⁵ and two adjacent substituents on ring C are optionally combined with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said condensed ring being optionally substituted with a halogen, oxo group or —R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted on any substituted ring carbon with a halogen, oxo or -R ⁵ group and on any substituted ring nitrogen by -R ⁴ , provided that when the ring D is a six-membered aryl or heteroaryl ring, —R ⁵ represents hydrogen at each ortho position of ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, said phenyl, heteroaryl and heterocyclyl rings being optionally substituted with each group in an amount of up to three independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and a neighboring substituent combined with their intermediates atoms form the specified e ring fused to ring C;

R ^x represents T-R ³ ;

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

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, where any substitutable carbon atom in said condensed ring formed by R ² and R ^{2 ′} is substituted with halogen, oxo, —CN, NO ₂ , —R ⁷ or VR ⁶ , and any substitutable nitrogen in said ring formed by the radicals R ² and R ^{2 ′} , is 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 (optionally substituted 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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ ; and

R ^{9 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 .

Thus, the present invention relates to compounds of formulas VIIIa, VIIIb, VIIIc and VIIId shown below:

VIIIa Viiib VIIIc VIIId

Preferred R ^x groups in Formula VIII include T-R ³ , where T is a bond or methylene and R ³ is CN, —R, or —OR. When R ³ is —R, preferred R ³ groups include an optionally substituted group selected from a C _1-6 aliphatic group, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. When R ³ is —OR, preferred R groups include an optionally substituted C _1-6 aliphatic group, such as alkyl or dialkylaminoalkyl and aminoalkyl. Examples of a preferred R ^x group include acetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl, imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, NH ₂ CH ₂ CH ₂ NH and NH ₂ CH ₂ CH ₂ O.

Preferred R ⁹ groups in formula VIII, when present, include R, OR and N (R ⁴ ) ₂ . Examples of preferred R ⁹ 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 OH and NH ₂ CH ₂ CH ₂ O.

The groups R ² and R ^{2 'of} formula VIII can be taken together with each other 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. Examples of these fused rings are presented in the following compounds of formula VIII having a pyrazole-containing bicyclic ring system:

Preferred substituents on the fused ring R ² —R ^{2 ′} in formula VIII 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), wherein (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 in Formula VIII is monocyclic, preferred R ² groups include hydrogen, C _1-4 aliphatic, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkylamino and (N-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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-l-yl). Preferred R ^{2 ′} is hydrogen.

When G is ring C, phenyl and pyridinyl are preferred groups for ring C in formula VIII. When two adjacent substituents in ring C are taken together to form a fused ring, ring C is a bicyclic ring system. Preferred fused rings include a benzene or pyridine ring. Such rings are preferably fused at the ortho and meta positions of ring C. Examples of preferred bicyclic systems for ring C include naphthyl and isoquinolinyl. Preferred R ¹ groups include halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , - CO ₂ R ^6, -CONH _2, -NHCOR ^6, -OC (O) NH _2, or -NHSO ₂ R ^6. When R ¹ is an optionally substituted C _1-6 aliphatic group, halogens are most preferred optional substituents. Examples of preferred R ¹ groups include —CF ₃ , —Cl, —F, —CN, COCH ₃ , —OCH ₃ , —OH, —CH ₂ CH ₃ , —OCH ₂ CH ₃ , —CH ₃ , —CF ₂ CH ₃ , cyclohexyl, tert-butyl, isopropyl, cyclopropyl, —C≡, —C≡CH ₃ , —SO ₂ CH ₃ , —SO ₂ NH ₂ , —N (CH ₃ ) ₂ , —CO ₂ CH ₃ , —CONH ₂ , -NHCOCH ₃ , -OC (O) NH ₂ , -NHSO ₂ CH ₃ and -OCF ₃ .

In ring C, preferred R ⁵ substituents, when present, 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, —SO ₂ N (R ⁴ ) _2, and —N (R ⁴ ) SO ₂ R. More preferred R ⁵ substituents include —Cl, —F , -CN, -CF ₃ , -NH ₂ , NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group) ₂ , -O (C _1-4 aliphatic group), C _1-4 aliphatic a group and —CO ₂ (C _1-4 aliphatic group). Examples of such preferred substituents include —Cl, —F, —CN, —CF ₃ , —NH ₂ , —NHMe, —NMe ₂ , —OEt, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, and —CO ₂ Et.

When G is D, preferred monocyclic rings for ring D in formula VIII include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl and morpholinyl rings. When two adjacent substituents in ring D are taken together to form a fused ring, ring system D is bicyclic. Preferred bicyclic rings for ring D in Formula VI include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl and naphthyl. Examples of more preferred bicyclic ring D systems include naphthyl and isoquinolinyl.

Preferred R ⁵ substituents ^on ring D of formula VIII include halogen, oxo, CN, —NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , —N (R ⁴ ) SO ₂ R, —SR, —OR, —C (O) R or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or a C _1-6 aliphatic group. More preferred R ⁵ substituents include halogen, —CN, —oxo, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic groups. Examples of substituents for ring D include —OH, phenyl, methyl, CH ₂ OH, CH ₂ CH ₂ OH, pyrrolidinyl, OPh, CF ₃ , C≡, Cl, Br, F, I, NH ₂ , C (O) CH ₃ , isopropyl, tert-butyl, SEt, OMe, N (Me) ₂ , methylenedioxy and ethylenedioxy.

Preferred compounds of formula VIII have one or more, and more preferably all, of the features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents on it form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring, and R ¹ represents a halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3 a dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x represents T-R ³ where T is a bond or methylene; and

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring.

More preferred compounds of formula VIII have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-6} haloaliphatic group, a C _1-6 aliphatic group, phenyl or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H -isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x is T-R ³ , where T is a bond or methylene and R ³ is CN, —R or —OR;

(c) R ^{2 ′} is hydrogen and R ² is hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group, or R ² and R ^{2 ′} are taken together with their intermediate atoms to form substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring; and

(d) each R ^{5 is} independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) _2, or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula VIII have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^x is T-R ³ , where T is a bond or methylene and R ³ is —R or —OR, where R is an optionally substituted group selected from a C _1-6 aliphatic group, phenyl, or 5 A 6-membered heteroaryl or heterocyclyl ring;

(b) Ring C is a phenyl or pyridinyl ring optionally substituted with a group —R ⁵ , wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-4} aliphatic group optionally substituted with halogen or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl or naphthyl;

(c) R ² and R ^{2 ′} are taken together with their intermediate atoms to form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring optionally substituted with 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 or -CO (C _{1- 4 by} alkyl), where (C _1-4 alkyl) is an unbranched, branched or cyclic alkyl group;

(d) each R ⁵ group is independently selected from —Cl, —F, —CN,

-CF ₃ , -NH ₂ , -NH (C _1-4 aliphatic group), -N (C _1-4 aliphatic group), -O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group); and

(e) R ⁹ represents R, OR or N (R ⁴ ) ₂ .

Representative compounds of formulas VIII are shown below in table 7.

Table 7

In yet another embodiment, the present invention provides a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VIII.

Another object of the present invention is a method of treating a disease facilitated by treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula VIII. Another object of the present invention is 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 composition containing a compound of formula VIII. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula VIII. This method is especially useful for stopping or slowing down the development of Alzheimer's disease.

Another object of the present invention is a method of inhibiting phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula VIII. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting the activity of Aurora protein kinase in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula VIII.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula VIII. This method is especially useful for treating cancer, such as colon cancer, ovarian cancer, and breast cancer.

One object of the present invention is a method of inhibiting CDK-2 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula VIII.

Another object of the present invention is a method of treating a disease facilitated by treatment with a CDK-2 protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula VIII. This method is especially useful for the treatment of cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another object of the present invention is a method of inhibiting the activity of GSK-3, Aurora or CDK-2 in a biological sample, comprising contacting the biological sample with a GSK-3, Aurora or CDK-2 inhibitor of formula VIII or with a pharmaceutical composition containing it in an amount effective for inhibiting GSK-3, Aurora or CDK-2.

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

The compounds of formula I described above contain a pyrazole ring having the substituents R ² and R ^{2 ′} . When searching for other GSK-3 and Aurora protein kinase inhibitors, the applicants tried to replace the pyrazole fragment of formula I with other heteroaromatic rings. It was found that one of the more effective substitutions for the pyrazole ring is the triazole ring. Inhibitors having the indicated triazole ring, in other structural components, are similar to compounds of formula I. This embodiment of the present invention relates to these inhibitors represented by general formula IX:

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen or CR ⁹ and Z ² represents nitrogen or CH, provided that one of Z ¹ and Z ² represents nitrogen;

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position selected from -R ¹ , any substitutable non-aorto position of carbon in ring C is independently substituted with a radical —R ⁵ , and two adjacent substituents on ring C are optionally combined with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said condensed ring being optionally substituted with a halogen, oxo group or —R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted at any substituted carbon atom in the ring with an oxo group or a radical —R ⁵ , provided that when ring D is a six-membered aryl or heteroaryl ring, —R ⁵ represents hydrogen in each ortho position of the ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, wherein said phenyl, heteroaryl and heterocyclyl rings are optionally each substituted with up to three groups each independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and neighboring deputy, combined with their prom weft atoms form said ring fused to Ring C;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in said condensed ring formed by R ^x and R ^y radicals is substituted by oxo or T-R ³ and any substituted nitrogen atom in said ring formed by R ^x and R ^y radical is substituted by R ⁴ ;

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

R ² represents —R or —TWR ⁶ ;

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 (optionally substituted 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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ ; and

R ^{9 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), -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 .

The compounds of formula IX may exist in alternative tautomeric forms, as in tautomers 1-3, shown below. Unless otherwise specified, the presentation of any of these tautomers also includes the inclusion of two others.

The R ^x and R ^y groups in Formula IX 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 5-, 6-, 7- or 8- a membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, said R ^x —R ^y ring being optionally substituted. Examples of ring A systems in compounds IX-A to IX-DD are shown below, where Z ¹ is nitrogen or C (R ⁹ ) and Z ² is nitrogen or C (H).

Preferred ring A bicyclic systems in Formula IX include IX-A, IX-B, IX-C, IX-D, IX-E, IX-F, IX-G, IX-H, IX-I, IX-J, IX-K, IX-L and IX-M, more preferably IX-A, IX-B, IX-C, IX-F and IX-H, and most preferably IX-A, IX-B and IX-H.

In the monocyclic ring A system in Formula IX, preferred R ^x groups include hydrogen, an alkyl or dialkylamino, acetamido or C _1-4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or tert-butyl. Preferred R ^y groups when present include TR ³ , where T is a bond or methylene, and R ³ is —R, —N (R ⁴ ) _2, or —OR. Examples of a preferred R ^y group include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or dialkylamino, acetamido, optionally substituted phenyl, such as phenyl or halogen substituted phenyl, and methoxymethyl. In a bicyclic ring A ring in formula IX, the ring formed by R ^x and R ^y taken together may be substituted or unsubstituted. Suitable substituents include —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 , 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, or —N (R ⁴ ) ₂ , where R is optional substituted C _1-6 aliphatic group.

Preferred R ² groups in Formula IX include hydrogen, a C _1-4 aliphatic group, alkoxycarbonyl, (un) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl and (N) hetero . 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 (nC ₃ H ₇ ), CON (Et) CH ₂ CH ₂ CH ₃ , CONHCH ₂ CH (CH ₃ ) ₂ , CON (nC ₃ H ₇ ) ₂ , CO (3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl), CONHCH ₃ , CO (morpholin-1-yl), CO (4-methylpiperazin-1-yl), CONHCH ₂ CH ₂ OH, CONH ₂ and CO (piperidin-1-yl). A more preferred R ² group for compounds of formula IX is hydrogen.

An option that is particularly useful for the treatment of GSK-3-mediated diseases relates to compounds of formula X, where ring A is a pyrimidine ring:

or their pharmaceutically acceptable derivatives or prodrugs, where:

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position independently selected from —R ¹ , any substituted non-aorto carbon position ring C independently substituted with -R ^5, and two adjacent substituents on the ring C optionally combined together with their intervening atoms to form a fused saturated, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms, in brane from oxygen, sulfur or nitrogen, said fused ring is optionally substituted by halogen, oxo, or -R ⁸ radical;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, said phenyl, heteroaryl and heterocyclyl rings being optionally substituted with each group in an amount of up to three independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and a neighboring substituent combined with their intermediates atoms form the specified e ring fused to ring C;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in said condensed ring formed by R ^x and R ^y radicals is substituted by oxo or T-R ³ and any substituted nitrogen atom in said ring formed by R ^x and R ^y radical is substituted by R ⁴ ;

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

R ² represents —R or —TWR ⁶ ;

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 (optionally substituted 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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring; and

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ .

Compounds of formula X are structurally similar to compounds of formula II except for replacing the pyrazole ring moiety with a triazole ring moiety.

Preferred groups R ² , R ^x , R ^y and ring C of formula X are as described above for compounds of formula II.

Preferred compounds of formula X have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring;

(b) R ^x represents hydrogen or a C _1-4 aliphatic group, and R ^y represents T-R ³ , or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted 5-7 membered unsaturated or partially an unsaturated ring having 0-2 ring nitrogen atoms;

(c) R ¹ is halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ ,

-SO ₂ NH ₂ , -N (R ⁶ ) ₂ , -CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; and

(d) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group.

More preferred compounds of formula X have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with —R ⁵ , wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R ^x is hydrogen or methyl and R ^y is —R, N (R ⁴ ) ₂ or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a benzene ring or a 5-7 membered a carbocyclic ring, wherein said ring formed by the groups R ^x and R ^y is an optionally substituted group —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 ;

(c) R ¹ represents a halogen, C _1-6 halogen-aliphatic group, C _1-6 aliphatic group, phenyl or —CN;

(d) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group; and

(e) each R ^{5 is} independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ or —N (R ⁴ ) SO ₂ R.

Even more preferred compounds of formula X have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R ^x is hydrogen or methyl and R ^y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl, or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted benzene ring or a 6-membered carbocyclic ring;

(c) R ¹ is halogen, a C _1-4 aliphatic group optionally substituted with halogen, or —CN;

(d) R ² represents hydrogen or a C _1-6 aliphatic group; and

(e) each R ^{5 is} independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ ,

-O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group).

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur, where ring D is substituted on any substituted ring carbon with an oxo group or group

—R ⁵ and for any substitutable ring nitrogen with a —R ⁴ group, provided that when ring D is a six-membered aryl or heteroaryl ring, —R ⁵ is hydrogen at each ortho position of ring D;

R ^x and R ^y are taken together with their intermediate atoms to form a fused benzene ring or a 5-8 membered carbocyclic ring, where any substituted carbon atom in said fused ring formed by R ^x and R ^y is substituted by an oxo group or T-R ³ ;

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

R ² represents —R or —TWR ⁶ ;

R ^{3 is} selected from —R, halogen, = O, —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 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 ;

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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Compounds of formula XI are structurally similar to compounds of formula III except for replacing the pyrazole ring fragment with a triazole ring fragment. Preferred groups R ² , R ^x , R ^y and ring D of formula XI are as described above for compounds of formula III. Preferred compounds of formula XI have one or more, and more preferably all, features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2 , 3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted benzene ring or a 5-7 membered carbocyclic ring; and

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group.

More preferred compounds of formula XI have one or more, and more preferably all, features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro -1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x and R ^y taken together with their intermediate atoms to form a benzene ring or a 5-7 membered carbocyclic ring, wherein said ring formed by R ^x and R ^y groups is optionally substituted with —R, oxo, 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 ;

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group; and

(d) each R ^{5 is} independently selected from halogen, oxo, CN, NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , -N (R ⁴ ) SO ₂ R, -SR,

-OR, -C (O) R or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic group.

Even more preferred compounds of formula XI have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a benzene or 6-membered carbocyclic ring, wherein said rings formed by the groups R ^x and R ^y are optionally substituted with halogen, CN, oxo, C _1-6 alkyl , C _1-6 alkoxy, (C _1-6 alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy or 5-6 membered heteroaryl;

(b) each R ^{5 is} independently selected from halogen, —CN, oxo, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl C _6-10 aryl or C _1-6 aliphatic groups; and

(c) R ² represents hydrogen or a C _1-6 aliphatic group.

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, where the ring D is substituted on any substituted ring carbon with an oxo group or an —R ⁵ group and on any substituted ring nitrogen by an —R ⁴ group, provided that when the D ring is six-membered aryl or heteroaryl nth ring, —R ⁵ represents hydrogen at each ortho position of ring D;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^y are taken together with their intermediate atoms to form a fused benzene unsaturated or partially unsaturated 5-8 membered ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon in said condensed ring is optionally and independently substituted by a T-R ³ group and any substituted nitrogen in said ring is substituted by a R ⁴ group;

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

R ² represents —R or —TWR ⁶ ;

R ^{3 is} selected from —R, halogen, = O, —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 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 ;

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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring.

Compounds of formula XII are structurally similar to compounds of formula IV except for replacing the pyrazole ring moiety with a triazole ring moiety. Preferred groups R ² , R ^x , R ^y and ring D of formula XII are as described above for compounds of formula IV. Preferred compounds of formula XII have one or more, and more preferably all, features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2 , 3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x represents hydrogen or a C _1-4 aliphatic group and R ^y represents T-R ³ , or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated a ring having 1-2 heteroatoms; and

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group.

More preferred compounds of formula XII have one or more, and more preferably all, features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro -1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x is hydrogen or methyl and R ^y is —R, —N (R ⁴ ) ₂ or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a 5-7 membered unsaturated or a partially unsaturated ring having 1-2 ring nitrogen atoms, said ring being an optionally substituted group —R, halogen, oxo, —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 ;

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

(d) each R ^{5 is} independently selected from halogen, oxo, CN, NO ₂ , —N (R ⁴ ) ₂ , —CO ₂ R, —CONH (R ⁴ ), —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ , -N (R ⁴ ) SO ₂ R, -SR,

-OR, -C (O) R or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl, C _6-10 aryl or C _1-6 aliphatic group.

Even more preferred compounds of formula XII have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^x and R ^y are taken together with their intermediate atoms to form a 6-membered unsaturated or partially unsaturated ring with 1-2 ring nitrogen atoms, optionally substituted with halogen, CN, oxo, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy or 5-6 membered heteroaryl;

(b) each R ^{5 is} independently selected from halogen, —CN, oxo, —SR, —OR, —N (R ⁴ ) ₂ , —C (O) R, or a substituted or unsubstituted group selected from a 5-6 membered heterocyclyl C _6-10 aryl or C _1-6 aliphatic groups; and

(c) R ² represents hydrogen or a C _1-6 aliphatic group.

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

or their pharmaceutically acceptable derivatives or prodrugs, where:

Z ¹ represents nitrogen, CR ^a or CH and Z ² represents nitrogen or CH, provided that one of Z ¹ and Z ² represents nitrogen;

G represents ring C or ring D;

ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl rings, said ring C having one or two substituents in the ortho position independently selected from -R ¹ , any substitutable non-aorto position in ring C independently substituted with -R ^5, and two adjacent substituents on the ring C optionally combined together with their intervening atoms to form a fused saturated, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected of oxygen, sulfur or nitrogen, said fused ring is optionally substituted by halogen, oxo, or -R ⁸ radical;

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 has 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur, where ring D is substituted on any substituted ring carbon with an oxo group or group

—R ⁵ and for any substitutable ring nitrogen with a —R ⁴ group, provided that when ring D is a six-membered aryl or heteroaryl ring, —R ⁵ is hydrogen at each ortho position of ring D;

R ^{1 is} selected from halogen, —CN, —NO ₂ , TVR ⁶ , phenyl, a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclyl ring, or a C _1-6 aliphatic group, said phenyl, heteroaryl and heterocyclyl rings being optionally substituted with each group in an amount of up to three independently selected from halogen, oxo or —R ⁸ , said C _1-6 aliphatic group is optionally substituted with halogen, cyano, nitro or oxygen, or R ¹ and a neighboring substituent combined with their intermediates atoms form the specified e ring fused to ring C;

R ^x and R ^{y are} independently selected from T-R ³ , or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substituted carbon atom in said condensed ring formed by R ^x and R ^y radicals is substituted by oxo or T-R ³ and any substituted nitrogen atom in said ring formed by R ^x and R ^y radical is substituted by R ⁴ ;

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

R ² represents —R or —TWR ⁶ ;

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 (optionally substituted 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 , or two R ⁴ radicals at one and the same nitrogen atom, taken together with each other, form a 5-8-membered heterocyclyl or heteroaryl ring;

each R ⁵ is independently selected from -R, halo, -OR, -C (= O) R,

—CO ₂ R, —COCOR, —NO ₂ , —CN, —S (O) R, —SO ₂ R, —SR, —N (R ⁴ ) ₂ , —CON (R ⁴ ) ₂ ,

-SO ₂ N (R ⁴ ) ₂ , -OC (= O) R, -N (R ⁴ ) COR, -N (R ⁴ ) CO ₂ (optionally substituted C _1-6 aliphatic 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 , or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C;

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-O-, -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 are taken 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 taken together with the nitrogen atom to form a 5-8 membered heterocyclyl or heteroaryl ring;

each R ^{8 is} independently selected from an optionally substituted C _1-4 aliphatic group, —OR ⁶ , —SR ⁶ , —COR ⁶ , —SO ₂ R ⁶ , —N (R ⁶ ) ₂ ,

—N (R ⁶ ) N (R ⁶ ) ₂ , —CN, —NO ₂ , —CON (R ⁶ ) _2, or —CO ₂ R ⁶ ; and

R ^{a is} selected from 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, —OC (= O) N (R ⁴ ) _2, or an optionally substituted group selected from a C _1-6 aliphatic group With a _6-10 aryl group, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

The compounds of formula XIII can be represented with specific Z ¹ and Z ² as shown below:

Compounds of formula XIII are structurally similar to compounds of formula V except for replacing the pyrazole ring fragment with a triazole ring fragment. Preferred groups R ² , R ^x , R ^y , R ^a and ring G of formula XIII are as described above for compounds of formula V. Preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of :

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents on it form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl, or isoquinolinyl ring, and R ¹ represents a halogen, an optionally substituted C _1-6 aliphatic group, phenyl, —COR ⁶ , —OR ⁶ , —CN, —SO ₂ R ⁶ , —SO ₂ NH ₂ , —N (R ⁶ ) ₂ , —CO ₂ R ⁶ , -CONH ₂ , -NHCOR ⁶ , -OC (O) NH ₂ or -NHSO ₂ R ⁶ ; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3 a dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl ring;

(b) R ^x represents hydrogen or a C _1-4 aliphatic group and R ^y represents T-R ³ , or R ^x and R ^y are taken together with their intermediate atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated a ring having 0-2 ring nitrogen atoms; and

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl, heteroaryl or C _1-6 aliphatic group.

More preferred compounds of formula XIII have one or more, and more preferably all, features selected from the group consisting of:

(a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-6} haloaliphatic group, a C _1-6 aliphatic group, phenyl or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H -isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl or naphthyl;

(b) R ^x is hydrogen or methyl and R ^y is —R, N (R ⁴ ) or —OR, or R ^x and R ^y are taken together with their intermediate atoms to form a benzene or 5-7 membered carbocyclic ring wherein said ring formed by the groups R ^x and R ^y is an optionally substituted group —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 ;

(c) R ² represents hydrogen or a substituted or unsubstituted group selected from an aryl or C _1-6 aliphatic group; and

(d) each R ^{5 is} independently 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 ) ₂ , —N (R ⁴ ) COR, —SO ₂ N (R ⁴ ) ₂ or —N (R ⁴ ) SO ₂ R, wherein when ring G is ring D, ring D is a substituted oxo or R ⁵ group.

Even more preferred compounds of formula XIII have one or more, and more preferably all, features selected from the group consisting of:

(a) R ^x is hydrogen or methyl, and R ^y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, tert-butyl, alkyl or optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl or phenyl or R ^x and R ^y are taken together with their intermediate atoms to form a benzene ring or a 6-membered carbocyclic ring, wherein said ring formed by the groups R ^x and R ^y is optionally substituted with halogen, CN, oxo, C _1-6 alkyl C _1-6 alkoxy, (C _1-6 alkyl) carbonyl, (C _1-6 alkyl) sulfonyl, mon - or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkilaminokarboniloksi or 5-6 membered heteroaryl;

(b) Ring C is a phenyl or pyridinyl ring optionally substituted with a group —R ⁵ , wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl ring and R ¹ is halogen, C _{A 1-4} aliphatic group optionally substituted with halogen or —CN; or ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinolinyl or naphthyl;

(c) R ² represents hydrogen or a C _1-6 aliphatic group; and

(d) each R ^{5 is} independently selected from —Cl, —F, —CN, —CF ₃ , —NH ₂ , NH (C _1-4 aliphatic group), —N (C _1-4 aliphatic group) ₂ ,

-O (C _1-4 aliphatic group), C _1-4 aliphatic group and -CO ₂ (C _1-4 aliphatic group), and when ring G is a ring D, ring D is a substituted oxo or R ⁵ group.

Representative compounds of formula IX are shown below in table 8.

Table 8

In yet another embodiment, the present invention provides a composition comprising a compound of formula IX and a pharmaceutically acceptable carrier. One object of the present invention is a method of inhibiting GSK-3 protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula IX.

Another object of the present invention is a method of treating a disease facilitated by treatment with a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition containing a compound of formula IX.

Another object of the present invention is 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 composition containing a compound of formula IX. This method is especially useful for patients with diabetes.

Another object of the present invention is a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula IX. This method is especially useful for stopping or slowing the progression of Alzheimer's disease.

Another object of the present invention is a method of inhibiting phosphorylation of β-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition containing a compound of formula IX. This method is especially useful for the treatment of schizophrenia.

One object of the present invention is a method of inhibiting Aurora protein kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition containing a compound of formula IX.

Another object of the present invention is a method of treating a disease facilitated by treatment with an Aurora protein kinase inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula IX. This method is especially useful for treating cancer, such as colon cancer, ovarian cancer, and breast cancer.

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

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

Compounds of the present invention can be obtained in accordance with the synthesis methods described below, examples of synthesis presented in this description, and General methods known to specialists in this field.

General synthesis methods

The general synthesis methods described below represent a number of general reaction pathways used to prepare the compounds of the present invention. Methods AF are especially useful for preparing compounds of formula II. In most cases, ring C is represented as a phenyl ring containing an R ¹ substituent in the ortho position. However, it will be apparent to one skilled in the art that compounds with other groups represented by ring C can be prepared in a similar manner. Methods similar to AF methods are also useful for preparing other compounds of the present invention. The FI methods described below are particularly useful for preparing compounds of formula III or IV.

Method A

Method A is a general method for preparing compounds in which ring C is an aryl or heteroaryl ring. Starting dichloropyrimidine 1 can be prepared by a method similar to that described in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. Chlorine at position 4 of intermediate 1 can be substituted with aminopyrazole or aminoindazole to give intermediate 2 in a manner similar to that described in J. Med. Chem., 38, 3547-3557 (1995). Ring C is then introduced using boronic ester in palladium catalysis (see Tetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by the following procedure.

A suspension of 1H-quinazolin-2,4-dione (10.0 g, 61.7 mmol) in POCl ₃ (60 ml, 644 mmol) and N, N-dimethylaniline (8 ml, 63.1 mmol) is refluxed within 2 hours. Excess POCl _{3 was} evaporated in vacuo, the residue was poured onto ice and the precipitate was collected by filtration. The crude solid product 2,4-dichloroquinazoline can be used without further purification.

To a solution of 2,4-dichloroquinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 ml) was added 5-methyl-1H-pyrazol-3-yl-amine (3.2 g, 32.9 mmol) . The mixture was stirred at room temperature for 4 hours and the resulting precipitate was collected by filtration, washed with ethanol and dried in vacuo to give (2-chloroquinazolin-4-yl) - (5-methyl-1H-pyrazol-3-yl) amine.

To a solution of (2-chloroquinazolin-4-yl) - (5-methyl-1H-pyrazol-3-yl) amine (50 mg, 0.19 mmol) in DMF (1.0 ml) was added the desired arylboronic acid (0, 38 mmol), 2M Na ₂ CO ₃ (0.96 mmol) and tri-tert-butylphosphine (0.19 mmol). Under a nitrogen atmosphere, PdCl ₂ (dppf) (0.011 mmol) was added in one portion. Then the reaction mixture is heated at 80 ° C for 5-10 hours, cooled to room temperature and poured into water (2 ml). The resulting precipitate was collected by filtration, washed with water and purified by HPLC.

Method B

Methods B-F represent the route of administration of the pyrazole ring system after constructing ring C and the pyrimidine ring portion. The universal intermediate is 4-chloropyrimidine 4, which is readily prepared from pyrimidinone 3, as shown in method B (i). This reaction sequence is usually used for a wide variety of groups of ring C, including an aliphatic, aryl, heteroaryl or heterocyclyl group. See J. Med. Chem., 38.3547-3557 (1995).

For quinazoline ring systems (where R ^x and R ^y are taken together to form a benzene ring), a suitable intermediate 6 can be obtained by condensation of anthranilic acid or its derivative with benzamidine, as shown in method B (ii), or by condensation of benzoyl chloride with anthranilamide as shown in method B (iii). Many starting materials, such as, for example, substituted anthranilic acid, anthranilamide, benzamidine and benzoyl chloride, can be prepared by known methods. See Aust. J. Chem., 38, 467-474 and J. Med. Chem., 38, 3547-3557 (1995). Method B (iii) is illustrated by the following procedure.

To a solution of anthranilamide (33 mmol) in THF and CH ₂ Cl ₂ (1: 1, 70 ml) was added the desired benzoyl chloride (33 mmol) and triethylamine (99 mmol) at room temperature. The mixture is stirred for about 14 hours. The resulting precipitate was collected by filtration, washed with CH ₂ Cl ₂ and water and dried in vacuo. The crude 2-benzoylaminobenzamide can be used directly in the next step without further purification.

To a solution of the product obtained above (13 mmol) in ethanol (50 ml) was added NaOEt (26 mmol) at room temperature. The mixture was refluxed for 48-96 hours. The solvent was evaporated and the residue was neutralized with concentrated HCl to pH 7. The product was then collected by filtration and dried in vacuo to give 2-phenyl-3H-quinazolin-4-one, which could be used without further purification.

Tri-n-propylamine (24 mmol) was added to a suspension of the product obtained above (12 mmol) in POCl ₃ (120 mmol). The mixture was refluxed for 1 hour. After removal of excess POCl _{3 by} evaporation, the residue was dissolved in ethyl acetate and washed with 1N. NaOH (twice) and water (twice). The organic layer was dried over MgSO ₄ , the solvent was evaporated in vacuo and the crude product was purified by flash chromatography (eluting with 10% ethyl acetate in hexane) to give 4-chloro-2-arylquinazoline.

The desired aminopyrazole or aminoindazole (0.32 mmol) is added to a solution of 4-chloro-2-arylquinazoline (0.16 mmol) in DMF (or THF, ethanol). The mixture is heated in DMF (or THF under reflux) at 100-110 ° C for 16 hours (or in ethanol at 130-160 ° C for 16 hours) and then poured into water (2 ml). The precipitate was collected by filtration and purified by HPLC.

Method C

Method D (i)

In the above methods, C and D (i) use β-ketoesters 8 and 10, respectively, as pyrimidinone precursors. The substitution scheme for the R ^x and R ^y groups on the pyrimidinone ring is reversed if chlorocrotonate 11 is condensed with the desired benzamidine (Synth. Comm, (1986), 997-1002) instead of the corresponding β-ketoester 10. These methods are illustrated by the following general methods.

