MXPA06004277A

MXPA06004277A - 4-(pyrazol-3-ylamino) pyrimidine derivatives for use in the treatment of cancer

Info

Publication number: MXPA06004277A
Application number: MXPA/A/2006/004277A
Authority: MX
Inventors: Nowak Thorsten; Peter Thomas Andrew
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited; Nowak Thorsten; Peter Thomas Andrew
Priority date: 2003-10-17
Filing date: 2006-04-17
Publication date: 2006-10-17

Abstract

A compound of Formula (I);wherein the substituents are as defined in the text for use in modulating insulin-like growth factor 1 receptor activity in a warm blooded animal such as man.

Description

DERIVATIVES OF 4- (PIRAZOL-3-ILA INO) PYRIMIDINE FOR USE IN THE TREATMENT OF CANCER DESCRIPTION OF THE INVENTION The present invention relates to novel pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. The insulin-like growth factor (IGF) axis consists of ligands, receptors, binding proteins and proteases. The two ligands, IGF-I and IGF-II, are mitogenic peptides that signal through the interaction with the type 1 insulin-like growth factor receptor (IGF-1R), a hetero-tetrameric cell surface receptor. . The binding of any of these ligands stimulates the activation of a tyrosine kinase domain in the intracellular region of the β chain and results in the phosphorylation of several tyrosine residues resulting in the recruitment and activation of several signaling molecules. It has been shown that the intracellular domain transmits signals for mitogenesis, survival, transformation and differentiation in cells. The structure and function of IGF-1R has been reviewed by Adams et al (Cellular and Molecular Life Sciences, 57, 1050-1093, 2000). IGF-IIR (also known as mannose-6-phosphate receptor) has no kinase domain and does not signal mitogenesis, but it can act to regulate the availability of the ligand on the surface of the cell, counteract the effect of the IGF - 1R. IGF binding proteins (IGFBP) control the availability of circulating IGF and IGF release from these can be mediated through proteolytic cleavage. These other components of the IGF axis have been reviewed by Collet-Solberg and Cohen (Endocrine, 12, 121-136, 2000). There is considerable evidence linking IGF signaling with cell transformation and the initiation and progression of tumors. IGF has been identified as the main survival factor that protects cell death induced by oncogene (Harrington et al, EMBO J, 13, 3286-3295, 1994). It has been shown that cells lacking IGF-1R are refractory to transformation through different oncogenes (including SV40T and ras antigen) that efficiently transform corresponding wild-type cells (Sell et al., Mol. Cell Biol., 14, 3604-12, 1994). The over-regulation of IGF axis components has been described in several tumor cell lines and tissues, particularly breast tumors (Surmacz, Journal of Mammary Gland Biology &Neoplasia, 5, 95-105, 2000), prostate (Djavan et al. al, World J. Urol., 19, 225-233, 2001 and O'Brien et al, Urology, 58, 1-17, 2001) and colon (Guo et al, Gastroenterology, 102, 1101-1108, 1992). Conversely, IGF-IIR has been implicated as a tumor suppressor and is eliminated in some cancers (DaCosta et al, Journal of Mammary Gland Biology &Neoplasia, 5, 85-94, 2000). There is a growing number of epidemiological studies that link circulating IGF in increment (or increased ratio of IGF-1 to IGFBP3) with cancer risk (Yu and Rohan, J. Nati. Cancer Inst. 92, 1472-1489, 2000). Transgenic mouse models also involve IGF signaling at the onset of tumor cell proliferation (Lamm and Christofori, Cancer Res. 58, 801-807, 1998, Foster et al, Cancer Targets. Rev., 17, 317-324, 1998, and DiGiovanni e al, Proc. Nati, Acad. Sci., 97, 3455-3460, 2000). Several in vitro and in vivo strategies have provided proof of the main aspect that the inhibition of IGF-1R signaling reverses the transformed phenotype and inhibits tumor cell growth. These include neutralizing antibodies (Kalebic ei al Cancer Res., 54, 5531-5534m 1994), antisense oligonucleotides (Resnicoff et al, Cancer Res., 54 (Resnicoff et al, Cancer Res., 54, 2218-2222, 1994), triple helix-forming oligonucleotides (Rinninsland et al, Proc. Nati. Sci., 94, 5854-5859, 1997), antisense mRNA (Nakamura et al., Cancer Res., 60,760-765, 2000) and dominant negative receptors (D'Ambrosio et al., Cancer Res., 56, 4013-4020, 1996). Antisense oligonucleotides have shown that the inhibition of IGF-1R pressure results in the induction of apoptosis in cells in vivo (Resnicoff et al Cancer Res., 55, 2463-2469, 1995) and have been taken in man ( Resnicoff et al, Proc. Amer. Assoc. Cancer Res., 40 Abs 4816, 1999). However, none of these aspects is particularly attractive for the treatment of major solid tumor disease.

Since increased IGF signaling is involved in the growth and survival of tumor cells, and IGF-1R function blocking can reverse this, the inhibition of the tyrosine kinase domain of IGF-1R is an appropriate therapy through from which cancer can be treated. In vitro and in vivo studies with the use of dominant negative IGF-1R variants supports this. In particular, a point mutation in the ATP binding site that blocks receptor tyrosine kinase activity has been shown to be effective in preventing tumor cell growth (Kulik et al., Mol.Cell. Biol. 17, 1595 -1606, 1997). Several pieces of evidence imply that normal cells are less susceptible to apoptosis caused by the inhibition of IGF signaling, indicating that a therapeutic margin is possible with said treatment (Baserga, Trends Biotechnol., 14,150-2, 1996). There are few reports of tyrosine kinase inhibitors Selective IGF-1R. Parrizas eí al. They described tyrphostins that had some efficacy in vitro and in vivo (Parrizas et al., Endocrinology, 138: 1427-33 (1997)). These compounds were of modest potency and selectivity over the insulin receptor. Telik Inc. have described heteroaryl aryl ureas which have selectivity on insulin receptors but potentiate tumor cells in vitro and remain modest (Published Patent Application No. WO 00/35455).

Pyrimidine derivatives substituted at positions 2 and 4 through a substituted amino group having tyrosine kinase inhibitory activity IGF-IR are described in WO 03/048133. Compounds wherein the amino substituent nitrogen atom forms part of a heterocyclic ring are not described. WO 02/50065 discloses that certain pyrimidine derivatives substituted with pyrazolyl-amino have inhibitory activity of protein kinase, especially as inhibitors of Aurora-2 and glycogen synthase kinase-3 (GSK-3), and are used for the treatment of diseases such as cancer, diabetes and Alzheimer's disease. The disclosed compounds have a substituted amino substituent at the 2-position of the pyrimidine ring but again there is no description of the compounds wherein the nitrogen atom of the amino substituent forms part of a heterocyclic ring. The pyrazolyl-amino substituted pyrimidine derivatives having Aurora-2 inhibitory activity and glycogen kinase-3 synthase (GSK-3) wherein the 2-position of the pyrimidine ring is substituted by an N-linked heterocyclic ring are generically described in WO 02/22601, WO 02/22602, WO 02/22603, WO 02/22604, WO 02/22605, WO 02/22606, WO 02/22607 and WO 02/22608. In the vast majority of more than four hundred illustrated compounds, the pyrimidine ring is present as part of a fused ring system, however, and in none of the illustrated examples is the heterocyclic substituent in this position itself substituted by another substituent of ring. WO 01/60816 discloses that certain substituted pyrimidine derivatives have protein kinase inhibitory activity. This is not described in WO 01/60816 pyrimidine derivatives having a pyrazolyl-amino substituent at the 4-position on the pyrimidine ring and a N-linked saturated monoccyclic ring substituted at the 2-position on the pyrimidine ring. The present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups may be optionally substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 8 atoms carbon, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 atoms of carbon-amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkoxycarbonyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, -C (O) -OR3b, -OR3b, -NHR3b, -N [alkyl] from 1 to 6 carbon atoms] R3, -S (O) mR3a or -N (R3c) C (O) R3a, where R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms , C3 -C 8 -cycloalkyl-C 1-6 -alkyl or C 1-6 -alkoxy, m is 0, 1 or 2, R 3b represents a saturated 4, 5 or 6-membered heterocyclic monocyclic ring which comprises at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur and R3c represents hydrogen or alkyl of 1 to 6 carbon atoms, or R3 represents a saturated monocyclic heterocyclic ring of to 6 members comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a heteroaromatic ring of 5 to 6 comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 2,7-diazaspiro group [3.5], each of these groups or rings within R3 may be optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, tri- [ 1 to 4 carbon atoms] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, d i- [alkyol of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 ato carbon atoms, aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino-alkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkyo of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl from 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, d - [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms carbon, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c) C (O) R3a, wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring may optionally comprise one or more heterogeneous atoms selected from nit Oxygen, Sulfur Oxygen, any of these substituents may be optionally substituted by one or more alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano; -NQ1 represents an N-linked saturated monocyclic 5 to 6 membered ring containing a heterogeneous nitrogen atom and optionally comprises one or more additional heterogeneous ring atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro , cyano-NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (O) palquyl of 1 to 4 atoms of carbon, -C (O) NR6R7 and -SO2NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently forms a heterocyclic ring saturated and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated 5 to 6 membered monocyclic ring or unsaturated, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano -NR 0R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms carbon, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, -S (O) palokyl of 1 to 6 carbon atoms, -C (O) NR12R13 and -SO2NR 4R15, wherein R10 , R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10, R11, R12, R13, R14 and R15, when taken together with the nitrogen atom to which they are united, each independently you can form a saturated heterocyclic ring and n is 0, 1 or 2; and wherein any saturated monocyclic ring optionally carries 1 or 2 oxo or thioxo substituents. According to a further aspect of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups may optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 atoms of carbon; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl from 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alko] or C 1 -C 6 -alkyl] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkanoylamino of 2 to 6 carbon atoms, -C (O) R3, -OR3b, -SR3, NHR3b, -N [alkyl of 1 to 6 át carbon atoms] R3 or -S (O) mR3a wherein R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 16 atoms of carbon carbon or alkoxy of 1 to 6 carbon atoms m is 0, 1 or 2, and R3b represents a saturated 5 to 6 membered monocyclic ring containing one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, or R3 represents a ring 5-6 membered heterocyclic saturated monocyclic member, this ring comprises at least one heterogeneous ring atoms selected from nitrogen, oxygen and sulfur, each of these groups or rings within R3 optionally may be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, cyano, amino, alkylamino of 1 to 6 atoms carbon, d i- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1-3 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio or of 1 to 6 carbon atoms, alkylsuifonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyanoyanoylamino of 1 to 6 carbon atoms, or a monocyclic saturated ring of 4, 5, 6 or 7 members, said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, -NQ1 represents a saturated monocyclic ring N-linked from 5 to 6 members containing a heterogeneous nitrogen atom and optionally comprises one or more additional ring heterogeneous atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano -NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (O) palquilo of 1 to 4 át carbon omos, -C (O) NR6R7 and -SO2NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently forms a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, - S (O) nalkyl of 1 to 6 carbon atoms, -C (O) NR12R13 and - SO2NR14R15, wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10, R11, R12, R3, R14 and R15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring, and n is 0, 1 or 2. According to a further aspect of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups can optionally be substituted by halogen or an alkoxy group of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms or -S (O) mR3a, each of these groups within R3 can optionally be substituted by at least one substituent selected from alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, or a saturated monocyclic ring of 4, 5, 6 or 7 member, said ring optionally comprising one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, wherein R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon or alkoxy atoms of 1 to 6 carbon atoms, and m is 0, 1 or 2; -NQ1 represents a saturated monocyclic ring N-linked from 5 to 6 members containing a heterogeneous nitrogen atom and optionally comprises one or more additional heterogeneous ring atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, on any available ring atom, by one or more additional substituents, which may be the same or different, of alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl) and trifluoromethyl), halogen, nitro, cyano-NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms carbon, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (O) palquil of 1 to 4 atoms of carbon, -C (O) NR6R7 and -SO2NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently can form a ring saturated heterocyclic and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by at least one substituent selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR 10 R 11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, -S (O) nalkyl of 1 to 6 atom carbon, -C (O) NR12R13 and -SO2NR14R15, wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10, R11, R12, R13 , R14 and R15, when taken together with the nitrogen atom to which they are attached, independently each can form a saturated heterocyclic ring, and n is 0, 1 or 2. Unless otherwise indicated the term 'alkyl' when it is used alone or in combination, it refers to an alkyl portion of straight chain or branched chain. An alkyl group of 1 to 6 carbon atoms has from one to six carbon atoms, including methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl and the like. The references to 'alkyl of 1 to 4 carbon atoms' is therefore to be understood as representing a straight or branched chain alkyl portion having from 1 to 4 carbon atoms. References to individual alkyl groups such as 'propyl' are specific to the straight string version only, the versions for individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. Analogously, the terms 'alkoxy of 1 to 6 carbon atoms' and 'alkoxy of 1 to 4 carbon atoms', when used alone or in combination, will be understood to refer to branched straight chain groups having from one to six or one to four carbon atoms respectively, and include groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy. A "C2 to C6 alkenyl group" refers to a straight or branched chain group having from two to six carbon atoms such as vinyl, isopropenyl, allyl, and but-2-enyl. Similarly, a 'C2 to C6 alkynyl group' refers to a straight or branched chain group having from two to six carbon atoms, such as ethynyl, 2-propynyl and but-2-ynyl. The term 'cycloalkyl', when used alone or in combination, refers to a saturated alicyclic portion having from three to eight carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. References to cycloalkyl of 3 to 6 carbon atoms will therefore be understood to represent a saturated alicyclic portion having from 3 to 6 carbon atoms, representative examples of which were listed above. As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine. The term "optionally substituted" is used herein to indicate optional substitution by the specified group or groups in any suitable available position. Suitable values for any of the substituents herein, for example, the 'R' groups (R to R15, R3a, R3b or R3c) or for various groups of ungroup -N Q1 or Q3, in cl uyen: for halogen: fluoro, chlorine, bromine and iodine; for alkyl of 1 to 6 carbon atoms: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl; for alkenyl of 2 to 5 carbon atoms: vinyl, isopropenyl, allyl and but-2-enyl; for alkynyl of 2 to 6 carbon atoms: ethynyl, 2-propynyl and but-2-ynyl; for alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms: methoxymethoxy, methoxyethoxy, ethoxymethoxy, propoxymethoxy and butoxymethoxy; for C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl: methoxymethyl, methoxyethyl, ethoxymethyl, propoxymethyl and butoxymethyl; for tri- [C 1 -C 4 alkyl] silyl: trimethylsilyl, triethylsilyl, dimethylsilyl and methyl-diethylsilyl; for alkylthio of 1 to 6 carbon atoms: methylthio, ethylthio and propylthio; for alkylamino of 1 to 6 carbon atoms: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di- [C 1-6 alkyl] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino; for amino-alkyl of 1 to 6 carbon atoms: aminomethyl, aminoethyl, aminopropyl and aminobutyl; for C 1-6 alkylamino-C 1-6 -alkyl: methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminomethyl, propylaminomethyl, isopropylaminoethyl and butylaminomethyl; for di- [C 1-6 alkyl] amino-alkyl of 1 to 6 carbon atoms: dimethylaminomethyl, dimethylaminoethyl, dimethylaminobutyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, N-ethyl-N-methylaminomethyl, JN-ethyl-N. - methylaminomethyl, diisopropylaminoethyl; for alkylcarbonyl of 1 to 6 carbon atoms: methylcarbonyl, ethylcarbonyl, propylcarbonyl and tert-butylcarbonyl; for alkoxycarbonyl of 1 to 6 carbon atoms: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-alkylcarbamoyl of 1 to 6 carbon atoms: N-methylcarbamoyl, J-ethylcarbamoyl and N-propylcarbamoyl; for N, N-di- [alkyl of 1 to 6 carbon atoms] carbamoyl: N, j -dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl; for cycloalkyl of 3 to 8 carbon atoms: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; for cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl; for cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms: cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy; for cycloalkylcarbonyl of 3 to 8 carbon atoms: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl; for cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms: cyclopropylmethylcarbonyl, cyclobutylmethylcarbonyl, cyclopentylmethylcarbonyl cyclohexylmethylcarbonyl; for cycloalkylamino of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms: cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylaminopropyl, cyclobutylaminoethyl, cyclopentylaminoethyl, cyclopentylaminopropyl, cyclohexylaminoethyl and cycloheptylaminoethyl; for cycloalkyl of 3 to 8 carbon atoms-aicylamino of 1 to 6 carbon atoms: cyclopropylmethylamino, cyclopropylethylamino, cyclopentylmethylamino and cyclohexylmethylamino; for cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms: cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclopropylmethyl aminopropyl, cyclopropylethylaminoethyl, cyclopropylethylaminobutyl, cyclopentylmethylaminoethyl, cyclopentylmethyloaminobutyl cyclohexylmethyl aminoamethyl; for alkoxyamide of 1 to 6 carbon atoms: methoxyamino, ethoxyamino, propoxyamino and butoxyamino; for C 1 -C 6 alkanoyl: formyl, acetyl, propionyl, butyryl and isobuyryl; for alkanoylamino of 2 to 6 carbon atoms: acetamido and propionamido; for alkylsulfonyl of 1 to 6 carbon atoms: methylsulfonyl and ethylsulfonyl; and for alkylsulfinyl: methylsulfinyl and ethylsulphinyl.

A 'heterogeneous atom' is a nitrogen, sulfur or oxygen atom. When the rings include nitrogen atoms, these may be substituted as necessary to meet the nitrogen binding requirements or may be linked to the rest of the structure through the nitrogen atom. Nitrogen atoms can also be in the form of N-oxides. Sulfur atoms may be in the form of S, S (O) or SO2. A saturated 3, 4, 5, 6 or 7 membered monocyclic ring, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur 'may be a carbocyclic ring (i.e., an alicyclic ring having only ring carbon atoms) or is a heterocyclic ring containing three to seven atoms of which at least one is a heterogeneous atom selected from nitrogen, oxygen and sulfur, and said ring may, unless otherwise specified, be bound to carbon or nitrogen. When the monocyclic ring saturates 3, 4, 5, 6, or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur is a heterocyclic ring, the heterocyclic ring preferably contains one to four, preferably one to three, still most preferably one to two heterogeneous atoms independently selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclic ring may be bonded to carbon or nitrogen. Examples of suitable carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A 3, 4, 5, 6 or 7-membered saturated monocyclic heterocyclic ring may conveniently be selected from oxirane, azetinyl, dioxanyl, trioxanil, oxepanyl, dithianyl, trityanil, oxathyanyl, thiomordolinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl. (particularly azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl). A saturated heterocyclic ring bearing 1 or 2 oxo or thioxo substituents, for example, may be 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl , or 2,6-dioxopiperidinyl.

When reference is made to a saturated monocyclic ring of to 6 members' or to a '5 to 6 membered saturated monocyclic heterocyclic ring', it will be understood that it refers to rings containing 5 or 6 ring atoms, representative examples of which were listed above. When reference is made to a 'saturated 4, 5 or 6 membered monocyclic ring' or to a '4, 5 or 6 membered saturated monocyclic heterocyclic ring', it will be understood that this refers to rings containing 4, 5 or 6 atoms in the ring, representative examples of which were listed above. A 5-6 membered N-linked saturated monocyclic ring containing a heterogeneous nitrogen atom, and optionally comprising, one or more additional ring heterogeneous atoms selected from nitrogen, oxygen and sulfur is a saturated monocyclic heterocyclic ring containing five or six atoms in the ring which, in addition to the nitrogen atom through which it bonds to the rest of the structure, optionally comprises at least one heterogeneous atom selected from nitrogen, oxygen and sulfur. The saturated monocyclic heterocyclic ring containing five or six ring atoms preferably comprises one to three, preferably one to two heterogeneous atoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom through which it is bonded to the rest of the structure. Particular examples of such ring systems include pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.

A '5 to 6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur' is a monocyclic aromatic, fully unsaturated ring containing five or six atoms of which at least one is a heterogeneous atom selected from nitrogen, oxygen and sulfur, said ring, unless otherwise indicated, may be bonded to carbon or nitrogen.

Preferably, the 5- to 6-membered heteroaromatic ring contains one to four heterogeneous atoms independently selected from nitrogen, oxygen and sulfur. Particular examples of such ring systems include pyridyl, imidazole, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, isothiazolyl, triazolyl, tetrazolyl or thienyl. A saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, is a saturated or fully or partially unsaturated monocyclic ring containing five or six carbon atoms. which optionally at least one is a heterogeneous atom selected from nitrogen, oxygen and sulfur, said ring, unless otherwise indicated, may be bonded to carbon or nitrogen. The ring may have alicyclic or aromatic properties. An aromatic monocyclic ring can be aryl (such as phenyl) or heteroaromatic, representative examples of which are listed above.

As used herein, the term "heterocyclic ring" refers to a saturated monocyclic ring system having from 3 to 8 ring atoms wherein one or more ring carbons is replaced by a heterogeneous atom selected from nitrogen, oxygen and sulfur. Preferably, the heterocyclic ring contains from one to four, most preferably one to three, still preferably one to two, heterogeneous atoms independently selected from nitrogen, oxygen and sulfur. Examples include pyrrolidinyl and piperidinyl. When R3 is a 2,7-diazaspiro [3.5] nonane group, it is preferably linked to the pyrimidine ring through a nitrogen atom, particularly through the nitrogen atom at position 7. When the 2,7-diazaspiro group [3.5] nonane carries a substituent, this can be on any available carbon or nitrogen atom, for example, on any nitrogen atom that is not attached to the pyrimidine ring. A particular 2,7-diazaspiro [3.5] nona substituted group can be, for example, 2- (tert-butoxycarbonyl) -2,7-diazaspiro [3.5] nonane. When R4 and R5, or R6 and R7, or R8 and R9, or R10 and R11, or R12 and R13, or R14 and R15 form a saturated heterocyclic ring, the only heterogeneous atom present is the nitrogen atom to which R4 and R5 , or R6 and R7, or R8 and R9, or R0 and R1, or R12 and R13, or R14 or R15 are joined. The saturated heterocyclic ring is preferably a 4 to 7 membered ring, which includes the nitrogen atom to which R4 and R5, or R6 and R7, or R8 and R9, or R10 and R11, or R12 and R13, or R14 or R15 are united.

R1 is conveniently a cycloalkyl group of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms optionally substituted (such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl), but preferably is an alkyl group of 1 to 6 carbon atoms optionally substituted ( particularly an alkyl group of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, tert-butyl) or a cycloalkyl group of 3 to 8 optionally substituted carbon atoms (particularly a cycloalkyl group of 3 to 6 atoms carbon, such cyclopropyl, cyclopentyl, cyclohexyl). In particular, R 1 is an alkyl group of 1 to 6 carbon atoms unsubstituted (preferably 1 to 4 carbon atoms) or an unsubstituted cycloalkyl group of 3 to 8 carbon atoms (preferably 3 to 6 carbon atoms) carbon). In one embodiment of the invention, R 1 represents an alkyl group of 1 4 carbon atoms, especially methyl, ethyl or tertbutyl, more especially methyl or tert-butyl, even more especially methyl. In another embodiment, R1 represents a cycloalkyl group of 3 to 6 carbon atoms, especially cyclopropyl. R 2 can be hydrogen or trifluoromethyl, but is preferably halogen (such as fluorine, chlorine, bromine or iodine). In a preferred embodiment, R2 represents chlorine or fluorine (particularly chlorine). In another preferred embodiment, R2 is hydrogen. In one embodiment, R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms , cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 3 to 8 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, d i- [al least 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms , cycloalkyl of 3 to 8 carbon atoms - alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, d - [alkyl of 1 to 6 carbon atoms carbon] carbamoyl, -C (O) R3b, -OR3b, -NHR3, -N [C1 to 6 carbon atoms] R3, -S (O) mR3a or -N (R3c) C (O) R3a, in Don of R3a represents an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms, m is 0, 1 or 2, R3b represents a saturated monocyclic 4, 5 or 6 membered heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and R3c represents hydrogen or alkyl of 1 to 6 carbon atoms, or R3 represents a saturated monocyclic 5 to 6 membered heterocyclic ring comprising at least one heterogeneous atom of ring selected from nitrogen, oxygen and sulfur, or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 2,7-diazaspiro group [ 3.5] nonane. Each of these groups or rings within R3 may optionally be substituted by one or more (for example one or two, particularly one) substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, C 1 -C 6 alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1 -C 6 -alkoxy, halogen, hydroxyl, trifluoromethyl, tri- [C 1-6 alkyl] carbon atoms] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, amino-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 atoms carbon-alkyl of 1 to 6 carbon atoms, d i- [1 to 6 carbon atoms] amino-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, d - [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms no, alkylsulfonyl of A to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c) C (O) R3a wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents may optionally be substituted by one or more ( for example one or two, particularly one) alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano.

Any saturated monocyclic ring within R3 optionally carries 1 or 2 oxo or thioxo substituents. In another embodiment, R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms , C 3 -C 8 -cycloalkyl-C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, d - [alkyl of 1 to 6 carbon atoms] carbamoyl , -C (O) R3b, -OR3b, -NHR3b, -N [alkyl of 1 to 6 carbon atoms] R3b, -S (O) mR3a or -N (R3c) C (O) R3a, wherein R 3a represents an alkyl group of 1 to 6 carbon atoms, m is 0 and R3 represents a saturated monocyclic 4, 5 or 6 membered heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 5-6 membered saturated monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen and oxygen, or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected of nitrogen and oxygen, or R3 represents a 2,7-diazaspiro [3.5] nonane group. Each of these groups or rings within R3 may optionally be substituted by one or more (for example one or two, particularly one) substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkoxy, halogen, hydroxyl, trifluoromethyl, tri- [ 1 to 4 carbon atoms] silyl, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, amino-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, aicythedon of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c) C (O) R 3a wherein R 3a represents an alkyl group of 1 to 6 carbon atoms or alkoxy of 1 to 6 atoms carbon, and R3c represents hydrogen or alkyl of 1 to 6 carbon atoms, or a saturated monocyclic ring of 3, 4, 5 or 6 members, said ring optionally comprising one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents can optionally be substituted by one or more (for example one or two, particularly one) alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano. Any saturated monocyclic ring within R3 optionally carries 1 or 2 oxo substituents. In another embodiment, R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms , - amino, alkylamino of 1 to 3 carbon atoms, d - [alkyl of 1 to 3 carbon atoms] amino, cycloalkylamino of 3 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 3 carbon atoms, [C1-C3 alkyl] carbamoyl, -C (O) R3b, -OR3b, -NHR3b or -S (O) mR3a, wherein R3a represents an alkyl group of 1 to 3 carbon atoms, m is 0 and R3 represents a saturated 4, 5 or 6 membered monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 5-6 membered saturated monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen and oxygen, or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen and oxygen. Each of these groups or rings within R3 may optionally be substituted by one or more substituents as defined above, in particular by one or more (for example one or two, particularly one) substituents independently selected from alkyl of 1 to 3 carbon atoms. carbon, alkoxy of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms - alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms - alkoxy of 1 to 3 carbon atoms, halogen, hydroxyl , trifluoromethyl, amino, alkylamino of 1 to 3 carbon atoms, di- [alkyl of 1 to 3 carbon atoms] amino, amino-alkyl of 1 to 3 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 3 carbon atoms carbon, alkylthio of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, alkanoyl of 1 to 3 carbon atoms, an alkanoyloamino group - N (R3c) C (O) R3a, wherein R3a represents an alkyl group of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms, and R3c represents h idrogen or alkyl of 1 to 3 carbon atoms, or a saturated monocyclic ring of 3, 4, 5 or 6 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents may be optionally substituted by one or more (for example one or two, particularly one) alkyl groups of 1 to 2 carbon atoms, hydroxyl or cyano. Any saturated monocyclic ring within R3 optionally carries 1 oxo substituent. In another embodiment, R3 represents hydrogen or an alkyl group of 1 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, or R3 represents a saturated monocyclic heterocyclic ring of 5 to 6 members comprising at least one heterogeneous ring atom selected from nitrogen and oxygen. Each of these groups or rings within R3 may optionally be substituted by one or more (for example one or two, particularly one) substituents as defined above, in particular by one or more substituents independently selected from hydroxyl and alkoxy from 1 to 3 carbon atoms. Suitable values for R3 include, for example, hydrogen, hydroxyl, chloro, fluoro or iodo, or a methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, tert-butoxy, cyclopropyl, cyclobutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, cyclobutyloamino, cyclohexylamino, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylocarbamoyl, N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, azetidinylcarbonyl, methylthio, ethylthio, piperidinylamino, tetrahydropyranylamino, tetrahydropyranyloxy, pyrroiid inyl, morpholinyl, piperazinyl, oxadiazolyl or 2,7-diazaspiro [3.5] nonan-7-yl. Each of these groups or rings may be optionally substituted by one or more (for example one or two, particularly one) substituents as defined above. In particular, suitable values for R3 include, for example, hydrogen, hydroxyl, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl. , hydroxymethyl, methoxymethyl, ethoxymethyl, (2-methoxyethoxy) methyl, aminomethyl, methylaminomethyl, ethylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methiipiperazin-1-ylmethyl, pyrrolidin-1-ylmethyl, 2-hydroxyethyl, 2- methoxyethyl, 2-ethoxyethyl, 2- (ethoxycarbonyl) ethyl, 2- (N-methylcarbamoyl) ethyl, 3-hydroxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-aminoprop-1-yl, 3-N, N-dimethylaminopropyl, 3- (tert-butoxycarbonylamino) prop-1-yl, 3-pyrrolidin-1-ylpropyl, ethenyl, propenyl, butenyl, pentenyl, 3-hydroxyprop-1 -in-1-yl, 3-aminoprop-1-en-1-yl, 2- (methoxycarbonyl) ethen-1-yl, 3- (tert-butoxycarbonylamino) prop-1-en-1-yl, ethynyl , propynyl, butynyl, pentynyl, 3-hydroxyprop-1-yn-1-yl, 3-methoxyprop-1-yn-1-yl, 2- (trimethylsilyl) ethynyl, 3-aminopropyl-1-yl 1-yl, 3-methylaminoprop-1-yn-1-yl, 3- (d -methylamino) prop-1-yn-1-yl, 3- (N-methylacetamido) prop-1-yn-1-yl! 3-Acetamidoprop-1-yn-1-yl, methoxy, ethoxy, propoxy, butoxy, pentoxy, (5-oxopyrrolidin-2-yl) methoxy, tetrahydrofuran-3-ylmethoxy, 2-hydroxyethoxy, 2-ethoxyethoxy, 2- (2-hydroxyethoxy) ethoxy, 2-methoxyethoxy, (2-methoxyethoxy) ethoxy, 2-. { N- [2-hydroxyethyl] -N-methyl-amino} ethoxy, 2-morpholinoethoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy, 2- (imidazolid-2-on-1-yl) ethoxy, 3-hydroxypropyloxy, 2-hydroxyprop-1-yloxy, 3- methoxyprop-1-yloxy, 2-methoxyprop-1-yloxy, 3-morpholinoprop-1-yloxy, 3- (methylthio) prop-1-yloxy, 3- (methylsulfonyl) propyl-1-oxy, methoxycarbonyl, ter- butoxycarbonyl, N- (tert-butoxycarbonyl) amine, methylamino, 2-methoxyethylamino, 2-aminoethylamino, 2- (dimethylamine) ethylammon, (N-2-methoxyethyl) -N-methylamino, 3-isopropoxypropyl- 1-ylamino, 2- (2-hydroxyethoxy) ethylamino, 2- (acetoamido) ethylamino, 2- (morpholin-4-yl) ethylamino, 2-methylprop-1-ylamino, 2-hydroxyprop-1-ylamino, 3-methoxypropylamino , 3-ethoxypropylamino, 2-isopropoxyethylamino, tetrahydrofuran-2-ylmethylamino, dimethylamino, N- (2-hydroxyethyl) -N-ethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, 4-methylcyclohexylamino, 4-hydroxycycloheyoxylamino, carbamoyl, N-hydroxycarbamoyl, N -cyclopropyl carbamoyl, N-cyclopentylcarbamoyl, N-aminocarbamoyl, N- (acetylamino) carbamoyl, N-methylcarbamoyl, 2-hydroxyethylcarbamoyl, N- (2-hydroxypropyl) carbamoyl, N- (2,3-dihydroxypropyl) carbamoyl, N- (4-hydroxybutyl) carbamoyl, N- (2-methoxyethyl) carbamoyl, N- (2- (acetylamino) ethyl) carbamoyl, N- [2- (2-hydroxyethoxy) ethyl] carbamoyl, N- (carbamoylmethyl) carbamoyl, N- [2- (methylthio) ethyl] carbamoyl, N- (2-methoxyethyl) -N-methylcarbamoyl, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, azetidin-1-ylcarbonyl, (3-hydroxypyrrolidin-1-yl) carbonyl, methylthio, ethylthio, propylthio , 2,2,6,6-tetramethylpiperidin-4-ylamino, 4-tetrahydropyranylamino, tetrahydropyran-4-yloxy, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-methyl-piperazin-1-yl , 4-ethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl, 4- (3-hydroxypropyl) piperazin-1-yl, 4- (2-methoxyethyl) piperazin-1-yl, 4- (2-aminoethyl) piperazin-1-yl, 4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl, 4- (2-cyanoethyl) piperazin-1 -lo, 4- (tert-butoxycarbonyl) piperazin-1-yl, 1-ph rimethyl-piperazin-4-yl, 4-acetylpiperazin-1-yl, 4- (ethylsulfonyl) -piperazin-1-yl, 4-aminopiperidin-1-yl, 4- (N-tert-butoxycarbonylamino) piperidin-1 -ilo. 3-hydroxypyridinidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, cis-3,4-dihydroxypyrrolidin-1-yl, 5-methyl- [1,4] -oxadiazole -2-yl, 2,7-diazaspiro [3.5] nonan-7-yl and (tert-butoxycarbonyl) -2,7-diazaspiro [3.5] nonan-7-yl. More particularly, suitable values for R3 include, for example, hydrogen, hydroxyl, chlorine, iodine, methyl, ethyl, propyl, cyclopropyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, (2-methoxyethoxy) methyl, aminomethyl, methylaminomethyl, morpholinomethyl, 4-methylpiperazin-1-ylmethyl, pyrrolidin-1-ylmethyl, 2-methoxyethyl, 2- (ethoxycarbonyl) ethyl, 2- (N-methylcarbamoyl) ethyl, 3- hydroxypropyl, 3-methoxypropyl, 3-aminoprop-1-yl, 3-NN-dimethylaminopropyl, 3- (tert-butoxycarbonylamino) prop-1-yl, 3-pyrrolidin-1-ylpropyl, ethenyl, pent-3-en-1 -yl, 3-hydroxyprop-1-en-1-yl, 3-aminoprop-1-en-1-yl, 2- (methoxycarbonyl) ethen-1-yl, 3- (tert-butoxycarbonylamino) prop-1-en -1-yl, ethynyl, 3-hydroxyprop-1-yn-1-yl, 3-methoxyprop-1-yn-1-yl, 2- (trimethylsilyl) ethynyl, 3-aminoprop-1-yn-1 -yl, 3-methylaminoprop-1-yn-1-yl, 3- (dimethylamino) prop-1-yn-1-yl, 3- (N-methylacetamido) prop-1-yn-1-yl, 3-acetamidopropyl -1-in-1-yl, methoxy, ethoxy, (5-oxopyrrolidin-2-yl) methoxy (for example (2S) - (5-oxopyrrolidin-2-yl) methoxy or (2R) - (5-oxopyrrolidin-2-yl) methoxy), tetrahydrofuran- 3-ylmethoxy, 2-hydroxyethoxy, 2-ethoxyethoxy, 2- (2-hydroxyethoxy) ethoxy, 2-methoxyethoxy, (2-methoxyethoxy) ethoxy, 2-. { N- [2-hydroxyethyl] -N-methyl-amino} ethoxy, 2-morpholinoethoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy, 2- (midazolid-2-on-1-yl) ethoxy, 3-hydroxypropyloxy, 2-hydroxyprop-1- Ioxy (for example (2R) -2-hydroxyprop-1-yloxy), 3-methoxyprop-1-yloxy, 2-methoxyprop-1-yloxy (for example (2S) -2-methoxyprop-1-yloxy ), 3-morpholinoprop-1-yloxy, 3- (meth ylthio) prop-1-yloxy, 3- (methylsulfonyl) propyl-1-oxy, methoxycarbonyl, N- (tert-butoxycarbonyl) amino, methylamino, -methoxyethylamino, 2-aminoethylamino, 2- (dimethylamino) ethylamino, (N-2-methoxyethyl) -N-methylamino, 3-isopropoxyprop-1-ylamino, 2- (2-hydroxyethoxy) ethylamino, 2- (acetoam) do) ethylamino, 2- (morpholin-4-yl) eti lamino, 2-methylprop-1-amino, 2-hydroxyprop-1-ylamino (for example (2) -2-hydroxyprop-1-yl amino or (2S ) -2-hydroxyprop-1-ylamino), 3-methoxypropylamino, 3-ethoxypropylamino, 2-isopropoxyethylamino, tetrahydrofuran-2-ylmethylamino (for example (2R) -tetrahydrofuran-2-ylmethylamino), dimethylamino, N- (2-hydroxyethyl) -N-ethylamino, cyclobutylamino, 4-methylcyclohexylamino , 4-hydroxycyclohexylamino, carbamoyl, N-hydroxycarbamoyl, N-cyclopropylcarbamoyl, N-cyclopentylcarbamoyl, N-aminocarbamoyl, N- (α-cedylamino) carbamoyl, N-methylcarbamoyl, 2-hydroxyethylcarbamoyl, N- (2-hydroxypropyl!) carbamoyl (for example N - ((R) -2-hydroxypropyl) carbamoyl), N- (2,3-dihydroxypropyl) carbamoyl (for example N - ((2R) -2,3-dihydroxypropyl) carbamoyl), N - (4-hydroxybutyl) carbamoyl, N- (2-methoxyethyl) carbamoyl, N- (2- (acetylamino) ethyl) carbamoyl, N- [2- (2-hydroxyethoxy) ethyl] carbamoyl, N- (carbamoylmethyl) carbamoyl, N- [2- (methylthio) ethyl] carbamoyl, N- (2-methoxyethyl) -N-methylcarbamoyl, pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, azetidin-1-ylcarbonyl, (3-h id roxy pyrrolidin- 1- il) carbonyl (for example (3R) -3-hydroxypyrrolidin-1-ylcarbonyl), met iltio, 2,2,6,6-tetramethylpiperidin-4-ylamino, 4-tetrahydropyranylamino, tetrahydropyran-4-yloxy, pyrrolidin-1-yl, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4- ethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl, 4- (3-hydroxypropyl) piperazin-1-yl, 4- (2- me toxi ethyl) piperazin-1-yl, 4- (2-am i noeti I) piperazin-kilo, 4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl, 4- (2-cyanoethyl) ) piperazin-1-yl, 4- (tert-butoxycarbonyl) piperazin-1-yl, 1- formyl-piperazin-4-yl, 4-acetylpiperazin-1-yl, 4- (ethylsulphonyl) piperazin-1-yl, -aminopiperidin-1-yle, 4- (N-tert-butoxycarbonylamino) piperidin-1-yl, 3-idroxypyrrolidin-1-yl (for example (3R) -3-hydroxypyrrolidin-1-yl), 3-dimethylamino- pyrrolidin-1-yl (for example (3R) -3-d-methylamino-pyrro! idin-1-yl), cis-3,4-dihydroxypyrrolidin-1-yl, 5-methyl- [1, 3,4] -oxadiazol-2-yl, 2,7-diazaspyrro [3.5] nonan-7-yl and (tert-butoxycarbonyl) -2,7-diazaspyrro [3.5] nonan-7-yl. More particularly, suitable values for R3 include, for example, hydrogen, chlorine, iodine, methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, (2-methoxyethoxy) methyl, morpholinomethyl, 3-hydroxypropyl, 3-methoxypropyl, 3- NN-dimethylaminopropyl, ethenyl, 3-hydroxyprop-1-en-1-yl, ethinyl, 3-hydroxyprop-1-yn-1-yl, 3-methoxyprop-1-n-1-yl, 3-aminoprop -1-in-1-yl, 3-methylaminoprop-1-yn-1-yl, 3- (dimethylamino) prop-1-yn-1-yl, 3- (N-methylacetamido) prop-1-in -1-yl, 3-acetamidoprop-1-yn-1-yl, methoxy, ethoxy, (5-oxopyrrolidin-2-yl) methoxy (for example (2S) - (5-oxopyrrolidin-2-yl) methox Or (2R) - (5-oxopyridinidin-2-yl) methoxy), tetrahydrofuran-3-iimethoxy, 2-hydroxyethoxy, 2-ethoxyethoxy, 2- (2-hydroxyethoxy) ethoxy, 2-methoxyethoxy, (2-methoxyethoxy) ) ethoxy, 2-. { N- [2-hydroxyethyl] -N-methyl-amino} ethoxy, 2-morpholinoethoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy, 2- (imidazolid-2-on-1-yl) ethoxy, 3-hydroxypropyloxy, 2-hydroxyprop-1-yloxy (per Example (2R) -2-hydroxyprop-1-yloxy), 3-methoxyprop-1-yloxy, 2-methoxyprop-1-yloxy (for example (2S) -2-methoxyprop-1-yloxy), 3- morpholinopropyl- 1-yloxy, 3- (methylthio) prop-1-yloxy, 3- (methylsulfonyl) propyl-1-oxy, methylamino, 2-methoxyethylamino, 2- (methoxyethyl) amino, 2- (2-hydroxyethoxy) ethylamino, 2- (morpholin-4-yl) ethylamino, 2-methylprop-1-ylamino, 2-hydroxyprop-1-ylamino (for example (2R) -2-hydroxyprop-1-ylamino or (2S) -2-hydroxypropyl -1-ylamino), 3-methoxypropylamino, 3-ethoxypropylamino, 2-isopropoxyethylamino, tetrahydrofuran-2-ylmethylamino (for example (2R) -tetrahydrofuran-2-ylmethylamino), dimethylamino, N- (2-hydroxyethyl) -N-ethylamino , cyclobutylamino, carbamoyl, N-cyclopropylcarbamoyl, N-methylcarbamoyl, 2-hydroxyethylcarbamoyl, N- (2-hydroxypropyl) carbamoyl (for example N - ((R) -2-hydroxypropyl) carbamoyl), N- (2-methoxyethyl) ) carbamoyl, N- [2- (methylthio) ethyl] ac rbamoyl, pyrrolidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, methylthio, 4-tetrahydropyranylamino, tetrahydropyran-4-yloxy, indolyl idrol, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl , 4-ethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4- (2-hydroxyethyl) -piperazin-1-yl4- (3-hydroxypropyl) -piperazin-1-yl, 4- (2-methoxyethyl) piperazin-1-yl, 4- (2-cyanoethyl) piperazin-1-yl, 4-acetylpiperazin-1- ilo, 4- (ethylsulphonyl) piperazin-1-yl, 3-hydroxypyrrolidin-1-yl (for example (3R) -3-hydroxypyrrolidin-1-yl), 3-dimethylamino-pyrrolidin-1-yl (for example ( 3R) -3-dimethylamino-pi rrol id in 1-yl) and 1-formyl-piperazin-4-yl. In one embodiment, R3 is conveniently selected from hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carbon, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, carbamoyl, -C ( O) R3b, -OR3, -SR3b, -NHR3b, - [(alkyl of 1 to 6 carbon atoms] R3b or -S (O) mR3a (wherein R3a and R3b are as defined above), or a heterocyclic ring 5 or 6 membered saturated monocyclic ring, said ring comprises at least one heterogeneous atom in the ring selected from nitrogen, oxygen and sulfur, each of these groups or rings may optionally be substituted by one or more (for example one or two, particularly one) substituents as defined above In another embodiment, R3 is conveniently selected hydrogen ion or a substituted or unsubstituted group selected from alkyl of 1 to 6 carbon atoms (preferably alkyl of 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, tert-butyl, cycloalkyl of 3 to 8 carbon atoms (preferably cycloalkyl of 3 to 6 carbon atoms), such as cyclopropyl, cyclopentyl, cyclohexyl, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms (preferably cycloalkyl of 3 to 6 atoms) carbon-alkyl of 1 to 4 carbon atoms) such as cyclopropylmethyl, alkoxy of 1 to 6 carbon atoms (preferably alkoxy of 1 to 4 carbon atoms), such as methoxy, ethoxy, propoxy, sopropoxy and butoxy, alkylcarbonyl of 1 to 6 carbon atoms such as methylcarbonyl, cycloalkylcarbonyl of 3 to 8 atoms such as cyclopropylcarbonyl, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms such as cyclopropylmethylcarbonyl, alkoxycarbonyl of 1 to 6 atoms carbon atoms, alkylamino of 1 to 6 carbon atoms such as methylamino or ethylamino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamido of 1 to 6 carbon atoms or -S (O) mR3a. Suitable substituents on R3 include one or more (eg, one, two or three, in particular one or two, more particularly one) substituents independently selected from alkoxy of 1 to 6 carbon atoms (such as methoxy or ethoxy), alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms (such as methoxyethoxy) or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members (for example, 4 to 7 members), said ring optionally it may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur (such as cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperazinyl). Particular substituents for the group R3, when substituted, include, for example, one or more (for example one or two, particularly one) substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms. carbon, halogen, hydroxyl, trifluoromethyl, amino, alkylamino of 1 to 6 carbon atoms and d [alky1 to 6 carbon atoms] amino, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members ( for example from 4 to 7 members), said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur. When R3 carries a substituent that is a saturated monocyclic ring of 3, 4, 5, 6 or 7 members (e.g., 4 to 7 members), said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, this ring preferably comprising nitrogen and, optionally, one or two additional heterogeneous atoms selected from nitrogen, oxygen and sulfur. For example, the saturated monocyclic substituent ring of 3, 4, 5, 6 or 7 members (for example 4 to 7 members) in R3 may comprise pyrrolidine. In one embodiment, R3 represents hydrogen. Preferably, -NQ1 represents a saturated five- or six-membered monocyclic ring containing a heterogeneous nitrogen atom and optionally at least one additional ring heterogeneous atom (eg, one, two, three or four heterogeneous ring atoms, which they can be the same or different) selected from nitrogen, oxygen and sulfur. In one embodiment, the 5 to 6 membered N-linked saturated monocyclic ring containing a heterogeneous nitrogen atom of -NQ1 optionally comprises one or two additional heterogeneous ring atoms (which may be the same or different) selected from nitrogen, oxygen and sulfur. In a further embodiment, -NQ1 represents a saturated five- or six-membered monocyclic ring containing a heterogeneous nitrogen atom.