To a solution of β-ketoester (5.2 mmol) and amidinium chloride (5.7 mmol) in ethanol (5 ml) was added sodium ethoxide (7.8 mmol). The mixture was refluxed for 7-14 hours. After evaporation, the resulting residue was dissolved in water, acidified with concentrated HCl to pH 6 and then filtered to obtain a solid product of 2-aryl-3H-pyrimidin-4-one (yield 75-87%), which, if necessary, could be purified by flash column chromatography . POCl ₃ (4 ml) and n-Pr ₃ N (1.4 ml) were added to the resulting pyrimidinone (3.7 mmol). The mixture was refluxed for 1 hour. After evaporation of excess POCl _{3, the} residue was dissolved in ethyl acetate, washed with 1N. a solution of NaOH (three times) and NaHCO ₃ (once) and dried over MgSO ₄ . The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 10% ethyl acetate in hexane to give 2-aryl-4-chloropyrimidine as a pale yellow syrup. The resulting crude product may be treated with 3-aminopyrazole or 3-aminoindazole as described above.

Method D (ii)

Method D (ii) shows a general way of preparing the compounds of the invention, such as compound 40, wherein R ^y is N (R ⁴ ) ₂ . See Il Farmaco, 52 (1) 61-65 (1997). To replace the 6-chloro group, morpholine is used here as an example. This method is illustrated by the following method.

To a solution of 2-methylmalonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmol), a suitable amidine salt (5 mmol) in ethanol (10 ml) was added and the reaction mixture was refluxed for 2-24 hours. The residue was dissolved in water and acidified by the addition of 2N. HCl. The resulting precipitate was filtered off and further purified by flash chromatography (5-35% yield) to give pyrimidinedione 37. POCl ₃ (32 mmol) and tri-n-propylamine (6.4 mmol) were added to pyrimidinedione 37 (1.6 mmol) and the reaction mixture was refluxed for 1 hour. After evaporation of excess POCl _{3, the} residue was dissolved in ethyl acetate, made basic by the addition of 1N. NaOH was separated and the aqueous phase was extracted two more times with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and evaporated. Purification by flash chromatography affords dichloropyrimidine (38) as a yellow oil in 23% yield.

A solution of product 38 (0.33 mmol) in methanol (5 ml) is treated with an amine, in this case, for example, morpholine (0.64 mmol) and refluxed for 1 hour. After evaporation of the solvent, the residue was purified by flash chromatography to give monochloropyrimidine 39 as a colorless oil in 75% yield.

Monochloropyrimidine 39 (0.19 mmol) can be treated with 3-aminopyrazole or 3-aminoindazole in essentially the same way as described above in methods A and B.

Method E

As shown in method E, acyl isocyanate 12 can be condensed with enamine to give pyrimidinone 9 (J. Org. Chem. (1993), 58, 414-418; J. Med. Chem., (1992), 35, 1515-1520 ; J. Org. Chem., (1967), 32, 213-214). This method is illustrated by the following General method.

Enamine is obtained by W. White, et al, J. Org. Chem. (1967), 32, 213-214. Acyl isocyanate is prepared by G. Bradley, et al, J. Med. Chem. (1992), 35, 1515-1520. The binding reaction is followed by the procedure of S. Kawamura, et al, J. Org. Chem., (1993), 58, 414-418. To enamine (10 mmol) in tetrahydrofuran (30 ml) at 0 ° C under nitrogen atmosphere, a solution of acyl isocyanate (10 mmol) in tetrahydrofuran (5 ml) is added dropwise over 5 minutes. After stirring for 0.5 hour, acetic acid (30 ml) was added and then ammonium acetate (50 mmol). The mixture was refluxed for 2 hours with continuous removal of tetrahydrofuran. The reaction mixture was cooled to room temperature and poured into water (100 ml). The precipitate was filtered off, washed with water and ether, and dried to obtain 2-aryl-3H-pyrimidin-4-one.

Method F

Method F demonstrates a general way of preparing the compounds of the invention in which R ^x and R ^y are taken together with each other to form a 5-8 membered partially unsaturated or unsaturated ring having 1-3 heteroatoms. The condensation of 2-aminocarboxylic acid, such as 2-aminonicotinic acid 13, and acid chloride 7 gives oxazinone 14. Treatment of compound 14 with ammonium hydroxide gives benzamide 15, can be cyclized with 2- (substituted) pyrido [2,3-d ] [1,3] pyrimidin-4-one 16. This method is illustrated by the following procedure.

2- (Trifluoromethyl) benzoyl chloride (4.2 ml, 29.2 mmol) was added dropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture was heated at 158 ° C for 30 minutes and then cooled to room temperature. The reaction mixture is poured into 200 ml of water, resulting in the formation of oil, which solidifies with stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to obtain 2- (2-trifluoromethylphenyl) pyrido [2,3-d] [1,3] oxazin-4-one (2.56 g, 60% yield), which can be used in the next step without further purification.

2- (2-Trifluoromethylphenyl) pyrido [2,3-d] [1,3] oxazin-4-one (2.51 g) was stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight. The resulting precipitate was filtered off and washed with water and diethyl ether. The precipitate was dried in vacuo at 50 ° C. overnight to give 2- (2-trifluoromethylbenzoylamino) nicotinamide (850 mg, 33% yield).

2- (2-Trifluoromethylbenzoylamino) nicotinamide (800 mg, 2.6 mmol) was dissolved in 10 ml of ethanol. Potassium ethoxide (435 mg, 5.2 mmol) was added to the solution, and the mixture was refluxed for 16 hours. The reaction mixture was evaporated in vacuo to give a gummy residue which was dissolved in water and acidified with 10% sodium hydrogen sulfate to pH 7. The resulting precipitate was filtered off and dried in vacuo at 50 ° C to give 2- (2-trifluoromethylphenyl) -3H-pyrido [2 , 3-d] pyrimidin-4-one.

Method G

Method G is similar to method B (i) described above. This method is illustrated by the following General method.

2- (3,4-Dichlorophenyl) -3H-quinazolin-4-one (1 g, 3.43 mmol) was suspended in phosphorus oxychloride (4 ml) and the reaction mixture was stirred at 110 ° C. for 3 hours. Then, the solvent was evaporated, and the residue was carefully treated with aqueous saturated NaHCO ₃ solution, cooled with ice. The solid was collected by filtration and washed with ether to give 4-chloro-2- (3,5-dichlorophenyl) quinazoline as a white solid (993 mg, 93%).

To 4-chloro-2- (3,5-dichlorophenyl) quinazoline (400 mg, 1.29 mmol) in THF (30 ml) was added 3-amino-5-methylpyrazole (396 mg, 2.58 mmol) and the reaction mixture heated at 65 ° C. overnight. Then the solvents were evaporated and the residue was triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to obtain [2- (3,4-dichlorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine as white solid (311 mg, 65%): mp. 274 ° C; ¹ H NMR (DMSO) δ 2.34 (3H, s), 6.69 (1H, s), 7.60 (1H, m), 7.84 (1H, d), 7.96 (2H, d) ), 8.39 (1H, dd), 8.60 (1H, d), 8.65 (1H, d), 10.51 (1H, s), 12.30, (1H, s); IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 (M + H) ⁺ .

The THF solvent used in the preceding step may be replaced with other organic solvents such as ethanol, N, N-dimethylformamide or dioxane.

Method H

Method H shows the conversion of a halogen-bearing aryl group represented by ring D (X represents Br or I) into other compounds of formula III. Method H (i) shows the binding of phenylboronic acid to ring D to give compound 18, and method H (ii) shows the binding of acetylene to give compound 19. The substituent X in compound 17 can be bromine or iodine. These methods are illustrated by the following methods.

Method H (i). To a mixture of [2- (4-bromophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in a mixture of THF-water (1/1, 4 ml) add Na ₂ CO ₃ (219 mg, 2.06 mmol), triphenylphosphine (9 mg, 1/15 mol%) and palladium acetate (1 mg, 1 / 135 mol%). The mixture was heated at 80 ° C. overnight, the solvent was evaporated, and the residue was purified by flash chromatography (gradient of CH ₂ Cl ₂ / MeOH) to give (2-biphenyl-4-ylquinazolin-4-yl) - (5-methyl-2H- pyrazol-3-yl) amine as a yellow solid (99 mg, 51%): ¹ H NMR (DMSO) δ 2.37 (3H, s), 6.82 (1H, s), 7.39-7 57 (4H, m), 7.73-7.87 (6H, m), 8.57 (2H, d), 8.67 (1H, d), 10.42 (1H, s), 12, 27 (1H, s); MS 378.2 (M + H) ⁺ .

Method H (ii). To a mixture of [2- (4-bromophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (114 mg, 0.3 mmol) and trimethylsilylacetylene (147 mg, 1.5 mmol ) in DMF (2 ml) add CuI (1.1 mg, 1/50 mol.%), Pd (PPh ₃ ) ₂ Cl ₂ (4.2 mg, 1/50 mol.%) and triethylamine (121 mg, 0.36 mmol). The mixture was heated at 120 ° C. overnight and the solvent was evaporated. The residue was triturated in ethyl acetate and the residue was collected by filtration.

To the precipitate obtained above suspended in THF (3 ml) was added tetrabutylammonium fluoride (1M in THF, 1.1 eq.). The reaction mixture was stirred at room temperature for two hours and the solvent was evaporated. The residue was purified by flash chromatography (CH ₂ Cl ₂ / MeOH gradient) to give [2- (4-ethynylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (68 mg, 70 %): ¹ H NMR (DMSO) δ 2.34 (3H, s), 4.36 (1H, s), 6.74 (1H, s), 7.55 (1H, m), 7.65 ( 2H, d), 7.84 (2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M + H) ⁺ .

Method I

This method is a general way to obtain the proposed compounds in which ring D is a heteroaryl or heterocyclyl ring directly attached to pyrimidine at position 2 via a nitrogen atom. Substitution of the 2-chloro group using, for example, piperidine in this case can be carried out by a method similar to that described in J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated by the following method.

To a solution of (2-chloroquinazolin-4-yl) - (1H-indazol-3-yl) amine (1 equivalent, 0.1-0.2 mmol) in N, N-dimethylacetamide (1 ml), add the desired amine (3 equivalent). The resulting mixture was maintained at 100 ° C. for 6 hours and then purified by reverse phase HPLC.

Method j

Method J relates to the preparation of compounds of formula V by substitution of chlorine in a suitably substituted pyridyl ring. Method J (i) is a route for preparing compounds of formula Va (see Indian J. Chem. Sect. B, 35, 8, 1996, 871-873). Method J (ii) is a route for preparing compounds of formula Vb (see Bioorg. Med. Chem., 6, 12, 1998, 2449-2458). For convenience, chloropyridines 21 and 23 are represented with a phenyl substituent corresponding to ring D in formula V. It will be apparent to those skilled in the art that method J is also useful for preparing compounds of formula V in which ring D is heteroaryl, heterocyclyl, carbocyclyl or other aryl rings . Method J is illustrated by the following methods.

Method J (i). (5-Methyl-2H-pyrazol-3-yl) - (2-phenylquinolin-4-yl) amine. To 4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983, 121-128) (0.53 g, 2.21 mmol) in diphenyl ether (5 ml) was added 3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the mixture was heated at 200 ° C. overnight with stirring. Petroleum ether (20 ml) was added to the mixture to be cooled, and the resulting crude precipitate was filtered off and further washed with petroleum ether. The crude solid was purified by flash chromatography (SiO ₂ , DCM-MeOH gradient) to give the title compound as a white solid: mp. 242-244 ° C; ¹ H NMR (DMSO) δ 2.27 (3H, s), 6.02 (1H, s), 7.47 (2H, d), 7.53-7.40 (2H, broad m), 7 67 (1H, m), 7.92 (1H, m), 8.09 (2H, d), 8.48 (2H, m), 9.20 (1H, s), 12.17 (1H, broad.s); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M + H) ⁺ .

Method J (ii). (5-Methyl-2H-pyrazol-3-yl) - (3-phenylisoquin-lin-1-yl) amine. To 1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983, 121-128) (0.33 g, 1.37 mmol) in dry DMF (5 ml) was added 3-amino-5-methylpyrazole (0.27 g, 2.74 mmol) and potassium carbonate (0.57 g, 4.13 mmol) and the mixture was refluxed for 6 hours. The mixture was cooled and most of the DMF was evaporated. The residue was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , DCM-MeOH gradient) to give the title compound as a colorless oil: ¹ H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s) 7.41 (1H, m), 7.52 (2H, m), 7.62 (1H, m), 7.81 (1H, m), 8.07 (1H, d), 8.19 ( 2H, m), 8.29 (1H, s), 8.54 (1H, d); MS 301.2 (M + H) ⁺ .

Method K

Method K is a way of obtaining compounds of formula VI. The universal starting material is 2,4,6-trichloro- [1,3,5] triazine 25, in which the substituents represented by chlorine can be successively substituted. Substitution of one of the chlorine atoms with an aryl Grignard reagent or arylboronic acid is described in PCT application WO 01/25220 and Helv. Chim. Acta, 33, 1365 (1950). Substitution of one of the chlorine atoms with a heteroaryl ring is described in WO 01/25220; J. Het. Chem., 11,417 (1974); and Tetrahedron 31, 1879 (1975). These reactions give 2,4-dichloro- (6-substituted) [1,3,5] triazine 26, which is a useful intermediate for the preparation of compounds of formula VI. In another embodiment, intermediate 26 can be obtained by building a triazine ring by known methods. See US patent No. 2832779 and US patent No. 2691020 together with J. Am. Chem. Soc., 60, 1656 (1938). In turn, one of the chlorine atoms of compound 26 can be substituted as described above to give 2-chloro- (4,6-disubstituted) [1,3,5] triazine 27. Treatment of compound 27 with a suitable aminopyrazole gives the desired a compound of formula VI.

Method L

Method L is a route for preparing compounds of formula VII. For illustrative purposes, trifluoromethylchalcon 28 is used as starting material, but it will be apparent to one skilled in the art that other rings may be used instead of trifluoromethylphenyl and phenyl rings of Compound 28. Substituted chalcones can be obtained by known methods, for example as described in Indian J. Chemistry, 32B, 449 (1993). Condensation of the chalcone with urea gives pyrimidinone 29, which can be treated using POCl ₃ to give chloropyrimidine 30. See J. Chem. Eng. Data, 30 (4), 512 (1985) and Egypt. J. Chem., 37 (3), 283 (1994). In an alternative preparation of compound 30, one of the aryl rings attached to pyrimidine is introduced by replacing the 4-chloro 2,4-dichloro- (6-aryl) pyrimidine group with an arylboronic acid using a palladium catalyst such as (Ph ₃ P) ₄ Pd , in the presence of a base such as sodium carbonate, as described in Bioorg. Med. Lett., 9 (7), 1057 (1999). Replacing the chlorine in compound 30 with a suitable aminopyrazole gives the compounds of the present invention, such as compounds 31. The last step of this method is illustrated by the following procedure.

[4- (Methylpiperidin-1-yl) pyrimidin-2-yl] - (5-methyl-2H-pyrazol-3-yl) amine. To a solution of 2-chloro-4- (4-methylpiperidin-1-yl) pyrimidine (obtained by a procedure similar to that described in Eur. J. Med. Chem., 26 (7), 729 (1991)) (222 mg, 1.05 mmol) in BuOH (5 ml), 3-amino-5-methyl-2H-pyrazole (305 mg, 3.15 mmol) was added and then the reaction mixture was refluxed overnight. The solvent was evaporated and the residue was dissolved in ethanol / water (1/3, 4 ml). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and with ether two times to obtain the title compound as a white solid (143 mg, 50%): mp. 193-195 ° C; ¹ H NMR (DMSO) δ 0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s), 2.83 (2H, t ), 4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, broad s), 11.71 (1H, s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3 (M + H) ⁺ .

Method M

Method M is a process for preparing compounds of formula VIII. A general procedure for replacing chlorine in 4-chloro-6-substituted-pyridazine 32 with suitably substituted pyrazole to give compound VIIIa is described in J. Het. Chem., 20, 1473 (1983). Similar reactions can also be carried out: (a) with 3-chloro-5-substituted-pyridazine 33 to give compound VIIIb, as described in J. Med. Chem., 41 (3), 311 (1998); (b) with 5-chloro-3-substituted- [1,2,4] triazine 34 to give compound VIIIc as described in Heterocycles, 26 (12), 3259 (1987); and (c) with 3-chloro-5-substituted- [1,2,4] triazine 35 to give compound VIIId as described in Pol. J. Chem., 57, 7 (1983); Indian J. Chem. Sect. B, 26, 496 (1987); and agric. Biol. Chem., 54 (12), 3367 (1990). An alternative method for preparing compounds of formula VIIIc is described in Indian J. Chem. Sect. B, 29 (5), 435 (1990).

Compounds of formula IX are prepared by methods essentially analogous to those described above for pyrazole-containing compounds of formula I. Methods A-J can be used to prepare triazole-containing compounds of formula IX by substituting aminopyrazole with aminotriazole. Specific examples of such methods are synthesis examples 415-422 described below. An intermediate aminotriazole derivative can be prepared by the methods described in J. Org. Chem., USSR, 27 952-957 (1991).

Some synthetic intermediates useful in the preparation of the protein kinase inhibitors of the present invention are new. Thus, another object of the present invention is a 3-aminoindazole of formula A:

where R ¹⁰ represents one to three substituents, each of which is independently selected from fluorine, bromine, C _1-6 haloalkyl, nitro or 1-pyrrolyl. Examples of such compounds include the following compounds:

Another object of the present invention is 4-chloropyrimidine of the formula B:

where R ^x and R ^y are as defined above, R ^{1 is} selected from H, Cl, F, CF ₃ , CN, or NO ₂ ; and R ⁵ represents one to three substituents, each of which is independently selected from H, Cl, F, CF ₃ , NO ₂ or CN, provided that R ¹ and R ^{5 are} not Cl at the same time. Examples of compounds of formula B are shown below:

Another object of the present invention is a compound of formula C:

where R ^x , R ^y , R ² and R ^{2 'are} defined above. Examples of compounds of formula C are shown below:

Another object of the present invention is a compound of formula D:

where R ⁵ , R ^x and R ^{y are as} defined above. Examples of compounds of formula D and other useful intermediate pyrimidinone derivatives are shown below:

For a more complete understanding of the present invention, the following examples are described. It should be noted 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 microns, 2.1 x 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 microns, 4.6 x 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 returning to the initial conditions . Total working time is 31.5 minutes. Flow rate: 1.0 ml / min.

HPLC method C:

Column: Cyano, 5 μm, 4.6 x 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 x 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 x 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 [2- (2-Chlorophenyl) -5,6-dimethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-1): ¹ H NMR (500 MHz, DMSO -d ₆ ) δ 10.4 (s, broad, 1H), 7.74 (m, 2H), 7.68 (m, 1H), 7.60 (m, 1H), 6.39 (s, 1H); 2.52 (s, 3H); 2.30 (s, 3H); 2.22 (s, 3H); MS 314.1 (M + H).

Example 2 [2- (2-Chlorophenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-2): The compound was obtained in yield thirty%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.72 (m, 4H), 1.91 (m, 2H), 3.02 (m, 4H), 7.05 (t, 1H), 7 33 (t, 1H), 7.39 (m, 1H), 7.47 (d, 1H), 7.55 (m, 3H), 7.59 (d, 1H), 10.4, (m , 1H); 13.11 (br s, 1H); EI-MS 390.2 (M + H); HPLC method A, R _t 2.99 min.

Example 3 (5-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4-yl] amine (II -3): Compound II-18 (90 mg, 0.17 mmol) was treated with an equal weight of Pd / C (10%) in 4.4% formic acid in MeOH at room temperature for 14 hours. The mixture was filtered through celite, the filtrate was evaporated and the crude product was purified by HPLC to obtain 18 mg (24%) of the desired product as a pale yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.9 (s, 1H), 9.51 (s, 1H), 9.26 (s, 2H), 7.72 (d, 1H), 7 63 (t, 1H), 7.58 (t, 1H), 7.49 (m, 2H), 7.21 (td, 1H), 7.15 (dd, 1H), 4.24 (s, 2H), 3.56 (m, 2H), 2.95 (m, 2H) ppm, MS (ES +): m / e = 429.22 (M + H); HPLC method A, R _t 2.88 min.

Example 4 [2- (2-Chlorophenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-4): The compound was obtained in 52% yield as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.72 (m, 4H), 1.92 (m, 2H), 3.00 (m, 4H), 7.02 (td, 1H), 7 , 20 (dd, 1H), 7.40 (m, 1H), 7.42 (d, 1H), 7.52 (m, 3H), 10.5 (m, 1H), 13.50 (br. s, 1H); EI-MS 408.2 (M + H); HPLC method A, R _t 3.00 min.

Example 5 [2- (2-Chlorophenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-5): Received in 51% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.71 (m, 4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.24 (td, 1H), 7 41 (m, 2H); 7.54 (m, 4H); 10.5 (m, 1H); 13.1 (br s, 1H); EI-MS 408.2 (M + H); HPLC method A, R _t 3.05 min.

Example 6 [2- (2-Chlorophenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-6 ): Obtained by method C with a yield of 72%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.72 (m, 4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.31 (m, 2H), 7 41 (m, 1H); 7.54 (m, 3H); 10.5 (m, 1H); 13.6 (br s, 1H); EI-MS 426.2 (M + H); HPLC method A, R _t 3.21 min.

Example 7 (7-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) 5,6,7,8-tetrahydroquinazolin-4-yl] amine (II-7): Obtained in 62% yield . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.5 (s, broad. 1H), 10.1 (s, broad., 1H), 7.75 (m, 4H), 7.33 ( d, 1H), 7.17 (dd, 1H), 7.00 (td, 1H), 2.80 (m, 2H), 2.71 (m, 2H), 1.89 (broad 4H) m .d .; LC-MS (ES +) 428.44 (M + H). (ES-) 426.43 (MH); HPLC method A, R _t 3.02 min.

Example 8 (5-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydroquinazolin-4-yl] amine (II-8): Obtained in yield 53 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.1 (s, 1H), 10.2 (s, broad, 1H), 7.75 (m, 4H), 7.50 (dd, 1H ), 7.27 (dd, 1H), 7.21 (td, 1H), 2.80 (m, 2H), 2.72 (m, 2H), 1.88 (m, 4H) ppm. ; MS (ES +) 428.43 (M + H). (ES-) 426.43 (MH); HPLC method A, R _t 3.01 min.

Example 9 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydroquinazolin-4-yl] amine (II-9): Obtained from yield 37%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.7 (s, 1H), 10.2 (s, broad, 1H), 7.80 (d, 1H), 7.76 (t, 1H ), 7.69 (m, 2H), 7.31 (t, 1H), 7.18 (d, 1H), 2.81 (t, br., 2H), 2.72 (t, br., 2H), 1.90 (m, 4H) ppm; MS (ES +) 446.42 (M + H). (ES-) 444.37 (MH); HPLC method A, R _t 3.09 min.

Example 10 (5-Trifluoromethyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydroquinazolin-4-yl] amine (II-10): Obtained by method C in ethanol with a yield of 35%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.2 (s, 1H), 10.1 (s, broad, 1H), 8.01 (s, 1H), 7.76 (d, 1H ), 7.66 (m, 4H), 7.57 (d, 1H), 2.79 (m, 2H), 2.73 (m, 2H), 1.89 (m, 4H) ppm. MS (ES +) 478.45 (M + H). (ES-) 476.42 (MH); HPLC method A, R _t 3.21 min.

Example 11 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] amine (II-11 ): Received in 60% yield. White solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.72 (m, 4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.15 (dd, 1H), 7 30 (td, 1H), 7.66 (m, 2H), 7.72 (t, 1H), 7.78 (d, 1H), 10.2 (m, 1H), 13.5 (br. s, 1H); EI-MS 460.2 (M + H); HPLC method A, R _t 3.13 min.

Example 12 (6-Benzyl-2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl) - (5-fluoro-1H-indazol-3-yl ) amine (II-12): Obtained in 49% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.8 (s, 1H), 9.11 (s, 1H), 7.68 (d, 1H), 7.58 (t, 1H), 7 53 (t, 1H), 7.44 (m, 4H), 7.37 (t, 2H), 7.29 (t, 1H), 7.19 (m, 2H), 3.78 (s, 2H), 3.61 (s, 2H), 2.81 (s, broad 4H) ppm; LC-MS (ES +) 519.24 (M + H); HPLC method A, R _t 3.11 min.

Example 13 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] amine (II-13): Obtained in yield 40 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.70 (m, 4H), 1.90 (m, 2H), 3.00 (m, 4H), 7.01 (t, 1H), 7 30 (td, 1H), 7.44 (d, 1H), 7.49 (d, 1H), 7.68 (m, 3H), 7.77 (d, 1H), 10.01 (m, 1H); 12.83 (s, 1H); EI-MS 424.2 (M + H); HPLC method A, R _t 3.17 min.

Example 14 (7-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] amine (II-14): Received in 78% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.71 (m, 4H), 1.91 (m, 2H), 3.00 (m, 4H), 6.38 (td, 1H), 7 16 (dd, 1H), 7.31 (d, 1H), 7.68 (m, 3H), 7.77 (d, 1H), 10.25 (m, 1H), 13.40 (br. s, 1H); EI-MS 442.2 (M + H); HPLC method A, R _t 3.12 min.

Example 15 (5-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl] amine (II-15): Received in 63% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.71 (m, 4H), 1.91 (m, 2H), 3.00 (m, 4H), 7.20 (td, 1H), 7 25 (dd, 1H), 7.49 (dd, 1H), 7.69 (br t, 2H), 7.74 (m, 1H), 7.79 (d, 1H), 10.35 ( m, 1H), 13.00 (br s, 1H); EI-MS 442.2 (M + H); HPLC method A, R _t 3.21 min.

Example 16 (7-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl] amine (II -16): A solution of compound (II-12) (45 mg, 0.087 mmol) in methanol (4.4% HCOOH) was treated with an equal weight of Pd / C (10%) at room temperature for 14 hours. The mixture was filtered through celite, the filtrate was evaporated and the crude product was purified by preparative HPLC to give 15 mg (41%) of the desired product as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.9 (s, 1H), 9.52 (s, 1H), 9.32 (s, 2H, TFA-OH), 7.72 (d, 1H), 7.59 (m, 2H), 7.49 (m, 2H), 7.21 (m, 1H), 7.15 (m, 1H), 4.31 (s, 2H), 3, 55 (s, 2H); 3.00 (m, 2H) ppm; LC-MS (ES +) 429.20 (M + H); HPLC method A, R _t 2.79 min.

Example 17 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydroquinazolin-4-yl] amine (II-17): Obtained in 58% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.0 (s, 1H), 10.3 (s, broad, 1H), 7.74 (m, 4H), 7.51 (d, 1H ), 7.47 (d, 1H), 7.32 (t, 1H), 7.03 (t, 1H), 2.82 (m, 2H), 2.73 (m, 2H), 1.90 (m, 4H) ppm, LC-MS (ES +) 410.21 (M + H); HPLC method A, R _t 2.99 min.

Example 18 (7-Benzyl-2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl) - (5-fluoro-1H-indazol-3-yl ) amine (II-18): Obtained from compound B11 in 92% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.9 (s, 1H), 10.5 (s, broad, 1H), 9.58 (s, 1H, TFA-OH), 7.71 (d, 1H), 7.52 (m, 9H), 7.19 (m, 2H), 4.57 (s, 2H), 4.20 (m, 2H), 3.70 (m, 2H) 3.00 (m, 2H) ppm; LC-MS (ES +) 519.23 (M + H); HPLC method A, R _t 3.23 min.

Example 19 (1H-Indazol-3-yl) - [6-methyl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] amine (II-19): Obtained in 42% yield. Melting point 235-237 ° C. ¹ H NMR (500 MHz, DMSO) δ 2.44 (3H, s), 7.09 (1H, J = 7.5 Hz, t), 7.40 (1H, J = 7.1 Hz, t) , 7.49 (1H, J = 8.3 Hz, d), 7.70 (3H, m), 7.79 (1H, J = 7.3 Hz, t), 7.87 (1H, J = 8.3 Hz, d), 8.03 (1H, J = 7.7 Hz, d), 10.3 (1H, s), 12.6 (1H, s) ppm, HPLC method A R _t 2.958 min; MS (, FIA) 370.2 (M + H) @ ⁺ .

Example 20 (1H-Indazol-3-yl) - [6-phenyl2- (2-trifluoromethylphenyl) pyrimidin-4-yl] amine (II-20): Obtained in 32% yield. ¹ H NMR (500 MHz, DMSO) δ 6.94 (1H, J = 7.4 Hz, t), 7.24 (1H, J = 7.4 Hz, t), 7.33 (1H, J = 8.4 Hz, d), 7.42 (3H, m), 7.57 (1H, J = 7.3 Hz, t), 7.68 (2H, m), 7.75 (1H, J = 7.9 Hz, d), 7.93 (3H, m), 8.18 (1H, broad s), 10.45 (1H, broad s), 12.5 (1H, broad s) m .d .; HPLC method A, R _t 4.0 min. MS (FIA) 432.2 (M + H) ⁺ .

Example 21 (1H-Indazol-3-yl) - [6- (pyridin-4-yl) -2- (2-trifluoromethylphenyl) pyrimidin-4-yl] amine (II-21): Obtained in 12% yield. ¹ H NMR (500 MHz, DMSO) δ 7.16 (1H, J = 7.4 Hz, t), 7.46 (1H, J = 7.6 Hz, t), 7.56 (1H, J = 8.3 Hz, d), 7.80 (1H, J = 7.2 Hz, t), 7.90 (2H, m), 7.97 (1H, J = 7.8 Hz, d), 8 09 (1H, br.s), 8.22 (2H, J = 4.9 Hz, d), 8.45 (1H, br.s), 8.93 (2H, J = 4.8 Hz, d ), 10.9 (1H, broad s), 12.8 (1H, broad s) ppm; HPLC method A, R _t 3,307 min. MS (FIA) 433.2 (M + H) ⁺ .

Example 22 (1H-Indazol-3-yl) - [6- (pyridin-2-yl) -2- (2-trifluoromethylphenyl) pyrimidin-4-yl] amine (II-22): Obtained in 42% yield. ¹ H NMR (500 MHz, DMSO) δ 7.07 (1H, J = 7.4 Hz, t), 7.36 (1H, J = 7.4 Hz, t), 7.46 (1H, J = 7.4 Hz, d), 7.53 (1H, J = 5.0 Hz, t), 7.70 (1H, J = 7.4 Hz, t), 7.79 (1H, J = 7, 1 Hz, t), 7.83 (1H, J = 7.4 Hz, d), 7.88 (1H, J = 7.8 Hz, d), 7.97 (1H, J = 7.7 Hz , t), 8.02 (1H, J = 5.5 Hz, broad d), 8.36 (1H, J = 7.8 Hz, d), 8.75 (2H, J = 4.1 Hz d) 10.5 (1H, broad s); 12.7 (1H, broad s) ppm; HPLC method A, R _t 3,677 min; MS (FIA) 433.2 (M + H) ⁺ .

Example 23 [6- (2-Chlorophenyl) -2- (2-trifluoromethylphenyl) pyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-23): Received in 44% yield. ¹ H NMR (500 MHz, DMSO) δ 7.08 (1H, J = 7.5 Hz, t), 7.37 (1H, J = 7.5 Hz, t), 7.45 (1H, J = 8.4 Hz, d), 7.51 (2H, m), 7.61 (1H, J = 7.4, 1.9 Hz, dd), 7.69 (2H, m), 7.79 ( 2H, J = 4.0 Hz, d), 7.86 (3H, J = 7.8 Hz, d), 8.04 (2H, J = 6.2 Hz, broad.d), 10.7 ( 1H, broad s), 12.6 (1H, broad s) ppm; HPLC method A, R _t 3,552 min; MS (FIA), 466.2 (M + H) @ ⁺ .

Example 24 [5,6-Dimethyl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-24): Obtained in 35% yield; so pl. 183-186 ° C. ¹ H NMR (500 MHz, DMSO) δ 2.14 (3H, s), 2.27 (3H, s), 6.85 (1H, J = 7.5 Hz, t), 7.15 (1H, J = 7.6 Hz, t), 7.32 (3H, m), 7.38 (1H, J = 7.5 Hz, t), 7.42 (1H, J = 7.4 Hz, t) 7.53 (1H, J = 7.6 Hz, d), 8.88 (1H, s), 12.5 (1H, s) ppm; HPLC method A, R _t 2.889 min; MS (FIA) 384.2 (M + H) '.

Example 25 [5,6-Dimethyl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-25): Obtained in 44% yield. Melting point 160-163 ° C. ¹ H NMR (500 MHz, DMSO) δ 2.27 (3H, s), 2.40 (3H, s), 7.15 (2H, m), 7.44 (2H, m), 7.52 { 1H, J = 7.4 Hz, t), 7.57 (1H, J = 7.4 Hz, t), 7.67 (1H, J = 7.8 Hz, d), 9.03 (1H, s), 12.75 (1H, s) ppm; HPLC method A, R _t 2,790 min; MS (FIA) 402.2 (M + H) @ ⁺ .

Example 26 [2- (2-Chlorophenyl) -5,6-dimethylpyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-26): Obtained in 30% yield. ¹ H NMR (500 MHz, DMSO) δ 2.14 (3H, s), 2.33 (3H, s), 6.84 (1H, J = 7.4 Hz, t), 7.13 (1H, J = 7.4 Hz, t), 7.19 (1H, J = 6.9 Hz, broad t), 7.27 (1H, J = 7.4 Hz, d), 7.32 (3H, broad m), 7.37 (1H, J = 7.1Hz, d), 10.0 (1H, broad), 12.8 (1H, broad s) ppm; 8 2.919 min; MS (FIA) 350.1 (M + H) @ ⁺ .

Example 27 [5,6-Dimethyl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-27): Obtained in 92% yield. ¹ H NMR (500 MHz, DMSO) δ 2.33 (3H, s), 2.50 (3H, s), 6.91 (1H, m), 7.15 (1H, m), 7.30 ( 1H, J = 8.1 Hz, d), 7.65 (3H, m), 7.76 (1H, J = 7.5 Hz, d), 10.0 (1H, s), 13.4 ( 1H, s) ppm; HPLC method A, R _t 3,053 min; MS (FIA) 402.2 (M + H) @ ⁺ .

Example 28 (5,7-Difluoro-1H-indazol-3-yl) - [5,6-dimethyl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] amine (II-28): Obtained in 50% yield . ¹ H NMR (500 MHz, DMSO) δ 2.42 (3H, s), 2.63 (3H, s), 7.22 (1H, J = 7.6Hz, d), 7.38 (1H, J = 9.3, 1.7 Hz, dt), 7.71 (1H, m), 7.75 (1H, J = 7.0 Hz, d), 7.79 (1H, J = 6.7 Hz d) 7.86 (1H, J = 8.0 Hz, d), 10.0, (1H, s), 13.2 (1H, s) ppm; HPLC method A, R _t 3.111 min; MS (FIA) 420.2 (M + H) @ ⁺ .

Example 29 [2- (2-Chlorophenyl) -5,6-dimethylpyrimidin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-29): Obtained in 58% yield. ¹ H NMR (500 MHz, DMSO) δ 2.47 (3H, s), 2.66 (3H, s), 7.44 (2H, m), 7.53 (1H, m), 7.64 ( 3H, m), 10.4 (1H, broad), 13.8 (1H, broad s) ppm; HPLC - Method A, R _t 2.921 min; MS (FIA) 386.1 (M + H) @ ⁺ .

Example 30 [2- (2-Chlorophenyl) -5,6-dimethylpyrimidin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-30): Obtained in 70% yield. ¹ H NMR (500 MHz, DMSO) δ 2.35 (3H, s), 2.51 (3H, s), 7.03 (1H, J = 7.8, 4.4 Hz, dt), 1, 22 (1H, m), 7.33 (1H, J = 7.4 Hz, t), 7.42 (1H, m), 9.19 (1H, s), 13.3 (1H, s) m .d .; HPLC method A, R _t 2.859 min; MS, (FIA) 368.2.

Example 31 [2- (2-Chlorophenyl) -5,6-dimethylpyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-31): Received in 86% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.49 (3H, s), 2.68 (3H, s), 7.38 (1H, J = 9.0 Hz, t), 7.54 (2H, m), 7.67 (4H, m), 10.5 (1H, broad), 13.2 (1H, broad s) ppm; HPLC method A, R _t 2,850 min; MS (FIA) 368.1 (M + H) ⁺ .

Example 32 [2- (2,4-Dichlorophenyl) -5,6-dimethylpyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-32): Obtained in 52% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.46 (3H, s), 2.64 (3H, s), 7.16 (1H, J = 7.5 Hz, t), 7.46 (1H, J = 7.6 Hz, t), 7.61 (2H, m), 7.68 (2H, J = 8.2 Hz, d), 7.82 (1H, m), 10.2 (1H, broad), 13.0 (1H, broad s) ppm; HPLC method A, R _t 2.983, min; MS (FIA) 384.1 (M + H).

Example 33 (5-Methyl-2H-pyrazol-3-yl) - [2- (2-methylphenyl) -quinazolin-4-yl] amine (II-33): ¹ H NMR (DMSO) δ 1.21 (3H , s), 2.25 (3H, s), 6.53 (1H, s), 7.38 (4H, m), 7.62 (1H, d), 7.73 (1H, d), 7 81 (1H, d); 7.89 (1H, t); 8.70 (1H, s); 12.20 (1H, s); MS 316.3 (M + H) ⁺ .

Example 34 [2- (2,4-Difluorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-34): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.4 (br s, 1H), 10.8 (br s, 1H), 8.58 (d, 1H), 7.97 (m, 1H), 8.36 (m, 1H) 7.85 (m, 1H); 7.60 (m, 1H); 6.62 (s, 1H); 2.30 (s, 3H); MS 338.07 (M + H).

Example 35 [2- (2,5-Dimethoxyphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-35): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.5 (br s, 1H), 8.68 (br, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.86 (d, J = 8.2 , Hz, 1H), 7.65 (t, J = 7.5, Hz, 1H), 7.45 (s, 1H), 7.14 (m, 2H), 6.51 (s, 1H), 3.79 (s, 3H); 3.67 (s, 3H); 2.14 (s, 3H); MS 362.2 (M + H).

Example 36 [2- (2-Chlorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-36): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.8 (broad, 1H), 8.80 (d, J = 8.3 Hz, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78 (m, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.0 Hz, 1H), 7 55 (t, J = 7.4 Hz, 1H); 6.56 (s, 1H); 2.18 (s, 3H); MS 336.1 (M + H).

Example 37 [2- (2-Methoxyphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-37): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.78 (s, br., 1H), 8.00 (t, J = 7.4 Hz, 1H), 7.90 (m, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H) 6.58 (s, broad. 1H); 3.90 (s, 3H); 2.21 (s, 3H); MS 332.1 (M + H).

Example 38 [2- (2,6-Dimethylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-38): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.2 (s, broad 2H), 8.88 (d, J = 7.7 Hz, 1H), 8.05 (t, J = 7.7 Hz, 1H), 7.80 (m , 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 6.36 (s, 1H), 2.16 (s , 3H); 2.15 (s, 6H); MS 330.1 (M + H).

Example 39 [2- (2-Acetylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-39): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.35 (s, br., 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.11 (t, J = 8.0 Hz, 2H), 7.89 (m, 2H), 7.77 (m, 2H), 6.93 (s, 1H), 2.33 (s, 3H), 2.04 (s, 3H), MS 344.1 (M + H).

Example 40 [2- (2,3-Dimethylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-40): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.6 (s, broad, 1H), 12.1 (s, broad, 1H), 8.91 (d, J = 7.7 Hz, 1H), 8.14 (t, J = 7.2 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.89 (t, J = 7.7, Hz, 1H), 7.58 (d, J = 7 , 6 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 6.60 (s, 1H), 2, 43 (s, 3H); 2.35 (s, 3H); 2.32 (s, 3H); MS 330.1 (M + H).

Example 41 (5-Methyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-41): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.3 (s, 1H), 10.5 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 7.92 (m, 2H), 7.85 (m, 3H ), 7.56 (t, J = 8.1 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 6.63 (s, 1H), 2.27 (s, 3H ); MS 370.1 (M + H).

Example 42 [2- (2-Ethylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-42): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.80 (m, 1H), 8.02 (s, br., 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 (m, 1H), 7.62 ( d, J = 7.6 Hz, 1H), 7.54 (m, 1H), 7.41 (m, 2H), 6.40 (s, 1H), 2.75 (q, J = 7.1 Hz, 2H), 2.17 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H); MS 330.1 (M + H).

Example 43 (2-Biphenyl-2-ylquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (II-43): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8 76 (d, J = 7.6 Hz, 1H), 8.04 (m, 1H), 7.75 (m, 6H), 7.30 (m, 5H), 5.34 (s, 1H) 2.14 (s, 3H); MS 378.2 (M + H).

Example 44 [2- (2-Hydroxyphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-44): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.9 (s, br., 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.87 (m, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.92 (m, 2H), 6.45 (s, 1H); 2.27 (s, 3H); MS 318.1 (M + H).

Example 45 [2- (2-Ethoxyphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-45): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.1 (s, br., 1H), 8.75 (d, J = 8.3 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.55 (s, 1H), 4 11 (q, J = 6.9 Hz, 2H); 2.16 (s, 3H); 1.22 (t, J = 6.9 Hz, 3H); MS 346.1 (M + H).

Example 46 [5- (Thiophen-2-yl) -2H-pyrazol-3-yl] - [2- (2-trifluoro-methylphenyl) quinazolin-4-yl] amine (II-46): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.04 (d, J = 8.3 Hz, 1H), 8.05 (dd, J = 7.3, 8.2 Hz, 1H), 7.93 (d, J = 6.5 Hz, 1H), 7.81 (m, 5H), 7.34 (d, J = 5.0 Hz, 1H), 7.25 (m, 1H), 7.00 (m, 1H); 6.87 (s, 1H); MS 438.1 (M + H).

Example 47 [4- (Thiophen-2-yl) -2H-pyrazol-3-yl] - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-47): Obtained by Method B. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.97 (m, 1H), 7.08 (m, 1H), 7.27 (m, 1H), 7.36 (m, 1H), 7.66 ( m, 2H), 7.77 (m, 3H), 7.83 (m, 1H), 8.00 (m, 1H), 8.18 (s, 1H), 8.62 (d, J = 8 , 2 Hz, 1H); 10.7 (br s, 1H); El-MS 438.1 (M + H); HPLC method A, R _t 2.97 min.

Example 48 (4-Phenyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-48): Obtained by Method B. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.05 (br s, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.25 (m, 3H), 7.43 (m, 2H), 7 60 (m, 2H), 7.73 (m, 2H), 7.80 (d, 1H), 7.95 (m, 1H), 8.12 (br s, 1H), 8.60 ( m, 1H); 10.6 (br s, 1H); El-MS 432.2 (M + H); HPLC method A, R _t 3.04 min.

Example 49 (5-tert-Butyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-49): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.76 (d, J = 8.3 Hz, 1H), 7.94 (m, 2H), 7.79 (m, 4H), 7.70 (t, J = 7.6 Hz, 1H ), 6.51 (s, 1H), 1.16 (s, 9H); MS 412.2 (M + H).

Example 50 (5-Phenyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-50): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.09 (s, 1H), 7.36 (td, J = 7.8, 1.1 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.65 (broad d, J = 8.1 Hz, 2H), 7.78 (m, 2H), 7.90 (m, 4H), 7.95 (d, J = 7.7 Hz, 1H), 8.00 (t, J = 7.8 Hz, 1H), 8.81 (d, J = 8.6 Hz, 1H), 11.29 (br s, 1H); EI-MS 432.1 (M + H); HPLC method A, R _t 3.24 min.

Example 51 (4,5-Diphenyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-51): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.13 (m, 1H), 7.18 (m, 5H), 7.36 10 (m, 5H), 7.62 (m, 3H), 7.73 (m, 2H), 7, 85 (m, 1H), 8.48 (d, J = 8.7 Hz, 1H), 10.02 (s, 1H), 13.19 (s, 1H); EI-MS 508.2 (M + H); HPLC method A, R _t 3.39 min.

Example 52 (4-Carbamoyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-52): Obtained in 40% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 12.77 (s, 1H), 11.80 (s, 1H), 10.80 (s, 1H), 8 35-7.42 (m, 9H); MS 399.13 (M + H) HPLC Method A, R _t 2.782 min.

Example 53 (2H-Pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-53): Obtained in 38% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 10.65 (s, 1H), 8.75 (d, 1H), 7.91-7.68 (m, 8H), 6.87 (s, 1H), MS: (M + H) 356.17, HPLC method A, R _t 2.798 min.

Example 54 (5-Hydroxy-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-54): Obtained in 36% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.75 (s, 1H), 8.03-7.75 (m, 9H), 5.97 (s, 1H); MS 372.18 (M + H); HPLC method A, R _t 2.766 min.

Example 55 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-55): Obtained in 30% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.21 (s, 1H), 10.45 (s, 1H), 8.68 (s, 1H), 7.89-7.45 (m, 8H), 5 6.48 (s, 1H), 0.89 (m, 2H), 0.62 (s, 2H), MS 396.18 (M + H); HPLC method A, R _t 3.069 min.

Example 56 (5-Methoxymethyl-2H-pyrazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-56): Obtained in 33% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.51 (s, 1H), 10.48 (s, 1H), 8.60 (s, 1H), 7.81-7.55 (m, 7H), 6.71 (s, 1H), 4.28 (s, 2H), 3.18 (s, 3H), MS 400.19 (M + H): HPLC method A, R _t 2.881 min.

Example 57 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-57): 51 mg (78% yield) was obtained as a pale yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.7 (s, 1H), 10.4 (s, 1H), 8.55 (d, 1H), 7.81 {t, 1H), 7 71 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.46 (m, 4H), 7.3-6 (d, 1H), 7.22 ( t, 1H); 6.91 (t, 1H) ppm; LC-MS (ES +) 406.16 (M + H). (ES-) 404.19 (MH); HPLC Method A, Rt 3.00 min.

Example 58 (4-Chloro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-58): Received in DMF (70% yield) as pale yellow solid matter. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.3 (s, broad, 1H), 10.9 (s, broad, 1H), 8.60 (d, 1H), 7.97 ( t, 1H), 7.81 (d, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.63 (dd, 1H), 7.57 (m, 2H), 7.43 (d, 1H); 7.28 (dd, 1H); 7.08 (d, 1H) ppm; LC-MS (ES +) 440.10 (M + H). (ES-) 438.12 (MH); HPLC method A, R _t 3.08 min.

Example 59 (5-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-59): Received in DMF (34% yield) as pale yellow solid matter. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.0 (s, 1H), 10.6 (s, 1H), 8.72 (d, 1H), 7.99 (t, 1H), 7 89 (d, 1H), 7.79 (d, 1H), 7.75 (t, 1H), 7.68 (m, 3H), 7.56 (dd, 1H), 7.39 (d, 1H), 7.28 (t, 1H) ppm; LC-MS (ES +) 424.12 (M + H). (ES-) m / e = 422.13 (MH); HPLC method A, R _t 3.05 min.

Example 60 (7-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-60): Received in DMF (51% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 10.6 (s, 1H), 8.68 (d, 1H), 7.95 (t, 1H), 7 85 (d, lH), 7.72 (m, 2H), 7.63 (m, 2H), 7.58 (m, 1H), 7.43 (d, 1H), 7.18 (dd, 1H), 7.00 (m, 1H) ppm; LC-MS (ES +) 424.11 (M + H). (ES-) 422.15 (MH); HPLC method A, R _t 3.06 min.

Example 61 (5-Methyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-61): Received in DMF (81% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.0 (s, broad, 1H), 8.79 {broad, 1H), 8.11 (broad, 1H), 7.96 (d , 1H), 7.82 (m, 5H), 7.46 (s, 1H), 7.41 (d, 1H), 7.20 (d, 1H), 2.33 (s, 3H) m. d .; MS (ES +) 420.15 (M + H). (ES-) 418.17 (MH); HPLC method A, R _t 3.07 min.

Example 62 [2- (2,6-Dichlorophenyl) quinazolin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-62): Obtained in DMF (yield 37%) as yellow solid matter. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.0 (s, 1H), 10.8 (s, 1H), 8.72 (d, 1H), 7.97 (t, 1H), 7 90 (d, 1H), 7.75 (t, 1H), 7.53 (m, 3H), 7.43 (t, 1H), 7.35 (d, 1H), 7.23 (t, 1H) ppm; LC-MS (ES +) 424.08 (M + H). (ES-) 422.10 (MH); HPLC method A, R _t 3.06 min.

Example 63 [2- (2-Chlorophenyl) quinazolin-4-yl] - (1H-indazol-3-yl) amine (II-63): Obtained in 91% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.06 (t, 1H), 7.36 (t, 1H), 7.39 (t, 1H), 7.52 (m, 3H), 7 62 (d, 1H), 7,72 (d, 1H), 7,82 (m, 1H), 7,90 (d, 1H), 8 ₀₅ (m, 1H), 8,76 (d, 1H), 11.5 (m, 1H), 13.02 (s, 1H); EI-MS 372.1 (M + 1); HPLC method A, R _t 2.93 min.

Example 64 (5-Trifluoromethyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-64): Received in DMF (yield 57%) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.4 (s, broad, 1H), 11.4 (broad, 1H), 8.72 (d, 1H), 8.12 (s, 1H), 7.98 (t, 1H), 7.83 (d, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.60 (m, 4H), 7, 52 (d, 1H) ppm; LC-MS (ES +) 474.12 (M + H). (ES-) 472.17 (MH); HPLC method A, R _t 3.25 min.

Example 65 (4-Trifluoromethyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-65): Received in DMF (8% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.7 (s, broad. 1H), 11.2 (br., 1H), 8.70 (d, 1H), 8.05 (s, 1H), 7.85 (m, 3H), 7.65 (m, 4H), 7.51 (m, 2H) ppm; LC-MS (ES +) 474.13 (M + H). (ES-) 472.17 (MH); HPLC method A, R _t 3.15 min.

Example 66 [2- (2,6-Dichlorophenyl) quinazolin-4-yl] - (1H-indazol-3-yl) amine (II-66): Received in DMF (30% yield) as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.9 (s; 1H), 11.1 (s, 1H), 8.69 (d, 1H), 7.95 (t, 1H), 7 82 (d, 1H) ', 7.73 (t, 1H), 7.56 (d, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.39 (m , 2H); 7.26 (t, 1H); 6.92 (t, 1H) ppm; LC-MS (ES +) 406.11 (M + H). (ES-) 404.12 (MH); HPLC method A, R _t 3.00 min.

Example 67 (1H-Indazol-3-yl) - [2- (2-methylphenyl) quinazolin-4-yl] amine (II-67): Obtained in 55% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.15, (s, 3H), 7.09 (t, 1H), 7.26 (d, 1H), 7.31 (t, 1H), 7.39 (t, 1H), 7.42 (m, 1H), 7.55 (d, 1H), 7.64 (d, 1H), 7.74 (d, 1H), 7.89 (m , 1H), 7.96 (d, 1H), 8.10 (m, 1H), 8.81 (d, 1H), 12.0 (m, 1H), 13.18 (s, 1H); EI-MS 352.2 (M + 1); HPLC method A, R _t 2.93 min.

Example 68 (7-Trifluoromethyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-68): Received in DMF (75% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.5 (s, broad. 1H), 11.2 (s, broad. 1H), 8.68 (d, 1H), 7.97 { t, 1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.74 (t, 1H), 7.70 (d, 1H), 7.68 (d, 1H), 7.64 (m, 2H), 7.57 (m, 1H), 7.14 (t, 1H) ppm; LC-MS (ES +) 474.11 (M + H). (ES-) 472.14 (MH); HPLC method A, R _t 3.24 min.

Example 69 (6-Trifluoromethyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-69): Obtained by Method B in DMF (78% yield) as yellow solid matter. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.4 (s, broad. 1H), 11.1 (s, broad. 1H), 8.67 (d, 1H), 7.95 ( t, 1H), 7.82 (m, 3H), 7.72 (m, 2H), 7.63 (m, 2H), 7.57 (t, 1H), 7.23 (d, 1H) m .d .; LC-MS (ES +) 474.12 (m, + H).

(ES-) 472.15 (MH); HPLC method A, R _t 3.28 min.

Example 70 (5-Nitro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-70): Received in DMF (yield 72%) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.6 (s, broad. 1H), 11.4 (s, broad. 1H), 8.75 (s, 1H), 8.72 ( d, 1H), 8.09 (dd, 1H), 7.98 (t, 1H), 7.83 (d, 1H), 7.75 (t, 1H), 7.70 (m, 2H), 7.61 (m, 3H) ppm; LC-MS (ES +) 451.14 (M + H). (ES-) 449.12 (MH); HPLC method A, R _t 3.02 min.

Example 71 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-71): Obtained in DMF (60% yield) as yellow solid matter. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.7 (s, broad. 1H), 11.2 (s, broad. 1H), 8.73 (d, 1H), 8.03 (t , 1H), 7.88 (d, 1H), 7.80 (m, 2H), 7.70 (m, 3H), 7.32 (m, 2H) ppm; LC-MS (ES +) 442.14 (M + H). (ES-) 440.14 (MH); HPLC method A, R _t 3.11, min.

Example 72 (4-Pyrrol-1-yl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-72): Obtained in DMF (yield 33%) in as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.4 (s, broad. 1H), 11.0 (s, broad. 1H), 8.53 (d, 1H), 7.98 ( t, 1H), 7.75 (m, 4H), 7.62 (m, 2H), 7.52 (d, 1H), 7.43 (t, 1H), 7.05 (d, 1H), 6.80 (s, 2H); 5.61 (s, 2H) ppm; LC-MS (ES +) 471.18 (M + H). (ES-) 469.18 (MH); HPLC method A, R _t 3.12 min.

Example 73 (5-amino-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-73): Solution of compound II-70 (70 mg, 0.16 mmol ) in MeOH (2 ml), Raney Ni was treated until the solution became colorless (approximately 1.5 g Raney Ni was added). After stirring at room temperature for 40 minutes, the mixture was filtered through celite, the resulting celite was washed with MeOH (5 times) and the solvent was evaporated in vacuo to give a crude product, which was then purified by HPLC to give the title compound as a yellow solid (10 mg, 15%). Mp 221-223 ° C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.2 (s, broad. 1H), 10.7 (s, broad. 1H), 9.80 (broad 2H), 8.68 ( d, 1H), 7.97 (t, 1H), 7.87 (d, 1H), 7.75 (m, 2H), 7.65 (m, 5H), 7.30 (d, 1H) m .d .; MS (ES +) 421.16 (M + H). (ES-) 419.17 (MH); HPLC method A, R _t 2.41 min.

Example 74 [2- (2-Chlorophenyl) quinazolin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-74): Received in DMF (yield 35%) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.7 (s, 1H), 11.7 (s, broad, 1H), 8.80 (d, 1H), 8.15 (t, 1H ), 7.99 (d, 1H), 7.88 (t, 1H), 7.68 (d, 1H), 7.60 (m, 2H), 7.53 (t, 1H), 7.46 (t, 1H), 7.25 (dd, 1H), 7.04 (m, 1H) ppm; LC-MS (ES +) 390.16 (M + H); HPLC method A, R _t 3.00 min.

Example 75 [2- (2-Chlorophenyl) quinazolin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-75): Obtained in DMF. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.2 (s, 1H), 11.7 (s, broad, 1H), 8.80 (d, 1H), 8.10 (t, 1H ), 7.91 (m, 2H), 7.70 (d, 1H), 7.58 (m, 4H), 7.50 (t, 1H), 7.29 (t, 1H) ppm. ; LC-MS (ES +) 390.17 (M + H); HPLC method A, R _t 3.00 min.

Example 76 [2- (2-Chlorophenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-76): Received in DMF (55% yield) as yellow solid matter. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (s, 1H), 11.5 (s, broad, 1H), 8.76 (d, 1H), 8.08 (t, 1H ), 7.93 (d, 1H), 7.84 (t, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.50 (t, 1H), 7.44 (m, 2H); 7.36 (t, 1H) ppm; LC-MS (ES +) 408.15 (M + H). (ES-) 406.17 (MH); HPLC method A, R _t 3.08 min.

Example 77 [2- (2-Chlorophenyl) quinazolin-4-yl] - (5-trifluoromethyl-1H-indazol-3-yl) amine (II-77): Received in DMF (66% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.5 (s, 1H), 11.4 (s, broad, 1H), 8.79 (d, 1H), 8.29 (s, 1H ), 8.07 (t, 1H), 7.93 (d, 1H), 7.84 (t, 1H), 7.72 (d, 1H), 7.63 (d, 2H), 7.53 (d, 1H), 7.48 (t, 1H), 7.36 (t, 1H) ppm; LC-MS (ES +): m / e = 440.16 (M + H); (ES-): m / e = 438.18 (MH); HPLC method A, R _t 3.22 min.

Example 78 [2- (2-Cyanophenyl) quinazolin-4-yl] - (1H-indazol-3-yl) amine (II-78): Obtained in 13% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.9 (brs, 1H), 10.8 (br., 1H), 8.73 (br.s, 1H), 7.97 (m, 4H), 7.74 (m, 1H), 7.5 (m, 4H), 7.42 (m, 1H), 7.08 (m, 1H) ppm; MS (FIA) 363.2 (M + H); HPLC method A, R _t 2.971 min.

Example 79 (5-Bromo-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-79): Received in DMF (64% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.4 (s, broad, 1H), 11.6 (s, broad, 1H), 8.93 (d, 1H), 8.21 (t, 1H ), 8.14 (s, 1H), 8.05 (d, 1H), 7.95 (m, 4H), 7.86 (t, 1H), 7.65 (d, 1H), 7.59 (d, 1H) ppm; MS- (ES +) 486.10 (M + H). (ES-) 484.09 (MH); HPLC method A, R _t 3.22 min.

Example 80 (6-Chloro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-80): Received in DMF (yield 94%) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.1 (s, 1H), 11.2 (s, broad, 1H), 8.73 (d, 1H), 8.03 (t, 1H ), 7.87 (d, 1H), 7.79 (m, 2H), 7.73 (m, 2H), 7.67 (m, 2H), 7.58 (s, 1H), 7.04 (dd, 1H) ppm, LC-MS (ES +) 440.14 (M + H). (ES-) 438.16 (MH); HPLC method A, R _t 3.25 min.

Example 81 (7-Fluoro-6-trifluoromethyl-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-81): Obtained in DMF (yield 30%) in as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.9 (s, broad, 1H), 11.0 (s, broad, 1H), 8.64 (d, 1H), 7.94 (t, 1H ), 7.81 (d, 1H), 7.71 (m, 2H), 7.60 (m, 4H), 7.20 (dd, 1H) ppm, LC-MS (ES +) 492, 18 (M + H). (ES-) 490.18 (MH); HPLC method A, R _t 3.44 min.

Example 82 (6-Bromo-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-82): Received in DMF (yield 40%) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.1 (s, 1H), 11.2 (s, broad, 1H), 8.73 (d, 1H), 8.03 (t, 1H ), 7.87 (d, 1H), 7.80 (m, 2H), 7.73 (m, 3H), 7.67 (m, 1H), 7.61 (d, 1H), 7.15 (dd, 1H) ppm; MS (ES +) 486.07 (M + H); HPLC method A, R _t 3.28 min.

Example 83 [2- (2,4-Bistrifluoromethylphenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-83): Obtained in DMF in 28% yield. ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.81 (d, J = 8.4Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m , 3H); 7.40-7.34 (m, 1H); 7.29-7.14 (m, 1H); LC-MS (ES +) 510.14 (M + H); HPLC method C, R _t, 8.29 min.

Example 84 (5,7-Difluoro-1H-indazol-3-yl) - [2- (4-fluoro-2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-84): Obtained in 48% yield. ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.74-8.63 (m, 1H), 8.23-8.10 (m, 1H), 7.99-7.90 (m, 2H ), 7.89-7.80 (m, 1H), 7.71-7.61 (m, 1H), 7.61-7.50 (m, 1H), 7.24-7.15 (m , 1H); 7.14-7.02 (m, 1H); LC-MS (ES +) 460.14 (M + H); HPLC method C, R _t 7.59 min.

Example 85 [2- (2-Bromophenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-85): Received in THF (yield 21%). ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.81 (d, J = 8.4Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m , 3H); 7.40-7.34 (m, 1H); 7.29-7.14 (m, 1H); LC-MS (ES +) 510.14 (M + H); HPLC method C, R _t, 8.29 min.

Example 86 (5,7-Difluoro-1H-indazol-3-yl) - [2- (5-fluoro-2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-86): Received in THF (26% yield) ) ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.62 (d, J = 8.4Hz, 1H), 8.16-8.02 (m, 1H), 7.96-7.73 (m , 3H), 7.59-7.48 (m, 1H), 7.48-7.35 (m, 1H), 7.21-7.09 (m, 1H), 7.09-6.89 (m, 1H); LC-MS (ES +) 460.16 (M + H); HPLC method C, R _t 7.28 min.

Example 87 [2- (2,4-Dichlorophenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-87): Received in THF (yield 16%). ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.81 (d, J = 8.4Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m , 3H); 7.40-7.34 (m, 1H); 7.29-7.14 (m, 1H); LC-MS (ES +) 510.14 (M + H); HPLC method C, R _t, 8.29 min.

Example 88 [2- (2-Chloro-5-trifluoromethylphenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-88): Obtained in THF (yield 33% ) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.66 (d, J = 8.3Hz, 1H), 8.06-7.84 (m, 3H), 7.81-7.63 (m, 3H); 7.48-7.16 (m, 2H); LC-MS (ES +) 476.16 (M + H); HPLC method C, R _t 19.28 min.

Example 89 (4-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-89): Obtained in NMP (79% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.2 (s, 1H), 10.8 (s, broad, 1H), 8.63 (d, 1H), 7.97 (t, 1H ), 7.85 (d, 1H), 7.74 (m, 2H), 7.64 (t, 1H), 7.57 (m, 2H), 7.32 (m, 2H), 6.82 (m, 1H) ppm; LC-MS (ES +) 424.17 (M + H); HPLC method A, R _t 3.14 min.

Example 90 (1H-Indazol-3-yl) - [8-methoxy-2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-90): THF was used as the solvent to obtain the title compound as TFA salts (23% yield). HPLC method A, R _t 2.97 min. (95%) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.9 (1H, broad s), 11.0-10.7 (1H, broad s), 8.25 (1H, m ), 7.75-7.50 (8H, s), 7.30 (1H, m), 6.90 (1H, m), 4.0 (3H, s); MS (m / z) 436.2 (M + H).

Example 91 (5-Fluoro-1H-indazol-3-yl) - [8-methoxy-2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-91): TFA was used as a solvent to obtain the title the title compound as a TFA salt (23% yield). HPLC method A, R _t 3.10 min. (99%); ¹ H NMR (DMSO-d ₆ , 500 MHz): 13.0 (1H, broad s), 11.0-10.7 (1H, broad s), 8.25 (1H, m), 7, 75-7.50 (7H, m), 7.35 (1H, m), 7.25 (1H, m), 4.0 (3H, s); MS (m / z) 454.2 (M + H).

Example 92 (7-Fluoro-1H-indazol-3-yl) - [8-methoxy-2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-92): THF was used as a solvent to obtain the title the title compound as a TFA salt (98 mg, 58% yield). HPLC method A, R _t 3.20 min. (92%); ¹ H NMR (DMSO-d ₆ , 500 MHz) δ 13.45 (1H, broad s), 11.0 - 10.7 (1H, broad s), 8.25 (1H, m), 7, 75-7.60 (5H, m), 7.50 (1H, m), 7.40 (1H, m), 7.15 (1H, m), 6.95 (1H, m) 4.0 ( 3H, s); MS (m / z) 454.2 (M + H).

Example 93 (5,7-Difluoro-1H-indazol-3-yl) - [8-methoxy-2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-93): THF was used as solvent to give the title compound as the TFA salt (36% yield). HPLC method A, R _t 3.27 min. (95%); ¹ H NMR (DMSO-d ₆ , 500 MHz): 13.65 (1H, broad s), 11.0 - 10.7 (1H, broad s), 8.22 (1H, m), 7, 75-7.60 (5H, m), 7.40 (1H, m), 7.35 (1H, m), 7.19 (1H, m), 4.0 (3H, s); MS (m / z) 472.2 (M + H).