In a particularly preferred embodiment, -NQ1 represents pyrrolidinyl or piperidinyl (most preferably pyrrolidinyl). The ring NQ1 can be substituted in any position that can be substituted in the ring through the ring Q2. Preferably, NQ1 is substituted by Q2 on a ring atom adjacent to the nitrogen atom which binds -NQ1 to the pyrimidine ring of the compounds of the invention. Q2 conveniently represents a heteroaromatic ring of to 6 members comprising at least one heterogeneous ring atom (eg, one, two, three or four heterogeneous ring atoms, which may be equal or different) selected from nitrogen, oxygen and sulfur and may be for example, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl. Preferably, Q2 represents a five or six membered heteroaromatic ring comprising one or two heterogeneous ring atoms, which may be the same or different, selected from nitrogen and oxygen, such as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl , tetrazoyl or isoxazolyl (particularly tetrazolyl or isoxazolyl). In a further embodiment, Q2 represents a five or six membered heteroaromatic ring comprising a heterogeneous ring of nitrogen and one oxygen atom. In a particularly preferred embodiment, Q2 represents an isoxazolyl ring. In another embodiment, Q2 represents a five or six membered heteroaromatic ring comprising from one to four heterogeneous nitrogen ring atoms, for example, Q2 may represent pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl. . Q2 can conveniently be linked to ring NQ1 through any available ring atom, for example it can be linked through a carbon atom or ring nitrogen. Where Q2 comprises at least one heterogeneous ring atom then preferably Q2 is linked to ring NQ1 through a ring carbon atom adjacent to a heterogeneous atom. In addition to being substituted by Q3, Q2 is optionally substituted by at least one substituent (eg, one, two, three or four substituents, which may be the same or different) independently selected from alkyl of 1 to 6 carbon atoms, particular alkyl of 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), alkoxy of 1 to 6 carbon atoms, in particular C 1 -C 4 alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy), (each of the alkyl substituent groups of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms being optionally substituted by at least one substituent, for example one, two, three or four substituents, independently selected from halogen (such as fluorine, chlorine, bromine or iodine), amino, hydroxyl and trifluoromethyl), halogen (such as fluorine, chlorine, bromine or iodine), nitro, c ianp, -NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, particularly alkenyl of 2 to 4 carbon atoms (such as ethenyl), cycloalkyl of 3 to 8 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl) and cyclohexyl), cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms (such as cyclopropylmethyl), alkoxycarbonyl of 1 to 4 carbon atoms, particularly alkoxycarbonyl of 1 to 3 carbon atoms (such as methoxycarbonyl or ethoxycarbonyl), alkylcarbonyl of 1 to 4 carbon atoms, particularly alkylcarbonyl of 1 to 3 carbon atoms (such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl or n-butylcarbonyl), alkylcarbonylamino of 1 to 4 carbon atoms, particularly alkylcarbonylamino from 1 to 3 carbon atoms (such as methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl, -S (O) p-alkyl of 1 to 4 carbon atoms, particularly of 1 to 2 carbon atoms (such as methylthio, ethylthio, methylsulfinyl, eti Isuif in i lo, mesyl and ethylsulfonyl), -C ( O) NR6R7 and -SO2NR8R9 (wherein p, R6, R7, R8 and R9 are as defined above). R4, R5, R6, R7, R8, and R9 each conveniently independently can represent hydrogen or alkyl of 1 to 6 carbon atoms, preferably alkyl of 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl , or conveniently R4 and R5, or R6 and R7, or R8 and R9, when taken together with the nitrogen atom to which they are attached, independently each can form a saturated heterocyclic ring such as pyrrolidinyl or piperidinyl. In one embodiment, Q2 is optionally substituted by at least one substituent independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen and cycloalkyl of 3 to 8 carbon atoms. Q3 is conveniently a substituted or unsubstituted alkyl of 1 to 6 carbon atoms (preferably alkyl of 1 to 4 carbon atoms) such as methyl, ethyl, propyl or butyl, a cycloalkyl group of 3 to 8 carbon atoms (preferably cycloalkyl of 3 to 6 carbon atoms) such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a cycloalkyl group of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms such as cyclopropylmethyl or a saturated or unsaturated monocyclic ring of 5 to 6 carbon atoms. to 6 members optionally comprising at least one heterogeneous ring atom (eg, one, two, three or four heterogeneous atoms) selected from nitrogen, oxygen and sulfur such as phenyl, pyridyl, midazole, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, triazolyl, tetrahydrofuranyl or thienyl (particularly pyridyl, pyrazinyl, thiazolyl, tetrahydrofuranyl or pyrimidinyl) ). In one embodiment, Q3 represents a substituted or unsubstituted group selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or a substituted or unsubstituted, saturated or unsaturated monocyclic ring of 5 to 6 members comprising optionally at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur. For example, Q3 may represent a substituted or unsubstituted group selected from methyl, cyclopropyl, pyridyl, pyrazinyl, thiazolyl, tetrahydrofuranyl or pyrimidinyl. In a further embodiment, Q3 is preferably a substituted or unsubstituted group selected from alkyl of 1 to 4 carbon atoms (especially methyl), cycloalkyl of 3 to 6 carbon atoms (especially cyclopropyl) or an optionally unsaturated monocyclic ring of 5 to 6 members comprising one or two heterogeneous ring atoms, which may be the same or different, selected from nitrogen, oxygen and sulfur, such as imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl (especially pyrazin-2-yl), pyridazinyl , pyrimidinyl (especially pyrimidin-2-yl), pyrrolyl, oxazolyl, siathiazolyl, triazolyl, tetrahydrofuranyl or thienyl, especially pyridyl (preferably pipd-2-yio or pyrid-3-yl) or thiazolyl (especially thiazole-2-) ilo or thiazol-4-ylo) or tetrahydrofuranyl (especially tetrahydrofuran-3-yl). The optional substituents suitable for Q3 are one or more (e.g., one, two, three or four) substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by at least one substituent (e.g. , one, two, three or four substituents) independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 atoms carbon, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, -S (O) n alkyl of 1 to 6 carbon atoms, -C ( O) NR12R13, and -SO2NR14R15 (where n, R10, R11, R12, R13, R14 and R15 are as defined above). Conveniently, R 10, R 11, R 12, R 13, R 14 and R 15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms such as methyl, or R 10 and R 11, or R 12 and R 13, or R 14 and R 15, when taken together with the nitrogen atom to which they are attached, each may conveniently form a saturated heterocyclic ring such as pyrroiidinyl or piperidinyl. It will be appreciated that the number and nature of the substituents on the rings in the. Compounds of the invention will be selected in order to avoid spherically undesirable combinations. In a preferred group of compounds of the formula (I) according to the invention, R 1 represents an alkyl group of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R2 represents halogen; R3 represents hydrogen; -NQ1 represents a saturated 5 or 6 membered monocyclic ring containing a heterogeneous nitrogen atom and optionally at least one additional ring heterogeneous atom selected from nitrogen, oxygen and sulfur; Q2 represents a substituted 5 or 6 membered heteroaromatic ring comprising one or two heterogeneous ring atoms, which may be equal or different, selected from nitrogen and oxygen; and Q3 represents an alkyl group of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms or an optionally unsaturated monocyclic ring of 5 to 6 members comprising one or two heterogeneous ring atoms, which may be the same or different, selected from nitrogen, oxygen and sulfur. Particularly preferred compounds within this group are those wherein -NQ1 represents pyrrolidinyl or piperidinyl (particularly pyrrolidinyl); Q2 represents soxazolyl or tetrazolyl (particularly, soxazolyl); and Q3 represents methyl, cyclopropyl, tetrahydrofuranyl, pyrazinyl, thiazolyl, pyrimidinyl or pyridyl. Other particularly preferred compounds within this group are those wherein -NQ1 represents pyrrolidinyl or piperidinyl; Q2 represents isoxazolyl or tetrazolyl; and Q3 represents methyl, cyclopropyl, thiazolyl, tetrahydrofuranyl or pyridyl. Other particularly preferred compounds within this group are those wherein -NQ1 represents pyrrolidinyl or piperidinyl; Q2 represents isoxazolyl; and Q3 represents methyl, cyclopropyl, thiazolyl or pyridyl. Other particularly preferred compounds within this group are those wherein -NQ1 represents pyrrolidinyl; Q2 represents soxazolyl; and Q3 represents cyclopropyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridyl. The values suitable for the group of the sub-formula (i) (which is attached to the 2-position of the pyrimidine ring of the formula (I)): (i) include, for example, 2- [3- (pyrid-2-yl) isoxazol-5-ii] pyrrolidin-1-yl, 2- (3-methylisoxazol-5-yl] pyrrolidin-1-yl, 3-cyclopropylisoxazole- 5- l] pyrrolidin-1-yl, 2- [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-yl, 2- [3- (thiazol-4-yl) isoxazole-5 -ii] pyrrolidin-1-yl, 2- [3- (pyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl, 2- (3- (pyrid-2-yl) isoxazole-5- I) piperidin-1-yl, 2- (3 { Tetrahydrofuran-3-yl}. Isoxazol-5-yl] pyrrolidin-1-yl, 2- [3- (2 ~ methoxypipd-3-yl) isoxa-ol-5-yl] pyrrolidin-1-yl, 2- (2-methyl-2H-tetrazol-5-yl) pyrrolidin-1-yl, 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl, 2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-i, 2-. { 3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl and 2-. { 3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl (wherein, to avoid any doubt, it is the pyrrolidin-1-yl or piperidin-1-yl group which is attached to the 2-position of the pyrimidine ring of the Formula (I)). In particular, suitable values for the group of sub-formula (i) above include, for example, 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl, 3-cyclopropylisoxazole -5-isoxazol-5-yl] pyrrolidin-1-yl, 2- [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-Mo, 2- [3- ( thiazol-4-yl) isoxazol-5-ii] pyrrolidin-1-yl, 2- [3- (pyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl, 2- (3-. tetrahydrofuran-3-yl.}. isoxazol-5-yl] pyrrolidin-1-yl, 2- [3- (2-methoxypyrid-3-yl) is oxazol-5-yl] pyrrol id i n-1 - ilo, 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl, 2-. {3- (pyridin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl, 2-. {3- (3-methoxypyrazn-2-yl) isoxazol-5-yl} pyrrolidin-1-yl and 2-. {3- (3 -hydroxypyrazin-2-yl) -soxazol-5-yl}. pyrrolidn-1-yl One particular embodiment of the present invention is a compound of the formula (la): (la) or a pharmaceutically acceptable salt thereof, wherein: R1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms- alkyl of 1 to 6 carbon atoms, each of these groups can optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms, R 2 represents hydrogen, halogen or trifluoromethyl; R 3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 8 atoms carbon, cycloalk ilo of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamido of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di - [C 1-6 alkyl] carbamoyl, -C (0) R 3b, -OR 3b, -SR 3b, -NHR 3b, -N [C 1-6 alkyl] R 3b, -S (O) mR 3a or -N (R3c) C (0) R3a, wherein R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 atoms of carbon or alkoxy of 1 to 6 carbon atoms, m is 0, 1 or 2, R3b represents a saturated monocyclic 4, 5 or 6 membered heterocyclic ring, comprising at least one heterogeneous ring atom selected of nitrogen, oxygen and sulfur and R3c represents hydrogen or alkyl of 1 to 6 carbon atoms, or R3 represents a saturated monocyclic 5 to 6 membered heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur; or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur; or R3 represents a 2,7-diazaspiro [3.5] nonane group, each of these groups or rings within R3 can optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, tri- [ alkyl of 1 to 4 carbon atoms] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 6 carbon atoms, cycloalkylamino of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms of alkylamino 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-cycloalkylamino of 1 to 3 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylarybamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c ) C (0) R3a, wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents may optionally be substituted by one or more alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (0) palquilo of 1 to 4 át carbon atoms, -C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5, or R6 and R7, or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano. ~ NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms alkylcarbonylamino of 1 to 6 carbon atoms , phenylcarbonyl, -S (0) n-alkyl of 1 to 6 carbon atoms, wherein R 10, R 11, R 12, R 13, R 14 and R 15 each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R10 and R11, or R12 and R13, or R14 and R15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and n is O, 1 or 2; and wherein any saturated monocyclic ring optionally carries 1 or 2 oxo or thioxo substituents. According to another embodiment of the present invention, there is provided a compound of the formula (Ia), or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups optionally can be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 atoms of carbon; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl from 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl] from 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms- alkylamino of 1 to 6 carbon atoms, alkoxyamido of 1 to 6 carbon atoms, carbamoyl, alkanoylamino of 2 to 6 carbon atoms, -C (O) R3, -OR3, -SR3b, -NHR3b, -N [(alkyl from 1 to 6 ato carbon atoms] R3 or -S (0) mR3a, wherein R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms, m is 0, 1 or 2, and R3 represents a saturated monocyclic ring of 5 to 6 members containing one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, or R3 represents a 5-6 membered saturated monocyclic heterocyclic ring, said ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur; each of these groups or rings within R3 may optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, di- [ alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl from 1 to 6 carbon atoms, di- [C 1-6 alkylcarbamoyl, alkylthio having 1 to 6 carbon atoms, alkylsulfonyl having 1 to 6 carbon atoms, alkylsulfinyl having 1 to 6 carbon atoms, alkanoylamino having 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, or a saturated monocyclic ring of 4, 5, 6 or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro , cyano, -NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (0) palquil of 1 to 4 carbon atoms carbon, -C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, R4 and R5, or R6 and R7, or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring, and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phen < RTI ID = 0.0 > ilcarbonyl < / RTI >1 to 6 carbon atoms, or R10 and R1, or R12 and R13, or R14 and R15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring, and n is 0, 1 or 2.

In this embodiment, Q2 particularly represents a 5-6 membered heterocyclic ring, comprising at least one ring nitrogen and, optionally, at least one additional ring heterogeneous atom selected from nitrogen, oxygen and sulfur. More particularly, Q2 represents a 5-6 membered heteroaromatic ring comprising at least one ring nitrogen and, optionally, at least one additional ring heterogeneous atom selected from nitrogen and oxygen. For example, Q2 may represent isoxazolyl (particularly isoxazol-5-yl) or tetrazolyl (particularly tetrazol-5-yl). In particular, Q2 is isoxazolyl (for example isoxazol-5-yl). Ring Q2 is substituted by Q3 as defined above and, optionally, is further substituted, at any available ring atom, by one or more additional substituents as defined above. Another particular embodiment of the present invention is a compound of the formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups may optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms , cycloalkylcarbonyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] bamoyl, -C (0) R3b, -OR3b, -SR3, -NHR3b, -N [alkyl of 1 to 6 carbon atoms] R3b, -S (0) mR3a or -N (R3c) C (0) R3a, wherein R 3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms , m is 0, 1 or 2, R3b represents a saturated 4, 5 or 6 membered monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur and R3 represents hydrogen or alkyl of 1 to 6 carbon atoms, or R3 represents a 5-6 membered saturated monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a group 2 , 7-diazaspiro [3.5] nonane, each of these ring groups within R3 can optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, tri - [(a l or 1 to 4 carbon atoms] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, di - [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, d i- [alkyl of 1 to 6 carbon atoms] aminoalkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N ( R3c) C (0) R3a wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents may be optionally substituted by one or more alkyl groups of 1 to 4 carbon atoms, hydroxy or cyano; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen nitro, cyano -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, feni lcarbonyl, S (0) nalkyl of 1 to 6 carbon atoms, -C (0) NR12R13 and -S02NR1 R15., wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R 10 and R 11, or R 12 and R 13, or R 14 and R 15, when taken together with the nitrogen atom to which they are attached, independently each forms a saturated heterocyclic ring, and n is 0, or 2; and wherein any saturated monocyclic ring optionally carries 1 or 2 oxo or thioxo substituents. According to another embodiment of the present invention, there is provided a compound of the formula (Ib), or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups can optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 atoms of carbon; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon-alkylcarbonyl atoms of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, d i- [alkole of 1 to 6 carbon atoms] amino , cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkanoylamino of 2 to 6 carbon atoms, -C (0) R3b, -OR3b, -SR3b, -NHR3b, -N [alkyl of 1 to 6 carbon atoms] R3b, or -S (0) mR3a, wherein R3a represents a g alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, n is 0, 1 or 2, and R3b represents a saturated 5- to 6-membered monocyclic ring containing one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur; or R3 represents a saturated 5- to 6-membered monocyclic heterocyclic ring, said ring comprises at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, each of these groups or rings within R3 may optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, cyano, amino , alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 atoms carbon, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms alkylsulfonyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, or a saturated monocyclic ring of 4, 5, 6 or 7 members, said ring optionally comprising one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms carbon, phenylcarbonyl, -S (0) nalkyl of 1 to 6 carbon atoms, -C (0) NR12R13 and -SO2NR14R15, wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10 and R11, or R12 and R13, or R14 and R15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring, and n is 0.1. or 2. In this embodiment, Q3 is particularly selected from an alkyl group of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur , and wherein Q3 is optionally substituted by one or more substituents as defined above. A particular embodiment of the present invention is a compound of the formula: (le): (the) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups may optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 at 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms , cycloalkylcarbonyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, d i - [C1 to C6 alkoxy] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms , carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, -C (Q) R 3, -OR 3b, -SR 3b, -NHR 3b, -N [alkyl of 1 to 6 carbon atoms] R 3b, -S (O) mR > 3a N (R3c) C (O) R3a, wherein R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms carbon, or alkoxy of 1 to 6 carbon atoms, n is 0, 1 or 2, R3b represents a saturated monocyclic 4, 5 or 6 membered heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and R3c represents hydrogen or alkyl of 1 to 6 carbon atoms, or R3 represents a 5- to 6-membered heterocyclic saturated monocyclic ring, comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 2,7-diazaspiro [3,5] nonane group, each of these groups or rings Within R3 it can be optional is substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, tri- [to C 1 to 4 carbon atoms] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, aminoalkyl of 1 to 6 carbon atoms, C 1-6 alkylamino-C 1-6 -alkyl, dl- [C 1-6 -alkyl] aminoalkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms-C 1 -C 6 -alkyl 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c) C (0) R3a, wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen sulfur, any of these substituents may be optionally substituted by one or more alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano; -Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or further additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano -NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkoxycarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (0) palquil of 1 to 4 atoms of carbon, -C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated 5 to 6 membered monocyclic ring or unsaturated, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR 10 R 11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, ilcarbonyl, -S (0) nalkyl of 1 to 6 carbon atoms, -C (0) NR12R13 and -S02NR14R15, wherein R10, R11, R12, R13, R4 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R 10, R 11, R 12, R 13, R 14 and R 15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and n is 0, 1 or 2; and wherein any saturated monocyclic ring optionally carries 1 or 2 oxo or thioxo substituents. According to a further aspect of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups optionally can be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 atoms of carbon; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkyl carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino from 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkanoylamino of 2 to 6 carbon atoms, -C (0 R3, -0R3b, -SR3b, NHR3b, -N [alkyl of 1 to 6 carbon atoms] R3 or -S (0) mR3a wherein R3a represents a group at 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 6 carbon atoms or alkoxy of 1 to 6 carbon atoms is 0, 1 or 2, and R3b represents a saturated 5 to 6 membered monocyclic ring containing one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, or R3 represents a saturated 5-6 membered heterocyclic monocyclic ring, this ring comprises at least one heterogeneous atoms of selected ring of nitrogen, oxygen and sulfur, each of these groups or rings within R3 may optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, cyano, amino, alkylamino of 1 to 6 atoms carbon, di- [alkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms , carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, d i- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio or of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl alkanoylamino of 1 to 6 carbon atoms, or a saturated monocyclic ring of 4 to 7 members, said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, Q2 represents a heteroaromatic ring from 5 to 6 members comprising by at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR4R5, carboxyl, hydroxyl, alkenyl 2; to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms , alkylcarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (0) palquil of 1 to 4 carbon atoms, -C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each one independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl from 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl , -S (0) nalkyl of 1 to 6 carbon atoms, -C (0) NR12R13 and -S02NR 4R15, wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R 10, R 11, R 12, R 13, R 14 and R 15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring, and n is 0, 1 or 2. In this embodiment, Q2 particularly represents a 5-6 membered heteroaromatic ring, comprising at least one ring nitrogen and, optionally, at least one additional ring heterogeneous atom selected from nitrogen, oxygen and sulfur. More particularly, Q2 represents a 5-6 membered heteroaromatic ring comprising at least one ring nitrogen and, optionally, at least one additional ring heterogeneous atom selected from nitrogen and oxygen. For example, Q2 may represent isoxazolyl (particularly, soxazol-5-ylo).