Example 94 [2- (2-Chloropyridin-3-yl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-94): Obtained in DMF. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.62 (br s, 1H, 11.06-10.71 (m, 1H), 8.16-7.70 (m, 4H), 7 60-7.09 (m, 3H); LC-MS (ES +) 409.14 (M + H); HPLC method A, R _t 2.89 min.

Example 95 [2- (2-Chloro-4-nitrophenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-95): Obtained in THF. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 10.74 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 2.05 Hz, 1H), 8.18-8.08 (m, 1H), 8.07-7.60 (m, 4H-), 7.53-7.10 (m, 2H); LC-MS (ES +) 453.15 (M + H); HPLC method d, R _t 3.63 min.

Example 96 [2- (4-amino-2-chlorophenyl) quinazolin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-96): Solution of compound II-95 (8 mg, 0.018 mmol) of tin chloride dihydrate (22 mg, 0.1 mmol) in ethanol (2 ml) was heated at 100 ° C for 24 hours. The reaction mixture was diluted with EtOAc (10 ml), washed with 1 N. NaOH solution (2 x 10 ml), saturated brine and dried over anhydrous sodium sulfate to give a crude product. Purification of the product was carried out by flash chromatography on silica gel (elution with 1-3% MeOH in CH ₂ Cl ₂ ). The title compound was isolated as a pale yellow solid (1.2 mg, 16% yield). LC-MS (ES +) 423.12 (M + H). HPLC method C, R _t 13.78 min.

Example 97 (4,5,6,7-Tetrahydro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-97): Obtained in 34% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.58 (m, 2H), 1.66 (m, 2H), 2.24 (m, 2H), 2.54 (m 2H), 7, 63 (m, 3H), 7.71 (t, 1H), 7.75, (d, 1H), 7.78 (d, 1H), 7.85 (t, 1H), 8.53 (d, 1H), 9.99 (s, 1H), 12.09 (s, 1H); EI-MS 410.2 (M + 1); HPLC method A, R _t 3.05 min.

Example 98 (1H-pyrazolo [4,3-b] pyridin-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-98): Obtained in DMF (yield 37%) in as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.1, (s, broad., 1H), 11.2 (s, broad., 1H), 8.73 (d, 1H), 8.54 (dd, 1H), 8.12 (d, 1H), 8.06 (t, 1H), 7.90 (d, 1H), 7.84 (t, 1H), 7.75 (d, 1H) 7.69 (m, 2H); 7.65 (t, 1H); 7.47 (dd, 1H) ppm; LC-MS (ES +) 407.18 (M + H); HPLC method A, R _t 2.77 min.

Example 99 (1H-pyrazolo [3,4-b] pyridin-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-99): Received in DMF (yield 45%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.5 (s, broad. 1H), 11.3 (s, broad. 1H), 8.78 (d, 1H), 8.49 ( d, 1H), 8.17 (d, 1H), 8.03 (t, 1H), 7.89 (d, 1H), 7.80 (m, 2H), 7.74 (m, 2H), 7.68 (m, 1H), 7.08 (dd, lH), ppm, MS (ES +) 407.16 (M + H). (ES-) 405.16 (MH); HPLC method A, R _t 2.80 min.

Example 100 (6-Methyl-1H-pyrazolo [3,4-b] pyridin-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-100): Obtained in DMF (yield eleven%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.2 (s, broad. 1H), 10.8 (s, broad. 1H), 8.57 (d, 1H), 7.95 ( t, 1H), 7.82 (d, 1H), 7.72 (t, 1H), 7.65 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H, hidden DMCO), 2.20 (s, 3H) ppm, LC-MS (ES +) 435.22 (M + H). (ES-) 433.25 (MH); HPLC method A, R _t 2.94 min.

Example 101 (6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo [4,3-c] pyridazin-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-101): Received in DMF (6% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.6 (s, 1H), 11.0 (s, broad, 1H), 8.60 (d, 1H), 7.95 (t, 1H ), 7.88 (d, 1H), 7.80 (d, 1H), 7.68 (m, 4H), 7.40 (s, 3H), 7.22 (s, 2H), 6.61 (s, 1H) ppm, LC-MS (ES +) 500.21 (M + H). (ES-) 498.16 (MH); HPLC method A, R _t 3.00 min.

Example 103 [6-Methyl-2- (2-trifluoromethoxyphenyl) pyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (II-103): MS 412.13 (M + H) ; HPLC method E, R _t 1.248 min.

Example 104 (5-Furan-2-yl-2H-pyrazol-3-yl) - [6-methyl-2- (2-trifluoromethoxyphenyl) pyrimidin-4-yl] amine (II-104): MS 402.12 ( M + H); HPLC method E, R _t 1.188 min.

Example 105 [6-Ethyl-2- (2-trifluoromethoxyphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-105): MS 364.14 (M + H) ; HPLC method E, R _t 1.112 min.

Example 106 [2- (2-Chlorophenyl) pyrido [2,3-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (II-106): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 10.78 (s, 1H), 7.73-7.47 (m, 7H), 6.72 (s, 1H), 2, 21 (s, 3H), MS: (M + H) 337.02, HPLC method A, R _t 2,783 min.

Example 107 (5-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] amine (II-107): Received in 68 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.16 (t, 2H), 2.88 (m, 2H), 2.98 (t, 2H), 7.21 (td, 1H), 7 29 (dd, 1H), 7.50 (dd, 1H), 7.65 (t, 1H), 7.67 (t, 1H), 7.73 (t, 1H), 7.79 (d, 1H), 10.22 (br s, 1H); 12.99 (br s, 1H); EI-MS 414.2 (M + H); HPLC method A, R _t 2.92 min.

Example 108 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) pyrido [2,3-d] pyrimidin-4-yl] amine (II-108): HPLC method A, R _t 2 78 minutes (95%); ¹ H NMR (DMSO-d ₆ , 500 MHz): 12.95 (1H, broad s), 11.45 δ 11.15 (1H, broad s), 9.20 (2H, m), 7, 85-7.70 (2H, m), 7.70-7.55 (4H, m), 7.50 (1H, m), 7.35 (1H, m), 7.05 (1H, m) ; MS (m / z) 407.03 (M + H).

Example 109 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethyl-phenyl) pyrido [2,3-d] pyrimidin-4-yl] amine (II-109): Yellow di-TFA salt (25% yield). HPLC (Method A) 3.10 min. (95%); ¹ H NMR (DMSO-d ₆ , 500 MHz): 13.8-13.6 (1H, broad s), 11.4-11.2 (1H, broad s), 9.15 (2H, m ), 7.85-7.75 (2H, m), 7.75-7.62 (3H, m), 7.32 (2H, m); MS (m / z) 442.98 (M + H).

Example 110 [2- (2-Chlorophenyl) pyrido [2,3-d] pyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-110): From 2-aminonicotinic acid and 2-chlorobenzoyl chloride the title compound was obtained as a di-TFA salt (28% yield). HPLC method A, R _t 2.85 min. (95%); ¹ H NMR (DMSO-d ₆ , 500 MHz): 12.90 (1H, s), 11.10 - 10.90 (1H, broad s), 9.05 (2H, m), 7.75- 7.60 (2H, m), 7.51 (1H, m), 7.45-7.25 (5H, m), 6.95 (1H, m); MS (m / z) 372.99 (M + H).

Example 111 (5-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidin-4-yl] amine (II-111): Received in 43% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.46 (m, 2H), 1.53 (m, 2H), 1.77 (m, 4H), 2.95 (m, 2H), 3 04 (m, 2H), 7.22 (m, 2H), 7.50 (dd, 1H), 7.72 (m, 3H), 7.80 (d, 1H), 10.5 (m, 1H), 13.05 (br s, 1H); EI-MS 456.2 (M + H); HPLC method C, R _t 11.93 min.

Example 112 [2- (2-Chlorophenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-112): Obtained in 67 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.18 (m, 2H), 2.89 (m, 2H), 3.02 (t, 2H), 7.24 (td, 1H), 7 42 (m, 2H), 7.49 (td, 1H), 7.52 (dd, 1H), 7.54 (d, 1H), 7.57 (dd, 1H), 10.50 (br. s, 1H); 13.06 (br s, 1H); EI-MS 380.1 (M + 1); HPLC method C, R _t 9.68 min.

Example 113 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] amine (II-113): Obtained in 37% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.65 (m, 2H), 2.85 (m, 2H), 2.99 (t, 2H), 7.02 (t, 1H), 7 32 (t, 1H), 7.47 (d, 1H), 7.55 (d, 1H), 7.68 (t, 1H), 7.74 (t, 1H), 7.80 (d, 1H), 10.37 (br s, 1H), 12.91 (br s, 1H); EI-MS 396.1 (M + H); HPLC method B, R _t 9.88 min.

Example 114 (7-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] amine (II-114): Obtained in yield 40 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.15 (m, 2H), 2.87 (m, 2H), 2.97 (t, 2H), 6.99 (td, 1H), 7 , 17 (dd, 1H), 7.38 (d, 1H), 7.65 (m, 2H), 7.71 (t, 1H), 7.78 (d, 1H), 10.21 (br. s, 1H); 13.40 (br s, 1H); EI-MS 414.1 (M + H); HPLC method C, R _t 9.99 min.

Example 115 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] amine (II-115): Obtained by the method With a yield of 52%. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.16 (m, 2H), 2.89 (m, 2H), 2.97 (t, 2H), 7.19 (dd, 1H), 7 29 (td, 1H), 7.63 (t, 1H), 7.66 (d, 1H), 7.71 (t, 1H), 7.78 (d, 1H), 10.16 (br. s, 1H); 13.55 (br s, 1H); El-MS 432.1 (M + H); HPLC method C, R _t 10.09 min.

Example 116 [2- (2-Chlorophenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-116): Obtained in 56% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.16 (m, 2H), 2.85 (m, 2H), 3.01 (t, 2H), 7.06 (t, 1H), 7 34 (t, 1H), 7.40 (t, 1H), 7.48 (m, 2H), 7.53 (d, 1H), 7.56 (d, 1H), 7.63 (d, 1H), 10.39 (br s, 1H), 12.91 (s, 10 1H); EI-MS 362.1 (M + H); HPLC method A, R _t 3.09 min.

Example 117 [2- (2-Chlorophenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-117): Obtained in yield 63 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.15 (m, 2H), 2.87 (m, 2H), 3.00 (t, 2H), 7.01 (td, 1H), 7 19 (dd, 1H), 7.39 (t, 1H), 7.45 (m, 2H), 7.51 (d, 1H), 7.55 (d, 1H), 10.35 (br. s, 1H); 13.45 (br s, 1H); EI-MS 380.1 (M + H); HPLC method A, R _t R _t 3.15 min.

Example 118 [2- (2-Chlorophenyl) -6,7-dihydro-5H-cyclopentapyrimidin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-118): Obtained from 60% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.18 (m, 2H), 2.91 (m, 2H), 3.01 (t, 2H), 7.32 (t, 1H), 7 33 (td, 1H), 7.41 (t, 1H), 7.48 (t, 1H), 7.53 (d, 1H), 7.55 (dd, 1H), 10.35 (br. s, 1H); 13.45 (br s, 1H); EI-MS 398.1 (M + H); HPLC method A, R _t R _t 3.24 min.

Example 119 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidin-4-yl] amine (II-119): Obtained in yield 36 % ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.47 (m, 2H), 1.53 (m, 2H), 1.78 (m, 4H), 2.96 (m, 2H), 3 06 (t, 2H), 7.03 (t, 1H), 7.47 (t, 1H), 7.72 (d, 1H), 7.73 (d, 1H), 7.72 (m, 3H), 7.81 (d, 1H), 10.52 (m, 1H), 12.97 (br s, 1H); EI-MS 438.2 (M + 1); HPLC method A, R _t 3.37 min.

Example 120 (7-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidin-4-yl] amine (II-120): Received in 40% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.46 (m, 2H), 1.52 (m, 2H), 1.77 (m, 4H), 2.94 (m, 2H), 3 04 (m, 2H), 7.00 (td, 1H), 7.17 (dd, 1H), 7.30 (d, 1H), 7.70 (m, 3H), 7.79 (d, 1H), 10.5 (m, 1H), 13.49 (br s, 1H); EI-MS 456.1 (M + H); HPLC method A, R _t 3.43 min.

Example 121 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidin-4-yl] amine (II-121 ): Received in 48% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.46 (m, 2H), 1.52 (m, 2H), 1.77 (m, 4H), 2.95 (m, 2H), 3 03 (m, 2H), 7.14 (d, 1H), 7.30 (t, 1H), 7.73 (m, 3H), 7.80 (d, 1H), 10.5 (m, 1H), 13.62 (br s, 1H); EI-MS 475.1 (M + 1); HPLC method A, R _t 3.52 min.

Example 122 [6-Cyclohexyl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-122): Obtained in 45% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.30 (2H, m), 1.46 (2H, m), 1.65 (2H, m), 1.76 (2H, m), 1 91 (2H, m), 2.61 (1H, br.m), 7.08 (1H, t, J = 7.4Hz), 7.27 (1H, d, J = 8.0 Hz), 7.35 (1H, t, J = 7.1 Hz), 7.50 (1H, t, J = 7.0 Hz), 7.58 (1H, t, J = 7.4 Hz), 7, 66 (3H, m), 7.72 (1H, d, J = 7.8 Hz), 8.0 (1H, broad), 9.87 (1H, broad) ppm, HPLC method D, R _t 3.57 min; LC-MS 438.17 (M + H) ⁺ .

Example 123 [6- (2-Fluorophenyl) -2- (2-trifluoromethylphenyl) pyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-123): Obtained in 8% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.18 (3H, m), 7.37 (1H, m), 7.43 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 7.9 Hz), 7.55 (1H, t, J = 7.6 Hz), 7.65 (1H, t, J = 7.4 Hz), 7.79 (1H d, J = 7.9 Hz), 7.85 (1H, d, J = 7.6 Hz), 8.19 (2H, m), 8.70 (1H, d, J = 8.5 Hz ) ppm; HPLC method D, R _t 4.93, min; LC-MS 450.13 (M + H) ⁺ .

Example 124 (6-Fluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (II-124): Received in DMF (87% yield) as a yellow solid . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.0 {s, 1H), 11.1 (s, broad, 1H), 8.66 (d, 1H), 7.95 (t, 1H ), 7.80 (d, 1H), 7.72 (m, 2H), 7.62 (m, 4H), 7.21 (dd, 1H), 6.84 (td, 1H) ppm. LC-MS (ES +) 424.15 (M + H); HPLC method A, R _t 3.05 min.

Example 125 3- [2- (2-Trifluoromethylphenyl) quinazolin-4-ylamino] -1H-indazole-5-carboxylic acid methyl ester (II-125): To a solution of compound II-79 (100 mg, 0.21 mmol) in DMF (2 ml) MeOH (1 ml), DIEA (54 μl, 0.31 mmol) and PdCl ₂ (dppf) (4 mg, 0.005 mmol) were added. The flask was purged with CO three times and then equipped with a cylinder of CO. The reaction mixture was heated at 80 ° C for 14 hours, after which it was poured into water. The resulting precipitate was collected and washed with water. The crude product was then purified first on a flash column (silica gel, 50% ethyl acetate in hexane) and then by preparative HPLC to give compound II-125 (32%) as a yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.3 (s, broad, 1H), 11.3 (s, broad, 1H), 8.70 (d, 1H), 8.36 (s, 1H ), 7.97 (t, 1H), 7.82 (m, 2H), 7.71 (m, 3H), 7.58 (m, 2H), 7.51 (d, 1H), 3.75 (s, 3H) ppm; LC-MS (ES +) 464.13 (M + H); HPLC method A, R _t 3.12 min.

Example 208 (5-Methyl-2H-pyrazol-3-yl) - [2- (2-naphthyl-1-yl) -quinazolin-4-yl] amine (II-208): ¹ H NMR (500 MHz, DMSO -d ₆ ) δ 8.92 (s, 1H), 8.73 (m, 1H), 8.39 (m, 1H), 8.09 (m, 2H), 7.95 (m, 3H), 7.62 (m, 3H); 6.78 (s, 1H); 2.32 (s, 3H); MS 352.2 (M + H).

Example 209 [2- (2-Chlorophenyl) pyrido [2,3-d] pyrimidin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-214): Received from 4-chloro -2- (2-chlorophenyl) pyrido [2,3-d] pyrimidine (100 mg, 0.36 mmol) and 7-fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow di-TFA salt (93 mg, 46% yield). HPLC method A, R _t 3.04 min ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.67 (1H, s), 11.40-11.25 (1H, br s), 9, 35-9.25 (2H, m), 7.95 (1H, m), 7.80-7.47 (5H, m), 7.35 (1H, m), 7.15 (1H, m) ; MS (m / z), MH ⁺ 391.1.

Example 210 [2- (2-Chlorophenyl) pyrido [2,3-d] pyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-215): Received from 4-chloro -2- (2-chlorophenyl) pyrido [2,3-d] pyrimidine (100 mg, 0.36 mmol) and 5-fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow di-TFA salt (45 mg, 22% yield). HPLC method A, R _t 3.00 min; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.0 (1H, s), 10.90 (1H, broad s), 9.15-9.05 (2H, m), 7.70 ( 1H, m), 7.60-7.30 (6H, m), 7.20 (1H, m); MS (m / z), MH ⁺ 391.1.

Example 211 [2- (2-Chlorophenyl) pyrido [2,3-d] pyrimidin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-216): Received from 4 -chloro-2- (2-chlorophenyl) pyrido [2,3-d] pyrimidine (100 mg, 0.36 mmol) and 7-difluoro-1H-indazol-3-ylamine (112 mg, 0.66 mmol). Purification by preparative HPLC afforded the title compound as a yellow di-TFA salt (130 mg, 62% yield). HPLC method A, R _t 3.12 min; ¹ H NMR (DMSO, 500 MHz): 13.80-13.60 (1H, broad s), 11.30-11.10 (1H, broad s), 9.20-9.10 (2H, m) 7.80 (1H, m); 7.60-7.30 (6H, m); MS (m / z), MH ⁺ 409.1.

Example 212 [2- (2-Chlorophenyl) pyrido [3,4-d] pyrimidin-4-yl] - (1H-indazol-3-yl) amine (II-217): Prepared from 4-chloro-2- ( 2-chlorophenyl) pyrido [3,4-d] pyrimidine (100 mg, 0.36 mmol) and 1H-indazol-3-ylamine (88 mg, 0.66 mmol). Purification by preparative HPLC afforded the title compound as a yellow di-TFA salt (72 mg, 33% yield). HPLC method A, R _t 3.21 min; ¹ H NMR (DMSO, 500 MHz): 12.95 (1H, s), 10.90 (1H, s), 9.25 (1H, s), 8.75 (1H, 15 m), 8 55 (1H, m), 7.65 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m), 7.00 (1H, m); MS (m / z), MH ⁺ 373.1.

Example 213 [2- (2-Chlorophenyl) pyrido [3,4-d] pyrimidin-4-yl] - (7-fluoro-1H-indazol-3-yl) amine (II-218): Received from 4-chloro -2- (2-chlorophenyl) pyrido [3,4-d] pyrimidine (100 mg, 0.36 mmol) and 7-fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow di-TFA salt (48.7 mg, 22% yield). HPLC method A, R _t 3.35 min; ¹ H NMR (DMSO, 500 MHz): 12.95 (1H, s), 10.90 (1H, s), 9.25 (1H, s), 8.75 (1H, m), 8, 55 (1H, m), 7.70-7.35 (5H, m), 7.25 (1H, m), 6.95 (1H, m) ,; MS (m / z), MH + 391.08.

Example 214 [2- (2-Chlorophenyl) pyrido [3,4-d] pyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine (II-219): Received from 4-chloro -2- (2-chloro-5-fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow di-TFA salt (57.2 mg, yield 26%). HPLC method A, R _t 3.27 min; ¹ H NMR (DMSO, 500 MHz): δ 13.05 (1H, s), 10.95 (1H, s), 9.25 ( 1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.60 (1H, m), 7.55, (1H, m), 7.50-7.30 ( 5H, m), 7.25 (1H, m); MS (m / z), MH + 391.1.

Example 215 [2- (2-Chlorophenyl) pyrido [3,4-d] pyrimidin-4-yl] - (5,7-difluoro-1H-indazol-3-yl) amine (II-220): Received from 4 -chloro-2- (2-chloro-7-difluoro-1H-indazol-3-ylamine (112 mg, 0.66 mmol). Purification by preparative HPLC afforded the title compound as the yellow di-TFA salt (57.2 mg, 26% yield). HPLC method A, R _t 3.45 min. ¹ H NMR (DMSO, 500 MHz): δ 13.65 (1H, s), 11.0 (1H, s), 9, 25 (1H, s), 8.80 (1H, m), 8.50 (1H, m), 7.60 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m); MS (m / z), MH ⁺ 409.1.

Example 216 6-Fluoro-1H-indazol-3-ylamine (A1): ¹ H NMR (DMSO, 500 MHz): δ 11.4 (s, 1H), 7.68 (dd, 1H), 6.95 ( dd, 1H), 6.75 (td, 1H), 5.45 (s, 2H) ppm; LC-MS (ES +) 152.03 (M + H); HPLC method A, R _t 2.00 min.

Example 217 5-Fluoro-1H-indazol-3-ylamine (A2): ¹ H NMR (DMSO, 500 MHz): δ 11.3 (s, 1H), 7.43 (d, 1H), 7.22 ( m, 1H), 7.08 (m, 1H), 5.29 (s, 2H) ppm; LC-MS (ES +) 152.01 (M + H); HPLC method A, R _t 1.93 min.

Example 218 5.7-Difluoro-1H-indazol-3-ylamine (A3): ¹ H NMR (500 MHz, CD ₃ OD): δ 7.22 (dd, J = 2.0, 8.45HZ, 1H) 7.04-6.87 (m, 1H); LC-MS (ES +) 169.95 (M + H); HPLC method C, R _t 2.94 min.

Example 219 7-Fluoro-1H-indazol-3-ylamine (A4): ¹ H NMR (500 MHz, DMSO): δ 11.8 (s, 1H), 7.42 (d, 1H), 6.97 ( m, 1H), 6.78 (m, 1H), 5.40 (s, 2H) ppm; LCMC (KS +) 152.01 (M + H); HPLC method A, R _t 2.00 min.

Example 220 7-Fluoro-6-trifluoromethyl-1H-indazol-3-ylamine (A5): ¹ H NMR (500 MHz, DMSO): δ 12.5 (s, 1H), 7.75 (d, 1H), 7.25 (m, 1H); 5.85 (m, 1H) ppm; MS (FIA) 220.0 (M + H); HPLC method A, R _t 2.899 min.

Example 221 6-Bromo-1H-indazol-3-ylamine (A6): ¹ H NMR (500 MHz, DMSO): δ 11.5 (s, 1H), 7.65 (d, 1H), 7.40 ( s, 1H), 7.00 (d, 1H), 5.45 (br s, 1H) ppm; MS, (FIA) 213.8 (M + H); HPLC method A, R _t 2,441 min.

Example 222 4-Fluoro-1H-indazol-3-ylamine (A7): ¹ H NMR (500 MHz, DMSO): δ 11.7 (s, 1H), 7.17 (m, 1H), 7.05 ( d, 1H), 6.7 (br 1H), 6.60 (dd, 1H), 5.20 (br s, 2H) ppm; MS (FIA) 152.0 (M + H); Method A, R _t 2.256 min.

Example 223 5-Bromo-1H-indazol-3-ylamine (A8): ¹ H NMR (500 MHz, DMSO): δ 11.55 (br s, 1H), 7.95 (s, 1H), 7, 30 (d, 1H), 7.20 (d, 1H), 5.45 (br s, 2H) ppm; MS (FIA) 213.8 (M + H); Method A, R _t 2.451 min.

Example 224 5-Nitro-1H-indazol-3-ylamine (A9): ¹ H NMR (500 MHz, DMSO): δ 9.00 (s, 1H), 8.20 (d, 1H), 7.45 ( d, 1H); 6.15 (br s, 1H-) ppm; Method A, R _t 2.184 min.

Example 225 4-Pyrrol-1-yl-1H-indazol-3-ylamine (A10): ¹ H NMR (500 MHz, DMSO): δ 7.20 (s, 2H), 7.00 (s, 2H), 6.75 (m, 1H), 6.25 (s, 2H), 4.30 (d, 1H) ppm; Method A, R _t 2.625 min.

Example 226 4-Chloro-5,6-dimethyl-2- (2-trifluoromethylphenyl) pyrimidine (B1): Obtained as a colorless oil in 75% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.70 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 2.54 (s, 3H), 2.36 (s, 3H) ppm; MS (FIA) 287.0 (M + H); HPLC method A, R _t 3.891 min.

Example 227 4-Chloro-2- (2-chlorophenyl) -5,6-dimethylpyrimidine (B2): Obtained as a yellow-orange oil in 71% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.73 (m, 1H), 7.52 (m, 1H), 7.39 (m, 2H), 2.66 (s, 3H), 2, 45 (s, 3H) ppm; MS (FIA) 253.0 (M + H); HPLC method A, R _t R _t 4.156 min.

Example 228 4-Chloro-6-methyl-2- (2-trifluoromethylphenyl) pyrimidine (B3): Received as a pale yellow oil in 68% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.72 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 2.54 (s, 3H) ppm; MS (FIA) 273.0 (M + H); HPLC method A, R _t 3,746 min.

Example 229 4-Chloro-6-cyclohexyl-2- (2-trifluoromethylphenyl) pyrimidine (B4): Obtained as a yellow oil in 22% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.70 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.19 (s, 1H), 2.65 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H), 1.5 (m, 2H), 1, 3 (m, 2H); 1.2 (m, 2H) ppm; MS (FIA) 341.0 (M + H).

Example 230 4-Chloro-6-phenyl-2- (2-trifluoromethylphenyl) pyrimidine (B5): Obtained as a yellow oil in 53% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.08 (dd, J = 7.9, 1.6 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7, 77 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H); 7.47 (m, 3H) ppm; MS (FIA) 335.0 (M + H); HPLC method A, R _t 4.393 min.

Example 231 4-Chloro-2- (2,4-dichlorophenyl) -5,6-dimethylpyrimidine (B6): Obtained as a white solid in 91% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.62 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 7.0 Hz, 1H), 7.27 (dd, J = 8.3, 2.0 Hz, 1H), 2.55 (s, 3H), 2.35 (s, 3H) ppm; MS (FIA) 287, 289 (M + H); HPLC method A, R _t 4.140 min.

Example 232 4-Chloro-6- (2-chlorophenyl) -2- (2-trifluoromethylphenyl) pyrimidine (B7): Obtained as a yellow oil in 52% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.75 (m, 3H), 7.65 (m, 2H), 7.53 (m, 1H), 7.44 (m, 1H), 7, 36 (m, 2H) ppm; MS (FIA) 369.1 (M + H); HPLC method A, R _t 4.426, min.

Example 233 4-Chloro-6- (2-fluorophenyl) -2- (2-trifluoromethylphenyl) pyrimidine (B8): Obtained as a yellow oil in 95% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.24 (t, J = 7.9 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H) 7.43 (m, 1H); 7.23 (t, J = 7.6 Hz, 1H); 7.13 (m, 1H) ppm; MS (FIA) 353.0 (M + H).

Example 234 4-Chloro-6-pyridin-2-yl-2- (2-trifluoromethylphenyl) pyrimidine (B9): Obtained as a pale yellow oil in 50% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.68 (m, 1H), 8.48 (dd, J = 7.9, 0.8 Hz, 1H), 8.38 (d, J = 2 , 3 Hz, 1H), 7.84 (m, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.38 (m, 1H) ppm; MS (FIA) 336.0 (M + H); HPLC method A, R _t 4.575 min.

Example 235 6-Benzyl-4-chloro-2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (B10): ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.70 (d, 1H), 7.62 (d, 1H), 7.55 (t, 1H), 7.48 (t, 1H), 7.32 (m, 4H), 7.25 ( m, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 2.99 (t, 2H), 2.80 (t, 2H) ppm; LCMC (ES +) 404.17 (M + H); HPLC method A, R _t 3.18 min.

Example 236 7-Benzyl-4-chloro-2- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine (B11): ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.69 (d, 1H), 7.60 (d, 1H), 7.54 (t, 1H), 7.47 (t, 1H), 7.28 (m, 4H), 7.20 ( m, 1H), 3.68 (s, 2H), 3.67 (s, 2H), 2.86 (t, 2H), 2.79 (t, 2H) ppm, MS (ES +) 404 , 18 (M + H); HPLC method A, R _t 3.12 min.

Example 237 4-Chloro-2- (4-fluoro-2-trifluoromethylphenyl) quinazoline (B12): ¹ H NMR (500 MHz, CD ₃ OD): δ 8.43 (d, J = 8.1Hz, 1H), 8.20-8.05 (m, 2H), 8.05-7.82 (m, 2H), 7.71-7.51 (m, 2H,), LC-MS (ES +) 327.09 ( M + H). HPLC method d, R _t 4.56 min.

Example 238 4-Chloro-2- (2-chloro-5-trifluoromethylphenyl) quinazoline (B13): LC-MS (ES +) 342.97 (M + H). HPLC method d, R _t 4.91 min.

Example 239 4-Chloro-2- (2-chloro-4-nitrophenyl) quinazoline (B14): LC-MS (ES +) 319.98 (M + H). HPLC method d, R _t 4.45 min.

Example 240 4-Chloro-2- (2-trifluoromethylphenyl) quinazoline (B15): Obtained in 57% yield. White solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.79 (t, 1H), 7.86 (t, 1H), 7.94 (m, 3H), 8.15 (dd, 1H), 8 20 (td, 1H); 8.37 (m, 1H); EI-MS 308.9 (M).

Example 241 4-Chloro-2- (2-trifluoromethylphenyl) -6,7-dihydro-5H-cyclopentapyrimidine (B16): Obtained in 22% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.19 (m, H), 3.01 (t, 2H), 3.08 (t, 2H), 7.49 (t, 1H), 7 55 (t, 1H); 7.62 (d, 1H); 7.71 (d, 1H); EI-MS 299.0 (M + H).

Example 242 4-Chloro-2- (2-chlorophenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine (B17): Obtained by Method C in 82% yield as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.67 (m, 4H), 1.87 (m, 2H), 3.02 (m, 4H), 7.28 (m, 2H), 7.40 , (m, 1H); 7.65 (m, 1H); EI-MS 293.0 (M + 1).

Example 243 4-Chloro-2- (2-trifluoromethylphenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidine (B18): Obtained in 38% yield as a brown oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.35 (m, 2H), 1.41 (m, 2H), 1.76 (m, 4H), 2.96 (m, 4H), 7.48 (t, 1H), 7.56 (t, 1H), 7.66 (d, 1H), 7.70 (d, 1H); EI-MS 341.0 (M + 1).

Example 244 4-Chloro-8-methoxy-2- (2-trifluoromethylphenyl) quinazoline (B19): Derived from 8-methoxy-2- (2-trifluoromethylphenyl) -3H-quinazolin-4-one (1.0 g , 3.12 mmol), triethylamine hydrochloride (472 mg, 3.43 mmol) and POCl ₃ . Purification by flash chromatography afforded a white solid (89% yield). HPLC method A, R _t 4.10 min. (98%), MS (m / z) 258.08 (M + H).

Example 245 2- (4-Chloroquinazolin-2-yl) benzonitrile (B20): Obtained as a yellow solid in 1.5% yield. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.47 (d, 1H), 8.24 (d, 1H), 8.16 (d, 1H), 8.07 (impurity), 7.94 (t 1H), 7.92 (impurity), 7.86 (d, 1H), 7.68 (m, 2H), 7.65 (impurity), 7.54 (impurity), 7.49 (t, 1H ), 4.2 (impurity), 1.05 (impurity) ppm; MS (LC / MS) 266.05 (M + H); HPLC method A, R _t 3.88 min.