Ring Q2 is substituted by Q3 and, optionally, is further substituted, at any available ring atom, by one or more additional substituents as defined above. Another particular embodiment of the present invention is a compound of formula (Id): (Id) or a pharmaceutically acceptable salt thereof, wherein: R1 represents trifiuoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 alkyl atoms of 1 to 6 carbon atoms carbon, each of these groups may be optionally substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 at 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkyrocarbonyl of 1 to 6 carbon atoms , cycloalkylcarbonyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylalkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, [C 1-6 alkyl] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] rbamoyl, -C (0) R3b, -OR3b, -SR3b, -NHR3b, -N [(alkyl of 1 to 6 carbon atoms] R3b, -S (0) mR3a or -N (R3o) C (0) R3a wherein R 3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms , m is 0, 1 or 2, R3b represents a saturated, monocyclic 4, 5 or 6 membered heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur and R3C represents hydrogen or alkyl of 1 to 6 carbon atoms, or R3 represents a 5-6 membered saturated monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a saturated monocyclic heterocyclic ring to 6 members comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 2,7-diazopyrol [3,5] nonane group, each of these groups or rings within R3 optionally may be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, tri - [(alkyl of 1 to 4 carbon atoms) silyl, cyano, amino, alkylamine to 6 carbon atoms, d, - [alkyl] from 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, di- (1 to 6 alkoxy) carbon atoms] aminoalkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms-alkyl from 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [C 1-6 alkylcarbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoyl amino-N (R3c) C (0) R3a group wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents may optionally be substituted by one or more alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, -S ( 0) n alkyl of 1 to 6 carbon atoms, -C (0) NR12R13 and -S02NR14R15, wherein R10 and R11, R12, R13, R14 and R15, each independently represents hydrogen or alkyl of 1 to 6 carbon atoms , or R10 and R11, or R12 and R13 or R14 and R15, when taken together with the nitrogen atom to which they are attached, independently each can form a saturated heterocyclic ring and n is 0, 1 or 2; and wherein any saturated monocyclic ring optionally carries 1 or 2 oxo or thioxo substituents. According to another embodiment of the present invention, there is provided a compound of the formula (Id), or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups can optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 atoms of carbon; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms - alkoxycarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamyl of 1 to 6 carbon atoms, di - [(alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkylamyl of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkanoylamino of 2 to 6 carbon atoms, -C (0) R3b, -0R3, -SR3b, -NHR3b, -N [(alkyl of 1 to 6 carbon atoms] R3 or -S (0) mR3a, wherein R3a represents a group alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms, m is 0, 1 or 2 and R3b represents a saturated 5 to 6 membered monocyclic ring containing one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur: or R3 represents a saturated 5- or 6-membered heterocyclic ring, which may comprise at least a heterogeneous ring atom selected from nitrogen, oxygen and sulfur; each of these groups or rings within R3 may optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy from 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, d i - [(alkyl of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 atoms of carbon, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, d - [(at 1 to 1 in to 6 carbonscarbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoylamino of 1 to 6 carbon atoms or a monocyclic saturated ring of 4 to 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano, -NR10R11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms. carbon, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, feni lcarbonyl, -S (Q) n alkyl of 1 to 6 carbon atoms, -C (O) NR? 2R13 and -SO2NR14R15, wherein R10 and R11, R 2, R13, R14 and R15, each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R10 and R11, or R12 and R13 or R14 and R15, when taken together with the nitrogen atom to which they are attached, independently each can form a saturated heterocyclic ring and n is 0, 1 or 2. In this embodiment, Q3 is particularly selected from an alkyl group of 1 to 6 atoms carbon or cycloalkyl of 3 to 6 carbon atoms or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents as defined herein above. Particular compounds of the invention include, for example, any one or more of the compounds of the formula (I), selected from: 5-Chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pipmindine; 5-Chloro-2- [2- (3-methyl-oxazol-5-yl] pyrrolidin-1-yl] -4- (5-tert-butyl-1H-pyrazol-3-ylamino) pyrimidine; -Cloro-2- [2- (3-methylisoxazol-5-yl] pyrrolidin-1-yl] -4- (5-cyclopropyl-1 Hp -razol-3-ylamino) pyrimidine; 5-Chloro-2- [2- (3-cyclopropylisoxazol-5-yl] pyrrolidin-1-yl] -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; 5-CIOR-2- [2- (3-cyclopropyl Iisoxazol-5-yl] pyrrolidin-1H-yl] -4- (5-methy1-1H-pyrazol-3-ylammon) pyrimidine; 5-Chloro-2- [2- (3-methylisoxazole- 5-yl] pyrrolidin-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; 5-Chloro-2-. {2- [3- (thiazole-2-yl) il) isoxazol-5-yl] pyrrolidin-1H-yl.} -4- (5-methyl-1H-pyrazol-3-ylammon) pyrimidine; 5-Chloro-2-. {2 - [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-yl] -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; 2- { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl.} -4- (5-cyclopropyl-1H-pyrrazol-3-ylamino) ) pyrimidine: 5-Chloro-2- {2- [3- (pyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methylene) 1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- { 2- [3- (pipd-3-yl) isoxazol-5-ylpyrrolidin-1-yl} -4- (5-cyclopropyl-1 H-pyrrazol-3-ylamino) pyrimidine; 2- [2- (3-Cyclopropylisoxazol-5-yl) pyrrolidin-1-yl] -6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 2- [2- (3-Cyclopropylisoxazol-5-yl) pyrrolidin-1 H -yl] -6-methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- (2- (3- (pyrid-2-yl) -soxazol-5-yl) piperidin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) pipmidine; 5-Chloro-2- [2- (3. {Tetrahydrofuran-3-yl) isoxazole-5-yl] pyrrolidin-1-yl] -4- (5-methyl-1H-pyrrazole-3) Lamino) pyrimidine: 5-Chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2- (3 { Tetrahydrofuran-3-yl}. Soxazol-5-yl] pyrrolidin-1-yl] -pyrimidine; 6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. {2- 2- [3 (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-pyrimidine; -Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] piperidin-1-yl} pyrimidine; 5-CIoro-2-. { 2- [3- (2-methoxyp-3-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1Hp -razol-3-ylamino) pyrimidine; 5-Fluoro-4- (5-methyl-1H-p-arazoI-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrroiidin-1-yl} -primidine; 4- (5-Cyclopropyl-1 H-pi-razo-l-3-ylamino) -5-f luoro -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrroiidin-1-yl} pyrimidine; S-5-Chloro-2-. { 2- [3-methylisoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrrazol-3-ylamino) pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] irolidin-1 il} pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] irolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2-. { 3- (pyrid-2-yl.) Soxazol-5-yl-lyrrolidin-1-yl] pyrimidine; 4- (5-Methyl-1 H -pyrazol-3-ylamino) -6-methyl-2- [2- (3- (pyrid-2-yl) -soxazol-5-yl) pyrrolidin-1-yl] pyrimidine; 4- (5-cyclopropyl-1H-pyrazole) 3-ylamino) -6-methyl-2- [2- (3-methylisoxazole-5-yl) pyrrolidin-1-yl] pyrim] di; 6-Ethyl-4- (5-methyl-1H -pyrazol-3-ylamino) -2- [2-. {3- (pyrid-2-yl) isoxazoyl-5-yl} -rololidin-1-yl] pyrimidine; 3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. {3- (pyrid-2-yl) soxazol-5-yl}. Pyrrolid N-1-yl] pyrimidine; 6-Methoxymethyl-4- (5-methyl-1H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylammon) -6-methoxymethyl-2- [2-. { 3- (pyrid-2-yl) soxazol-5-yl} pyrrolidin-1-i I] pyrimidine; 6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2 ~. { 2- [3- (tiazol-2-yl) soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-3-yl) soxazol-5-ll} pyrrolidin-1-yl] pyrimidine; 4- (5-Methyl-1H-p -razol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2-. { 3- (pyrid-2-yl) soxazol-5-yl} pyrrolidin-1H-yl] pyrimidine; 4- (5-Met.l-1H-p.razole-3-ylamine) -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrro lidin-1-yl} 6-trifluoromethylpyrimidine: 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrro lidin-1-yl} -6-trifluoromethylprimidine; S-6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimide; S-5-Chloro-2-12- [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-5-Chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrididine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Chloro-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-5-Chloro-2-. { 2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (3-N, N-Dimethylaminopropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2i!) Soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6- (3-Pyrrolidin-1-ylpropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6- Methoxycarbonyl 1-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6- (2-Hydroxyethylcarbamoyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -6- (pyrrolidin-1-ylcarbonyl) pyridin; 6-Methoxy-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl)) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 5-Cloro-4- (3-cyclopropyl-1H-pyrazol-5-ylamino) -2- [2- (2-methyl-2H-tetrazol-5-yl) p iro i i d i n-1-yl] pyrimidine; 6-N ~ Ethylpiperazinyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6-N-Methylpiperazil-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrroxy-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrmidin; 6- (3- (N, ND-methylamino) propin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- (2- (3- (pyrid2-yl) Isoxazol-5-yl) pyrrolidin-1-yl) pyrimidine; 6-Methylamino-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2- (3-pyridin-2-ylisoxazol-5-yl) pyrrolidin-1-yl] pyrimidine; 6- (2-Methoxyethyl) amino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrmidine; 6-Methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1 H-1I} -4- (5-methyl-1 H-pyrazol-3-i mi) pyrimidine; 6- (N-Methylcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methy1-1H-pyrazol-3-ylamino) pyrimidine; 6-Morpholinocarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (N- (2-Methoxyethyl) carbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl} -4- (5-methyl-1H-pyrazol-3-ylammon) pyrimidine; 6- (N-Hydroxycarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-Carbamoyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrohdin-1-iI} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- (N- (2-Methoxyethyl) carbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine; S-6- [N- (2-M-ethoxy-ethyl) -N-methylcarbamoyl] -2-. { 2- [3- (p, pd-2-I) isoxazo I-5-yl] pyrrolidinyl-il} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- [N- (2- (Acetylamino) ethyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- [N- [2- (2-Hydroxyethoxy) ethyl] carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- [N - ((R) -2-Hydroxypropyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- [N- (4-Hydroxybutyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-y! Amino) pyrimidine; S-6- [N - ((2R) -2,3-Dihydroxypropyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine; S-6- [N- (Carbamoylmethyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4 (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6 - ((3R) -3-H -droxypyrrolidin-1-ylcarbonyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-. { N- [2- (Methylthio) ethyl] carbamoyl] -2-. { 2- [3- (pyrid-2-yl) -soxazoI-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6- (N-Cyclopropylcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- (N-Cindy pentyl carbamoyl) -2-. { 2- [3- (pyrid-2-y1) isoxazole-5-y1] pi rrol id i n- 1-il} -4- (5-methyl-1H-pyrrazol-3-ylamino) pyrididine; S-6- (Azetidin-1-ylcarbonyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6- (N-Methylcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (N-Aminocarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- [N- (Acetylamino) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; 6- (5-Methyl- [1,3,4] -oxadiazol-2-yl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrididine; 6-Hydroxymethyl-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5- methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (Morpholinomide) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1Hp -razol-3-ylamino) pyrimidine; 6- (4-Methylpiperazin-1-methyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (Methylaminomethyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4-. (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (Pyrrolidin-1-ylmethyl) -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-Aminomethyl-2-. { 2- [3- (pyrid-2-yl) issoxazole-5-yl] pyrroidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Hydroxymethyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1Hp -razol-3-ylamino) pyrimidine; S-6- Ethoxy methyl-2-. { 2- [3- (p i rid-2-i I) isoxazol-5-i I] pyrrolidin-1 -i l} -4- (5-methyl-1 Hp -razol-3-ylamide) pyrimidine; S-6 - [(2- Methoxyethoxy) methyl] -2-. { 2- [3- (p i rid -2-yl) isoxazol-5-i I] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine; S-5-Chloro-2-. { 2- [3- (pyrazin-2-yl) soxazo! -5-yl] pyrrolidi-1-M} -4- (5-cyclopropyl-1H-pyrazol-3-ylammon) pyrimidine; S-6-Methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -6- (2-methoxyethylamino) pyrimidine; S-6-Methylamino-. { 2- [3- (pyrazin-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; S-4- (5-Cyclopropyl-1 H-pyrrazol-3-ylamino) -6-methoxy-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl} pyrimidine; 6-Pyrrolidin-1-1-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2,2,6,6-Tetramethylpiperdin-4-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-lodo-4- (5-methy1-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pir rol i din-1-I] pyrimidine; S-E-6- [3-tert-Butoxycarbonylamino) prop-1H-en-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2 [2-. { 3- (pyrid-2-yl) -soxazoI-5-yl} pyrrolidin-1 H -yl] pyrimidine; S-6-Ethenyl-4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl.) Isoxazol-5-yl.} Pyrrolidin-1-yl] pyrimidine; SE-6- (3- H id roxiprop-1H-en- 1-yl) -4- (5-methy1-1 Hp i razol-3-amin) -2- [2-. {3- (pyrid-2-yl) -soxazol-5-yl.} pyrrolidin-1-yl] pyrimidine; S-6- [3-tert-butoxycarbonylamino) prop-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylammon) - 2- [2-. { 3 (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Aminoprop-1-yl] -4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-E-6- [3-Aminoprop-1 H-en-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Methylaminoprop-1-yn-1-yl] -4 ~ (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Methoxyprop-1-yn-1-M] -4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Hydroxyprop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazole-5-yi} pyrrolidin-1-yl] pyrididine; S-6- [2- (Trimethylsilyl) ethynyl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2I) -soxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- (N-Methylacetamido) prop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3 (pyrid-2-yl) lsoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- (Dimethylamino) prop-1-yn-1-yl] -4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-l} pyrrolidin-1-I] pyrimidine; S-6- [3-Acetamidoprop-1-yn-1-yl] -4- (5-methy1-H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (Ethoxycarbonyl) ethyl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyridinine; SE-6- [2- (Methoxycarbonyl) ethen-1 -yl] -4- (5-methy1H-pyrazol-3-ylamino) -2- [2-13- (pyrid2- il) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Etin-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazole-5-yl} pyrrolidin-1-yl] pyrimidine; 6-Methoxymethyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; S-6-Methoxymethyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-1. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S ~ 6-Methoxymethyl-4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-i,) iso xazo l-5-yl} pyrrolidin-1-i I] pyrimidine; S-6- [3-Aminoprop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazoI-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (N-Methylcarbamoyl) ethyl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin 1-yl] pyrim id ina; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazole-5-yl] pyrrolidin- 1-yl] pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-llamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl ] pyrimidine; 6- (N-tert-Butoxycarbonyl) amino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1 H -yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine; 6- (4-Aminopiperidin-1-yl) 2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (4- (N-tert-Butoxycarbonylamino) piperazin-1-yl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-P¡ peraz¡n-1-l-2-. { 2- [3- (pyrid-2-y) I) soxazol-5-yl] pyrrolidin-1-yl 1-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6-. { 4- [2- (2-Hydroxyethoxy) ethyl] piperazine-1-ii} -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidyl-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- (1-Formyl-piperazin-4-yl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylammon) pyrididin; S-6-Piperazin-1-yl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5- methyl-1H-pyrazol-3-ylammon) pyrimidine; S-6- (4-lsopropylpiperazin-1-lyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl} -4- (5-methyl-1H-pyrazol) -3-ylamino) pyrimidine; S-6 - [(4- (2-Hydroxyethyl) piperazin-1-yl)] - 2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methy1-1H-pyrazol-3-ylamino) pipmidine; S-6 - [(3R) -3-Hydroxypyrrolid-1-yl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine; S-6 - [(3R) -3-Dimethylamino-pyrrolidin-1H-yl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrididine; S-6- (4-Tetrahydropyranylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1 H -yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimide; S-6-Morpholino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- (2-Methoxyethyl) amino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6 - [(N-2-Methoxyethyl) -N-methylamino] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrrazol-3-ylamino) pyrimidine; S-6 - ((2R) -2-Hydroxyprop-1-lalamine) -2-. { 2- [3- (pyrid-2-yl) isoxazoi-5-yl] pyrrolidin-1-yl} -4 (5-methy1-1H-pyrrazol-3-ylamino) pyrimidine; S-6- [N- (2-Hydroxyethyl) -N-ethylamino] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Dimethylammon-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Methylamino-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1 Hp -razol-3-ylammon) pyrimidine; S-6-Chloro-2-. { 2- [3- (p -razin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-Mofolino-2-. { 2- [3- (p -razn-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methy1- 1H-pyrazol-3-ylamino) pyrimidine; 6-Chloro-2-. { 2- [3- (pipd-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-chloropropyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (2-Hydroxyethoxy) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrrazol-3-ylammon) pyrimidine; 6- [4-tert-Butoxycarbonyl] piperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3 (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrididine; 6- (4-Acetyl piperazin-1-yl) -4- (5-methyl-1 H-pyrazole-3-ylam) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} p i Rrolidin-1-yl] pyrimidine; 6- [2-tert.-Bu tonic rbonyl) -2,7-diaza spiro [3.5] nonan-7-yl] -4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [ 2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1H-yl] pyrimidine; 6- (2, 7-Diaza spiro [3.5] nonan-7-yl) -4- (5-methyl-1H-pi-razo l-3-lamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4- (2-Aminoethyl) piperazin-1 H -yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) lsoxazol-5-yl} pyrrolidin-1-yl] pyridin; S-6- [4- (3-Hydroxypropyl) piperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4- (2-Cyanoethyl) piperazin-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) lsoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S -6- [4- (2-M-ethoxy etl) piperazin-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (4-Acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4- (Ethylsulfonyl) piperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazoI-5-yl} pyrrolidin-1-yl] pyrimidine; S-6 ~ [2- (2-Hydroxyethoxy) ethylamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1- i I] pyrimidine; S-6- [2- (Acetoamido) ethylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2-Aminoethylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2 i) i so xa zol5-il} pyrrolidin-1-i I] pyrimidine; S-6- [4-Methylclohexylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrroidin-1-i I] pyrimidine; S-6- [4-Hydroxycyclohexylamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [cis-3,4-Dihydroxypyrrolidin-1-yl] -4- (5-methyl-1 H-pyrrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-methyl-1H-pyrazole-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (3-methoxy-pyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1 H-i] pyrimidine; S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-hydroxypyrazin-2-yl) isoxazole-5-l} pyrrolidin-1-i I] pyrimidine; S-6- [4-Methypiperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [Cyclobutylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrroiidin-1-yl] pyrimide; S-6- [3-lsop ropoxiprop-1 -lamino] -4 ~ (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6- [2- (Morpholin-4-yl) ethylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1H-i I] pyrimidine; S-6- [2- (Dimethylamino) etiIamino] -4- (5-methyI-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6 - [(2S) -2-H id roxiprop-1-ylamine] ~ 4- (5-methy-1-1 H-pyrazole-3-yam not) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- Metí I prop-1-¡llamí no] -4- (5-met¡ 1-1 H-p¡razol-3-i lamí no) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Methoxypropylamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4-Ethylpiperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Ethoxypropylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1H-yl] pyrimidine; S-6 - [(2R) -Tetrahydrofuran-2-ylmethylamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3 (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1H-yl] pyrimidine; S-6- (2-lsopropoxyethylamino) -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1H-yl] pyrimidine; S-6-Morpholino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methylamino-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyridin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidin; S-6-Met l-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxyprazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methoxy-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrimidin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-cyclopropyl-1H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrimidin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrididine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -5-fluoro-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -6-methyl-2-. { 2- [3- (pyrimid-2-yl) Soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -6-methyl-2-. { 2- [3- (pyrazin-2-l) Soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylammon) -6-methyl-2-. { 2- [3- (pyrid-2-yl) -soxazo! -5-yl] pyrrolidin-1-yl} pyrimidine; 6- (3-Hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidina; S-6- (3-Hydroxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyramide; S-6-Propyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 13- (pyrid-2-yl) isoxazole-5-yl} p irro M d i n- 1 i I] pyrimidine; S-6- (2-Hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-y1] pyrimidine; S-6-Morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (4-Methylpiperazin-1-yl) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (2-pyrazinyl) isoxazole-5-yl} p i rrol din-1-il] pirim id i na; S-6-Methoxy-4- (5-methyl-1H-pyrazol-3-ylamine) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (p, pd-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pirro lid i n-1-I] pyrimidine; S-6-Morpholinocarbonyl-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5 i i} p i rro I i d i n - 1 - i I] pyrimidine; S-6-CarbamoyI-4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Met l-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-ii} pyrrolidin-1 -i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2- {N- [2-hydroxyethyl] -N-methyl-amino} ethoxy) 2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-morpholinoethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazole 5-I} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylammon) -6- (methylthio) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-ii} pyrrolidin-1-yl] pyrimidine; 4- (5- Met i 1-1 H-pyrazol-3-ylamino) -6- (tetrahydrofuran-3-methoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidin; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2- (2-hydroxyethoxy) ethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (3-hydroxypropyloxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- [2- (2-methoxyethoxy) ethoxy] -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-ethoxyethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (3-morpholinoprop-1-yloxy) -2- [2-. { 3- (p iri d-2-i I) iso xa zol-5-il} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (3-methoxyprop-1-yloxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-4- (5-Meti 1-1 H-p razo l-3-i mi no) -6- [2- (2-oxo pyrrolidin-1-yl) ethoxy] -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1 H -pyrazol-3-ylamino) -6 - [(2S) -2-methoxyprop-1-yloxy] -2- [2-. { 3- (pyrid-2-yl) iso xa zol-5-yl} p i rrolid i n- 1 -i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- [3- (methylthio) prop-1-yloxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1H-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylammon) -6 - [(2S) -5-oxopyrrolidin-2-yl) methoxy] -2- [2-. { 3 (pyrid-2-yl) -soxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1 H-pyrrazol-3-ylammon) -6 - [(2R) -5-oxopyrrolidin-2-yl) methoxy] -2- [2-. { 3 (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamine) -6- [2- (imidazolid-2-on-1-yl) ethoxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl lpyridinidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-ethoxy-2- [2-. { 3- (pyrid-2-yl) isoxazole-5-l} p i rrol id i n 1 -i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-hydroxy-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pi rrol id i n- 1 -i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Meti 1-1 H-pyrazol-3-ylamino) -6 - [(2R) -2-h id roxiprop- 1 -i lox] -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2-. { 3- (pyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamine) -6-methoxy-2- [2-. { 3- (pyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2-. { 3- (thiazol-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (tetrahydropyran-4-yloxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Fluoro-4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Chloro-4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (thiazol-4-yl) iso xa zol-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrro lidin-1 -yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrro ldin-1-yl] pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazoI-5-yl} p i Rrolidin-1-yl] pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -5-Fuoro-2- [2-. { 3- (thiazol-2-yl) Soxazol-5-il} pyrrole din-1-yl] pyrimidine; S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1 H-I] pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazoI-2-yl) isoxazol-5-yl} p r-R-din-1-yl] pyrimidine; S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazoI-2-yl) isoxazol-5-yl} pyrrolidin-1-y1] pyrimidine; S-6-Morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethylamino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazole-5-l} p i rrol id i n- 1 -i I] pyrimidine; S-6-Methylamino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (t.azol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (4-Methylpiperazin-lyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- (Methylsulfonyl) propylated 1-1 H-oxy] -4- (5-methylated 1-1 H-pyrrazol-3-ylamy no) -2- [2-1. { 3- (pyrid-2-yl) isoxazol-5-yl lpyrrolidin-1-l] pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2-. { 3- (p -razin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pipminidine; S-6-Methyl-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxyprazraz-2-yl) -soxazol-5-yl} pyrrolidin-1H-I) pyrimidine; S-6-Chloro-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazothn-2- l) isoxazol-5-yl} pyrroline din-1-yl] pyrimidine; S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) -soxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6-Methoxy-4- (5-ethyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrimid-2-yl) iso xa zol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6-Ethyl-4- (5-ethyl-1H-pyrazol-3-llamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1] pipmidine; S-6-Methylamino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidn-1-yl] pyrimidine; S-6-Ethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pirimid-2-l) Soxazol-5-il} pyrrolidin-1-yl] pyrimidine; S-6-Cyclopropyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Cyclopropyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1H-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazoI-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolid N-1-yl] pyrimidine; S-5-Fluoro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl ] pyrimidine; S-5-Fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) Soxazol-5-yl] pyrrolidin-1-yl] pyrimidine; S-6- (2-Hydroxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2- [3- (2-methoxy-pyrid-3-yl) isoxazole-5 -yl] pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1 - [] pyrimidine; S-6-Chloro-4- (5-etl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) is oxazol-5-yl] pyrrolidin- 1-yl] pyrimidine; S-6- (2-Hydroxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-m-ethoxy-p-rid-3-y) isoxazole- 5-i I] pyrrolidin-1-yl] pyrim id i na; S-5-Fluoro-4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1 -i I] pyrimidine; S-6- (2-Hydroxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) -soxazol-5-yl ] pyrrolidin-1-i I] pyrimidine; S-6-Methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-ethyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidin; S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5- i] p ? rrol id i n- 1 Hi I] pyrimidine; S-6-Methyl-4- (5-ethyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-l} p i rro I id i n 1 -i I] pyrimidine; S-6-Morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-hydroxypyrazin-2-yl) isoxazoI-5-yl} pyrrolidin-1-yl] pyrimidine; and S-6- (3-Methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; and pharmaceutically acceptable salts thereof. When the compounds according to the invention contain one or more asymmetrically substituted carbon atoms, the invention includes all stereoisomers, including enantiomers and diastereomers, and mixtures that include their racemic mixtures. Also included are its tautomers and their mixtures. The racemates can be separated into individual enantiomers using known procedures (see Advanced Organic Chemistry: 3rd edition: author J March, p104-107). A suitable process involves the formation of diastereomeric derivatives through the reaction of the racemic material as a chiral auxiliary, followed by separation, for example, by chromatography of the diesteromers and then cleavage of the auxiliary species. It should be understood that certain compounds of the formula (I) can exist in solvated form as well as in unsolvated forms such as, for example, hydrated forms. It should be understood that the invention encompasses all these solvated forms that modulate the activity of the insulin-like growth factor-1 receptor in a human or animal. It should also be understood that certain compounds of the formula (I) may exhibit polymorphism and that the invention encompasses all of these forms that modulate the activity of the insulin-like growth factor-1 receptor in a human or animal. The compounds according to the invention can be provided as pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include base salts such as an alkali metal salt, for example, sodium, an alkaline earth metal salt, for example, calcium or magnesium, an organic amine salt, for example, triethylamine, morpholine, ? / - methylpiperidine,? / - ethyl piperidine, procaine, dibenzylamine, / V, / V-dibenzylethylamine or amino acids, for example, Usin. In another aspect, when the compound is sufficiently basic, suitable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, bromohydrate, citrate, maleate and salts formed with phosphoric and sulfuric acid. The present invention further provides a process for the preparation of a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which comprises: (i) reacting a compound of the formula (II) wherein L1 represents a leaving group (eg, halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R1, R2 and R3 are as defined in formula (I) except that any functional group is protected if necessary , with a compound of the formula (III), where Q1 and Q2 are as defined in formula (I) except that any functional group is protected if necessary; or (ii) reacting a compound of the formula (IV) wherein L2 represents a leaving group (eg, halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R2, R3, Q1 and Q2 are as defined in the formula (I), except that any functional group is protected if necessary, with a compound of the formula (V), wherein R1 is as defined in formula (I) except that any functional group is protected if necessary; or (iii) reacting a compound of the formula (VI) where Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of the formula (VII) wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, R21 independently represents an alkyl group of 1 to 6 carbon atoms and R2 and R3 are as defined in formula (I), except that any functional group is protected if necessary; or (v) reacting a compound of the formula (VIII) wherein R1, R2, R3, NQ1 and Q2 are as defined in formula (I) except that any functional group is protected if necessary with hydrazine; or (v) for compounds of the formula (I) wherein R3 is an alkoxy group of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, amino, -OR3b, -SR3b, -NHR3, -N [alkyl of 1 to 6 carbon atoms] R3b or -S (0) mR3a wherein m is 0 and R3a and R3b are as defined above (and the R3 group is optionally substituted by at least one group as defined above), reacting a compound of the formula (IX) wherein L3 represents a leaving group (for example halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R1, R2, Q1 and Q2 are as defined in the formula (I), except that any functional group is protected if necessary, as a compound of the formula H-Xa, wherein Xa is selected from OR22, NH2, NHR22, N (R22) 2, NH2, OR3b, SR3b, NHR3b , N [alkyl of 1 to 6 carbon atoms] R3 and SR3b, wherein R22 is an alkyl group of 1 to 6 carbon atoms, optionally substituted, and R3a and R3b are each as defined above, except that any group functional is protected if necessary; or (vi) for compounds of the formula (I) wherein R3 is an optionally substituted 5 or 6 membered saturated monocyclic heterocyclic ring comprising at least one nitrogen in the ring and, optionally, one or more additional heterogeneous atoms selected from nitrogen, oxygen and sulfur, reacting a compound of the formula (IX) with a compound of the formula (Xb) wherein Q 4 is an optionally substituted 5 or 6 membered saturated monocyclic heterocyclic ring, comprising one or more additional heterogeneous atoms selected from nitrogen, oxygen and sulfur, in addition to the nitrogen atom shown above, said ring is optionally substituted by at least one ring as defined above, or with an optionally substituted 2,7- diazaspiro [3,5] nonato group; or (vii) for compounds of the formula (I) wherein R3 is an alkylene group of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms and the group R3 is optionally substituted by at least one group as defined above, by reacting a compound of the formula (IX), with a compound of the formula (Xc) or the formula (Xc ') H. C-23 / H H (XC) wherein R23 is selected from hydrogen and an alkyl group of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, optionally substituted; (viii) for the compounds of the formula (I) wherein R3 is attached to the pyrimidine ring through a carbon atom, reacting a compound of the formula (IX), with a compound of the formula M-R3, in wherein R3 is appropriately selected from the groups R3 as defined above, and M is a metal group, such as ZnBr, B (OH) 2, CuCN or SnBu3; (ix) for the compounds of the formula (I) wherein R3 is an alkoxycarbonyl group of 1 to 6 carbon atoms (and the group R3 is optionally substituted by at least one group as defined above), by reacting a compound of the formula (X) wherein R1, R2, Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of the formula HO-alkyl of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms is optionally substituted by at least one group as defined above and any functional group is protected if necessary; or (x) for compounds of the formula (I), wherein R3 is a 5-membered heteroaromatic ring comprising at least one heterogeneous atom selected from nitrogen, oxygen and sulfur (and the group R3 is optionally substituted by at least one group as defined above), conduct an internal condensation reaction using an appropriate starting material and a suitable dehydrating agent. For example, for the compounds of the formula (I), wherein R3 is a group 1, 3,4-oxadiazole, reacting a compound of the formula (XI) wherein Z represents any suitable substituent for R3 as defined above , and R1, R2, Q1 and Q2 are as defined in formula (I) except that any functional group is protected if necessary, with a suitable dehydrating agent, such as (methoxycarbonylsulfanoyl) triethylammonium hydroxide; or (xi) for compounds of the formula (I) wherein R3 is an alkyl group of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms substituted by at least one group as defined above, reacts a compound of the formula (XII) (XII) wherein L3 represents a leaving group as defined above, W represents an alkyl group of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms or alkoxy of 1 to 6 optionally substituted carbon atoms, and R1, R2, Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of the formula H-Xa, (Xb) , (Xc), (Xc '), or M-R3 as defined above; and optionally after (i), (i), (iii), (iv), (v), (vi), (v,), (viii), (x), (x) or (xi) performing one or more of the following: converting the obtained compound to a further compound of the invention, forming a pharmaceutically acceptable salt of the compound. The process (i) can conveniently be carried out in the presence of a suitable inert solvent or diluent, for example, a ketone, such as acetone or an alcohol such as ethanol, butanol or n-hexanol, or an aromatic hydrocarbon such as toluene or? / -methyl pyrrolid-2-one, optionally in the presence of a suitable base, for example an organic amine base such as diisopropylethylamine and at a temperature in the scale of 0 ° C to reflux, particularly at reflux. The process (ii) can conveniently be carried out in the presence of a suitable inert solvent or diluent, for example, a ketone, such as acetone or an alcohol such as ethanol, butanol or n-hexanol, or an aromatic hydrocarbon such as toluene or? / -methyl pyrrolid-2-one, optionally in the presence of a suitable acid, for example, an acid such as anhydride acid chloride and at a temperature in the scale of 0 ° C to reflux, particularly at reflux. Procedures (i) and (i) each alternatively conveniently can be performed under standard Buchwaid conditions (see, for example, J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc. , 119, 8451; J. Org. Chem., 62, 1568 and 6066), for example in the presence of palladium acetate, in a suitable inert solvent or diluent, for example, an aromatic solvent such as toluene, benzene or xylene, with a suitable base, for example, an inorganic base such as cesium carbonate and an inorganic base such as potassium-butoxide, in the presence of a suitable ligand such as 2,2'-bis (diphenylphosphino) -1, 1 ' -bubble and at a temperature in the range of 25 to 80 ° C. The process (iii) can conveniently be carried out in an inert solvent or suitable diluent such as N-methylpyrrolidonone or butanol at a temperature in the range of 100 to 200 ° C., in particular on the scale of 150 to 170 ° C. The preferred reaction is conducted in the presence of a suitable base such as, for example, sodium methoxide or potassium carbonate. The process (iv) can be carried out in an inert solvent or suitable diluent, for example, an alcohol such as ethanol or butanol, at a temperature in the range of 50 to 120 ° C, in particular in the range of 70 to 100 °. C. The processes (v) and (vi) can conveniently be carried out in the presence of an inert solvent or suitable diluent, for example a ketone such as acetone or an alcohol such as methanol, ethanol, butanol or n-hexanol or an aromatic hydrocarbon such as toluene or? / - methyl-pyrrolid-2-one, optionally in the presence of a suitable base. A suitable base could be sodium hydride or an organic amine base such as diisopropylethylamine.

Another suitable base could be an alkali metal alkoxide, for example, sodium methoxide or sodium ethoxide. The procedures (v) and (vi) can conveniently be made at a temperature in the scale of 0 ° C to reflux, particularly at reflux. Conveniently, these methods can also be performed by heating the reagents in a sealed container using a suitable heating apparatus such as a microwave heater. The process (vii) can conveniently be carried out in the presence of an inert solvent or suitable diluent, for example acetonitrile, THF or dioxane, in the presence of a suitable base and a suitable catalyst. A suitable base could be an organic amine base, for example, triethylamine or diisopropylethylamine. A suitable catalyst could be, for example, copper iodide / palladium (II) -bis (triphenyl) phosphine chloride. The process (vii) can conveniently be carried out at a temperature in the range of 0 ° C to reflux, particularly at reflux. Conveniently, this procedure can also be performed by heating the reagents in a sealed container using a suitable heating apparatus such as a microwave heater.