Example 246 6-Methyl-2- (2-trifluoromethylphenyl) -3H-pyrimidin-4-one (D3): Obtained as a yellow solid in 50% yield. ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 12.7 (br s, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H) 6.3 (s, 1H); 2.21 (s, 3H) ppm; MS (FIA) 255.0 (M + H); HPLC method A, R _t 2.578 min.

Example 247 6-Cyclohexyl-2- (2-trifluoromethylphenyl) -3H-pyrimidin-4-one (D4): Obtained as an off-white solid in 54% yield. ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 12.9 (br s, 1H), 7.9 (m, 4H), 5.3 (s, 1H), 2.5 (m, 1H) 1.9 (m, 5H); 1.4 (m, 5H) ppm; MS (FIA) 323.1 (M + H); HPLC method A, R _t 3.842 min.

Example 248 2- (2-Chloro-5-trifluoromethylphenyl) -3H-quinazolin-4-one (D10): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.32-8.25 (m, 1H), 8.01 (s, 1H), 7.91-7.72 (m, 1H), 7.66-7.55 (m, 1H), LC-MS (ES +) 325.01 (M + H). HPLC method D, R _t 3.29 min.

Example 249 2- (4-Fluoro-2-trifluoromethylphenyl) -3H-quinazolin-4-one (D14): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.28 (d, 8, OHz, 1H), 7.94-7.84 (m, 1H), 7.84-7.77 (m, 1H), 7.76-7.67 (m, 2H), 7.65-7.53 (m, 2H ), LC-MS (ES +) 309.06 (M + H). HPLC method D, R _t 2.88 min.

Example 250 2- (4-Nitro-2-chlorophenyl) -3H-quinazolin-4-one (D15): LC-MS (ES +) 302.03 (M + H). HPLC method D, R _t 2.81 min.

Example 251 2- (5-Fluoro-2-trifluoromethylphenyl) -3H-quinazolin-4-one (D17): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.28 (d, R _t J = 8.05Hz , 1H), 7.96 (dd, J = 5.05, 8.55HZ, 1H), 7.89 (t, J = 7.9Hz, 1H), 7.78-7.69 (m, 1H) 7.66-7.46 (m, 3H); LC-MS (ES +) 309.14 (M + H). HPLC method d, R _t 2.90 min.

Example 252 (1H-Indazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-1): Obtained by Method A in DMF in an amount of 70 mg (50% yield) as a pale yellow solid. ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 13.1 (s, broad, 1H), 8.48 (d, 1H), 7.91 (d, 2H), 7.76 (broad. 2H ), 7.45 (m, 2H), 7.36 (d, 1H), 7.20 (m, 4H), 6.86 (t, 1H) ppm, MS (ES +) 338.07 ( M + H); (ES-) 336.11 (MH); HPLC method A, R _t 2.88 min.

Example 253 (5-Methyl-2H-pyrazol-3-yl) - (2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl) amine (III-7): Obtained by Method A. ¹ H NMR ( 500 MHz, DMCO-d ₆ ) δ 12.1 (s, broad. 1H), 8.70 (s, broad. 1H), 8.37 (d, J = 6.7 Hz, 2H), 7 54 (m, 3H), 6.67 (s, 1H), 2.82 (m, 2H), 2.68 (m, 2H), 2.37 (s, 3H), 1.90 (s, broad 4H); MS 306.1 (M + H).

Example 254 (5-Methyl-2H-pyrazol-3-yl) - (2-phenyl-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl) amine (III-8): HPLC method E , R _t 1,124 min.

Example 255 (5-Methyl-2H-pyrazol-3-yl) - (2-pyridin-4-yl-quinazolin-4-yl) amine (III-9): Yellow solid, mp. 286-289 ° C, ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 2.35 (3H, s), 6.76 (1H, s), 7.61 30 (1H, m), 7.89 (2H, m), 8.32 (2H, d), 8.70 (1H, d), 8.78 (2H, d), 10.56 (1H, broad s), 12.30 (1H, broad.s); IR (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2 (M + H) ⁺

Example 256 (7-Chloro-2-pyridin-4-ylquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (III-28): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 2.35 (3H, s), 6.75 (1H, s), 7.65 (1H, d), 7.93 (1H, s), 8.30 (2H, d), 8, 73 (1H, d), 8.79 (2H, d), 10.69 (1H, s), 12.33 (1H, s); MS m / z 337.2 (M + H) ⁺ .

Example 257 (6-Chloro-2-pyridin-4-ylquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (III-29): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 2.31 (3H, C); 6.74 (lH, s), 7.89 (1H, s), 8.30 (2H, d), 8.80 (2H, d), 8.91 (1H, s), 10.63 (1H s) 12.29 (1H, s); MS 337.2 (M + H) ⁺ .

Example 258 (2-Cyclohexylquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (III-30): ¹ H NMR (DMCO) δ 2.35 (3H, s), 1, 70 (3H, m), 1.87 (2H, d), 1.99 (2H, d), 2.95 (1H, t), 6.72 (1H, s), 7.75 (1H, d) ), 7.88 (1H, s), 7.96 (1H, s), 8.83 (1H, s), 11.95 (1H, s), 12.70 (1H, s); MS 308.4 (M + H) ⁺ .

Example 259 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-31): mp 246 ^about C; ¹ H NMR (400 MHz) δ 2.35 (3H, s), 6.70 (1H, broad s), 7.51-7.57 (4H, m), 7.83-7.84 (2H d) 8.47-8.50 (2H, d), 8.65 (1H, d), 10.4 (1H, s), 12.2 (1H, broad s); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302.1 (M + H) ⁺ .

Example 260 [2- (4-Iodophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-32): ¹ H NMR (DMCO-d ₆ ) δ 2.34 (3H, s), 6.72 (1H, s), 7.56 (1H, d), 7.84 (2H, d), 7, 93 (2H, d), 8.23 (2H, d) 8.65 (1H, s); 10.44 (1H, s); 12.24 (1H, s); MS 428.5 (M + H) ⁺ .

Example 261 [2- (3,4-Dichlorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-33): Suspension 2- (3,4-dichlorophenyl) - 3H-quinazolin-4-one (1 g, 3.43 mmol) in phosphorus oxychloride (4 ml) was stirred at 110 ° C. for 3 hours. The solvent was removed by evaporation and the residue was carefully treated with cold aqueous saturated NaHCO ₃ solution. The resulting solid was collected by filtration and washed with ether to give 4-chloro-2- (3,5-dichlorophenyl) quinazoline as a white solid (993 mg, 93%). To the above compound (400 mg, 1.29 mmol) in THF (30 ml) was added 3-amino-5-methylpyrazole (396 mg, 2.58 mmol) and the resulting mixture was heated at 65 ° C. overnight. The solvents were evaporated and the residue was triturated with ethyl acetate, filtered and washed with a minimum amount of ethanol to give compound III-33 as a white solid (311 mg, 65%): mp. 274 ^about C; ¹ H NMR (DMCO) δ 2.34 (3H, s), 6.69 (1H, s), 7.60 (1H, m), 7.84 (1H, d), 7.96 (2H, d) ), 8.39 (1H, dd), 8.60 (1H, d), 8.65 (1H, d), 10.51 (1H, s), 12.30 (1H, s); IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 (M + H) @ ⁺ .

Example 262 [2- (4-Bromophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-34): mp 262-265 ^{° C; 1} H NMR (DMCO) δ 2.34 (3S, s), 6.73, (1H, s), 7.55 (1H, m), 7.74 (2H, d), 7.83 (2H, m), 8.40 (2H, s), 8.65 (1H, s), 10.44 (1H, s), 12.25 (1H, s); IR (solid) 1603, 1579, 1546, 1484, 1408, 1365; MS 380.1 / 382.1 (M + H) ⁺ .

Example 263 [2- (4-Chlorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-35): mp > 300 ^° C; ¹ H NMR (DMCO) δ 2.34 (3H, s), 6.74 (1H, s), 7.53-7.62 (3H, m), 7.84 (2H, d), 8.47 (2H, d), 8.65 (1H, d), 10.44 (1H, s), 12.26 (1H, s); IR (solid) 1628, 1608, 1584, 1546, 1489, 1408, 1369, 1169; MS 336.2 (M + H) @ ⁺ .

Example 264 [2- (3,5-Dichlorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-36): ¹ H NMR (DMCO) δ 2.34 ( 3H, s), 6.69 (1H, s), 7.96 (1H, d), 8.21 (3H, m), 8.56 (1H, d), 8.60 (2H, d), 10.51 (1H, s); 12.30 (1H, s); IR (solid) 1546, 1331, 802, 763, 729, 658, 652; MS 370.5 (M + H) @ ⁺ .

Example 265 [2- (4-Cyanophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-37): mp 263 ^about C; ¹ H NMR (DMCO) δ 2.34 (3H, s), 6.72 (1H, s), 7.61 (1H, d), 7.88 (2H, s), 8.04 (2H, d) ), 8.63 (2H, d), 8.67 (1H, s), 10.52 (1H, s), 12.27 (1H, s); IR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.2 (M + H) ⁺ .

Example 266 [2- (3-Iodophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-38): mp. 234-235 ^about C; ¹ H NMR (DMCO) δ 2.35 (3H, s), 6.73 (1H, s), 7.35 (1H, m), 7.56 (1H, m), 7.85 (3H, m) ), 8.47 (1H, m), 8.65 (1H, m), 8.86 (1H, s), 10.49 (1H, s), 12.28 (1H, br s); IR (solid) 1560, 1541, 1469, 1360; MS 428.1 (M + H) ⁺ .

Example 267 [2- (4-Ethylsulfanylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-39): mp 229-231 ^about C; ¹ H NMR (DMCO) δ 1.29 (3H, t), 2.35 (3H, s), 3.07 (2H, q), 6.76 (1H, s), 7.43 (2H, d ), 7.51 (1H, m), 7.81 (2H, m), 8.41 (2H, d), 8.64 (1H, d), 10.38 (1H, s), 12.24 (1H, broad s); IR (solid) 1587, 1574, 1555, 1531, 1484, 1412, 1369; MS 362.1 (M + H) ⁺ .

Example 268 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-40): mp 218-219 ^about C; ¹ H NMR (DMCO-d ₆ ) δ 0.70-0.80 (2H, m), 0.90-1.00 (2H, m), 6.70 (1H, s), 7.45-7 55 (4H, m), 7.80-7.85 (2H, m), 8.45-8.55 (2H, m), 8.65 (1H, d), 10.40 (1H, s ), 12.27 (1H, s); IR (solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 997, 828, 803, 780, 762, 710; MS 328.2 (M + H) ⁺ .

Example 269 [2- (4-tert-Butylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-41): mp> 300 ° C; ¹ H NMR (DMCO-d ₆ ) δ 1.35 (9H, s), 2.34 (3H, s), 6.79 (1H, s), 7.55 (3H, d), 7.85 ( 2H, d), 8.39 (2H, d), 8.62 (1H, d), 10.35 (1H, s), 12.22 (1H, s); IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409, 1371, 1359, 998, 841, 825, 766, 757; MS 358.3 (M + H) ⁺ .

Example 270 [2- (4-Chlorophenyl) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (III-42): ¹ H NMR (DMCO-d ₆ ) δ 0.77 (4H, broad m), 2.05 (1H, m), 6.59 (1H, s), 7.60 (1H, d), 7.85 (2H, d), 7.91 (2H, d) 8.22 (2H, d), 8.65 (1H, s), 10.51 (lH, s), 12.33 (1H, s); MS 362.1 (M + H) ⁺ .

Example 271 (2-Benzo [1,3] dioxol-5-ylquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-43): ¹ H NMR (DMCO) δ 2 33 (3H, s), 6.13 (2H, s), 6.78 (1H, s), 7.11 (1H, d), 7.80 (1H, t), 7.94 (1H, s), 8.09 (3H, m), 8.25 (1H, d), 10.34 (1H, s), 12.21 (1H, C); MS 346.5 (M + H) ⁺ .

Example 272 [2- (4-Dimethylaminophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-44): ¹ H NMR (DMCO-d ₆ ) δ 2.02 (6H, C), 2.39 (3H, s), 6.83 (1H, s), 7.71 (1H, d), 7.98 (2H, s), 8.04 (2H, d) 8.33 (2H, d), 8.67 (1H, s), 11.82 (1H, s), 12.72 (1H, s); MS 345.3 (M + H) ⁺ .

Example 273 [2- (3-Methoxyphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-45): mp. 226 ^{° C; 1} H NMR (DMCO-d ₆ ) δ 2.34 (3H, s), 3.92 (3H, s), 6.72 (1H, s), 7.21 (1H, d), 7.57 ( 1H, t), 7.79 (1H, t), 8.02 (3H, m), 8.14 (1H, s), 8.79 (1H, d), 10.39 (1H, s), 12.22 (1H, s); IR (solid) 1599, 1572, 1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 (M + H) @ ⁺ .

Example 275 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dichlorophenyl) quinazolin-4-yl] amine (III-46): ¹ H NMR (DMCO-d ₆ ) δ 0 86 (2H, d), 1.02 (2H, d), 1.69 (1H, m), 6.56 (1H, s), 7.57 (1H, d), 7.84 (4H, m), 8.40 (1H, s), 8.58 (1H, s), 8.64 (1H, s), 10.53 (1H, s), 12.36 (1H, s); MS 396.0 (M + H) ⁺ .

Example 276 (2-Biphenyl-4-ylquinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (III-47): To a mixture of [2- (4-bromophenyl) quinazolin-4- il] - (5-methyl-2H-pyrazol-3-yl) amine (III-34) (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in a mixture of THF-water (1 : 1, 4 ml) Na ₂ CO ₃ (219 mg, 2.06 mmol), triphenylphosphine (9 mg, 1/15 mol%) and palladium acetate (1 mg, 1: 135 mol%) were added. The resulting mixture was heated at 80 ° C. overnight, the solvents were evaporated, and the residue was purified by flash chromatography (gradient of dichloromethane-MeOH) to give compound III-21 as a yellow solid (99 mg, 51%): ¹ H NMR (DMCO ) δ 2.37 (3H, s), 6.82 (1H, s), 7.39-7.57 (4H, m), 7.73-7.87 (6H, m), 8.57 ( 2H, d), 8.67 (1H, d), 10.42 (1H, s), 12.27 (1H, s); MS 378.2 (M + H) ⁺ .

Example 277 [2- (4-Ethylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-48): To the mixture [2- (4-bromophenyl) quinazolin-4 -yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-34) (114 mg, 0.3 mmol) and trimethylsilylacetylene (147 mg, 1.5 mmol) in DMF (2 ml) was added CuI (1.1 mg, 1:50 mol%), Pd (PPh ₃ ) ₂ Cl ₂ (4.2 mg, 1:50 mol%) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120 ° C. overnight and the solvent was evaporated. The residue was triturated in ethyl acetate and the resulting precipitate was collected by filtration. The collected solid was suspended in THF (3 ml) and TBAF (1 M in THF, 1.1 eq.) Was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, DCM-MeOH gradient) to give compound III-48 as a white solid (68 mg, 70%): ¹ H NMR (DMCO) δ 2.34 (3H, s), 4 36 (1H, s), 6.74 (1H, s), 7.55 (1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M + H) ⁺ .

Example 278 [2- (3-Ethinylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-49): mp. 204-207 ^{° C; 1} H NMR (DMCO) δ 2.34 (3H, s), 4.28 (1H, s), 6.74 (1H, s), 7.55-7.63 (3H, m), 7.83 -7.87 (2H, m), 8.49 (1H, d), 8.57 (1H, s), 8.65 (1H, d), 10.46 (1H, s), 12.27 ( 1H, s); IR (solid) 1598, 1574, 1541, 1489, 1474, 1422, 1365; MS 326.1 (M + H) ⁺ .

Example 279 [2- (3-Methylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-50): Suspension of 1H-quinazolin-2,4-dione (10, 0 g, 61.7 mmol) in POCl ₃ (60 ml, 644 mmol) and N, N-dimethylaniline (8 ml, 63.1 mmol) were refluxed for 2 hours. Excess POCl ₃ was removed in vacuo, the residue was poured onto ice, and the resulting precipitate was collected by filtration. The crude solid product 2,4-dichloroquinazoline (6.5 g, 53% yield) was washed with water and dried in vacuo for use in the next step without further purification. To a solution of 2,4-dichloroquinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 ml) was added 5-methyl-1H-pyrazol-3-ylamine (3.2 g, 32.9 mmol) and the resulting the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol and dried in vacuo to obtain 4.0 g (93% yield) of (2-chloroquinazolin-4-yl) - (5-methyl-1H-pyrazol-3-yl) amine, which was used on the next step without further purification. To a solution of (2-chloroquinazolin-4-yl) - (5-methyl-1H-pyrazol-3-yl) amine (50 mg, 0.19 mmol) in DMF (1.0 ml) was added m-tolylboronic acid (0 , 38 mmol), 2M Na ₂ CO ₃ (0.96 mmol) and tri-tert-butylphosphine (0.19 mmol). The flask was purged with nitrogen and PdCl ₂ catalyst (dppf) was added in one portion. Then the reaction mixture was heated at 80 ° C for 10 hours, cooled to room temperature and poured into water (2 ml). The resulting precipitate was collected by filtration, washed with water and purified by HPLC to give compound III-50 as a pale yellow solid (61 mg, 75%): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.3 (broad s, 1H), 10.4 (br s, 1H), 8.75 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.78 (s, 2H), 7.55 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 6.80 (s, 1H), 2.47 (s, 3H), 2, 30 (s, 3H); MS 316.1 (M + H).

Example 280 [2- (3,5-Difluorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-51): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.3 (br s, 1H), 10.8, (br s, 1H), 8.63 (d, 1H), 7.95 (d, 2H), 7.85 (m, 2H ), 7.58 (t, 1H), 7.41 (t, 1H), 6.59 (s, 1H), 2.27 (s, 3H); MS 338.1 (M + H).

Example 281 [2- (3-Chloro-4-fluorophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-52): ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.4 (br s, 1H), 10.8 (br s, 1H), 8.65 (d, 1H), 8.50 (d, 1H), 8.36, (m , 1H), 7.85 (m, 1H), 7.60 (m, 1H), 6.62 (s, 1H), 2.30 (s, 3H); MS 354.1 (M + H).

Example 282 (5-Methyl-2H-pyrazol-3-yl) - [2- (3-trifluoromethylphenyl) quinazolin-4-yl] amine (III-53): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.2 (broad, 1H), 10.45 (broad, 1H), 7.53 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.06 (d , J = 8.2 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 6.43 (t, J = 7.8 Hz, 1H), 6.32 (t, J = 7.6 Hz, 1H), 5.51 (s, 1H), 2.03 (s, 3H); MS 370.2 (M + H).

Example 283 [2- (3-Cyanophenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-54): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.96 (m, 2H), 8.28 (d, J = 7.3 Hz, 1H), 8.16 (s, br., 2H), 8.06 ( t, J = 7.8 Hz, 1H), 7.88 (m, 1H), 6.96 (s, 1H), 2.58 (s, 3H); MS 327.1 (M + H).

Example 284 [2- (3-Isopropylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-55): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.89 (d, J = 7.5 Hz, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 8.08 (m, 2H), 7.81 (t, broad) ., 1H), 7.67 (m, 2H), 6.88 (s, 1H), 3.12 (m, 1H), 2.40 (s, 3H), 1.38 (d, J = 6 9 Hz, 6H); MS 344.2 (M + H).

Example 285 (5-Methyl-2H-pyrazol-3-yl) - (2-pyridin-3-yl-quinazolin-4-yl) amine (III-56): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.84 (d, J = 7.3 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H), 7.87 (m, 2H), 7.77 (m, 1H), 7.60 (t, J = 7.2 Hz, 1H), 6.67 (s, 1H) 2.28 (s, 3H); MS 303.1 (M + H).

Example 286 [2- (3-Acetylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-57): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 8.55 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7 , 0 Hz, 1H), 7.76 (m, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.48 (s, broad, 1H), 6.60 (s, 1H); 2.49 (s, 3H); 2.03 {s, 3H); MS 344.1 (M + H).

Example 287 [2- (3,5-Ditrifluoromethylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-58): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.7 (s, broad. 1H), 8.95 (s, 2H), 8.63 (d, J = 8.2 Hz, 1H), 8.25 (s, 1H), 7, 86 (m, 2H), 7.58 (t, J = 6.9 Hz, 1H), 6.62 (s, 1H), 2.26 (s, 3H); MS 438.1 (M + H).

Example 288 [2- (3-Hydroxymethylphenyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-59): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 7.9 Hz, 1H), 8.33 (s, 1H), 8.17 (s, broad, 1H), 7.95 (s, broad, 1H), 7 89 (s, broad. 1H), 7.62 (m, 3H), 6.72 (s, 1H), 5.53 (s, 1H), 4.60 (s, 2H), 2.28 (s, 3H); MS 332.1 (M + H).

Example 289 (5-Methyl-2H-pyrazol-3-yl) - [2- (3-phenoxyphenyl) -quinazolin-4-yl] amine (III-60): mp 231-232 ° C; ¹ H NMR (DMSO-d ₆ ) δ 2.21 (3H, s), 6.59 (1H, s), 7.10-7.22 (4H, m), 7.41-7.45 (2H , m), 7.54-7.59 (2H, m), 7.81 (2H, s), 8.09 (1H, s), 8.27 (1H, m), 8.64 (1H, m) 10.40 (1H, s); 12.20 (1H, s); IR (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 (M + H) ⁺ .

Example 290 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-phenoxyphenyl) quinazolin-4-yl] amine (III-61): mp 193-195 ° C; ¹ H NMR (DMSO-d ₆ ) δ 0.67 (2H, m), 0.93 (2H, m), 1.87 (lH, m), 6.56 (1H, s), 7.06- 7.20 (4H, m), 7.40-7.43 (2H, m), 7.55-7.59 (2H, m), 7.81 (2H, s), 8.11 (1H, s), 8.27 (1H, m), 8.63 (1H, m), 10.43 (1H, s), 12.26 (1H, s); IR (solid) 1589, 1574, 1527, 1483, 1369, 1226; MS 420.7 (M + H) ^{@ +} .

Example 291 (5-Methyl-2H-pyrazol-3-yl) - (2-thiophen-3-yl-quinazolin-4-yl) amine (III-62): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.78 (s, broad, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.68 (s, 1H), 7.98 (dd, J = 7.9, 7.5 Hz, 1H), 7.89 (m, 2H), 7.81 (m, 1H), 7.68 (t, J = 7.5 Hz, 1H), 6.69 (s, 1H) 2.30 (s, 3H); MS 308.1 (M + H).

Example 292 (2-Phenylquinazolin-4-yl) - (2H-pyrazol-3-yl) amine (III-63): mp 247-249 ° C; ¹ H NMR (DMSO) δ 6.99 (1H, br s), 7.49-7.58 (5H, m), 7.81 (1H, br s), 7.83 (2H, m) 8.47-8.49 (2H, m), 8.66 (1H, d), 10.54 (1H, s), 12.59 (1H, s); IR (solid) 3145, 2922, 1622, 1597; MS 288.2 (M + H) ⁺ .

Example 293 (2H-Pyrazol-3-yl) - (2-pyridin-4-yl-quinazolin-4-yl) amine (III-64): mp. 285-286 ° C; ¹ H NMR (DMSO) δ 6.99 (1H, br s), 7.65 (1H, m), 7.81-7.94 (3H, m), 8.3-8.35 (2H, m), 8.73 (1H, d), 8.84-8.90 (2H, m), 10.76 (1H, s), 12.6 (1H, s); IR (solid) 3180, 2972, 1600, 1574; MS 289.2 (M + H) @ ⁺ .

Example 294 (5-Ethyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-65): mp 221-222 ^{° C; 1} H NMR (DMSO) δ 1.31 (3H, t), 2.68 (2H, d), 6.80 (1H, s), 7.50-7.60 (4H, m), 8.45 -8.55 (2H, m), 8.65-8.75 (1H, m), 10.44 (1H, s), 12.27 (1H, s); IR (solid) 3190, 1622, 1595, 1575, 1533, 1482, 1441, 1420, 1403, 1361, 758, 711; MS 316.2 (M + H) ⁺ .

Example 295 (2-Phenylquinazolin-4-yl) - (5-propyl-2H-pyrazol-3-yl) amine (III-66): mp 204-205 ° C; ¹ H NMR (DMSO-d ₆ ) δ 1.02 (3H, t), 1.66-1.75 (2H, m), 2.69 (2H, t), 6.80 (1H, s), 7.45-7.60, (4H, m), 7.80-7.88 (2H, m), 8.45-8.50 (2H, m), 8.65 (1H, d), 10 39 (1H, s); 12.25 (1H, s); IR (solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827, 808, 763, 709, 697; MS 330.2 (M + H) ⁺ .

Example 296 (5-Isopropyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-67): mp 218-219 ° C; ¹ H NMR (DMSO-d ₆ ) δ 1.36 (6H, d), 3.05 (1H, m), 6.86 (1H, s), 7.48-7.59 (4H, m), 7.80-7.88 (2H, m), 8.49-8.58 (2H, m), 8.66 (1H, d), 10.47 (1H, s), 12.30 (1H, from); IR (solid) 3173, 2968, 1619, 1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707, 666, 659; MS 330.2 (M + H) ⁺ .

Example 297 (5-tert-Butyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-68): mp 136-137 ^about C; ¹ H NMR (DMSO-d ₆ ) δ 1.38 (9H, s), 6.87 (1H, broad s), 7.51-7.57 (4H, m), 7.84-7.85 (2H, m), 8.49-8.51 (2H, m), 8.65 (1H, d), 10.43 (1H, s), 12.21 (1H, br s); IR (solid) 3162, 2963, 1621, 1590, 1572; MS 344.2 (M + H) ⁺ .

Example 298 (5-tert-Butyl-2H-pyrazol-3-yl) - (2-pyridin-4-yl-quinazolin-4-yl) amine (III-69): mp > 300 ^° C; ¹ H NMR (DMSO) δ 1.38 (9H, s), 6.82 (1H, br s), 7.63 (1H, m), 7.86-7.91 (2H, m), 8 32-8.33 (2H, d), 8.69 (1H, d), 8.75-8.76 (2H, d), 10.60 (1H, s), 12.31 (1H, broad) .from); IR (solid) 3683, 3149, 2963, 1621; MS 345.2 (M + H) ⁺ .

Example 299 (5-Cyclopentyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-70): mp 240-241 ^about C; ¹ H NMR (DMSO-d ₆ ) δ 1.68-1.89 (6H, m), 2.03-2.17 (2H, m), 3.14-3.22 (1H, m), 6 80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.89 (2H, m), 8.45-8.52 (2H, m), 8.67 (1H, d), 10.52 (1H, s), 12.26 (1H, s); IR (solid) 2957, 1621, 1591, 1571, 1531, 1476, 1438, 1405, 1370, 1325, 999, 951, 801, 775, 761, 747, 710695, 668, 654; MS 356.2 (M + H) ^{@ +} .

Example 300 (5-Phenyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-71): mp 207-209 ^about C; ¹ H NMR (DMSO) δ 7.38-7.40 (1H, m), 7.50-7.58 (6H, m), 7.82-7.88 (4H, m), 8.51 ( 2H, m), 8.67 (1H, s), 10.58 (1H, s), 13.11 (1H, br s); IR (solid) 3345, 3108, 1627, 1612; MS 364.2 (M + H) ⁺ .

Example 301 (5-Carboxy-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-72): (5-Methoxycarbonyl-2H-pyrazol-3-yl) - (2-phenylquinazoline -4-yl) amine (III-73) (345 mg, 1 mmol) in THF (6 ml) was treated with NaOH (1 M, 4.0 ml), stirred at 50 ° C for 5 hours, cooled to room temperature and neutralized by adding 1 M HCl. The mixture was concentrated in vacuo to remove THF, after which it was diluted with water and the resulting precipitate was filtered off. The resulting solid was dried at 80 ° C in vacuo to give compound III-72 as an off-white solid (312 mg, 94%): mp. 289-291 ^about C; ¹ H NMR (DMSO) δ 7.45 (1H, br s), 7.50-7.60 (5H, m), 7.80-7.88 (2H, m), 7.40-7, 50 (2H, m), 8.60-8.70 (1H, d), 10.70 (1H, s), 13.00-13.80 (2H, broad s); IR (solid) 1699, 1624, 1607, 1570.1539, 1506, I486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332.3 (M + H) @ ⁺ .

Example 302 (5-Methoxycarbonyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-73): mp 271-273 ^{° C; 1} H NMR (DMSO) δ 3.95 (3H, s), 7.50-7.65 (5H, m), 7.80-7.98 (2H, m), 8.40-8.50 ( 2H, m), 8.65-8.73 (1H, m), 10.80 (1H, C), 13.80 (1H, s); IR (solid) 3359, 1720, 1624, 1597, 1561, 1538, 1500, 1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763 703, 690, 670; MS 346.3 (M + H) ⁺ .

Example 303 (5-Hydroxymethyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-74): Solution (5-methoxycarbonyl-2H-pyrazol-3-yl) - (2- phenylquinazolin-4-yl) amine (III-73) (345 mg, 1 mmol) in anhydrous THF (10 ml) was treated with lithium borohydride (125 mg, 5.75 mmol) at 65 ° C for 5 hours. The mixture was cooled to room temperature and then combined with 2 M HCl and ethyl acetate. Solid sodium bicarbonate was added to obtain a pH of 8, and the resulting mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated. Purification by flash chromatography (SiO ₂ , methanol-dichloromethane gradient) gave compound III-74 (95 mg, 30%) as an off-white solid: ¹ H NMR (DMSO) δ 4.58 (2H, d, CH2 ), 5.35 (1H, s, OH), 6.94 (1H, s), 7.50-7.60 (4H, m), 7.85-7.90 (2H, m), 8, 48-8.54 (2H, m), 8.69 (1H, 1H), 10.40 (1H, s), 12.48 (1H, s); IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532, 1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780, 7124; MS 318.2 (M + H) ⁺ .

Example 304 (5-Methoxymethyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-75): mp 190-191 ^about C; ¹ H NMR (DMSO) δ 3.34- (3H, s), 4.45 (2H, s), 7.00 (1H, s), 7.50-1.62 (4H, m), 7, 82-7.90 (2H, m), 8.45-8.52 (2H, m), 8.65 (1H, broad s), 10.50 (1H, s), 12.30 (1H, from); IR (solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, 954, 834, 813, 766, 707, 691; MS 332.3 (M + H) @ ⁺ .

Example 305 [5- (3-Hydroxyprop-1-yl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-76): Solution (5-benzyloxypropyl-2H-pyrazol- 3-yl) - (2-phenylquinazolin-4-yl) amine (III-78) (200 mg, 0.46 mmol) in toluene (4 ml) and acetonitrile (8 ml) was mixed with trimethylsilyl iodide (0.64 ml, 4.6 mmol) at 55 ° C for 3 hours to obtain an amber-colored solution. The resulting mixture was diluted with ethyl acetate and an aqueous solution of sodium bicarbonate. The resulting layers were separated, the organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (SiO ₂ , gradient methanol-dichloromethane) gave a yellow oil (115 mg). Rubbing with dichloromethane gave compound III-76 as an off-white solid, dried at 75 ° C in vacuo (83 mg, 52%): mp. 164-165 ° C; ¹ H NMR (DMSO) δ 1.80-1.90 (2H, m), 2.70-2.80 (2H, m), 3.50-3.60 (2H, m), 4.59 ( 1H, s), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.82-7.90 (2H, m), 8.48-8.53 (2H, m), 8.63 (1H, s), 10.40 (1H, s), 12.25- (1H, s); IR (solid) 1622, 1587, 1574, 1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952, 833, 762, 734, 706, 690, 671, 665; MS 346.0 (M + H) @ ⁺ .

Example 306 [5- (3-Methoxyprop-1-yl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-77): mp 169-170 ^about C; ¹ H NMR (DMSO-d ₆ ) δ 1.86-1.97 (2H, m), 2.75 (2H, t), 3.30 (3H, s), 3.45 (2H, t), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.90 (2H, m), 8.45-8.55 (2H, m), 8, 67 (1H, d), 10.30 (1H, C), 12.25 (1H, C); IR (solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360.3 (M + H) ^{@ +} .