The process (viii) can conveniently be carried out in the presence of an inert solvent or suitable diluent for example THF or dioxane, in the presence of a suitable catalyst. A suitable catalyst could be a palladium (0) catalyst, for example tetrakis (triphenyl) phosphine-palladium (0). As the person skilled in the art would appreciate, the palladium (0) catalyst can be prepared in situ. The process (viii) can conveniently be prepared at a temperature on the scale of 0 ° C to reflux, particularly at reflux. The process (ix) can conveniently be carried out in the absence of an inert solvent or diluent and at a temperature on the scale of ambient temperature to reflux, particularly to reflux. The process (x) is conveniently carried out in the presence of a suitable acid, for example, concentrated sulfuric acid. The process (x) can conveniently be carried out in the presence of an inert solvent or suitable diluent, for example, dichloromethane, THF or dioxane. The process (x) can conveniently be carried out at a temperature on the scale of 0 ° C to reflux, in particular at reflux. The process (xi) can conveniently be carried out under the conditions discussed above for process (v). The compounds of formulas (II), (III), (IV), (V), (VI), (VII), (VIII), HXa, (Xb), (Xc), (Xc ') and M- R3 are either commercially available, are known in the literature or can be prepared using known techniques, for example, by analogy with the procedures described in WO 03/048133. The compounds of the formulas (IX), (X), (XI) and (XII) can be prepared using the procedures (i) and (i) above. Examples of methods of preparing certain of these compounds are given below in the examples. The compounds of the formula (I) can be converted to additional compounds of the formula (I) using standard procedures conventional in the art. Examples of the types of conversion reactions that may be used include introduction of a substituent through an aromatic substitution reaction or a nucleophilic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reactants and reaction conditions for such procedures are well known in the chemical field. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid; the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of nucleophilic substitution reactions include the introduction of an alkoxy group or an alkylamino group, a dialkylamino group or a heterocycle containing N under standard conditions. Particular examples of reduction reactions include the reduction of a carbonyl group to a hydroxyl group with sodium borohydride or a nitro group to an amino group through catalytic hydrogenation with a nickel catalyst or through treatment with iron in the presence of hydrochloric acid with heating; and particular examples of the oxidation reactions include oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. Other conversion reactions that may be used include acid catalyzed esterification of carboxylic acids with alcohols. An example of a suitable conversion reaction is the conversion of a compound of the formula (I), wherein R3 is an alkenyl group of 1 to 6 carbon atoms to a compound of the formula (I), wherein R3 is a alkyl group of 1 to 6 carbon atoms substituted by a di- [C 1-6 alkyl] amino group or through a saturated monocyclic ring of 4 to 7 members, said ring comprises nitrogen and one or more heterogeneous atoms independently selected nitrogen, oxygen and sulfur. Said conversion can be achieved using standard procedures, for example, through the conversion of the alkenyl group to a dihydroxyalkyl group with osmium tetroxide, oxidation to the corresponding ketone with a suitable oxidation agent (e.g., sodium periodate) and the conversion of the desired substituent ketone group as defined above through reaction with the appropriate amine in the presence of a suitable reducing agent (for example sodium cyanoborohydride). Another example of a suitable conversion reaction is the conversion of a compound of the formula (I), wherein R3 is an alkoxycarbonyl group of 1 to 6 carbon atoms optionally substituted to a compound of the formula (I), wherein R3 is optionally substituted carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, or i- [alkyl of 1 to 6 carbon atoms or carbamoyl or an optionally substituted C (0) R3 group, wherein R3b is as defined above. Said conversion can be achieved using standard procedures, for example, through the reaction of the compound of the formula (I), wherein R3 is an alkoxycarbonyl group having 1 to 6 carbon atoms optionally substituted with ammonia, with a primary amine, secondary or tertiary optionally substituted or with an optionally substituted H-R3b group. As the person skilled in the art will appreciate, this conversion can be conducted starting from the carboxylic acid and preparing an activated ester, for example, using 4- (4,6-dimethoxy [1, 3,5] triazin-2 chloride. -yl) -4-methyl-morpholinium, which can then be reacted with the necessary amine. Another example of a suitable conversion reaction is the conversion of a compound of the formula (I), wherein R3 is an alkoxycarbonium group of 1 to 6 carbon atoms to a compound of the formula (I), wherein R3 is a hydroxyl-alkyl group of 1 to 6 carbon atoms. Said conversion can be achieved using standard procedures, for example, through reduction using lithium borohydride or lithium-aluminum hydride. It will be appreciated that the preparation of the compounds of the formula (I) may involve, at various stages, the addition and removal of one or more protecting groups. The protection and deprotection of functional groups is described in "Protective Groups in Organic Synthesis ", 2nd edition, TW Greene and PGM Wuts, Wiley-Interscience (1991) When a pharmaceutically acceptable salt of a compound of the formula (I) is required, for example, an acid addition salt can be obtained, for example, through the reaction of said compound with a suitable acid using a conventional method As mentioned hereinabove, some of the compounds according to the present invention may contain one or more chiral centers and, therefore, may exist as stereoisomers The stereoisomers can be separated using conventional techniques, for example chromatography or fractional crystallization.The enantiomers can be isolated through separation of a racemate, for example, through fractional crystallization, resolution or HPLC.The diastereoisomers can be isolated through separation by virtue of the different physical properties of diastereoisomers, p or, for example, through fractional crystallization, HPLC or flash evaporation chromatography. Alternatively, particular stereoisomers can be made through chiral synthesis from chiral starting materials under conditions that will not cause racemization or epimerization, or via derivatization, with a chiral reagent. When a specific stereoisomer is isolated, it is conveniently isolated substantially free for other stereoisomers, for example, containing less than 20%, particularly less than 10% and more particularly less than 5% by weight of other stereoisomers. In the previous section with regard to the preparation of the compounds of the formula (I), the term "inert solvent" refers to a solvent that does not react with the starting materials, reagents, intermediates or products in a manner that adversely affects the performance or production of the desired product. Those skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative form and on some occasions, in a more convenient manner, the individual steps of the aforementioned process can be performed in a different order, and / or Individual reactions can be performed at different stages along the entire route (ie, chemical transformations can be performed at different intermediates to those previously associated with a particular reaction). The compounds of the formula (I) have activity as pharmaceuticals, in particular as modulators or inhibitors of insulin-like growth factor-1 receptor activity (IGF-IR) can be used in the treatment of diseases-proliferative and hyperproliferative conditions, examples of which include the following cancers: (1) carcinoma, including that of the bladder, brain, breast, colon, liver, kidney, lung , ovary, pancreas, prostate, stomach, cervix, colon, thyroid and skin; (2) hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma; (3) hematopeytic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promylocytic leukemia; (4) tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and (5) other tumors including melanoma, seminoma, tetratocarcinoma, neuroblastoma, and glioma. The compounds of the invention are especially useful in the treatment of breast and prostate tumors. According to a further aspect, therefore, the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined for use in therapy of the body of the human being or of an animal. In particular, the invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above for modulating the activity of the insulin-like growth factor-1 (IGF-IR) receptor in a human or animal The invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above in the manufacture of medicaments for use in therapy, in particular to modulate the activity of the insulin-like growth factor-1 receptor (IGF-IR) in a human or animal It will be appreciated that "therapy" also includes "prophylaxis" unless otherwise indicated. The terms "therapeutic" and "therapeutically" will be understood, accordingly. In a further aspect, the present invention provides a method for treating cancer, which comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof as It was defined earlier. The invention further provides a method for modulating insulin-like growth factor-1 receptor activity (IGF-IR), which comprises administering to a patient with need thereof, a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof as defined above. The compounds of the formula (I) and their pharmaceutically acceptable salts can be used as such, but will generally be administered in the form of a pharmaceutical composition wherein the compounds of the formula (I) / salt (active ingredient) are in association with a pharmaceutically acceptable auxiliary, diluent or vehicle. Depending on the mode of administration, the pharmaceutical composition will preferably comprise 0.55 to 99% by weight (percent by weight), preferably 0.05 to 80% by weight, most preferably 0.10 to 70% by weight, and most preferably 0.10% by weight. 50% by weight of the active ingredient, all percentages by weight are based on the total composition. The present invention also provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in association with a pharmaceutically acceptable auxiliary, diluent or carrier. The invention further provides a method for the preparation of a pharmaceutical composition of the invention, which comprises mixing a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined above, with a pharmaceutically auxiliary, diluent or carrier. acceptable. The pharmaceutical compositions can be administered topically (for example, to the skin or lung and / or respiratory tract) in the form of, for example, creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, for example through oral administration in the form of tablets, capsules, syrups, powders or granules; or through parenteral administration in the form of solutions or suspensions; or through subcutaneous administration; or through rectal administration in the form of suppositories; or transdermally. The compositions of the invention can be obtained through conventional procedures using conventional pharmaceutical excipients, well known in the art. In this way, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants such as ascorbic acid. The tablet formulations may be uncovered or covered both to modify their disintegration and for subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance, in any case, using conventional coating agents and well-controlled procedures. known in the art.

Compositions for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, where the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions usually contain the Active ingredient in a finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing agents or humectants such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecamethyleneneoketanol, or products of condensation of ethylene oxide with partial esters derived from degrees acids and a hexitol such as polyoxyethylene sorbitol monoolate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants such as ascorbic acid, coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame). Oily substances can be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). a thickening agent such as beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set forth above, and flavoring agents may be added to provide a good tasting oral preparation.These compositions may be preserved by the addition of an antioxidant such as ascorbic acid, powders and dispersible granules suitable for prep The addition of an aqueous suspension through the addition of water generally contains the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or humectants and suspending agents are illustrated by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as, for example, liquid paraffin or a mixture of any of these. Suitable emulsifying agents can be, for example, natural existence gums such as acacia gum or tragacanth gum, phosphatides of natural origin such as soy, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides. (for example sorbitan monooleate) and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. The syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and / or coloring agent. The pharmaceutical compositions can also be in the form of a sterile injectable aqueous or oily suspension, which can be formulated according to known procedures using one or more of the appropriate dispersing agents or humectants and suspending agents, which have already been mentioned above. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally stable solvent diluent, for example, a solution in 1,3-butanediol. The suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, can generally be obtained by formulating an active ingredient with a conventional, typically acceptable vehicle or diluent, using a conventional procedure well known in the art. The compositions for administration by insufflation may be in the form of a finely divided powder containing particles with an average diameter of, for example, 30μ or much less, the same powder comprising either the active ingredient alone or diluted with one or more physiologically acceptable vehicles, such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of sodium cromoglycate, known agent. The compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used, and the aerosol device is conveniently arranged to deliver a measured amount of the active ingredient. It will be appreciated that the dose administered will vary depending on the compound employed, the mode of administration, the treatment desired and the indicated disorder. Typically, a daily dose of the active ingredient on the scale of 0.5 mg to 75 mg of active ingredient per kilogram of body weight is received, given if divided doses are required, the precise amount of the compound received and the route of administration depending on the weight , age, sex of the patient being treated and the particular disease condition that is being treated in accordance with principles known in the art. The anti-proliferative treatment defined hereinbefore may be applied as a single therapy and may involve, in addition to the compounds of the invention, surgery or radiotherapy or conventional chemotherapy. Said chemotherapy may include one or more of the following categories of antitumor agents: (i) antiproliferative / antineoplastic drugs and their combinations, as used in medical oncology, such as alkylating agents (eg, cis-platinum, carboplatin, cyclophosphamide, mustard of nitrogen, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example, antifolates such as 5-fluorouracil of fluoropyrimidines and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids, such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotero); and topoisomerase inhibitors (e.g. etopoxide of epipodophyllotoxins and teniposide type, amsacrine, topotecan and camptothecin); (I) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and yodoxifen), down-regulators of estrogen receptor (for example fulvestrant), anti-androgens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate) ), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole and exemestane) and 5a-reductase inhibitors such as Finasteride; (iii) agents that inhibit cancer cell invasion (eg, marimastat type metalproteinase inhibitors and urokinase plasminogen activator receptor function inhibitors); (iv) inhibitors of growth factor function (e.g. inhibitors including growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbB2 antibody, trastuzumab [Herceptin ™] and anti- body antibody). erbB1 cetuximab [C225], farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example other inhibitors of the epidermal growth factor family, for example, family tyrosine kinase inhibitors EGFR such as JA (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD 1839), N _- (3-ethylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amino (Cl 1033)), for example inhibitors of the family of the platelet-derived growth factor and, for example, inhibitors of the hepatocyte growth factor family; (v) anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor (e.g. anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin ™], compounds such as those described in the Requests Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work through other mechanisms (eg, linomide, inhibitors of the integrin avß3 function and angiostatin. vi) vascular damage agents such as Combrestastatin A4, and compounds described in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those that are directed to the objectives listed above, such as ISIS 2503, an anti-ras antisense; (viii) aspects of gene therapy, including, for example, aspects to replace aberrant genes such as p53 aberrant BRCA1 or aberrant BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) aspects such as those that use thymidine cytosine kinase deaminase or a bacterial nitroreductase enzyme and aspects to increase the patient's tolerance to chemotherapy or radiotherapy, such as multiple drug resistance gene therapy; and (ix) aspects of immunotherapy, including, for example, ex vivo and n-vivo aspects to increase the immunogenicity of tumor cells in patients, such as transfection with cytokines such as interleukin 2, interleukin 4 or stimulation factor of granulocyte-macrophage colony, aspects for reducing T-cell energy, aspects using transfected immune cells such as dendritic cells transfected with cytosine, aspects using transfected cytosine tumor cell lines, and aspects using anti-idiotypic antibodies. Said joint treatment can be achieved through simultaneous dosing, sequential or separate from the individual components of the treatment. Said combination products employ the compounds of this invention within the dose scale described above and the other pharmaceutically active ingredient within their approved dose scale. In accordance with this aspect of the invention, a pharmaceutical product comprising a compound of the formula is prepared (I), or a pharmaceutically acceptable salt thereof, as defined above, and an additional anti-tumor agent as defined above for the joint treatment of cancer. The activity and selectivity of the compounds according to the invention can be determined using an appropriate assay as described in, for example, WO 03/048133, and detailed below.

Examples The invention will now be further described with reference to the following illustrative examples, in which, unless otherwise indicated: (i) temperatures are given in degrees Celsius (° C); the operations were carried out at room temperature, that is, at a temperature in the range of 18 to 25 ° C; (ii) the organic solutions were dried over anhydrous magnesium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascal, 4.5-30mmHg) with a bath temperature of up to 60 ° C; (ni) chromatography means flash chromatography on silica gel; Thin layer chromatography (TLC) was performed on silica gel plates; (iv) in general, the course of the reactions was followed through the TLC and the reaction times are provided only by illustration; (v) the final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and / or mass spectral data; (vi) the returns are provided only for illustration and are not necessarily those that can be obtained through the development of diligent procedure; the preparations were repeated if more than one material was required; (vii) when given, the NMR data are in the form of delta values for higher diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz, in DMSO -d6 unless otherwise indicated. The following abbreviations were used: s, individual band; d, double band; t, triplet; q, quad band; m, multiple bands, b, broad; (viii) chemical symbols have their usual meanings; units YES and symbols are used; (X) solvent ratios are given in terms of volume: volume (v / v); and (x) the mass spectra were run with an electron energy of 70 volts electron in the chemical ionization mode (Cl) using a direct exposure probe; where the indicated ionization was affected by the impact of electrons (El), fast atom bombardment (FAB), or electroaspersion (ESP); values are provided for m / z; generally only the ions that indicate the mass of origin are reported; Unless otherwise indicated, the mass ion is (MH) +; (xi) the following abbreviations were used: THF tetrahydrofuran; EtOAc ethyl acetate; DCM dichloromethane; DMSO dimethyl sulfoxide DIPEA diisopropylethylamine; NMP N-methylpyrrolid-2-one; tBuOH tert-butyl alcohol; TFA trifiuoroacetic acid; DMF N, N-dimethylformamide; and DMA N, N-dimethylacetamide.

Example 1 5-Chloro-2-f2r3- (pyrid-2-inisoxazole-5-ippyrrolidin-1-yl> -4- (5-methyl-1H-pyrazole-3-ylane) pyrimidine A mixture of 2, 5-dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 10 of WO 03/048133) (158 mg, 0.648 mmol), 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidine (Method 12) (212 mg, 0.972 mmol) in di-isopropylethylamine (282 μL, 1.62 mmol) was stirred and heated to 140 ° C in n-hexanol (7.0 mL) under nitrogen for 9 hours. The total volume of hexanol was then removed by evaporation and the residue was partitioned between ethyl acetate and water.The ethyl acetate layer was separated, washed with 1.0 molar phosphate pH regulator pH4 (x2) , then with water and finally brine.The organic layer was dried (Na2SO4), filtered and evaporated and the crude product was absorbed on an SCX2 ion exchange column of 10g solute.

DCM / methanol (4: 1) to remove two neutral points and then with dichloromethane / 2M methanolic ammonia (4: 1) to elute the product.

The purified product was dissolved in a minimum volume of DCM and a slight excess of 1.0 M of ethereal acid chloride was added to the stirred solution. More diethyl ether was added and the solid product was collected by filtration, washed with diethyl ether and dried to give the hydrochloride salt of the title compound (300 mg, 100%). NMR (DMSO-oí6 + d4 acetic acid at 100 ° C): 2.13 (m, 3H), 2.4 (m, 1H), 3.7 (m, 1H), 3.86 (m, 1H), 3.86 (m, 1H), 5.45 (d, 1H), 6.12 (s, 1H) 6.75 (s, 1H), 7.45 (t, 1H), 7.9 (m, 2H), 8.07 (s, 1H), 8.65 (d, 1H); m / z 423 [MH] +. Examples 2 to 11 were prepared using the same method as in Example 1.

A: 2,5-Dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine B: 2,5-D-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine C: 2,5-Dichloro-4- (5-tert-butyl-1 H -pyrazol-3-ylamino) pyrimidine The preparation of the AC compounds is described in WO 03/048133.

EXAMPLE 12 2-l "2- (3-Cyclopropyl isoxazol-5-yl) pi rrol din-1 I] -6-methoxymethyl-4- (5-methyl-1H-pyrazole-3-) ilamino) pyrimidine A mixture of 4-chloro-2- [2- (3-cyclopropylisoxazol-5-yl] pyrrolidin-1-yl] -6-methoxymethylpyrimidine (Method 19) (250 mg, 0.746 mmol ), 3- amino-5-methyl-1 H-pyrazole (109 mg, 1.2 mmol) and hydrogen chloride (0.56 ml of a 4M solution in dioxane, 2.24 mmol) in NMP (5 ml) was heated at 120 ° C for After 18 hours, the mixture was allowed to cool and was directly applied to a SCX2 solute ion exchange column.

DCM / methanol (4: 1) to remove the neutral and then with 7M methanolic ammonia to elute the product. The partially purified product was then purified by chromatography on silica gel eluting with DCM methanol (100: 0 increasing in polarity to 95: 5). The product was titrated with diethyl ether / DCM and the solid product was collected through filtration to give the title compound (100 mg, 34%) as a white solid. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 0.65 (m, 2H), 0.88 (m, 2H), 1.97 (m, 4H), 2.17 (s, 3H), 2.25 (m, 1H) , 3.35 (s, 3H), 3.63 (m, 2H), 4.13 (dd, 2H), 5.28 (d, 1H), 5.85 (s, 1H), 6.00 (s, 1H), 6.33 (s, 1H); m / z 396 [MH] +.

Example 13 2-r2- (3-Cyclopropylisoxazol-5-yl) pyrrolidin-1-yn-6-methoxymethyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine The title compound is prepared by the same method as described for Example 12 starting from 3-amino-5-cyclopropyl-1H-pyrazole (Method 7 of WO 03/048133) (130 mg, 41%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 0.65 (m, 4H), 0.86 (m, 4H), 1.85 (m, 2H), 2.00 (m, 3H), 2.25 (m, 1H) , 3.32 (s, 3H), 3.63 (m, 2H), 4.12 (dd, 2H), 5.30 (d, 1H), 5.86 (s, 1H), 5.95 (s, 1H), 6.32 (s, 1H); m / z 422 [MH] +.