Example 307 [5- (3-Benzyloxyprop-1-yl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-78): mp 177-178 ^about C; ¹ H NMR (DMSO) δ 1.92-2.03 (2H, m), 3.76-3.85 (2H, m), 3.52-3.62, (2H, m), 4.51 (2H, s), 6.82 (1H, s), 7.28-7.40 (5H, m), 7.46-7.58 (4H, m), 7.80-7.85 (2H , m), 8.47-8.52 (2H, m), 8.66 (1H, d), 10.45 (1H, s); IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426, 1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3 (M + H) ⁺ .

Example 308 [5- (3-Aminoprop-1-yl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-79): Solution [5- (3-tert-butoxy -carbonylaminoprop-1-yl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) -amine (III-80) (250 mg, 0.56 mmol) in dichloromethane (3 ml) at 0 ° C was treated with TFA (2 ml). The mixture was warmed to room temperature and then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane (3 x 5 ml) and ether, and then triturated with dichloromethane to give a crystalline TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3 ml) and water (3 ml). Potassium carbonate was added in portions until a pH of 8 was obtained, after which the mixture was allowed to crystallize. The product was collected by filtration and dried at 80 ° C in vacuo to give compound III-79 as an off-white powder (122 mg, 63%): mp. 205-207 ^about C; (DMCO) 61.68-1.83 (2H, m), 2.65-2.80 (4H, m), 6.80 (1H, s), 7.50-7.60 (4H, m) 7.80-7.90 (2H, m), 8.45-8.53 (2H, m), 8.65 (1H, d), 10.45 (1H, br s); IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345.3 (M + H) +.

Example 309 [5- (3-tert-Butoxycarbonylaminoprop-1-yl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-80): mp. 199-200 ° C; ¹ H NMR (DMSO) δ 1.37 (9H, s), 1.71-1.82 (2H, m), 2.67 (2H, t), 3.00-3.11 (2H, m) , 7.81 (1H, s), 7-99 (1H, s), 7.50-7.60 (4H, m), 7.80-7.85 (2H, m), 8.48-8 52 (2H, m), 8.63 (1H, d), 10.40 (1H, s), 12.26 (1H, m); IR (solid) 2953, 1687, 1622, 1594, 1573, 1535, 1481, 1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848, 807, 768, 740, 728 710.693; MS 445.3 (M + H) ⁺ .

Example 310 (5-Isopropylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-81): ¹ H NMR (DMSO-d ₆ ) δ 1.20 (d, J = 6.6 Hz, 6H), 4.13 (m, 1H), 7.42 (br s, 1H), 7.61 (dd, J, = 7.0, 7.7 Hz, 2H), 7 66 (t, J = 7.1 Hz, 1H), 7.71 (m, 1H), 7.99 (m, 2H), 8.39 (m, 1H), 8.42 (d, J = 7.1 Hz, 2H), 8.74 (d, J = 8.2 Hz, 1H), 11.41 (br s, 1H); EI-MS 373.2 (M + H); HPLC method C, R _t 14.09 min.

Example 311 (5-Allylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-82): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.02 (m, 2H), 5.15 (m, 1H), 5.23 (m, 1H), 5.94 (m, 1H), 7.45 (br s, 1H), 7.60 (t, J = 6 , 9 Hz, 2H), 7.64 (m, 1H), 7.72 (m, 1H), 7.98 (m, 2H), 8.43 (m, 2H), 8.72 (d, J = 8.2 Hz, 1H), 8.84 (br s, 1H), 11.34 (br s, 1H); EI-MS 371.2 (M + H); HPLC method C, R _t 13.67 min.

Example 312 [5- (2-Methoxyethylcarbamoyl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-83): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3, 32 (s, 3H), 3.48 (m, 4H), 7.36 (br s, 1H), 7.62 (m, 2H), 7.63 (m, 1H), 7.71 (m , 1H), 7.98 (m, 2H), 8.41 (dd, J = 1.4, 7.0, 2H), 8.70 (m, 2H), 11.30 (br s, 1H ); EI-MS 389.2, (M + H); HPLC method C, R _t 12.37 min.

Example 313 (5-Benzylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-84): ¹ H NMR (DMSO-d ₆ ) δ 4.52 (d, J = 6.0 Hz, 2H), 7.29 (m, 1H), 7.38 (d, J = 4.2 Hz, 4H), 7.58 (t, J = 7.5 Hz, 2H), 7 , 63 (m, 1H), 7.72 (m, 1H), 7.98 (m, 2H), 8.43 (d, J = 7.7 Hz, 2H), 8.72 (d, J = 7.5 Hz, 1H), 9.23 (br s, 2H), 11.34 (br s, 1H); EI-MS 421.2 (M + H); HPLC method C, R _t 16.76 min.

Example 314 (5-Cyclohexylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-85): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.16 (m, 1H), 1.34 (m, 4H), 1.62 (d, J = 2.6 Hz, 1H), 1.76 (m, 2H), 1.85 (m, 2H), 3.79 ( m, 1H), 7.43 (m, 1H), 7.60 (t, J = 7.2 Hz, 2H), 7.65 (t, J = 7.1 Hz, 1H), 7.71 ( ddd, J = 2.2, 5.4, 8.2 Hz, 1H), 7.98 (m, 2H), 8.35 (m, 1H), 8.43 (dd, J = 1.4, 7.2 Hz, 2H), 8.72 (d, J = 8.2 Hz, 1H), 11.34 (br s, 1H); EI-MS 413.5 (M + H) ;, HPLC method C, R _t 17.18 min.

Example 315 (5-Diethylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-86): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.18 (broad. s, 3H), 1.25 (broad s, 3H), 3.49 (broad s, 2H), 3.69 (broad s, 2H), 7.21 (s, 1H), 7.59 (t, J = 6.9 Hz, 2H), 7.62 (m, 1H), 7.70 (m, 1H), 7.96 (m, 2H), 8.39 (d, J = 7, 1 Hz, 2H), 8.74 (d, J = 8.4 Hz, 1H), 11.37 (br s, 1H); EI-MS 387.2 (M + H); HPLC method C, R _t 14.50 min.

Example 316 [5- (2-Benzylmethylcarbamoyl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-87): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3, 33 (s, 3H), 4.75 (s, 2H), 7.26 (m, 1H), 7.31 (m, 1H), 7.38 (m, 4H), 7.58 (m, 2H) ), 7.70 (m, 1H), 7.95 (m, 3H), 8.26 (m, 1H), 8L40 (d, J = 7.8 Hz, 2H), 8.75 (m, 1H ), 11.2 (br s, 1H); EI-MS 435.2, (M + H); HPLC method C, R _t 16.77 min.

Example 317 (2-Phenylquinazolin-4-yl) - (5-propylcarbamoyl-2H-pyrazol-3-yl) amine (III-88): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 0.94 (t, J = 7.3 Hz, 3H), 1.57 (m, 2H), 3.24 (q, J = 6.5 Hz, 2H), 7.39 (br s, 1H), 7.60 (t, J = 7.3 Hz, 2H), 7.64 (m, 1H), 7.71 (broad t, J = 6.5 Hz, 1H), 7.98 (m, 2H), 8 42 (d, J = 7.2 Hz, 2H), 8.61 (br s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 11.34 (br s, 1H); EI-MS 373.3 (M + H); HPLC method C, R _t 13.51 min.

Example 318 [5- (2-Ethylisopropylcarbamoyl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-89): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 0, 92 (t, J = 7.4 Hz, 6H), 1.52 (m, 2H), 1.59 (m, 1H), 3.79 (m, 2H), 7.53 (br s, 1H ), 7.57 (t, J = 7.5 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.71 (m, 1H), 7.99 (m, 2H ), 8.23 (broad d, J = 8.8 Hz, 1H), 8.46 (d, J = 7.5 Hz, 2H), 8.74 (d, J = 8.4 Hz, 1H ), 11.34 (br s, 1H); EI-MS 4.01.2 (M + H); HPLC method C, R _t 15.51 min.

Example 319 (5-Cyclopropylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-90): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 0.60 (m, 2H), 0.74 (m, 2H), 2.86 (m, 1H), 7.34 (br s, 1H), 7.62 (m, 3H), 7.70 (m, 1H), 7.97 (m, 2H), 8.41 (d, J = 7.9 Hz, 2H), 8.63 (br s, 1H), 8.72 (d, J = 7.8 Hz, 1H ), 11.35 (br s, 1H); El-MS 371.2 (M + H); HPLC method C, R _t 12.64 min.

Example 320 (5-Isobutylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-91): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 0.94 (d, J = 6.7 Hz, 6H), 1.88 (m, 1H), 3.12 (t, J = 6.4 Hz, 2H), 7.45 (br s, 1H), 7.58 ( t, J = 7.2 Hz, 3H), 7.64 (t, J = 7.1 Hz, 1H), 7.71 (m, 1H), 7.98 (m, 2H), 8.44 ( dd, J = 1.3, 7.9 Hz, 2H), 8.62 (broad s, 1H), 8.72 (d, J = 8.3 Hz, 1H), 11.33 (broad s , 1H); EI-MS 387.2 (M + H); HPLC method C, R _t 14.70 min.

Example 321 {5 - [(3S) -3-Methoxymethylpyrrolidin-1-carbonyl] -2H-pyrazol-3-yl} - (2-phenylquinazolin-4-yl) amine (III-93): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.00 (m, 2H), 2.12 (m, 1H), 3.29 (s, 3H), 3.45 (t, J = 8.7 Hz, 1H), 3 57 (dd, J = 3.2, 9.3 Hz, 1H), 3.86 (m, 1H), 3.92 (m, 1H), 4.36 (m, 2H), 7.45 ( broad s, 1H), 7.59 (t, J = 7.2 Hz, 2H), 7.63 (m, 1H), 7.69 (m, 1H), 7.97 (m, 2H), 8.40 (d, J = 7.5 Hz, 2H), 8.74 (d, J = 7.6 Hz, 1H), 11.38 (br s, 1H); EI-MS 429.2 (M + H); HPLC method C, R _t 13.84 min.

Example 322 (2-Phenylquinazolin-4-yl) - (5-m-tolylcarbamoyl-2H-pyrazol-3-yl) amine (III-94): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.33 ( s, 3H), 6.97 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.62 (m, 7H), 7.72 ( m, 1H), 7.98 (m, 2H), 8.46 (dd, J = 2.0, 7.9 Hz, 2H), 8.71 (m, 1H), 10.29 (s, 1H ), 11.31 (br s, 1H); EI-MS 421.2 (M + H); HPLC method C, R _t 17.11 min.

Example 323 (2-Phenylquinazolin-4-yl) - (5-p-tolylcarbamoyl-2H-pyrazol-3-yl) amine (III-95): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.30 ( s, 3H), 7.20 (d, J = 8.3 Hz, 2H), 7.62 (m, 5H), 7.68 (d, J = 8.3 Hz, 2H), 7.72 ( m, 1H), 7.98 (m, 2H), 8.46 (dd, J = 1.8, 7.0 Hz, 2H), 8.72 (m, 1H), 10.31 (s, 1H ), 11.36 (br s, 1H); El-MS 421.2 (M + H); HPLC method C, R _t 16.95 min.

Example 324 (5-Methylcarbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-96): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.82 (d, J = 4.6 Hz, 3H), 7.31 (br s, 1H), 7.62 (m, 3H), 7.69 (m, 1H), 7.97 (m, 2H), 8, 42 (d, J = 7.1 Hz, 2H), 8.59 (broad s, 1H), 8.71- (d, J = 8.0 Hz, 1H), 11.30 (broad s, 1H); EI-MS 345.1 (M + H); HPLC method C, R _t 11.02 min.

Example 325 [5- (Morpholin-4-carbonyl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-97): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.33 (m, 4H), 3.83 (m, 4H), 7.34 (br s, 1H), 7.53 (m, 4H), 7.86 (m, 2H), 8.43 (m, 2H), 8.67 (d, J = 8.6 Hz, 1H), 10.70 (s, 1H), 13.56 (s, 1H); EI-MS 401.2 (M + H); HPLC method A, R _t 2.68 min.

Example 326 [5- (1-Methylpiperazin-4-carbonyl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-98): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H), 2.43 (m, 4H), 3.87 (m, 4H), 7.33 (br s, 1H), 7.53 (m, 4H), 7 87 (m, 2H), 8.45 (m, 2H), 8.67 (d, J; = 7.6 Hz, 1H), 10.70 (s, 1H), 13.30 (s, 1H ); EI-MS 414.2 (M + H) ;, HPLC method A, R _t 2.38 min.

Example 327 [5- (2-Hydroxyethylcarbamoyl) -2H-pyrazol-3-yl] - (2-phenylquinazolin-4-yl) amine (III-99): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3, 36 (m, 2H), 3.52 (m, 2H), 4.79 (m, 1H), 7.50 (m, 5H), 7.83 (m, 2H), 8.50 (m, 4H ), 10.52 (br s, 1H), 13.25 (s, 1H); EI-MS 375.1 (M + H); HPLC method A, R _t 2.51 min.

Example 328 (5-Carbamoyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-100): To a solution of 2,5- dioxopyrrolidin-1-yl ester 5- (2-phenylquinazoline -4-ylamino) -1H-pyrazole-3-carboxylic acid (270 mg, 0.63 mmol) in DMF (20 ml) was added a solution of ammonia in 1,4-dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperature for 24 hours. After concentration of the solvents, the residue was introduced into water (20 ml). The resulting precipitate was collected to give compound III-100 (168 mg, 80%) as a yellow solid: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.77-7.51 (m, 6H), 7.86 (broad s, 2H), 8.11 (m, 1H), 8.50 (m, 2H), 8.63 (m, 1H), 10.52 (s, 1H), 11.25 (s, 1H); EI-MS 331.1 (M + H); HPLC method A, R _t 2.52 min.

Example 329 (4-Bromo-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-101): Obtained by method A as a yellow solid: mp 189 ° C; ¹ H NMR (DMSO-d ₆ ) δ 7.44-7.46 (3H, m), 7.58 (1H, m), 7.87 (2H, d), 8.15 (1H, s), 8.31-8.34 (2H, m), 8.49 (1H, d), 10.08 (1H, s), 13.13 (1H, s); IR (solid) 3286, 2969, 1738, 1632; MS 366.2 / 368.2 (M + H) ⁺ .

Example 330 (4-Bromo-5-methyl-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-102): mp 183-185 ° C; ¹ H NMR (DMSO) δ 2.33 (3H, br s), 7.44-7.46 (3H, m), 7.57 (1H, m), 7.84-7.87 (2H, m), 8.31-8.34 (2H, m), 8.48 (1H, d), 10.05 (1H, s), 12.91 (1H, br s); IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380.2 / 382.2 (M + H) ⁺ .

Example 331 (4-Cyano-2H-pyrazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-103): mp > 250 ° C; ¹ H NMR (DMSO) δ 7.47-7.49 (3H, m), 7.64 (1H, m), 7.91 (2H, m), 8.40-8.43 (2H, m) 8.53 (1H, d), 8.71 (1H, d), 10.61 (1H, s), 13.60 (1H, s); IR (solid) 3277, 3069, 2855, 2231, 1625; MS 313.2 (M + H) ⁺ .

Example 332 (5-Methyl-2H-pyrazol-3-yl) - (2-morpholin-4-yl-quinazolin-4-yl) amine (III-104): mp 223-224 ° C; ¹ H NMR (DMSO) δ 2.26 (3H, s), 3, -65 (4H, m), 3.75 (4H, m), 6.44 (1H, s), 7.12 (1H, d) 7.33 (1H, d), 7.56 (1H, t), 8.37 (1H, d), 10.01 (1H, s), 12.13 (1H, br s); IR (solid) 1621, 1578, 1537, 1475, 1434, 1385; MS 311.0 (M + H) ⁺ .

Example 333 (5-Methyl-2H-pyrazol-3-yl) - (2-piperazin-4-yl-quinazolin-4-yl) amine (III-105): mp 179-181 ° C; ¹ H NMR (DMSO) δ 2.26 (3H, s), 2.74 (4H, s), 3.71 (4H, s), 6.43 (1H, s), 7.08 (1H, t), 7.30 (1H, d), 7.53 (1H, t), 8.34 (1H, d), 9.50 (1H, s), 12.08 (1H, broad. from); IR (solid) 2853, 1619, 1603, 1566, 1549, 1539; MS 310.0 (M + H) ⁺ .

Example 334 [2- (4-Methylpiperidin-1-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-106): mp 148-150 ° C; ¹ H NMR (DMSO) δ 1.06 (3H, d), 1.03 (2H, m), 1.51-1.70 (3H, m), 2.26 (3H, s), 2.86 (2H, m), 4.73 (2H, d), 6.44 (1H, s), 7.06 (1H, d), 7.29 (1H, d), 7.52 (1H, t) 8.32 (1H, d); 9.92 (1H, s); 12.09 {1H, broad s); IR (solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MS 323.0 (M + H) @ ⁺ .

Example 335 [2- (4-Methylpiperazin-1-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-107): mp. 105-107 ° C; ¹ H NMR (DMSO) δ 2.21 (3H, s), 2.26 (3H, s), 2.34 (4H, m), 3.75 (4H, m), 6.45 (1H, s ), 7.09 (1H, t), 7.31 (1H, d), 7.54 (1H, t), 8.34 (1H, d), 9.96 (1H, s), 12.12 (1H, broad s); IR (solid) 2934, 2844, 2804, 1620, 1593, 1572, 1536, 1476; MS 324.0 ((M + H) ⁺ .

Example 336 (5-Methyl-2H-pyrazol-3-yl) - (2-piperidin-1-yl-quinazolin-4-yl) amine (III-108): mp 294 ° C; ¹ H NMR (DMSO) δ 1.45-1.58 (4H, m), 1.63 (2H, m), 2.26 (3H, s), 3.79 (4H, m), 6.45 (1H, broad s), 7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.33 (1H, d), 9.92 (1H, c), 12.11 (1H, broad s); IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 1382; MS 309.3 ((M + H) ⁺ .

Example 337 (2-Azepan-1-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-109): mp 269 ° C; ¹ H NMR (DMSO) δ 1.50 (4H, broad s), 1.76 (4H, broad s), 2.25 (3H, s), 3.78 (4H, t), 6.55 (1H, broad s), 7.03 (1H, t), 7.28 (1H, d), 7.50 (1H, t), 8.33 (1H, d), 9.92 (1H, s), 12.09 (1H, broad s); IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3 (M + H) ⁺ .

Example 338 [2- (4- (2-Hydroxyethylpiperidin-1-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-110): mp 175 ° C; ¹ H NMR (DMSO) δ 1.08 (2H, m), 1.38 (2H, m), 1.57-1.83 (3H, m), 2.26 (3H, s), 2 85 (2H, t), 3.47 (2H, m), 4.38 (1H, t), 4.75 (2H, d), 6.45 (1H, broad s), 7.06 ( 1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.32 (1H, d), 9.93 (1H, s), 12.12 (1H, br s ); IR (solid) 3365, 3073, 2972, 2868, 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 ((M + H) ⁺ .

Example 339 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methylpiperidin-1-yl) quinazolin-4-yl] amine (III-111): To a solution of (5-cyclopropyl-1H- pyrazol-3-yl) - (2-chloroquinazolin-4-yl) amine (118 mg, 0.41 mmol) in tert-butanol (3.0 ml) was added 4-methylpiperidine (0.49 ml, 4.1 mmol ) and the resulting mixture was refluxed overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOH-water (1: 3, 4 ml). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (2 times) and Et ₂ O (2 times) to give compound III-111 as a white solid (123 mg, 85%): mp. 190 ° C; ¹ H NMR (DMSO) δ 0.66 (2H, s), 0.93, (5H, broad s), 1.07 (2H, d), 1.66 (3H, C), 1.91 ( 1H, s), 2.85 (2H, t), 4.72 (2H, d), 6.33 (1H, s), 7.06 (1H, t), 7.29 (1H, d) 7.52 (1H, t), 8.31 (1H, d), 9.95 (1H, s), 12.18 (1H, br s); IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, 1394; MS 349.2 ((M + H) ⁺ .

Example 340 [2- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III- 112): mp 191 ° C; ¹ H NMR (DMSO) δ 1.65 (4H, s,), 2.26 (3H, s), 3.90 (4H, s), 3.93 (4H, s), 6.43 (1H, broad s), 7.09 (1H, t), 7.32 (1H, d), 7.54 (1H, t), 8.35 (1H, d), 9.99 (1H, broad s ), 12.13 (1H, broad s); IR (solid) 3069, 2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3 ((M + H) ⁺ .

Example 341 [2- (4-Cyclopentylaminopiperidin-1-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-113): mp. 191 ° C; ¹ H NMR (DMSO) δ 1.33 (2H, d), 1.65 (4H, s), 1.87 (2H, d), 2.20 (1H, s), 2.26 (3H, s ), 2.49 (2H, s), 3.00 (2H, s), 3.36 (2H, s), 4.61 (2H, d), 6.45 (1H, broad s), 7 07 (1H, s), 7.31 (1H, d), 7.52 (1H, s), 8.33 (1H, d), 9.94 (1H, broad s), 12.12 ( 1H, broad s); IR (solid) 3371, 2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 ((M + H) ⁺ .

Example 342 [2- (4-Hydroxypiperidin-1-yl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (III-114): mp 123 ° C; ¹ H NMR (DMSO) δ 1.34 (2H, d), 1.80 (2H, d), 2.26 (3H, s), 3.24 (2H, t), 3.72 (1H, broad) s), 4.39 (2H, d), 4.70 (1H, d), 6.44 (1H, broad s), 7.07 (1H, t), 7.30 (1H, d) 7.53 (1H, t), 8.33 (1H, d), 9.94 (1H, broad s), 12.11 (1H, broad s); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 ((M + H) ⁺ .

Example 343 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-hydroxy-4-phenylpiperidin-1-yl) quinazolin-4-yl] amine (III-115): mp 131 ° C; ¹ H NMR (DMSO) δ 0.64 (2H, q), 0.93 (2H, q), 1.68 (2H, d), 1.83-1.97 (3H, m), 3.20 -3.45 (2H, m), 4.69 (2H, d), 5.11 (1H, s), 6.37 (1H, br s), 7.08 (1H, t), 7, 20 (1H, t), 7.31 (3H, t), 7.49 (2H, d), 7.53 (1H, t), 8.33 (1H, d), 9.98 (1H, broad s) 12.18 (1H, broad s); IR (solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481, 1459, 1431, 1372, 1336, 1213, 994; MS 427.6, ((M + H) ⁺ .

Example 344 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (1,3-dihydroisoindol-2-yl) quinazolin-4-yl] amine (III-116): Obtained by the EI method as not quite white solid, mp 237 ° C: mp 237 ° C; ¹ H NMR (DMSO-d ₆ ) δ 0.79 (2H, s), 1.00 (2H, d), 1.99 (1H, m), 4.92 (4H, d), 6.72 ( 1H, broad s), 7.13 (1H, t), 7.33 (2H, s), 7.30-7.48 (3H, m), 7.58 (1H, t), 8.40 (1H, d), 10.12 (1H, s), 12.17 (1H, s); IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369.4 ((M + H) ⁺ .

Example 345 (2-Azepan-1-yl) quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) amine (III-117): mp 199-200 ° C; ¹ H NMR (DMSO-d ₆ ) δ 0.60-0.70 (2H, m), 0.90-1.00 (2H, m), 1.45-1.57 (4H, m), 1 70-1.85 (4H, m), 1.88-1.97 (1H, m), 3.75-3.87 (4H, m), 6.42 (1H, s), 7.02 (1H, t), 7.27 (1H, d), 7.49 (1H, t), 8.29 (1H, d), 9.91 (1H, s), 12.19 (1H, broad. from); IR (solid) 2929, 1624, 1595, 1581, 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, 1000, 825, 754; MS 349.2 ((M + H) ⁺ .

Example 346 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dihydro-1H-isoquinolin-2-yl) quinazolin-4-yl] amine (III-118): mp . 182-184 ° C; ¹ H NMR (DMSO) δ 0.75 (2H, d), 1.02 (2H, d), 1.96 (1H, m), 2.89 (2H, m), 4.05 (2H, m) ), 4.94 (2H, s), 6.46 (1H, s), 7.10 (1H, t), 7.21 (4H, d), 7.37 (1H, d), 7.55 (1H, d), 8.36 (1H, d), 10.05 (1H, s), 12.23 (1H, br s); IR (solid) 1621, 1581, 1560, 1537, 1479, 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 ((M + H) ⁺ .

Example 347 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,3-dihydroindol-1-yl) quinazolin-4-yl] amine (III-119): mp. 150-153 ° C; ¹ H NMR (DMSO) δ 0.74 (2H, d), 0.98 (2H, d), 1.96 (1H, m), 3.15 (2H, t), 4.25 (2H, t) ), 6.45 (1H, br s), 6.88 (1H, t), 7.09 (1H, t), 7.20 (2H, m), 7.53 (1H, d), 7 65 (1H, t), 8.43 (2H, s), 10.09 (1H, s), 12.28 (1H, s); IR (solid) 1621, 1588, 1577, 1564, 1537, 1487, 1455, 1425, 1386, 1259; MS 369.3 ((M + H) ⁺ .

Example 348 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-hydroxymethylpiperidin-1-yl) quinazolin-4-yl] amine (III-120): mp 142 ° C; ¹ H NMR (DMSO) δ 0.67 (2H, d), 0.96 (2H, d), 1.10 (2H, q), 1.55-1.70 (3H, m), 1.91 (1H, m), 2.85 (2H, t), 3.28 (2H, s), 4.48 (1H, s), 4.76 (2H, d), 6.34 (1H, C) 7.06 (1H, t), 7.30 (1H, d), 7.52 (1H, t), 8.31 (1H, d), 9.96 (1H, s), 12.19 ( 1H, s); IR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1186, 1091, 995, 941, 823; MS 365.8 ((M + H) ⁺ .

Example 349 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-dihydro-2H-quinolin-1-yl) quinazolin-4-yl] amine (III-121): mp . 137-145 ° C; ¹ H NMR (DMSO-d ₆ ) δ 0.55 (2H, d), 0.88 (2H, d), 1.78 (1H, m), 1.92 (2H, t), 2.75 ( 2H, t), 4.04 (2H, t), 6.20 (1H, broad s), 6.97 (1H, t), 7.14 (1H, m), 7.19 (1H, t) ), 7.42 (1H, d), 7.61 (1H, t), 7.67 (1H, d), 8.43 (1H, d), 10.04 (1H, s), 12.21 (1H, broad s); IR (solid) 1622, 1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383.3 ((M + H) ⁺ .

Example 350 (5-Methoxycarbonyl-2H-pyrazol-3-yl) - [2- (piperidin-1-yl) quinazolin-4-yl] amine (III-122): ¹ H NMR (500 MHz, CDCl ₃ ) δ l 7-1.8 (6H, m), 83.8 (4H, m), 83.9 (3H, s), 8 5.5 (1H, s), 8 7.15 (1H, t), 8 7.4 (1H, d), 8 7.6 (1H, t), 8.0 (1H, d), HPLC method B, (starting from 95% H ₂ O) R _t 7.4 min ; MS (ES +) 353.24 (M + H).

Example 351 [5- (Piperidin-1-carbonyl) -2H-pyrazol-3-yl] - [2- (piperidin-1-yl) quinazolin-4-yl] amine (III-123): HPLC method B, (starting from 95% H ₂ O: 0.1% TFA) R _t 8.0 min; MS (ES +) 406.30, (ES-) 404.30.

Example 352 (5-Hydroxymethyl-2H-pyrazol-3-yl) - [2- (piperidin-1-yl) quinazolin-4-yl] amine (III-124): To a solution of compound III-122 (10.0 mg , 0.028 mmol) in THF (6 ml) at ambient temperature, a 1 M solution of LiAlH ₄ in THF (0.05 ml, 0.05 mmol) was slowly added. After 15 minutes, the solution was quenched by adding water and 1 N. HCl. From the aqueous layer, the product was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give compound III-124 (4.0 mg, 44%). HPLC method B, (starting from 95% H ₂ O: 0.1% TFA) R _t 6.1 min; MS (ES +) 325.13, (ES-) 323.13.

Example 353 (5-Carbamoyl-2H-pyrazol-3-yl) - [2- (piperidin-1-yl) quinazolin-4-yl] amine (III-125): Solution of compound III-122 (1.5 g, 4.3 mmol) in a 2.0 M solution of NH ₃ in MeOH (100 ml) was heated at 110 ° C for 2 days. The dark brown reaction mixture was concentrated in vacuo to give a viscous oil, which was purified by column chromatography to give 0.7 g (50%) of compound III-125: ¹ H NMR (500 MHz, CD ₃ OD-d ₃ ) δ 1.6 ( 4H, m); 81.7 (2H, m), 8 3.3 (1H, s), 8 3.8 (4H, m), 8 5.5 (1H, C), 8 7.15 (1H, t), 8 7.45 (1H, d), 8 7.55 (1H, t), 8 8.0 (1H, d); HPLC method B, (starting from 95% H ₂ O: 0.1% TFA) R _t 5.9 min; MS (ES +) 338.13, (ES-) 336.15.

Example 354 (5-Carbamoyl-2H-pyrazol-3-yl) - [2- (4-methylpiperidin-1-yl) quinazolin-4-yl] amine (III-126): HPLC method B, (starting from 95 % H ₂ O: 0.1% TFA) R _t 6.4 min; MS (ES +) 352.19, (ES-) 350.20.

Example 355 (5,7-Difluoro-1H-indazol-3-yl) - (2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl) amine (III-127): ¹ H NMR (500 MHz) , DMSO-d ₆ ) δ 13.7 (s, 1H), 10.3 (s, broad, 1H), 7.90 (d, 2H), 7.52 (t, 1H), 7.45 ( m, 3H), 7.26 (d, 1H), 2.99 (m, 2H), 2.75 (m, 2H), 1.95 (broad 4H) ppm; MS (ES +) 378.24 (M + H);, (ES-) 376.23 (MH); HPLC method A, R _t 3.04 min.

Example 356 (2-Phenyl-5,6,7,8-tetrahydroquinazolin-4-yl) - (5-trifluoromethyl-1H-indazol-3-yl) amine (III-128): ¹ H NMR (500 MHz, DMSO -d ₆ ) δ 13.4 (s, 1H), 10.2 (s, broad, 1H), 8.13 (s, 1H), 7.86 (d, 2H), 7.78 (d, 1H), 7.69 (d, 1H), 7.50 (t, 1H), 7.35 (dd, 2H), 2.89 (m, 2H), 2.72 (m, 2H), 1, 90 (s, broad 4H) ppm; MS (ES +) 410.24 (M + H); (ES-) 408.23 (MH); HPLC method A, R _t 3.19 min.

Example 357 (7-Fluoro-1H-indazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-129): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.6 (s , 1H), 11.1 (s, broad, 1H), 8.65 (d, 1H), 8.03 (d, 2H), 7.95 (s, 2H), 7.67 (m, 1H ), 7.45 (m, 2H), 7.33 (t, 2H), 7.22 (dd, 1H), 6.99 (td, 1H) ppm, MS (ES +): m / e = 356.20 (M + H); HPLC method AR _t 3.00 min.

Example 358 (5-Fluoro-1H-indazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-130): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.2 (s , 1H), 11.3 (s, broad, 1H), 8.67 (d, 1H), 8.04 (d, 2H), 7.96 (s, 2H), 7.70 (m, 1H ), 7.58 (dd, 1H), 7.43 (m, 4H), 7.28 (td, 1H) ppm, MS (ES +) 356.20 (M + H); HPLC method A, R _t 3.00 min.

Example 359 (5.7-Difluoro-1H-indazol-3-yl) - (2-phenylquinazolin-4-yl) amine (III-131): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.7 (s, 1H), 8.65 (d, 1H), 8.04 (d, 2H), 7.95 (s, 2H), 7.68 (m, 1H), 7.45 (m, 1H) 7.35 (m, 4H) ppm, MS (ES +): m / e = 374.17 (M + H); HPLC method A, R _t 3.07 min.