Example 14 5-Chloro-2-f2-r3-pyrid-2-inisoxazol-5-ylpiperidin-1-yl > -4- (5-Methyl-1H-pyrazol-3-ylamino) pyrimidine 2- [3- (Pyrid-2-yl) isoxazol-5-yl] piperidine (Method 16 (a)) (137 mg, 0.6 mmol) was treated as described in Example 1 except that the reaction mixture was heated at 140 ° C for 18 hours and then treated with an ethylene diaminopropyl silica-based scavenger before processing as described in Example 1 to give the compound of the title (35 mg, 16%). NMR (DMSOdd, 100 ° C, 400 MHz): 1.53 (m, 2H), 1.75 (m, 2H), 1.93 (m, 1H), 2.2 (s, 3H), 2.25 (m, 1H), 2.9 (m , 1H), 4.6 (d, 1H), 6.13 (s, 2H), 6.7 (s, 1H), 7.4 (t, 1H), 7.85 (m, 2H), 8.05 (s, 1H), 8.17 (s, 1H), 8.68 (d, 1H), 11.75 (s, 1H); m / z 437 [MH] +.

Examples 15 to 24 Examples 15 to 24 were prepared using the method of Example 1: cn or cn cn ^ CD N. cn O cn cn do not ro 10 n o in cn cn ro 10 cn or cn n in IO ro cn ro o cn cn A: 2,5-Dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine B: 2,5-Dichloro-4- (5-chloropropyl-1H -pyrazzo-3-ylamino) pyrimidine cn co The preparation of compounds A and B is described in WO 03/048133. 1Purified by chromatography on silica gel with DCM / methanol (98: 2 increasing in polarity to 95: 5).

Example 25 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -6-methyl-2-r 2 -. { 3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-ippyrimidine A mixture of 4-hydroxy-6-methyl-2- [2-. { 3- (pyrid-2-yl) isoxazole-5-i I} p i r r o I i d i n - 1 - i l i i i i i i i a (Method 30) (200 mg, 0.62 mmol) in phosphoryl chloride (7 ml) was heated at 70 ° C, under nitrogen for 30 minutes. The volatiles were removed by evaporation and the residue was dissolved in DCM, washed with a saturated sodium hydrogen carbonate solution, dried (MgSO) and the solvent was removed by evaporation. The crude product was then treated as described in Example 12, with 3-amino-5-cyclopropyl-1 H-pyrazole (Method 7 of WO03 / 048133) (120 mg, 0.98 mmol), and 4M solution hydrogen chloride in dioxane (0.65 ml) in NMP (5 ml) to give the title compound (100 mg, 37%). NMR (DMSO): 0.64 (m, 2H), 0.84 (m, 2H), 1.76-1.82 (m, 1H), 1. 96-2.15 (m, 7H), 2.25-2.36 (m, 1H), 3.45-3.55 (m, 1H), 3.72-3.80 (m, 1H), 5.40 (d, 1H), 5.87 (s, 1H), 6.08 (s, 1H), 6.61 (s, 1H), 7.44 (dd, 1H), 7.86-7.95 (m, 2H), 8.60 (d, 1H), 9.30 (s, 1H); m / z 429 [MH] +.

Examples 26 to 36 Examples 26 to 36 were prepared by an analogous method to that described in Example 25 Example 26 4- (5-Meti 1-1 H-pyrazol-3-yl amino) -6-me i I -2-í2-. { 3- (pyrid-2-yl) isoxazol-5y-pyrrolidin-1-inpyrimidine Starting materials: 4-hydroxy-6-methyl-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyridine (Method 30) and 3-amino-5-methyl-1 H-pyrazole. Purified through chromatography on silica gel eluting with methanol / DCM (8:92) to give the title compound (42 mg, 22%). NMR (DMSO): 1.99-2.15 (m, 10H), 2.25-2.38 (m, 1H), 3.52-3.60 (m, 1H), 3.72-3.80 (m, 1H), 5.39 (d, 1H), 6.10 (s, 1H), 6.64 (s, 1H), 7.45 (dd, 1H), 7.86-7.98 (m, 2H) ), 8.62 (d, 1H), 9.22 (s, 1H); m / z 403 [MH] +.

Example 27 4- (5-Cyclo I opropyl -1 H -pyrazole-3 -i I amino) -6-methyl-2-y 2 - (3-methylisoxazol-5-yl) pyrrolidin-1-illpyrimidine Starting materials: 4-hydroxy-6-methyl-2- [2-. { 3- (methyl) isoxazoI-5-yl] pyrrolidin-1 -i I] pi ri mi d in a (Method 31) and 3-amino-5-cyclopropyl-1 H-pyrazole (Method 7 of WO03 / 048133). Yield: 70 mg, 25%. NMR (DMSO): 0.62 (m, 2H), 0.89 (d, 2H), 1.84-1.78 (m, 1H), 2.0-1.94 (m, 3H), 2.08 (s, 3H), 2.12 (s, 3H) , 3.48-3.55 (m, 1H), 3.63-3.73 (m, 1H), 5.30 (d, 1H), 6.0 (s, 1H), 6.08 (s, 1H), 9.21 (s, 1H), 11.8 (s) , 1 HOUR); m / z 364 [MH] -.

Example 28 6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-. { 3- (pyrid-2-n-isoxazol-5-yl) pyrrolidin-1-illPyrimidine Starting materials: 4-hydroxy-6-ethyl-2- [2-. {3- (pyrid-2) -yl) isoxazol-5-yl.} pyrrolidin-1-ylpyrimidine (Method 32) and 3-amino-5-methyl-1 H-pyrazole Yield: 150 mg, 38% NMR (DMSO): 1.02 -1.15 (m, 3H), 1.99-2.09 (m, 3H), 2.14 (s, 3H), 2.28-2.41 (m, 3H), 3.58-3.62 (m, 1H), 3.75-3.80 (m, 1H) , 5.38 (d, 1H), 6.14 (s, 1H), 6.68 (s, 1H), 7.45 (dd, 1H), 7.87-7.95 (m, 2H), 8.62 (d, 1H), 9.22 (s, 1H) ); m / z 417 [MH] +.

Example 29 6- (3-Methoxy ropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2- 3- (pyrid-2-yl) isoxazol-5-yl pyrrolidin-1-inpyrimidine Starting materials: 4-hydroxy-6- (3-methoxypropyl) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl] pyrimidine (Method 33) and 3-am i non-5-methyl-1 H-pyrazole. Yield: 56 mg, 14%. NMR (DMSO): 1.78-1.82 (m, 1H), 2.0-2.12 (m, 3H), 2.18 (s, 3H), 2.28-2.40 (m, 2H), 2.58-2.64 (m, 2H), 3.04-3.20 (m, 2H), 3.30 (s, 3H), 3.58-3.62 (m, 1H), 3.73-3.82 ( m, 1H), 5.38 (d, 1H), 5.90 (s, 1H), 6.10 (s, 1H), 6.65 (s, 1H), 7.48 (dd, 1H), 7.87-7.98 (m, 2H), 8.62 (d, 1H), 9.24 (s, 1H); m / z 461 [MH] +.

Example 30 6-Methoxymethyl-4- (5-m eti 1-1 H-pyrazole-3-i lamin o) -2-r 2 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-illpyrimidine Starting materials: 4-hydroxy-6-methoxymethyl-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Method 34) and 3-amino-5-methyl-1 H-pyrazole. Yield: 260 mg, 49%. NMR (DMSO): 2.0-2.15 (m, 3H), 2.20 (s, 3H), 3.30 (s, 3H), 3.65-3.8 (m, 2H), 4.15 (q, 2H), 5.45 (d, 1H) , 6.04 (s, 1H), 6.38 (s, 1H), 6.64 (s, 1H), 7.44 (dd, 1H), 7.88-7.90 (m, 2H), 8.65 (d, 1H), 8.90 (s, 1H) ).

Example 31 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -6-methoxymethyl-2-r 2 -. { 3 - (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-y-pyrimidine Starting materials: 4-hydroxy-6-methoxymethyl-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Method 34) and 3-amino-5-cyclopropyl-1 H-pyrrazol (Method 7 of WO-03/048133). Yield: 245 mg, 48%. NMR (DMSO): 0.63-0.65 (m, 2H), 0.84-0.9 (m, 3H), 1.80-1.89 (m, 1H), 2.04-2.10 (m, 2H), 2.11-2.18 (m, 1H), 2.32-2.40 (m, 1H), 3.35 (s, 3H), 3.68-3.80 (m, 2H), 4.18 (q, 2H), 5.45 (d, 1H), 6.0 (s, 1H), 6.38 (s, 1H), 6.65 (s, 1H), 7.44 (dd, 1H), 7.78-7.97 (m, 2H), 8.65 (d, 1H), 8.92 (s, 1H); m / z 459 [MH] +.

EXAMPLE 32 6 -Met oxy met i I -4- (5-m eti 1-1 H -pyrazol -3 -i I amino) -2-. { 2- T3 - (ti azo 1-2 -yl) isoxazol-5-ylpyrrolidin-1-yl} pyrimidine Starting materials: 4-hydroxy-6-methoxymethyl-2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Method 36) and 3-amino-5-methyl-1 H-pyrazole. Yield: 32 mg, 12%. NMR (DMSO): 2.0-2.15 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 3.33 (s, 3H), 3.65-3.79 (m, 2H), 4.14 (m, 2H) , 5.44 (d, 1H), 6.0 (s, 1H), 6.37 (s, 1H), 6.63 (s, 1H), 7.79 (d, 1H), 7.95 (d, 1H); m / z 439 [MH] +.

Example 33 6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-. { 3- (pyrid-3-yl) isoxazol-5-yl) pyrrolidin-1-n-pyrimidine Starting materials: 4-hydroxy-6-methoxymethyl-2- [2-. { 3- (pyrid-3-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyridine (Method 35 (a)) and 3-amino-5-methyl-1 H-pyrazole. Yield: 30 mg, 21%. NMR (DMSO): 2.07 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.33 (s, 3H), 3.7 (m, 2H), 4.16 (t, 2H), 5.43 (d, 1H), 6.03 (s, 1H), 6.37 (s, 1H), 6.77 (s, 1H), 7.47 (t, 1H) ), 8.13 (d, 1H), 8.65 (d, 1H), 8.87 (s, 1H), 8.98 (s, 1H), 11.5 (s, 1H); m / z 433 [MH] +.

Example 34 4- (5-Meti 1-1 H-pyrazole-3-i I amino) -6- (Pent-3-en-1-yl) -2-f2 -f3- (pyrid-2-yl) isoxazole -5-yl) pyrrolidin-1-pyrimidine Starting materials: 4-hydroxy-6- (pent-3-en-1-yl) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5yl} pyrrolidin-1-yl] pyrimidine (Method 35) and 3-amino-5-methyl-1 H-pyrazole. Yield: 341 mg, 56%. NMR (DMSO): 1.55 (d, 3H), 2.02-2.18 (m, 3H), 2.18 (s, 3H), 2.23-2.28 (m, 1H), 2.32-2.45 (m, 3H), 3.68-3.8 ( m, 2H), 5.34-5.40 (m, 3H), 6.05 (s, 1H), 6.18 (s, 1H), 6.65 (s, 1H), 7.43 (dd, 1H), 7.88-7.96 (m, 2H), 8.65 (d, 1H), 8.75 (s, 1H), 11.50 (s, 1H); miz 457 [MH] +.

Example 35 4- (5-Methyl-1H-pyrazol-3-ylamino) -2-f2-r3- (Pyrid-2-yl) isoxazole-5-illpyrrolidin-1-iP-β-trifluoromethylpyrimidine Starting materials: 4- Hydroxy-6-trifluoromethyl-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Method 37) and 3-amino-5-methyl-1 H-pyrazole. Yield: 115 mg, 38%. NMR (DMSO): 2.20 (m, 7H), 3.70 (br m, 2H), 5.42 (br d, 1H), 5.95 (br s, 1H), 6.62 (br m, 1H), 6.80 (br s, 1H ), 7.50 (m, 1H), 7.95 (m, 2H), 8.64 (m, 1H); m / z 457 [MH] +.

Example 36 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -2-. { 2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl) -6-trifluoromethylpyrimidine Starting materials: 4-hydroxy-6-trifluoromethyl-2- [2-. { 3- (pyrid-2-yl) isoxazole ~ 5-yl} pyrrolidin-1-yl] pyrimidine (Method 37) and 3-amino-5-cyclopropyl-1H-pyrrazol (Method 7 of WO-03/048133). Yield: 60 mg, 17%. NMR (DMSO): 0.70 (m, 2H), 0.90 (m, 2H), 1.90 (m, 1H), 2.15 (m, 4H), 3.78 (m, 2H), 5.50 (d, 1H), 6.05 (s) , 1H), 6.70 (s, 1H), 7.45 (m, 1H), 7.95 (m, 2H), 8.68 (d, 1H), 9.58 (br s, 1H), 11.78 (br s, 1H); m / z 483 [MH] +.

Examples 37 to 42 The following individual enantiomers of Examples 37 to 42 were prepared through separation of the racemic compound by chiral HPLC using a Chiralpak AD column using methanol or methanol / ethanol mixtures as eluent.

Example 37 S-6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) -soxazol-5-yl-1-pyrrolidin-1-ippirlmidine The compound of the title was prepared through separation of the racemic compound (Example 28).

Example 38 S-5-Chloro-2-f2-r3- (thiazol-2-yl) isoxazol-5-H-pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine The title compound was prepared through separation of the racemic compound (Example 7).

Example 39 S-5-Chloro-2- (2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yn-4- (5-cyclopropyl-1 H-pyrazol-3-ylamino pyrimidine The title compound was prepared through separation of the racemic compound (Example 9).

Example 40 S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-methyl-2-r2-. { 3- (pyrid-2-yl) -isoxazole-5-pyrrolidin-1-yl-1-pyrimidine The title compound was prepared through separation of the racemic compound (Example 26).

Example 41 S-5-Chloro-2-f2-f3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-n-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine The The title compound was prepared through separation of the racemic compound (Example 1).

Example 42 S-5-Chloro-2-f2-r3- (2-methoxypyrid-3-yl) -soxazol-5-n-pyrrolidin-1-yl > 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine The title compound was prepared through separation of the racemic compound (Example 19).

Example 43 6- (3-N, N-Dimethylaminopropyl) -4- (5-methyl-1 H -pyrazol-3-ylamino) -2-12-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-pyrimidine Osmium tetroxide (0.070 ml of a solution of 2. 5% / p in tBuOH) followed by water (0.38 ml) to a stirred solution of 4- (5-methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-y) - 2 [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 34) (100 mg, 2.2 mmol) in THF (2 ml), under nitrogen. Sodium periodate (150 mg, 6.5 mmol) was added and the mixture was stirred for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in methanol and acetic acid (0.066 ml) and a 2M solution of dimethylamine in THF (0.55 ml) was added. Sodium cyanoborohydride (28 mg) was added rapidly and the mixture was stirred at room temperature for 18 hours. The volatiles were then removed by evaporation, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate solution and then brine. The volatiles were removed by evaporation, and the residue was purified by chromatography on silica gel eluting with DCM / ethanol / aqueous ammonia (100: 0: 0 increasing in polarity to 85: 15: 0.3) to give the compound of the title (8mg, 11%). NMR (DMSO): 1.28-1.35 (m, 2H), 1.70-1.78 (m, 2H), 2.07-2.10 (m2H), 2.1 (s, 6H), 2.20 (s, 3H), 2.30-2.45 (m, 4H), 3.70-3.82 (m, 2H), . 47 (d, 1H), 6.08 (s, 1H), 6.20 (s, 1H), 6.65 (s, 1H), 7.45 (dd, 1H), 7. 87-7.99 (m, 2H), 8.68 (d, 1H); m / z 472 [MH] -.

Example 44 6- (3-Pyrrolidin-1-ylpropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-. { 3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-H-pyrimidine Example 44 is prepared by an analogous method to that described in Example 43 starting from 4- (5-methyl-1 H -pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 34) and pyrrolidine. Yield: 6 mg, 18%. NMR (DMSO): 1.55-1.68 (m, 4H), 1.68-1.78 (m, 2H), 2.0-2.17 (m, 4H), 2.18 (s, 3H), 2.28-2.45 (m, 8H), 3.65- 3.80 (m, 2H), 5.43 (d, 1H), 6.04 (s, 1H), 6.18 (s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.85-7.97 (m, 2H) , 8.63 (d, 1H), 8.74 (s, 1H); m / z 500 [MH] +.

Example 45 6-Methoxycarbon i I -4- (5-methyl-1-1H-pyrazol-3-yl-amino) -2-. { 2-r 3 - (pyr id-2-yl) isoxazol-5-ippyrrolidin-1-yl) pyrimidine A mixture of 2- acid. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimid-6-carboxylic acid (Method 43) (100 mg 0.21 mmol), methanol (10 ml) and 1 drop of 98% sulfuric acid was heated to reflux for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in water. The resulting solution was adjusted to a pH of 12 through the careful addition of a 10M solution of aqueous sodium hydroxide and then extracted with DCM. The extracts were combined and the volatiles were removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 95: 5). The purified product was titrated with diethyl ether and the resulting solid was collected through filtration to give the title compound (10 mg, 8.8%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.75 (m, 5H), 5.50 (dd, 1H) , 6.05 (s, 1H), 6.70 (S, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.88 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 447 [MH] +.

Example 46 6- (2-H id roxi eti I carbamoyl) -4- (5-met i 1-1 H-pyrazol-3-yl amino) -2-f 2-T3- (pyrid-2-yl) isoxazole -5-ill-pyrrolidin-1-yl) pyrimidine A mixture of 6-methoxycarbonyl-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) -soxazole-5-i I] pyrro-ldin-1-yl} pyrimidine (Example 45) (49.5 mg, 0.11 mmol) and ethanolamine (2.0 ml, 33.7 mmol) in methanol (4 ml) was heated at 88 ° C for 2 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2) the fractions which containing the product were combined and passed through a SCX-2 ion exchange column of 50 g of solute. The column was eluted with methanol to flow any neutral impurities, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with diethyl ether and the resulting solid was collected through filtration to give the title compound (27 mg, 57%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.35 (m, 2H), 3.55 (t, 2H) , 3.75 (m, 1H), 3.85 (m, 1H), 5.50 (dd, 1H), 6.10 (s, 1H), 6.72 (s, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.62 (d, 1H); m / z 476 [MH] +.

Example 47 4- (5-Methyl-1H-pyrazol-3-ylamino) -2-. { 2-r3- (pyrid-2-yl) isoxazol-5-yl-pyrrolidin-1-yl) -6 (pyrrolidin-1-ylcarbonyl) pyrimidine Example 47 was prepared by an analogous method to that described in Example 46 except that the starting material was treated with net pyrrolidine and the product was purified by chromatography on silica gel eluting with DCM / methane (100: 0 increasing in polarity to 90:10) to give the title compound (10 mg , 2.8%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.75 (m, 4H), 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.45 (m, 4H) , 3.70 (m, 1H), 3.85 (m, 1H), 5.40 (dd, 1H), 6.10 (s, 1H), 6.55 (S, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.88 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 486 [MH] +.

Example 48 6-Methoxy-4- (5-methyl-1 H-pyrazole-3-ylamin o) -2- (2-r 3 - (pyrid-2-ip) isoxazol-5-y-pyrrolidin-1-yl) pyrimidine A mixture of 6-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-ii] pyrrolidin-1-yl} pyrimidine (Example 17) (200 mg, 0.47 mmol), 25% NaOMe / MeOH solution (0.54 mL, 2.3 mmol) in methanol (3 mL) was heated under sealed conditions at 140 ° C for one hour. The mixture was allowed to cool and then adjusted to a pH of 7 through the careful addition of 2M ethereal hydrogen chloride. The mixture was then diluted with water and the aqueous mixture was extracted with DCM, the extracts were combined, dried (MgSO4) and the solvent was removed by evaporation. The residue was titrated with diethyl ether, the product was collected through filtration to give the title compound (98 mg, 50%) as a white solid. NMR (DMSO): 2.14-2.2 (m, 6H), 2.38 (m, 1H), 3.75 (m, 5H), . 44 (d, 1H), 5.75 (s, 1H), 5.94 (s, 1H), 6.66 (s, 1H), 7.4 (m, 1H), 7. 88 (m, 1H), 7.91 (m, 1H), 8.63 (m, 1H); m / z 419 [MH] +.