Example 360 (1H-Indazol-3-yl) - [2- (3-trifluoromethylphenyl) quinazolin-4-yl] amine (III-132): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.06 ( t, 1H), 7.42 (t, 1H), 1.59 (d, 1H), 7.63 (t, 1H), 7.66 (d, 1H), 7.71 (m, 1H), 7.80 (d, 1H), 7.98 (m, 2H), 8.33 (s, 1H), 8.46 (d, 1H), 8.71 (d, 1H), 11.04 (broad) s, 1H); 12.97 (s, 1H); EI-MS 406.1 (M + 1); HPLC method A, R _t 3.15 min.

Example 361 (2-Phenylquinazolin-4-yl) - (1H-pyrazolo [4,3-b] pyridin-3-yl) amine (III-133): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13 3 (s, broad. 1H), 11.4 (s, broad. 1H), 8.78 (d, 1H), 8.58 (dd, 1H), 8.24 (d, 1H), 8.10 (m, 2H), 7.95 (d, 2H), 7.86 (t, 1H), 7.56 (m, 2H), 7.44 (t, 2H) ppm, MS (ES +) 339.11 (M + H); HPLC method A, R _t 2.63 min.

Example 362 [5- (3-Methoxyphenyl) -6-oxo-5,6-dihydro-1H-pyrazolo- [4,3-c] pyridazin-3-yl] - (2-phenylquinazolin-4-yl) amine ( III-134): ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.65 (d, 1H), 8.17 (m, 3H), 8.10 (d, 1H), 7.90 (t, 1H), 7.75 (t, 1H), 7.58 (m, 2H), 7.25 (t, 1H), 6.95 (m, 2H), 6.85 (d, 1H), 6, 80 (s, 1H); 3.64 (s, 3H) ppm; MS (ES +): m / e = 462.2 (M + H).

Example 363 (6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo [4,3-c] pyridazin-3-yl) - (2-phenylquinazolin-4-yl) amine (III-135) : ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.61 (d, 1H), 8.13 (m, 3H), 8.05 (d, 1H), 7.85 (t, 1H), 7 70 (t, 1H), 7.58 (m, 2H), 7.32 (m, 5H), 6.79 (s, 1H) ppm, MS (ES +): m / e = 432, 2 (M + H).

Example 364 [5- (4-Methoxyphenyl) -6-oxo-5,6-dihydro-1H-pyrazolo- [4,3-c] pyridazin-3-yl] - (2-phenylquinazolin-4-yl) amine ( III-136): MS (ES +) 462.2 (M + H).

Example 365 [5- (2,4-Dichlorophenyl) -6-oxo-5,6-dihydro-1H-pyrazolo- [4,3-c] pyridazin-3-yl] - (2-phenylquinazolin-4-yl) amine (III-137): ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.63 (d, 1H), 8.17 (m, 4H), 7.89 (t, 1H), 7.73 ( t, 1H), 7.61 (t, 2H), 7.57 (d, 1H), 7.32 (m, 1H), 7.21 (d, 1H), 6.84 (s, 1H) m dd, MS (ES +): m / e = 500.1 (M + H).

Example 366 [6-Oxo-5- (trifluoromethylphenyl) -5,6-dihydro-1H-pyrazolo [4,3-c] pyridazin-3-yl] - (2-phenylquinazolin-4-yl) amine (III-138 ): ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.55 (d, 1H), 8.19 (d, 2H), 7.92 (m, 2H), 7.65 (m, 3H) 7.45 (t, 2H), 7.25 (t, 1H), 7.13 (t, 1H), 7.05 (t, 1H), 6.75 (s, 1H) ppm, MS (ES +): m / e = 500.2 (M + H).

Example 367 [6-Oxo-5- (4-phenoxyphenyl) -5,6-dihydro-1H-pyrazolo- [4,3-c] pyridazin-3-yl] - (2-phenylquinazolin-4-yl) amine ( III-139): MS (ES +) 524.3 (M + H).

Example 368 [5- (4-Chlorophenyl) -6-oxo-5,6-dihydro-1H-pyrazolo- [4,3-c] pyridazin-3-yl] - (2-phenylquinazolin-4-yl) amine ( III-140): MS (ES +) 466.2 (M + H).

Example 369 (2-Imidazol-1-ylquinazolin-4-yl) - (1H-indazol-3-yl) amine (III-141): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.10 (t , 1H), 7.44 (t, 1H), 7.50 (br s, 1H), 7.60 (d, 1H), 7.72 (m, 2H), 7.77 (m, 1H, ), 7.88 (d, 1H), 7.98 (t, 1H), 8.73 (d, 1H), 8.96 (s, 1H), 11.23 (s, 1H), 13.06 (s, 1H); EI-MS 328.1 (M + 1); HPLC method A, R _t 2.93 min.

Example 370 (1H-Indazol-3-yl) - [2- (2-methylimidazol-1-yl-quinazolin-4-yl] amine (III-142): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.48 (s, 3H), 7.10 (t, 1H), 7.43 (t, 1H), 7.57 (d, 1H), 7.60 (d, 1H), 7.67 (d , 1H), 7.76 (td, 1H), 7.86 (d, 1H), 7.91 (d, 1H), 8.01 (td, 1H), 8.72 (d, 1H), 11 15 (s, 1H); 13.10 (s, 1H); El-MS 342.1 (M + 1); HPLC method A, R _t 3.06 min.

Example 371 (1H-Indazol-3-yl) - (2-piperidin-1-ylquinazolin-4-yl) amine (III-143): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.48 (m 6H), 3.60 (m, 4H), 7.11 (t, 1H), 7.52 (t, 1H), 7.55 (d, 1H), 7.64 (d, 1H), 7 69 (d, 1H), 7.75 (d, 1H), 7.90 (t, 1H), 8.58 (d, 1H), 11.82 (br s, 1H), 13.25 ( s, 1H); EI-MS 345.1 (M + 1); HPLC method A, R _t 3.03 min.

Example 372 (1H-Indazol-3-yl) - [2- (octahydroquinolin-1-yl) -quinazolin-4-yl] amine (III-144): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 0 6-1.9 (m, 13H), 3.15 (m, 1H), 3.25 (m, 1H), 4.0 (m, 1H), 7.10 (t, 0.5H) 7.12 (t, 0.5H), 7.55 (m, 2H), 7.66 (d, 0.5 H), 7.69 (d, 0.5 H), 7.77 (d , 1H), 7.91 (t, 1H), 8.55 (d, 0.5 H), 8.59 (d, 0.5 H), 11.46 (s, 0.5 H), 11 , 54 (s, 0.5 H), 11.78 (s, 0.5 H), 11.84 (s, 0.5 H), 13.10 (s, 0.5 H), 13.12 (s, 0.5 H); EI-MS 399.3 (M + 1); HPLC method A, R _t 3.37 min.

Example 373 (1H-Indazol-3-yl) - [2- (2,6-dimethylmorpholin-4-yl) -quinazolin-4-yl] amine (III-145): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.0 (m, 6H), 4.0 (m, 6H), 7.12 (t, 1H), 7.41, (td, 1H), 7.56 (t, 1H), 7 58 (d, 1H), 7.68 (dd, 1H), 7.77 (t, 1H), 7.93 (t, 1H), 8.60 (d, 1H), 11.69 (s, 1H), 13.16 (s, 1H); EI-MS 375.3 (M + 1); HPLC method A, R _t 2.93 min.

Example 374 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylpyrimidin-4-yl) amine (IV-1): mp 245-246 ° C; ¹ H NMR (DMSO) δ 2.26 (3H, s), 6.32 (1H, s), 7.07 (1H, s), 7.48-7.54 (3H, m) 8.33-8.39 (3H, m); 9.87 (1H, s); 12.03 (1H, s); IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336; MS 252.2 (M + H) ⁺ .

Example 375 [6- (4-Acetamidophenylsulfanyl) -2-phenylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-3): Fenclorim suspension (4,6- dichloro-2-phenylpyrimidine) (0.1 g, 0.44 mmol), 3-amino-5-methylpyrazole (0.045 g, 0.47 mmol), N, N-diisopropylethylamine (0.08 ml, 0, 47 mmol) and sodium iodide (0.067 g, 0.44 mmol) in n-butanol (5 ml) were heated at 117 ° C for 18 hours. The solvent was removed in vacuo and the crude product was purified by flash chromatography (silica gel, gasoline: EtOAc = 3: 2) to give 0.037 g (29% yield) (6-chloro-2-phenylpyrimidin-4-yl) - (5- methyl-2H-pyrazol-3-yl) amine as an off-white solid. A suspension of the resulting pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanol was heated at 80 ° C. under nitrogen for 2 days. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The concentrate was dissolved in EtOAc and washed with saturated aqueous NaHCO ₃ . The organic layer was concentrated in vacuo and the crude product was purified by preparative HPLC. Residual disulfide, which can still remain in the mixture after HPLC, can be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to give compound IV-3 (7 mg, 13% yield) as an off-white solid: mp. 235-236 ° C; ¹ H NMR (DMSO) δ 2.10 (3H, s), 2.21 (3H, s), 6.33 (1H, broad s), 7.50 (3H, m), 7.7-7 59 (2H, m), 7.76-7.78 (2H, m), 8.25 (2H, m), 9.72, 10.26 and 11.93 (3 H, 3 x broad s ); IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3 (M + H) ⁺ .

Example 376 [2- (4-Methylpiperidin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-4): mp 215-216 ° C; ¹ H NMR (CD ₃ OD) δ 0.96 (3H, d), 1.16 (2H, m), 1.66 (3H, m), 2.27 (3H, s), 2.86 (2H , t), 4.58 (2H, m), 4.78 (2H, proton exchange), 6.13 (2H, m), 7.83 (1H, d); IR (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 (M + H) ⁺ .

Example 377 [2- (4-Methylpiperidin-1-yl) -5-nitropyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-5): mp. 185-187 ° C; ¹ H NMR (DMSO) δ 0.93 (3H, d), 1.06-1.18 (2H, m), 1.68-1.80 (3H, m), 2.26 (3H, s) 3.01-3.12 (2H, m), 4.63 (1H, d), 4.80 (1H, d), 6.39 (1H, s), 9.00 (1H, s), 10.41 (1H, s); 12.36 (1H, s); IR (solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2 (M + H) ⁺ .

Example 378 [5-Amino-2- (4-methylpiperidin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-6): To a solution of compound IV- 5 (48 mg, 0.151 mmol) in ethanol (2.0 ml) was added tin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixture was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into a mixture of 1 M NaOH-dichloromethane-propanol (18: 8: 4 ml) and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, dichloromethane-MeOH gradient) to give compound IV-6 as a gray solid (27 mg, 63%): ¹ H NMR (DMSO) δ 0.88 -1.04 (5H, m), 1.55-1.62 (3H, m), 2.21 (3H, s), 2.70 (2H, m), 3.36 (2H, m), 4.40 (2H, m), 6.37 (1H, s), 7.49 (1H, s), 8.40 (1H, s), 11.92 (1H, s); MS 288.2 (M + H) ⁺ .

Example 379 [5-amino-6-methyl-2- (4-methylpiperidin-1-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-7): t .pl. 172-175 ° C; ¹ H NMR (DMSO) δ 0.90 (3H, d), 1.03 (2H, m), 1.52-1.62 (3H, m), 2.13 (3H, s), 2.20 (3H, s), 2.69 (2H, m), 3.92 (2H, br s), 4.44 (2H, d), 6.35 (1H, s), 8.41 (1H, c) 11.85 (1H, broad s); IR (solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 (M + H) ⁺ .

Example 380 [6-Methyl-2- (4-methylphenyl) pyrimidin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) amine (IV-10): MS 342.34 (M + H) ; HPLC method E, R _t 1,334 min.

Example 381 [2- (4-Chlorophenyl) -6-methylpyrimidin-4-yl] - (5-furan-2-yl-2H-pyrazol-3-yl) amine (IV-11): MS 352.11 (M + H); HPLC method E, R _t 1.194 min.

Example 382 (5-Furan-2-yl-2H-pyrazol-3-yl) - (6-methyl-2-phenylpyrimidin-4-yl) amine (IV-12): MS 318.21 (M + H); HPLC method E, R _t 1,192 min.

Example 383 [6-Methyl-2- (4-trifluoromethylphenyl) pyrimidin-4-yl] - (5-phenyl-2-yl-2H-pyrazol-3-yl) amine (IV-13): MS 396.24 ( M + H); HPLC method E, R _t 1,419 min.

Example 384 (5-Furan-2-yl-2H-pyrazol-3-yl) - [6-methyl-2- (4-trifluoromethylphenyl) pyrimidin-4-yl] amine (IV-14): MS 386.08 ( M + H); HPLC method E, R _t 1.347 min.

Example 385 [2- (2,3-Dihydrobenzo [1,4] dioxin-2-yl) -6-methylpyrimidin-4-yl] - (5-furan-2-yl-2H-pyrazol-3-yl) amine (IV-15): MS 376.18 (M + H); HPLC method E, R _t 1.181 min.

Example 386 [2- (2,3-Dihydrobenzo [1,4] dioxin-2-yl) -6-ethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-16 ): MS 338.17 (M + H); HPLC method E, R _t 1,082 min.

Example 387 (6-Ethyl-2-phenylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IV-17): MS 280.18 (M + H); HPLC method E, R _t 1,024 min.

Example 388 (6-Methyl-2-phenylpyrimidin-4-yl) - (5-phenyl-2H-pyrazol-3-yl) amine (IV-19): MS 328.51 (M + H); HPLC method E, R _t 1,192 min.

Example 389 [6-Ethyl-2- (4-trifluoromethylphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-20): MS 348.5 (M + H) ; HPLC method E, R _t 1.224 min.

Example 390 (5-Furan-2-yl-2H-pyrazol-3-yl) - [6-methyl-2- (4-methylphenyl) pyrimidin-4-yl] amine (IV-21): MS 332.23 ( M + H); HPLC method E, R _t 1.139 min.

Example 391 (6-Methoxymethyl-2-phenylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IV-22): MS 296.31 (M + H); HPLC method E, R _t 0.971 min.

Example 392 (5,6-Dimethyl-2-phenylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IV-23): MS 280.2 (M + H); HPLC method E, R _t 0.927 min.

Example 393 (6-Methyl-2-phenylpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) amine (IV-24): MS 266.18 (M + H); HPLC method E, R _t 0.925 min.

Example 394 [6-Ethyl-2- (4-methylphenyl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-25): MS 294.46 (M + H) ; HPLC method E, R _t 1.174 min.

Example 395 [2- (4-Chlorophenyl) -6-ethylpyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-26): MS 314.42 (M + H); HPLC method E, R _t 1.213 min

Example 396 (5-Methyl-1H-pyrazol-3-yl) - (6-methyl-2-p-tolyl-pyrimidin-4-yl) amine (IV-27): MS 280.45 (M + H); HPLC method E, R _t 1,135 min

Example 397 (1H-Indazol-3-yl) - (6-methoxymethyl-2-phenylpyrimidin-4-yl) amine (IV-28): ¹ H NMR (500 MHz, DMSO) δ 3.57 (3H, s) 4.65 (2H, s), 7.23 (1H, J = 7.5 Hz, t), 7.52 (1H, J = 7.6 Hz, t), 7.63 (4H, m) 7.75 (1H, broad), 8.13 (1H, J = 5.5 Hz, broad.d), 8.44 (1H, J = 5.7 Hz, broad.d), 10.6 (1H, broad), 12.8 (1H, broad s) ppm; HPLC method A, R _t 2,944 min; MS (FIA) 332.1 (M + H).

Example 398 (5-Methyl-2H-pyrazol-3-yl) - (2-pyridin-4-ylthieno [3,2-d] pyrimidin-4-yl) amine (IV-29): ¹ H NMR (DMSO) δ 2.34 (3H, s), 6.66 (1H, s), 7.53 (1H, d), 7.84, (1H, d), 8.32 (2H, d), 8.70 (2H, d); MS 309.6 (M + H) @ ⁺ .

Example 399 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylpyrido [3,4-d] pyrimidin-4-yl) amine (IV-30): mp 225 ° C; ¹ H NMR (DMSO) δ 2.35 (3H, s), 6.81 (1H, s), 7.50-7.63 (3H, m), 8.45-8.52 (2H, m) 8.54 (1H, d), 8.62 (1H, d), 9.20 (1H, s), 10.79 (1H, s), 12.38 (1H, br s); IR (solid) 2958, 2917, 2852, 1593, 1565, 1524, 1467, 1450; MS 303.2 (M + H) @ ⁺ .

Example 400 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylpyrido [2,3-d] pyrimidin-4-yl) amine (IV-31): To a solution of 4-chloro-2-phenylpyrido - [2,3-d] pyrimidine (J. Pharm. Belg., 29, 1974, 145-148) (109 mg, 0.45 mmol) in THF (15 ml) was added 3-amino-5-methylpyrazole (48 mg, 0.5 mmol) and the resulting mixture was heated at 65 ° C overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with Et ₂ O. The solid was dissolved in EtOH-water and the pH was adjusted to pH 7. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO ₂ , gradient of a DCM) -MeOH mixture to give compound IV-31 as an off-white solid (69 mg, 50%): mp. 234 ° C; ¹ H NMR (DMSO) δ 2.14 (3H, s), 5.99 (1H, s), 7.20-7.40 (3H, m), 7.40-7.50 (3H, m) 8, 60 (1H, d), 8.79 (1H, d), 12.82 (1H, broad s); IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M + H) @ ⁺ .

Example 401 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenylpyrido [3,4-d] pyrimidin-4-yl) amine (IV-32): Off-white solid, mp. 232-233 ° C; ¹ H NMR (DMSO) δ 0.70-0.85 (2H, m), 0.90-1.05 (2H, m), 1.05-2.07 (1H, m), 6.75 ( 1H, s), 7.50-7.75 (3H, m), 8.40-8.70 (4H, m), 9.20 (1H, s), 10.80 (1H, s), 12 41 (1H); IR (solid) 3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS 329.2 (M + H) ⁺ .

Example 402 [2- (4-Methylpiperidin-1-yl) purin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IV-33): To a suspension of 2,4-dichloropurine (2 0 g, 10.6 mmol) in anhydrous ethanol (10 ml) was added 5-methyl-1H-pyrazol-3-ylamine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 hours. The resulting precipitate was collected by filtration, washed with ethanol and dried in vacuo to give 1.524 g (58% yield) (2-chloropurin-4-yl) - (5-methyl-1H-pyrazol-3-yl) amine, which was used without further purification in the next stage. To a solution of (2-chloropurin-4-yl) - (5-methyl-1H-pyrazol-3-yl) amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 ml, 8.01 mmol) and the reaction the mixture was refluxed overnight. The solvent was evaporated and the residue was dissolved in EtOH-water (1: 3, 4 ml). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (2 times) and Et ₂ O (2 times) to give compound IV-33 as a white solid (225 mg, 90%): mp. > 300 ° C; ¹ H NMR (DMSO) δ 0.91 (3H, d), 1.10 (2H, m), 1.65 (3H, m), 2.24, (3H, s), 2.84 (2H, m), 4.60 (2H, m), 6.40 (1H, s), 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 , (2H, m); IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M + H) ⁺ .

Example 403 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-methylpiperidin-1-yl) pyrrolo [3,2-d] pyrimidin-4-yl] amine (IV-34): white solid matter; ¹ H NMR (DMSO) δ 0.65 (2H, m), 0.91-0.96 (5H, m), 1.08 (2H, m), 1.58-1.64 (3H, m) , 1.89 (1H, m), 2.77 (2H, t), 4.57 (2H, d), 6.09 (1H, s), 6.38 (1H, s), 7.33 ( 1H, s), 9.42 (1H, s), 10.65 (1H, s), 12.02 (1H, br s); MS 338.3 (M + H) ⁺ .

Example 404 [6-Benzyl-2-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl] - (5-fluoro-1H-indazol-3-yl) amine ( IV-35): ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 13.0 (s, 1H), 10.4 (s, br. 1H), 9.73 (s, 1H, TFA-OH ), 8.00 (d, 2H), 7.64 (m, 2H), 7.59 (dd, 1H), 7.52 (m, 3H), 7.41 (t, 1H), 7.31 (m, 3H), 7.14 (dd, 1H), 4.58 (s, 2H), 4.35 (broad 2H), 3.74 (m, 2H), 3.17 (s, 2H) ppm, MS (ES +): m / e = 451.30 (M + H); HPLC method A, T _ret 2.96 min.

Example 405 (5-Fluoro-1H-indazol-3-yl) - (2-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4-yl) amine (IV-36): Prepared from compound IV-35 (0.13 mmol) by treatment with an equal weight of Pd / C (10%) in 4.4% HCOOH in MeOH at room temperature for 12 hours. The mixture was filtered through celite, the filtrate was evaporated and the crude product was purified by HPLC to give compound IV-36 as a yellow solid in 35% yield. ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 12.9 (s, 1H), 9.06 (s, 1H), 7.99 (d, 2H), 7.57 (dd, 1H), 7.34 (m, 1H), 7.28 (m, 3H), 7.22 (d, 1H), 3.83 (s, 2H), 3.05 (m, 2H), 2.72 (m , 2H) ppm, MS (ES +): m / e = 361.20 (M + H); HPLC method A, T _ret 2.68 min.

Example 406 (5-Methyl-2H-pyrazol-3-yl) - (3-phenylisoquinolin-1-yl) amine (V-1): To a solution of 1-chloro-3-phenylisoquinoline (J. Het. Chem., 20 1983, 121-128) (0.33 g, 1.37 mmol) in DMF (anhydrous, 5 ml) was added 3-amino-5-methylpyrazole (0.27 g, 2.74 mmol) and potassium carbonate (0 , 57 g, 4.13 mmol) and the resulting mixture was boiled under reflux for 6 hours. Then the reaction mixture was cooled and the solvent was removed in vacuo. The residue was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO ₂ , gradient of a DCM-MeOH mixture) to give compound V-1 as a colorless oil: ¹ H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s ), 7.41 (1H, m), 7.52 (2H, m), 7.62 (1H, m), 7.81 (1H, m), 8.07 (1H, d), 8.19 (2H, m), 8.29 (1H, s), 8.54 (1H, d); MS 301.2 (M + H) ⁺ .

Example 407 (1H-Indazol-3-yl) - [3- (2-trifluoromethylphenyl) isoquinolin-1-yl] amine (V-2): Solution of 1-chloro-3- (2-trifluoromethylphenyl) isoquinoline (100 mg, 0.326 mmol) and 1H-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 ml) were heated at 160 ° C and the solvent was evaporated with a stream of nitrogen. The remaining oil was then heated at 160 ° C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol-dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (1 x 25 ml), and then dried over magnesium sulfate. Purification by silica gel chromatography (mixture of 25-50% hexane-ethyl acetate) gave compound V-2 as a yellow solid (35 mg, 27%). ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 9.78 (br s, 1H), 8.62 (d, 1H), 7.9-7.85 (m, 1H), 7.78 -7.72 (m, 1H), 7.70-7.68 (m, 1H), 7.65-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7 52-7.45 (m, 3H), 7.41-7.38 (m, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 6.95 -6.92 (m, 1H); 5.76 (s, 1H); LC-MS (ES +) m / e = 405.18 (M + H); HPLC method DR _t 2.74 min.

Example 408 (5,7-Difluoro-1H-indazol-3-yl) - [3- (2-trifluoromethylphenyl) isoquinolin-1-yl] amine (V-3): Compound V-3 was prepared from 5.7-difluoro -1H-indazol-3-ylamine as a yellow solid (90 mg, 63%). ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 13.25 (s, 1H), 9.92 (br s, 1H), 8.61 (d, 1H), 7.9 (d, 1H ), 7.81-7.49 (m, 6H), 7.26-7.2 (m, 2H), 7.12-7.10 (m, 1H); LC-MS (ES +) m / e = 441.16 (M + H); HPLC method d, R _t 3.58 min.

Example 409 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylquinolin-1-yl) amine (V-4): To a mixture of 4-chloro-2-phenylquinoline (J. Het. Chem., 20 1983, 121-128) (0.53 g, 2.21 mmol) in diphenyl ether (5 ml) was added 3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the resulting mixture was heated at 200 ° C overnight with stirring. The reaction mixture was cooled to ambient temperature, then petroleum ether (20 ml) was added and the resulting precipitate was recovered by filtration. The crude solid was purified by flash chromatography (SiO ₂ , gradient of a DCM-MeOH mixture) to give compound V-4 as a white solid: mp. 242-244 ° C; ¹ H NMR (DMCO): δ 2.27 (3H, s), 6.02 (1H, s), 7.47 (2H, d), 7.53-7.40 (2H, broad m), 7.67 (1H, m), 7.92 (1H, m), 8.09 (2H, d), 8.48 (2H, m), 9.20 (1H, s), 12.17 (1H , broad.s); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M + H) ⁺ .

Example 410 (1H-Indazol-3-yl) - (2-phenylquinolin-4-yl) amine (V-5): ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 12.78 (s, 1H) 9.50 (s, 1H), 8.65 (d, 1H), 8.15 (s, 1H), 8.04-7.98 (m, 3H), 7.94 (s, 1H), 7.78-7.75 (m, 1H), 7.60-7.40 (m, 6H), 7.15-7.10 (m, 1H), LC-MS (ES +) m / e = 337 11 (M + H); HPLC method d, R _t 2.10 min.

Example 411 (2-Phenylquinolin-4-yl) - (1H-pyrazolo [4,3-b] pyridin-3-yl) amine (V-6): ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 13.6 (s, 1H), 11.4 (s, 1H), 8.94 (d, 1H), 8.61 (dd, 1H), 8.23 (d, 1H), 8.16 (dd , 1H), 8.12 (t, 1H), 7.89 (t, 1H), 7.86 (d, 1H), 7.65 (m, 4H), 7.54 (s, 1H), 7 52 (dd, 1H) ppm, MS (ES +): m / e = 338.11 (M + H); HPLC method A, HPLC method d, R _t 2.91 min.

Example 412 (1H-Indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinolin-4-yl] amine (V-7): ¹ H NMR (500 MHz, DMCO-d ₆ ): δ 12.68 (s, 1H), 9.51 (s, 1H), 8, 7 (d, 1H), 7.95-7.89 (m, 2H), 7.83-7.70 (m, 3H), 7.68-7.62 (m, 2H), 7.60 (s, 1H), 7.55-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7, 40-7.37 (m, 1H); 7.12-7.09 (m, 1H); LC-MS (ES +) m / e = 405.15 (M + H); HPLC method DR _t 2.25 min.

Example 413 (5,7-Difluoro-1H-indazol-3-yl) - [2- (2-trifluoromethylphenyl) quinolin-4-yl] amine (V-8): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 13.31 (s, 1H), 9.49 (s, 1H), 8.70-8.67 (m, 1H), 7.96-7.92 (m; 1H), 7.85- 7.66 (m, 7H), 7.63-7.60 (m, 1H), 7.42-7.40 (m, 1H), LC-MS (ES +) m / e = 441.18 (M + H); HPLC method DR _t 2.39 min.

Example 414 [2- (2-Trifluoromethylphenyl) quinolin-4-yl] - (1H-pyrazolo- [4,3-b] pyridin-3-yl) amine (V-9): ¹ H NMR (500 MHz, DMCO -d ₆ ) δ 13.6 (s, 1H), 11.6 (s, broad, 1H), 8.98 (d, 1H), 8.57 (dd, 1H), 8.12 (m, 3H), 7.97 (m, 2H), 7.86 (m, 3H), 7.49 (dd, 1H), 7.23 (s, 1H) ppm, MS (ES +): m / e = 406.20 (M + H); HPLC method AR _t 2.91 min.

Example 415 (2-Phenylquinazolin-4-yl) - (2H- [1,2,4] triazol-3-yl) amine (IX-154): off-white solid, mp. 266-267 ° C: ¹ H NMR (DMCO) δ 7.50-7.70 (4H, m), 7.85-8.00 (2H, m), 8.15-8.25 (2H, m ), 8.37-8.45 (2H, m), 8.58 (1H, d), 13.90 (1H, br s); IR (solid) 3344, 3059, 1630, 1609, 1570, 1557, 1543, 1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760, 676, 667, 654; MS 289.2 (M + H) @ ⁺ .

Example 416 (5-Methyl-2H- [1,2,4] triazol-3-yl) - (2-phenylquinazolin-4-yl) amine (IX-155): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 8.59 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H), 7.79 (m, 4H), 8.03 (m, 2H), 7.74 (m , 4H), 2.51 (s, 3H) ppm, MS (ES +): m / e = 303.08 (M + H); HPLC method A, R _t 2.64 min.

Example 417 (2H- [1,2,4] -triazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (IX-47): pale yellow solid (52% yield) ): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 8.54 (s, 1H), 8.15 (s, broad, 1H), 7.91 (t, 1H), 7.85 (m , 2H), 7.76 (m, 3H), 7.66 (t, 1H) ppm, MS (ES +): m / e = 357.13 (M + H); (ES-): m / e = 355.15 (MH); HPLC method A, R _t 2.81 min.

Example 418 (5-Methyl-2H- [1,2,4] triazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (IX-38): pale yellow solid ( yield 54%): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 8.44 (s, broad, 1H), 7.92 (m, 3H), 7.84 (m, 1H), 7, 77 (m, 2H), 7.68 (t, 1H), 2.28 (s, 3H) ppm, MS (ES +): m / e = 371.14 (M + H); (ES-): m / e = 369.18 (MH); HPLC method A, R _t 2.89 min.

Example 419 (5-Methylsulfanyl-2H- [1,2,4] triazol-3-yl) - [2- (2-trifluoromethylphenyl) quinazolin-4-yl] amine (IX-156): pale yellow solid ( yield 65%): ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 8.56, (broad, 1H), 7.90 (t, 1H), 7.84 (m, 2H), 7.78 (m, 2H), 7.67 (m, 2H), 2.51 (s, 3H, hidden DMCO) ppm, MS (ES +): m / e = 403.12 (M + H); (ES-): m / e = 401.16 (MH); HPLC method A, R _t 3.20 min.

Example 420 (1H- [1,2,4] Triazol-3-yl) - [3- (2-trifluoromethylphenyl) isoquinolin-1-yl] amine (IX-175): Solution of 1-chloro-3- (2- trifluoromethylphenyl) isoquinoline (0.326 mmol) and 1H- [1,2,4] triazol-3-ylamine (0.651 mmol) in ethanol (3 ml) were heated at 160 ° C and the solvent was evaporated with a stream of nitrogen. The remaining oil was then heated at 160 ° C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol-dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (1 x 25 ml), and then dried over magnesium sulfate. Purification by silica gel chromatography afforded compound IX-175 as a colorless oil (4% yield). ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H), 7.85-7.75 (m, 3H), 7.71-7.52 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m, 1H), LC-MS (ES +) 356, 16 (M + H); HPLC method d, R _t 3.55 min.

Example 421 (2-Phenylquinolin-4-yl) - (1H- [1,2,4] triazol-3-yl) amine (IX-176): pale yellow solid (30% yield): ¹ H NMR ( 500 MHz, DMCO-d ₆ ) δ 13.82 (s, 1H), 9.91 (s, 1H), 8.80 (s, 1H), 8.70-8.65 (m, 1H), 8 55 (s, 1H), 8.15-8.12 (m, 2H), 8.03-7.98 (m, 1H), 7.75-7.72 (m, 1H), 7.57 -7.49 (m, 3H); LC-MS (ES +) m / e = 288.11 (M + H); HPLC method d, R _t 1.55 min.

Example 422 (1H- [1,2,4] Triazol-3-yl) - [2- (2-trifluoromethylphenyl) quinolin-4-yl] amine (IX-177): pale yellow solid (46% yield) : ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 13.70 (s, 1H), 9.98 (s, 1H), 8.70 (d, 1H), 8.49 (s, 1H), 8.30, (s, 1H), 7.94-7.88 (m, 2H), 7.80-7.68 (m, 3H), 7.64-7.56 (m, 2H), LC -MS (ES +) m / e = 356.18 (M + H); HPLC method d, R _t 1.68 min.

Example 423 (1H-Indazol-3-yl) - [5-methyl-6-morpholin-4-yl-2- (2-trifluoromethylphenyl) pyrimidin-4-yl] amine (II-251): Colorless film, yield 2 %: ¹ H NMR (500 MHz, DMCO-d ₆ ) δ 7.84 (m, 2H), 7.71 (m, 3H), 7.41 (t, 2H), 7.14 (m, 1H) 3.74 (m, 4H); 3.69 (m, 4H); 1.24 (s, 3H) ppm; HPLC method AR _t 3.26 min; MS (FIA) 455.1 (M + H).

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 determining the amount 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 TO _i FOR INHIBITION OF 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 Molecular Devices Spectramax plate reader (Sunnyvale, Calif.), Reaction rates were obtained 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 K _i values of less than 0.1 μM for GSK-3: compounds II-1, II-105, II-33, II-34, II-36, II-39, II-38, II-39, II-40, II-41, II-42, II-46, II-57, II-59, II-60, II-61, II-62, II-63, II-64, II-66, II- 67, II-69, II-70, II-53, II-71, II-99, II-73, II-74, II-75, II-76, II-77, II-7, II-8, II-9, II-10, II-24, II-19, II-78, II-54, II-79, II-80, II-81, II-82, II-83, II-84, II- 56, II-86, II-20, II-25, II-26, II-85, II-21, II-27, II-28, II-87, II-88, II-29, II-11, II-12, II-30, II-31, II-13, II-14, II-15, II-16, II-17, II-18, II-79, II-23, II-2, II- 90, II-91, II-92, II-93, II-3, II-4, II-5, II-6, II-94, II-95, II-96, II-107, II-108, II-109, II-110, II-124, II-125, II-111, II-112, II-113, II-114, II-115, II-116, II-117, II-118, II- 119, II-120, II-121; II-208, III-8, III-7, III-9, III-37, III-38, III-39, III-40, III-42, III-45, III-46, III-47, III- 48, III-49, III-51, III-52, III-53, III-54, III-55, III-56, III-57, III-58, III-59, III-60, III-61, III-62, III-63, III-30, III-65, III-66, III-67, III-70, III-73, III-31, III-75, III-76, III-77, III- 33, III-34, III-106, III-108, III-109, III-111, III-35, III-116, III-117, III-118, III-119, III-120, III-121, III-127, III-128, III-141, III-130, III-131, IV-15, IV-16, IV-17, IV-20, IV-25, IV-26, IV-30, IV- 34, V-3 and IX-47.

The following compounds had K _i values between 0.1 and 1.0 μM for GSK-3: compounds II-103, II-104, II-35, II-44, II-45, II-49, II-50, II -97, II-101, II-22, II-32, III-41, III-43, III-44, III-28, III-50, III-29, III-64, III-71, III-74 , III-78, III-82, III-88, III-90, III-102, III-105, III-107, III-110, III-112, III-114, III-115, III-122, III -124, III-124, IV-1, III-l, III-138, III-140, III-142, III-129, III-132, III-134, III-135, III-136, IV-1 , IV-10, IV-11, IV-12, IV-13, IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV -6, IV-7, IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V-7, IX-38, IX-154 and IX-177 .

The following compounds had K _i values between 1.0 and 20 μM for GSK-3: compounds II-43, II-65, II-48, II-47, II-51, II-68, II-52, II-72 , II-100, II-98, II-89, III-68, III-81, III-83, III-91, III-94, III-95, III-96, III-97, III-98, III -99, III-100, III-101, III-103, III-123, III-137, III-139, III-143, III-145, III-146, V-4, V-8, IX-156 and ix-176.

EXAMPLE 2 BIOLOGICAL TEST

DEFINITION TO _i FOR INHIBITING AURORA-2

Compounds were tested as follows 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 BioRad Ultramark plate reader (Hercules, Calif.), Reaction rates were obtained 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: compounds II-33, II-34, II-36, II-37, II-40, II-41, II-55, III-7, III-9, III-37, III-38, III-39, III-40, III-41, III-42, III-44, III-45, III-46, III-47, III-48, III- 49, III-50, III-51, III-52, III-53, III-54, III-55, III-56, III-57, III-59, III-60, III-61, III-63, III-30, III-65, III-66, III-67, III-70, III-31, III-76, III-77, III-78, III-80, III-32, III-33, III- 34, III-106, III-108, III-109, III-110, III-111, III-112, III-114, III-35, III-115, III-116, III-117, III-118, III-119, III-120, III-121, IV-7, IV-30, IV-32 and IV-34.

The following compounds had K _i values between 0.1 and 1.0 μM for AURORA-2: compounds II-1, II-105, II-35, II-38, II-39, II-42, II-64, II -70, II-53, II-99, II-77, II-79, II-86, II-20, II-93, II-94, III-28, III-58, III-64, III-71 , III-73, III-74, III-75, III-102, III-105, III-107, III-113, III-124, III-1, III-130, IV-1, IV-3, IV -4, IV-6, IV-29, IV-33 and V-4.

The following compounds had K _i values between 1.0 and 20 μM for AURORA-2: compounds II-103, II-104, II-57, II-59, II-61, II-63, II-67, II-69 , II-75, II-76, II-10, II-19, II-78, II-54, II-80, II-82, II-21, II-90, II-91, II-96, II -107, III-68, III-79, III-82, III-101, III-103, III-127, III-141, III-129, III-132, IV-31, V-2, IX-47 IX-154 and IX-177.

EXAMPLE 3 BIOLOGICAL TEST

CDK-2 INHIBITION TEST

Compounds were tested as follows 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 BioRad Ultramark plate reader (Hercules, Calif.), Reaction rates were obtained 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.

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 erctid peptide. 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 <1 μM for ERK-2: III-109, III-111, III-115, III-117, III-118, III-120 and IV-4.

The following compounds had K _i values between 1 μM and 12 μM for ERK-2: III-63, III-40 and III-108.

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 BioRad Ultramark plate reader (Hercules, Calif.), Reaction rates were obtained after 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.

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 (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 K _i values for the compound.

The following compounds had K _i values of <100 nM for Src: III-31, III-32, III-33, III-34, III-35, III-47, III-65, III-66, III-37, III- 38, III-39, III-40, III-42, III-44, III-48, III-49, III-70, III-45, III-78, III-76 and IV-32.

The following compounds had K _i values between 100 nM and 1 μM for Src: III-63, III-71, III-75, III-73, III-72, III-74, III-80, III-50, IV-30 .

The following compounds had K _i values between 1 μM and 6 μM for Src: III-79, IV-1 and IV-31.

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 (41)

1. Derivatives of pyrazole of the formula II

or its pharmaceutically acceptable salt, where ring C is selected from phenyl or pyridinyl rings, wherein said ring C has one or two substituents in the ortho position independently selected from —R ¹ and any substitutable non-aorto position in ring C is independently and optionally substituted by a radical —R ⁵ , and two adjacent substituents on ring C are optionally combined with their intermediate atoms to form a phenyl ring; R ¹ selected from halogen; -CN; -IT; phenyl; A C _1-6 aliphatic group optionally substituted with halogen; —O — C _1-6 alkyl optionally substituted with halogen; or C (= O) C _1-6 alkyl; or R ¹ and a neighboring substituent, combined with their intermediate atoms, form said ring fused to ring C; R ^x and R ^{y are} independently selected from TR ³ ; or R ^x and R ^{y are} combined together with their intermediate atoms to form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in said fused ring formed by the radicals R ^x and R ^y , which includes a nitrogen atom, is optionally substituted by an oxo group, —O (C _1-6 alkyl) ohm, —S (C _1-6 alkyl) ohm or NH ₂ ; and any substitutable nitrogen atom in said ring formed by the radicals R ^x and R ^y is optionally substituted with a benzyl group; and any substitutable carbon atom in the benzene ring formed by R ^x and R ^{y is} optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) optionally substituted with an amino group; T is a bond; R ² and R ^{2 'are} independently selected from hydrogen, OH, C _1-6 alkyl, phenyl, cyclopropyl, thienyl, furyl or -TWR ⁶ - or R ² and R ^2' , combined with their intermediate atoms, form a condensed 6- a membered unsaturated or partially unsaturated ring having 0-2 ring heteroatoms selected from nitrogen, where each substituted carbon atom in said condensed ring formed by R ² and R ^{2 ′ is} optionally substituted with halogen, oxo, NO ₂ , NH ₂ , pyrrolyl, CO ₂ (C _1-6 alkyl) ohm or C _1-6 alkyl optionally substituted with halogen; and any substitutable nitrogen atom in said ring formed by R ² and R ^{2 ′} is optionally substituted with phenyl; R ³ selected from hydrogen; halogen; -CN; -N (R ⁴ ) ₂ ; -SO ₂ NH ₂ ; phenyl optionally substituted with halogen; phenoxy; pyridyl; imidazolyl; C _1-6 alkyl optionally substituted with N (R ⁴ ) ₂ or NHSO ₂ (C _1-6 alkyl) ohm; cyclohexyl optionally substituted with N (R ⁴ ) ₂ or NHSO ₂ (C _1-6 alkyl) ohm; morpholinyl, piperidinyl, or piperidinyl or piperazinyl, wherein the morpholinyl, piperidinyl, or piperazinyl mentioned above are optionally substituted with C _1-6 alkyl, O-phenyl, -C (= O) C _1-6 alkyl, -CO ₂ (C _1-6 alkyl) phenyl or -SO ₂ (C _1-6 alkyl) ohm; each R ^{4 is} independently selected from C _1-6 alkyl, —C (═O) C _1-6 alkyl, —CO ₂ (C _1-6 alkyl) phenyl, or CH ₂ phenyl; each R ^{5 is} independently selected from —C _1-6 alkyl optionally substituted with halogen, halogen, —O — C _1-6 alkyl—, NH ₂ and —NO ₂ ; or R ⁵ and a neighboring substituent taken together with their intermediate atoms form said ring fused to ring C; W represents —C (R ⁶ ) ₂ O—, —CO ₂ -, or —CON (R ⁶ ) -; each R ^{6 is} independently selected from hydrogen or C _1-4 alkyl; each R ^{7 is} independently selected from hydrogen or a C _1-4 aliphatic group optionally substituted with NH ₂ or NH (C _1-6 alkyl); or two R ⁷ at the same nitrogen atom combined with the nitrogen atom to form a morpholinyl or piperazyl ring, optionally substituted with C _1-6 alkyl. 2. The compound according to claim 1, where the specified compound has one or more characteristics selected from the group including: (a) ring C is a phenyl or pyridinyl ring optionally substituted with an —R ⁵ group, wherein when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is a naphthyl or quinolinyl ring; (b) R ^x represents hydrogen or a C _1-4 alkyl group, and R ^y represents TR ³ , or R ^x and R ^y taken together with their intermediate atoms form an optionally substituted 5-7 membered unsaturated or partially unsaturated a ring having 0-2 ring nitrogen atoms; wherein any substitutable carbon atom in said condensed ring R ^x and R ^y formed by the radicals R ^x and R ^y that includes a nitrogen atom is optionally substituted with an oxo group, —O (C _1-6 alkyl) ohm, —S (C _1-6 alkyl) ohm or NH ₂ ; and any substitutable nitrogen atom in said ring formed by the radicals R ^x and R ^y is optionally substituted with a benzyl group; and any substituted carbon atom in the benzene ring formed by R ^x and R ^{y is} optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) optionally substituted with an amino group; (c) R ¹ is halogen; A C _1-6 aliphatic group optionally substituted with halogen; phenyl; -C (= O) C _1-6 alkyl; —O (C _1-6 alkyl; or —CN and (d) R ^{2 '} is hydrogen and R ² is hydrogen phenyl, thienyl, furyl, C _1-6 alkyl, or cyclopropyl; or R ² and R ^{2 '} taken together with their intermediate atoms form a substituted or unsubstituted benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, where each substituted carbon atom in the specified condensed ring formed by the radicals R ² and R ^{2 '} optionally substituted with halogen, oxo, —NO ₂ , —NH ₂ , pyrrolyl, —CO ₂ (C _1-6 alkyl) ohm, or —C _1-6 alkyl optionally substituted with halogen; and any substitutable nitrogen atom in said ring formed by R ^x and R ^y is optionally substituted with phenyl. 3. The compound according to claim 2, where (a) ring C is a phenyl or pyridinyl ring, wherein said ring is optionally substituted with a —R ⁵ group, or ring C and two adjacent substituents therein form a bicyclic ring system selected from naphthyl or quinolinyl rings; (b) R ^x represents hydrogen or C _1-4 alkyl and R ^y represents TR ³ ; or R ^x and R ^y taken together with their intermediate atoms form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogen atoms; moreover, any substitutable carbon atom in the specified condensed ring formed by the radicals R ^x and R ^y , which includes a nitrogen atom, optionally substituted by an oxo group, —O (C _1-6 alkyl) ohm, —S (C _1-6 alkyl) ohm or NH ₂ ; and any substitutable nitrogen atom in said ring formed by the radicals R ^x and R ^y is optionally substituted with a benzyl group; and any substitutable carbon atom in the benzene ring formed by R ^x and R ^y is optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) optionally substituted with an amino group; (c) R ¹ is halogen optionally substituted with a halogen C _1-6 aliphatic group, phenyl, —C (═O) C _1-6 alkyl, —OC _1-6 alkyl, —OH or —CNH and (d) R ^{2 ′} is hydrogen and R ² is hydrogen, phenyl, thienyl, furyl, C _1-6 alkyl or cyclopropyl or R ² and R ^{2 ′} taken together with their intermediate atoms form a substituted or unsubstituted benzene, a pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, where each substituted carbon atom in said condensed ring formed by R ² and R ^{2 ′} is optionally substituted with halogen, oxo, —NO ₂ , —NH ₂ , pyrrolyl, —CO _{2 (C1-6} alkyl) th or C _1-6 alkyl optionally substituted by halo nom; and any substitutable nitrogen atom in said ring formed by R ^x and R ^y is optionally substituted with phenyl. 4. The compound according to claim 2, where the specified connection has one or more characteristics selected from the group including (a) ring C is a phenyl or pyridinyl ring, said ring is optionally substituted with a group —R ⁵ , or ring C and two adjacent substituents therein form a bicyclic ring system selected from a naphthyl ring; (b) R ^x is hydrogen or methyl, and R ^y is phenyl optionally substituted with halogen; phenoxy; -N (R ⁴ ) ₂ ; pyridyl; imidazolyl; C _1-6 alkyl optionally substituted with N (R ⁴ ) ₂ ; cyclohexyl optionally substituted with —N (R ⁴ ) ₂ ; morpholinyl; piperidinyl; or piperazinyl, wherein said morpholinyl, piperidinyl or piperazinyl is optionally substituted with C _1-6 alkyl, -C (= O) (C _1-6 alkyl) ohm, -CO ₂ (C _1-6 alkyl) - (phenyl) ohm or - SO ₂ C _1-6 alkyl; or R ^x and R ^y taken together with their intermediate atoms form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring, where any substituted carbon atom in the benzene ring formed by the radicals R ^x and R ^y is optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) optionally substituted with an amino group; (c) R ¹ is halogen, a C _1-6 aliphatic group optionally substituted with halogen, phenyl or —CN; (d) R ^{2 '} represents hydrogen, and R ² represents hydrogen, phenyl, or C _1-6 alkyl, or R ² and R ^2' , taken together with their intermediate atoms, form a substituted or unsubstituted benzene, pyridine, pyrimidine or a partially unsaturated 6-membered carbocyclic ring; and where each substituted carbon atom in said condensed ring formed by R ² and R ^{2 ′} is optionally substituted with halogen, oxo, —NO ₂ , —NH ₂ , pyrrolyl, —CO ₂ (C _1-6 alkyl) ohm, or —C _1-6 alkyl optionally substituted with halogen; and any substitutable nitrogen atom in said ring formed by R ^x and R ^y is optionally substituted with phenyl; and (e) each R ^{5 is} independently selected from halogen, —NO ₂ , —NH ₂ , C _1-6 alkyl optionally substituted with halogen, or —O — C _1-6 alkyl. 5. The compound according to claim 4, where (a) ring C is a phenyl or pyridinyl ring, wherein said ring is optionally substituted with a group —R ⁵ where, when ring C and two adjacent substituents therein form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl ring; (b) R ^x is hydrogen or methyl, and R ^y is phenyl optionally substituted with halogen; phenoxy; -N (R ⁴ ) ₂ ; pyridyl; imidazolyl; C _1-6 alkyl optionally substituted with N (R ⁴ ) ₂ ; cyclohexyl optionally substituted with —N (R ⁴ ) ₂ ; morpholinyl; piperidinyl; or piperazinyl, wherein said morpholinyl, piperidinyl or piperazinyl is optionally substituted with C _1-6 alkyl, -C (= O) (C _1-6 alkyl) ohm, -CO ₂ (C _1-6 alkyl) - (phenyl) ohm or - SO ₂ C _1-6 alkyl; or R ^x and R ^y taken together with their intermediate atoms form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring, where any substituted carbon atom in the benzene ring formed by the radicals R ^x and R ^y is optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) om optionally substituted with an amino group; (c) R ¹ is halogen; A C _1-6 aliphatic group optionally substituted with halogen; phenyl; or -CN; (d) R ^{2 '} represents hydrogen and R ² represents hydrogen, phenyl, or C _1-6 alkyl, or R ² and R ^2' , taken together with their intermediate atoms, form substituted or unsubstituted benzene, pyridine, pyrimidine or a partially unsaturated 6 membered carbocyclic ring; and where each substituted carbon atom in said condensed ring formed by R ² and R ^{2 ′} is optionally substituted with halogen, oxo, —NO _z , —NH ₂ , pyrrolyl, —CO ₂ (C _1-6 alkyl) ohm, or —C _1-6 alkyl optionally substituted with halogen; and any substitutable nitrogen atom in said ring formed by R ² and R ^{2 ′} is optionally substituted with phenyl; and (e) each R ^{5 is} independently selected from halogen, —NO ₂ , —NH ₂ , C _1-6 alkyl optionally substituted with halogen, or —OC _1-6 alkyl. 6. The compound according to claim 4, where the specified connection has one or more features selected from the group including: (a) R ^x is hydrogen or methyl and R ^y is methyl, ethyl, isopropyl, tert-butyl, 2-pyridyl, 4-pyridyl, piperidinyl or phenyl optionally substituted with halogen; or R ^x and R ^y taken together with their intermediate atoms form a 6-membered unsaturated or partially unsaturated carbocyclic ring, where any substitutable carbon atom in the benzene ring formed by the radicals R ^x and R ^y is optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) ohm optionally substituted with an amino group; (b) R ¹ is halogen, a C _1-4 aliphatic group optionally substituted with halogen; or -CN; (c) R ² and R ^{2 ′} taken together with their intermediate atoms form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, where each substituted carbon atom in said fused ring formed by R ² and R ^{2 ′} , optionally substituted with halogen, oxo, —NO ₂ , —NH ₂ , CO ₂ (—C _1-4 alkyl) ohm, or —C _1-4 alkyl optionally substituted with halogen, where (C _1-4 alkyl) is straight or branched alkyl group; and (d) each R ^{5 is} independently selected from —Cl, —F, —CF ₃ , —NH ₂ , or C _1-4 alkyl. 7. The compound according to claim 2, where (a) R ^x is hydrogen or methyl and R ^y is methyl, ethyl, isopropyl, tert-butyl, 2-pyridyl, 4-pyridyl, piperidinyl or phenyl optionally substituted with halogen; or R ^x and R ^y taken together with their intermediate atoms form a benzene ring, a pyridyl ring or a 6-membered partially unsaturated carbocyclic ring; (b) R ¹ is halogen, a C _1-4 aliphatic group optionally substituted with halogen; or -CN; (c) R ² and R ^{2 ′} taken together with their intermediate atoms form a benzene, pyridine, pyrimidine or partially unsaturated 6-membered carbocyclic ring, where each substituted carbon atom in said fused ring formed by R ² and R ^{2 ′ is} optional substituted by an oxo group, —NH ₂ , or —C _1-4 alkyl optionally substituted with halogen, where (C _1-4 alkyl) represents an unbranched or branched alkyl group; and (d) each R ^{5 is} independently selected from —Cl, —F, —CF ₃ , —NH _2, or C _1-4 alkyl. 8. A compound according to claim 7, wherein each of R ^x and R ^y is methyl or R ^x and R ^y, taken together with the pyrimidine ring to form an optionally substituted ring selected from quinazoline, and R ² and R ^{2 'are} taken together with the pyrazole ring, form an optionally substituted indazole ring. 9. The compound according to claim 1, where the specified compound is selected from the following compounds:

10. A pharmaceutical composition that inhibits GSK-3 or AURORA-2 activity, comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. 11. The pharmaceutical composition of claim 10, further comprising a second therapeutic agent selected from agents for treating diabetes, a chemotherapeutic agent or an anti-proliferative agent, an anti-inflammatory agent, immunomodulatory and immunosuppressive agents, a neurotrophic factor, an agent for the treatment of cardiovascular diseases, an agent for the treatment of liver diseases, an antiviral agent or an agent for the treatment of blood diseases. 12. The pharmaceutical composition according to claim 11, where the therapeutic agent is selected from insulin or insulin analogues, glitazones, alpha-glucosidase inhibitors, biguanides, insulin and sulfonylureas, sensitizers, adrimycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, tacotefer, platinum, corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, sulfasalazine; cyclosporine, tacrolimus, rapamycin, mofetil mucophenolate, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; acetylcholinesterase inhibitors, MAO inhibitors, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's drugs; beta-blockers, ACE inhibitors (ACEs), diuretics, nitrates, calcium channel blockers and statins; cholestyramine, antiviral agents; anti-leukemia drugs, growth factors, and gammaglobulin. 13. A method of inhibiting the activity of GSK-3 or AURORA in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 14. The method according to item 12, where the specified method inhibit the activity of GSK-3 in a patient. 15. A method of inhibiting the activity of GSK-3 or AURORA in a biological sample, comprising contacting said biological sample with a compound according to claims 1 to 9. 16. A method of treating a disease alleviated by a GSK-3 inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claims 1 to 9. 17. The method according to clause 16, further comprising the step of administering to the indicated patient a second drug selected from antidiabetic agents, chemotherapeutic agents or other anti-proliferative agents, anti-inflammatory agents, immunomodulatory and immunosuppressive agents, neurotrophic factor, ion channel blockers, riluzole and funds against Parkinson's disease; an agent for treating cardiovascular diseases, an agent for treating liver diseases, an agent for treating blood diseases, and agents for treating immunodeficiency disorders. 18. The method of claim 16, wherein said disease is diabetes. 19. The method of claim 16, wherein said disease is Alzheimer's disease. 20. The method of claim 16, wherein said disease is schizophrenia. 21. A method of enhancing glycogen synthesis in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 22. A method of reducing blood glucose in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 23. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 24. A method of inhibiting phosphorylation of β-catenin in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 25. A method of treating a disease facilitated by treatment with an AURORA inhibitor, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claims 1 to 9. 26. The method of claim 25, further comprising the step of administering to said patient a second drug from antidiabetic agents, chemotherapeutic agents or other anti-proliferative agents, anti-inflammatory agents, immunomodulatory and immunosuppressive agents, a neurotrophic factor, ion channel blockers, riluzole and anti-disease agents Parkinson; an agent for treating cardiovascular diseases, an agent for treating liver diseases, an agent for treating blood diseases, and agents for treating immunodeficiency disorders. 27. The method of claim 25, wherein said disease is cancer. 28. The pharmaceutical composition of claim 10 in combination with an anti-proliferative agent or chemotherapeutic agent. 29. A method of treating cancer in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9, wherein said cancer is melanoma or is selected from cancer of the intestines, lungs, stomach, and mammary glands. 30. The method according to clause 29, comprising the additional step of administering to the patient an anti-proliferative agent or chemotherapeutic agent, wherein the additional therapeutic agent is administered together with said composition in unit dose form or separately with said composition as part of a multiple form. 31. A method of treating Alzheimer's disease in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 32. A method of treating schizophrenia in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 33. A method of treating diabetes in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 34. A method of treating cancer in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a compound according to claims 1 to 9. 35. The compound of formula A

selected from the group including

36. The compound of formula B

where R ¹ represents CF ₃ ; R ⁵ represents one to three substituents, each of which is independently selected from Cl, F, CF ₃ or NO ₂ ; R ^x and R ^{y are} independently selected from TR ³ , or R ^x and R ^y taken together with their intermediate atoms form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, where any substitutable carbon atom in said condensed ring formed by R ^x and R ^y groups is optionally and independently substituted by an oxo group, —O (C _1-6 alkyl), —S (C _1-6 alkyl) or NH ₂ and any substitutable nitrogen atom in said ring formed by R ^x and R ^y groups is optionally substituted benzyl th group, and any substitutable carbon atom in the benzene ring formed by R ^x and R ^y is optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² or —O (C _1-6 alkyl) ohm, optionally substituted with an amino group T is a bond; R ³ is selected from hydrogen, halogen, -CN, N (R ⁴⁾ _2, -SO ₂ NH _2, phenyl optionally substituted with halogen, phenoxy, pyridyl, imidazolyl; C _1-6 alkyl optionally substituted with —N (R ⁴ ) ₂ or —NHSO ₂ (C _1-6 alkyl); cyclohexyl optionally substituted with —N (R ⁴ ) ₂ or —NHSO ₂ (C _1-6 alkyl); morpholinyl, piperidinyl or piperazinyl, wherein said morpholinyl, piperidinyl or piperazinyl is optionally substituted with C _1-6 alkyl, O-phenyl, C (= O) (C _1-6 alkyl), -CO ₂ - (C _1-6 alkyl) - (phenyl) or —SO ₂ C _1-6 alkyl; each R ^{4 is} independently selected from C _1-6 alkyl, —C (═O) (C _1-6 alkyl), —CO ₂ - (C _1-6 alkyl) - (phenyl), or CH ₂ phenyl. each R ^{7 is} independently selected from hydrogen or a C _1-4 aliphatic group optionally substituted with NH ₂ or NH (C _1-6 alkyl) ohm; or two R ⁷ at the same nitrogen atom taken together with the nitrogen atom form a morpholinyl or piperazinyl ring optionally substituted with C _1-6 alkyl. 37. The compound of formula C

where R ² and R ^{2 'are} independently selected from hydrogen, OH, C _1-6 alkyl, phenyl, cyclopropyl, thienyl, furyl or -TWR ⁶ , or R ² and R ^2' , taken together with their intermediate atoms, form a condensed 6 a membered unsaturated or partially unsaturated ring having 0-2 ring nitrogen heteroatoms, where any substitutable carbon atom in said condensed ring formed by R ² and R ^{2 ′} is substituted with halogen, oxo, NO ₂ , NH ₂ , pyrrolyl, CO ₂ (C _1-6 alkyl) th optionally substituted by halogen, and any substitutable nitrogen atom in said ring, paying ovannom groups R ² and R ^{2 ',} optionally substituted phenyl group; R ^x and R ^{y are} independently selected from TR ³ or R ^x and R ^y taken together with their intermediate atoms form a fused unsaturated or partially unsaturated 5-8 membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur, or nitrogen, where any substituted carbon atom in said condensed ring formed by R ^x and R ^y groups that contains a nitrogen atom is optionally and independently substituted by —O (C _1-6 alkyl) ohm, —S (C _1-6 alkyl) ohm or NH ₂ ; and any substitutable nitrogen atom in said ring formed by the groups R ^x and R ^y, an optionally substituted benzyl group; and any substitutable carbon atom in the benzene ring formed by R ^x and R ^y, an optionally substituted C _1-6 alkyl, N (R ^{7) 2,} -O (C _1-6 alkyl), optionally substituted amino group; T is a bond; W represents —C (R ⁶ ) ₂ O— or —CON (R ⁶ ) -; R ^{3 is} selected from hydrogen, halogen, —CN, —N (R ⁴ ) ₂ , —SO ₂ NH ₂ , phenyl optionally substituted with halogen, phenoxy, pyridyl, imidazolyl, C _1-6 alkyl, optionally substituted with N (R ⁴ ) _2, or NHSO ₂ (C _1-6 alkyl), cyclohexyl optionally substituted with N (R ⁴⁾ _2, or NHSO ₂ (C _1-6 alkyl), morpholinyl, piperidinyl, or piperidinyl, or piperazinyl wherein said morpholinyl above, piperidinyl or piperazinyl optionally substituted by C _1-6 alkyl, O-phenyl, -C (= O) C _1-6 alkyl, -CO ₂ (C _1-6 alkyl) -phenyl, or -SO ₂ (C _1-6 alkyl) th, each R ⁴ is independently selected from C _1-6 alkyl, -C (= O) C _1-6 alk la, -CO ₂ (C _1-6 alkyl) -phenyl, or CH ₂ phenyl; each R ^{6 is} independently selected from hydrogen or C _1-4 alkyl; and each R ⁷ is independently selected from hydrogen or C _1-4 aliphatic optionally substituted with NH ₂ or NH (C _1-6) alkyl, or two R ⁷ have the same nitrogen atom are combined together with the nitrogen atom to form morpholinyl or a piperazyl ring optionally substituted with C _1-6 alkyl; provided that R ^{2 is} not tert-butyl and R ^{2 is} not methyl when R ^x is Br, R ^y is hydrogen, R ^{2 '} is hydrogen. 38. The compound according to clause 37, where each of R ^x and R ^y represents methyl or R ^x and R ^y taken together with the pyrimidine ring, form a quinazoline ring. 39. The compound of claim 38, wherein R ² and R ^{2 ′} , taken together with the pyrazole ring, form an indazole ring. 40. The compound of formula D

wherein R ^x and R ^y are independently selected from TR ^3, or R ^x and R ^y, taken together with their intervening atoms to form a fused unsaturated or partially unsaturated, 5-8 membered ring having 0-2 ring heteroatoms selected from oxygen, sulfur or nitrogen, wherein any substitutable carbon atom in said fused ring formed by the groups R ^x and R ^y, which contains a nitrogen atom, and independently optionally substituted by -O (C _1-6 alkyl), -S (C _1-6 alkyl) or NH ₂ ; and any substitutable nitrogen atom in said ring formed by R ^x and R ^y groups is optionally substituted with a benzyl group; and any substitutable carbon atom in the benzene ring formed by R ^x and R ^y is optionally substituted with C _1-6 alkyl, N (R ⁷ ) ² , —O (C _1-6 alkyl) ohm, optionally substituted with an amino group; T is a bond; R ^{3 is} selected from halogen, —CN, —N (R ⁴ ) ₂ , —SO ₂ NH ₂ , phenyl optionally substituted with halogen, phenoxy, pyridyl, imidazolyl, C _1-6 alkyl, optionally substituted with N (R ⁴ ) ₂ , or NHSO ₂ (C _1-6 alkyl) ohm, optionally substituted with N (R ⁴ ) ₂ , or NHSO ₂ (C _1-6 alkyl) ohm, morpholinyl, piperidinyl, or piperidinyl or piperazinyl, wherein the morpholinyl, piperidinyl mentioned above or piperazinyl optionally substituted with C _1-6 alkyl, O-phenyl, -C (= O) C _1-6 alkyl, -CO ₂ (C _1-2 alkyl) phenyl, or -SO ₂ (C _1-6 alkyl) ohm; each R ^{4 is} independently selected from C _1-6 alkyl, —C (═O) C _1-6 alkyl, —CO ₂ (C _1-6 alkyl) phenyl, or CH ₂ phenyl; each R ^{5 is} independently selected from —C _1-6 alkyl optionally substituted with halogen, halogen, —O — C _1-6 alkyl, NH ₂ and NO ₂ ; each R ^{7 is} independently selected from hydrogen or a C _1-4 aliphatic group optionally substituted with NH ₂ or NH (C _1-6 ) alkyl, or two R ⁷ at the same nitrogen atom are combined with a nitrogen atom to form morpholinyl or piperazyl ring optionally substituted with C _1-6 alkyl. 41. The compound of claim 40, wherein each of R ^x and R ^y is methyl, or R ^x and R ^y taken together with the pyrimidine ring form a quinazoline ring.