Example 49 5-Chloro-4- (3-cyclopropyl-1H-pyrazol-5-ylamino) -2-r2- (2-methyl-2H-tetrazol-5-yl) pyrrolidin-1-ylpyrimidine Was stirred 1 -tert-butyloxy-2- (2-methyl-2H-tetrazol-5-yl) pyrrolidine (Method 46) (160 mg, 0.63 mmol) for one hour in TFA (2 ml) at room temperature. The TFA was removed by evaporation and the resulting product was added to a mixture of 2,5-dichloro-4- (3-cidopropyl-1 H-pyrazol-5-ylamino) pyrimidine (Method 20 of WO 03/048133) ( 152 mg, 0.57 mmol) and di-isopropylethylamine (330 μL, 1.9 mmol) in n-hexanol (4.0 mL). The resulting mixture was stirred and heated at 120 ° C under nitrogen for 12 hours. 3- (1, 2-diaminoethyl) propyl functionalized with silica gel (40 mg, 0.11 mmole) was added and the mixture was then heated at 140 ° C for 12 hours. The mixture was allowed to cool, filtered and the filtrate was applied directly to a solute SCX2 ion exchange column. The column was eluted with DCM / methanol (4: 1) to remove the neutral products and then with 7M of methanolic ammonia to elute the product. The product was titrated with diethyl ether and the solid product was collected through filtration, washed with diethyl ether and dried to give the title compound (82 mg, 38 ° 10). NMR (DMSO-d6 at 100 ° C): 0.72 (m, 2H), 093 (m, 2H), 1.87 (m, 1H), 2.06 (m, 3H), 2.41 (m, 1H), 3.71 (m, 2H), 4.27 (s, 3H) 5.47 (dd, 1H), 6.11 (br s, 1H), 7.92 (s, 1H) ); m / z 387 [MH] +.

Example 50 6-N-Ethylpiperazinyl-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f 2 -f3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl) pyrimidine A mixture of 6-chloro-2-. { 2- [3- (pip'd-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 17) (250 mg, 0.59 mmol) and N-ethylpiperazine (674 mg, 5.9 mmol) in anhydrous 1,4-dioxane (5 ml. ) was heated at 150 ° C for 40 minutes in sealed container under microwell irradiation. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / trifluoroacetic acid (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was further purified by chromatography on silica gel eluting with DCM / methanol / aqueous ammonia (100: 0: 0 increasing the polarity to 89: 20: 1) to give the compound of the title (200 mg, 68%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.08 (t, 3H), 2.05 (m, 3H), 2.18 (s, 3H), 2.87 (m, 6H), 2.35 (m, 1H), 2.87 (m, 6H), 3.57 (s, 4H), 3.65 (m, 1H), 3.75 (m, 1H), 5.35 (d, 1H), 5.55 (s, 1H), 5.95 (s, 1H), 6.60 (s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); m / z 501 [MH] +.

Examples 51 and 52 Examples 51 and 52 were prepared through an an method. { alogo to that described in Example 50, however, no normal phase chromatography was required, and the compounds were isolated by titration with diethyl ether / DCM and collected by filtration.

Example 51 6-N-Methylpiperazyl-2-f2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine Starting materials: 6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 17) and N-methylpiperazine. Yield: 201 mg, 70%. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2. 20 (s, 3H), 2.35 (m, 1H), 2.60 (s, 3H), 2.95 (m, 4H), 3.6 (m, 4H), 3. 70 (m, 1H), 3.75 (m, 1H), 5.35 (d, 1H), 5.95 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); m / z 487 IH] +.

Example 52 6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-r3- (pyrid-2-yl) isoxazole-5-pyrrolidin-1-yl > pyrimidine Starting materials: 6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 17) and morpholine. Yield: 239 mg, 85%. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.20 (m, 3H), 2.25 (s, 3H), 2.35 (m, 1H), 3.35 (m, 4H), 3.55 (m, 4H), 3.60-3.75 (m, 2H), 5.35 (d, 1H), 5.60 (s, 1H), 5.70 (s, 1H), 5.95 (s, 1H), 6.67 (s, 1H), 7.40 (m , 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); m / z 474 [MH] +.

Example 53 6- (3- (NN-Dimethylamino) propin-1-yl) -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- (2- (3 (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-yl) pyrimidine A mixture of 6-bromo-4- (5-metii-1 H-pyrazol-3-ylamino) -2- (2- (3- (pyrid- 2-yl) isoxazol-5-yl) pyrrolidine) pyrimidine (Method 49) (200 mg, 0.43 mmoies), palladium chloride (II) -bis (triphenylphosphine) (12 mg, 0.02 mmol), copper iodide (l) (2 mg, 0.02 mmol), triethylamine (0.300 ml, 2.1 mmol), 3- (N, N-dimethylamino) propyne (0.070 ml, 0.64 mmol) in acetonitrile (2 ml) was heated at 75 ° C for 15 h. minutes in a sealed container under microwave irradiation. The mixture was dissolved in ethyl acetate, the solution was decanted from the insolubles, the solution was washed with water, dried (MgSO4), and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM / methanol (90:10 increasing in polarity to 85:15). The purified product was titrated with ether and collected by filtration to give the title compound (44 mg, 25%). NMR (DMSO): 2.10 (m, 3H), 2.20 (s, 3H), 2.29 (s, 6H), 2.32- 2.45 (m, 1H), 3.45 (s, 2H), 3.66-3.80 (m, 2H) , 5.45 (d, 1H), 6.08 (s, 1H), 6.47 (s, 1H), 6.68 (s, 1H), 7.46 (d, 1H), 7.88-7.98 (m, 2H), 8.66 (d, 1H), 9.04 (s, 1H), 11.55 (s, 1H); m / z 470 [MH] +.

Example 54 6-Methylamino -4- (5-methyl-1 H -pyrazol-3-ylamino) -2-r2- (3-pyridin-2-yl-isoxazol-5-yl) pyrrolidin-1-in pyrimidine A mixture of 6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol! -3-ylamino) pyrimidine (Example 17) (250 mg, 0.59 mmol) and methylamine (4 mL of 2M in methanol, 8.0 mmol) was heated to 130 ° C for 90 minutes in sealed container under microwave irradiation. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / trifluoroacetic acid (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 exchange column of 50 g of isolute. The column was eluted with methanol to elute any material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (126 mg, 50%) as a yellow solid. NMR (DMSO-d6 at 100 ° C): 2.05 (m, 3H), 2.15 (s, 3H). 2.35 (m, 1H), 2.74 (s, 3H), 3.70 (m, 2H), 5.43 (d, 1H), 5.51 (br s, 1H), 5.91 (br s, 2H), 6.60 (s, 1H), 7.40 (m , 1H), 7.85 (, 1H), 7.95 (d, 1H), 8.04 (br s, 1H), 8.60 (d, 1H), 11.33 (br s, 1H); m / z 418 [MH] +.

Example 55 6- (2-Methoxyethyl) amino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-r3- (pyrid-2-yl) isoxazol-5-y-pyrrolidin-1-yl ) pyrimidine A mixture of 6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 17) (250 mg, 0.5 9 mmol) and 2-methoxyethylamine (443 mg, 5.9 mmol) in anhydrous 1,4-dioxane (5 ml. ) was heated at 150 ° C for 40 minutes in a sealed vessel under microwave irradiation. The reaction was processed as described in Example 54 to give the title compound (108 mg, 40%) as a creamy solid. NMR (DMSO-d6 + acetic diacid at 100 ° C): 2.00-2.15 (m, 3H), 2. 18 (s, 3H), 2.35 (m, 1H), 3.15 (s, 1H), 3.20-3.40 (m, 4H), 3.65 (m, 1H), 3.75 (m, 1H), 5.35 (d, 1H), 5.55 (s, 1H), 5.85 (s, 1H), 6.55 (s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); m / z 462 [MH] +.

Example 56 6-Methoxycarbonyl-2-f2-f3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl > -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine A mixture of 2- acid. { 2- [3- (pind-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-Methyl-1 H -pyrazol-3-ylamino) pyrimidin-6-yl-carboxylic acid (Method 43) (1.73 g, 4.0 mmol), methanol (300 ml) and 98% sulfuric acid (1 ml) was heated to reflux for 18 hours. The volatiles were removed by evaporation, the residue dissolved in water and the pH of the resulting solution adjusted to a pH of 12 with 10M sodium hydroxide. The aqueous solution was extracted with DCM and purified by chromatography on silica gel, eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (904mg, 51%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.75 (m, 5H), 5.50 (dd, 1H) , 6.05 (s, 1H), 6.70 s, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.88 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 447 [MH] +.

Example 57 6- (N-Methylcarbamoyl) -2-f2-r3- (pyrid-2-M) isoxazol-5-iH-pyrrolidin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 6-methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) lsoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 56) (62.5 mg, 0.14 mmol), 2N of a solution of methylamine in methanol (2.0 ml, 4.00 mmol) and methanol (3.0 ml) was heated at 65 ° C for 1 hour under microwave irradiation. The volatiles were removed by evaporation and the residue was dissolved in DCM and purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10). The purified product was titrated with diethyl ether and the resulting solid was collected through filtration to give the title compound (21 mg, 34%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.75 (m, 1H), 3.85 (m, 1H), 5.50 (d, 1H), 6.10 (s, 1H), 6.70 (s, 1H), 6.90 ( s, 1H), 7.40 (m, 1H), 7.87 (t, 1H), 7.93 (d, 1H), 8.65 (d, 1H); m / z 446 [MH] +.

Example 58 6-Morpholinocarbonyl-2-f2-r3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 6-methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methy1-1H-pyrazol-3-ylamino) pyrimidine (Example 56) (200 mg, 0.45 mmol) and morpholine (0.5 ml, 5.73 mmol) in anhydrous methanol (5.0 ml) ) was heated at 120 ° C for 18 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through the SCX-2 ion exchange column of 50 g of solute. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with diethyl ether. The resulting solid was collected through filtration to give the title compound (120 mg, 52%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.47 (m, 8H), 3.65 (m, 1H), 3.76 (m, 1H), 5.42 (dd, 1H), 6.07 (s, 1H), 6.45 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.60 (d, 1H); m / z 502 [MH] +.

Example 59 6- (N - (2-Methoxyethyl) carbamoyl) -2-f 2 -T3- (p ir id -2-yl) isoxazol-5-ippyrrolidin-1-yl) -4- (5-methyl-1H -pyrazol-3-ylamino) pyrimidine A mixture of 6-methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrmidine (Example 56) (200 mg, 0.45 mmol) and 2-methoxyethylamine (5 ml, 57.2 mmol) was heated to reflux for 18 hours. The reaction mixture was evaporated, the residue was dissolved in methanol and passed through a SCX-2 ion exchange column of 50 g of solute. The column was eluted with methanol to elute any neutral product, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10). The purified product was titrated with diethyl ether and the resulting solid was collected through filtration to give the title compound (78 mg, 36%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.25 (s, 3H), 3.40 (m, 4H), 3.75 (m, 1H), 3.85 (m, 1H), 5.45 (dd, 1H), 6.10 (s, 1H), 6.70 (s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.65 (d, 1H); m / z 490 [MH] +.

Example 60 6- (N-Hydroxycarbamoyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl) -4- (5-methyl-1 H -pyrazole-3-ylamino ) pyrimidine A mixture of 6-methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazoI-5-yl] pyrrolidin-1-yl} 4- (5-methy1-1H-pyrazol-3-ylamino) pyrimidine (Example 56) (200 mg, 0.45 mmol), hydroxylamine monohydrochloride (340 g, 4.86 mmol) and triethylamine (0.80 ml, 5.40 mM) mmoles) in anhydrous methanol (5 ml) was heated to reflux for 18 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (40 mg, 20%) as a foam.

NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.08 (, 3H), 2.15 (s, 3H), 2.37 (m, 1H), 3.74 (m, 1H), 3.80 (m, 1H), 5.54 (dd, 1H), 6.08 (s, 1H), 6.70 (s, 1H), 6.85 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.63 (d, 1H); m / z 448 [MH] +.

Example 61 6-Carbamoyl-2-f2-r3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl) -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine A mixture of 6-methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Example 56) (200 mg, 0.45 mmol) and a solution of 7N ammonia in methanol (7 mL, 49 mmol) was heated to 65 ° C. in a sealed container under microwave irradiation for 1 hour. The reaction mixture was evaporated, dissolved in methanol and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with diethyl ether. The resulting solid was collected through filtration to give the title compound (180.Omg, 93%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.18 (s, 3H), 2.40 (m, 1H), 3.78 (m, 1H), 3.84 (m, 1H) , 5.48 (dd, 1H), 6.10 (s, 1H), 6.70 (s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.62 (d, 1H); m / z 432 [MH] +.

Example 62 S-6-Methoxycarbonyl-2f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl > 4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine A mixture of S-2- acid. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-Methyl-1H-pyrazol-3-ylamino) pyridin-6-ii carboxylic acid (Method 50) (1.73 g, 4.0 mmol), methanol (300 ml) and 98% sulfuric acid (1 ml) was heated to reflux for 18 hours. The volatiles were removed by evaporation, the residue dissolved in water and the pH of the resulting solution adjusted to a pH of 12 with 10M sodium hydroxide. The aqueous solution was extracted with DCM and purified by chromatography on silica gel, eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (904. Omg, 51%).

NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.75 (m, 5H), 5.50 (dd, 1H) , 6.05 (s, 1H), 6.70 s, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.88 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1 HOUR); m / z 447 [MH] +.

Example 63 S-6- (N- (2-Methoxyethyl) carbamoyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl) -4 (5-methyl-1H-pyrazole -3-ylamino) pyrimidine 4- (4,6-Dimethoxy [1, 3,5] triazin-2-yl) -4-methyl-morpholinium chloride (149.3 mg, 0.54 mmol) was added to a mixture of S-acid -2-. { 2- [3- (pyrid-2-yl) lsoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylammon) pyrimidin-6-yl carboxylic acid (Method 50) (200 mg, 0.46 mmol) and anhydrous DMF (10 ml) and the reaction mixture was stirred at room temperature for 0.5 hours until a clear solution was formed (indicative of a successful formation of activated ester). 2-Methoxyethylamine (0.50 ml, 5.75 mmol) was added and the reaction was stirred at room temperature for a further 2 hours. The reaction mixture was then passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10). The purified product was titrated with diethyl ether and the resulting solid was collected through filtration to give the title compound (136mg, 58%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.18 (s, 3H), 2.40 (m, 1H), 3.25 (s, 3H), 3.42 (m, 4H), 3.75 (m, 1H), 3.83 (m, 1H), 5.46 (dd, 1H), 6.10 ( s, 1H), 6.70 (s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.62 (d, 1H); m / z 490 [MH] +.

Example 64 S-6-rN- (2-Methoxyethyl) -N-methylcarbamoy-2-f2-r3- (pyrid-2-yl) -isoxazole-5-pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol -3-ilamino) -pyrimidine 4- (4-chloro, 6-dimethoxy [1, 3,5] triazin-2-yl) -4-methyl-morpholinium (149.3 mg, 0.54 mmol) to a mixture of S-2- acid. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid (Method 50) (200 mg, 0.46 mmol) and anhydrous DMF (10 ml) and the reaction mixture was stirred at room temperature for 0.5 hours until a clear solution was formed. N- (2-Methoxyethyl) -N-methylamine (0.5 ml) was added and the reaction was stirred at room temperature for a further 2 hours. The reaction mixture was then passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10). The purified product was then re-purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarization to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (90 mg, 37%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.18 (s, 3H), 2.37 (m, 1H), 2.95 (s, 2H), 3.18 (s, 3H) , 3.40 (m, 3H), 3.50 (m, 1H), 3.69 (m, 1H), 3.76 (m, 1H), 5.45 (dd, 1H), 6.38 (s, 1H), 6.60 (s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.88 (d, 1H), 8.58 (d, 1H); m / z 504 [MH] +.

Example 65 S-6-fN- (2- (Acetylamino) ethyl) carbamoyl-2-f3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-yl) -4- (5-methyl-1 H-Pi Razo I -3-I Lamino) Pyrimidine 4- (4,6-dimethoxy [1, 3,5] triazin-2-ll) -4-methyl-morpholinium chloride (149.3mg, 0.54) mmoles) to a mixture of S-2- acid. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) -pyrimidin-6-yl carboxylic acid (Method 50) (200 mg, 0.46 mmol) and anhydrous DMF (5 ml) and the reaction mixture was stirred at room temperature for 0.5 hours until a clear solution formed. N-Acetyl-1,2-ethylenediamine (0.22 ml, 2.29 mmol) was added and the reaction was stirred at room temperature for a further 2 hours. The reaction mixture was filtered, the volatiles were removed from the filtrate through evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with diethyl ether and collected by filtration to give the title compound (115.7 mg, 49%).

NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.80 (s, 3H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.25 (m, 2H) 3.35 (m, 2H), 3.77 (m, 1H), 3.85 (m, 1H), 5.53 (dd, 1H), 6.10 (s, 1H), 6.71 (s, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.61 (d, 1H); m / z 517 [MH] +.

Examples 66 to 76 Examples 66 to 76 were prepared by an analogous method to that described for Example 65 using S-2- acid. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-llamino) -pyrimidin-6-yl carboxylic acid (Method 50) and the appropriate amine.

Example 66 S-6-fN-r2- (2-Hydroxyethoxy) ethylcarbamoyl} -2-f2-r3- (pyrid-2-yl) -isoxazol-5-iH-pyrrolidin-1-yl) -4- (5-methy1-1H-pyrrazol-3-ylamino) -pyrimidine Starting material amine: 2- (2-hydroxyethoxa) ethylamine. Yield: 123 mg, 49%. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.40 (m, 2H) 3.45 (m, 2H), 3.55 (m, 2H), 3.75 (m, 1H), 3.85 (m, 1H), 5.47 (dd, 1H), 6.10 (s, 1H), 6.71 (s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 520 [MH] +.

Example 67 S -6-TN - ((R) -2-H idroxypropyl) carbam oi II -2-f 2 -T3- (pyrid-2-yl) is oxazol-5-illpyrrolidin-1 -i I) -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine Amine starting material: (R) -2-hydroxypropylamine. Yield: 137 mg, 61%. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.05 (d, 3H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.46 (m, 2H), 3.75 (m, 1H), 3.85 (m, 1H), 3.90 (m, 1H), 5.44 (dd, 1H), 6.12 (s, 1H), 6.71 (s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 490 [MH] +.

Example 68 S-6-rN- (4-Hydroxybutyl) carbamoin-2-f2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl) -4- (5-methyl-1 H- pyrazol-3 -ilamino) pyrimidine Amine starting material: 4-hydroxybutylamine. This product was isolated without titration (153 mg, 66%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.45 (m, 2H), 1.55 (m, 2H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (, 1H), 3.25 (m, 2H), 3.40 (t, 2H), 3.76 (m, 1H), 3.84 (m, 1H), 5.44 (dd, 1H), 6.12 (s, 1H), 6.70 (s, 1H), 6.88 (s, 1H), 7.39 ( m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.61 (d, 1H); m / z 504 [MH] +.

Example 69 S-6-rN - ((2R) -2,3-Pihydroxypropyl) carbamoyl1-2-f2-r3- (pyrid-2-yl) -isoxazol-5-inpyrrolidin-1-yl > -4- (5-Methyl-1 H -pyrazol-3-ylamino) -pyrimidine Amine starting material: (2R) -2,3-dihydroxypropylamine. This product was isolated by titration with water (135 mg, 58%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.15 (m, 3H), 2.19 (s, 3H), 2.43 (m, 1H), 3.25 (m, 1H), 3.43 (m, 3H) , 3.65 (m, 1H), 3.76 (m, 1H), 3.85 (m, 1H), 5.50 (dd, 1H), 6.11 (s, 1H), 6.76 (s, 1H), 6.92 (s, 1H), 7.42 (m, 1H), 7.87 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 506 [MH] +.

Example 70 S-6-rN- (Carbamoylmethyl) carbamop-2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine This product was prepared using glycinimide hydrochloride and triethylamine (7.0 equivalents) and isolated without titration (141 mg, 62%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.18 (s, 3H), 2.40 (m, 1H), 3.80 (m, 2H), 3.85 (m, 2H), 5.50 (d, 1H), 6.08 (s, 1H), 6.74 (s, 1H), 6.90 ( s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 506 [NH] +.

Example 71 S-6 - ((3R) -3-Hydroxypyrrolidin-1-ylcarbonyl) -2-f2-r3- (pyrid-2-yl) -isoxazole-5-pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) -pyrimidine Amine starting material: (2R) -3-hydroxypyrrolidine. This product was isolated with titration (129 mg, 56%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.70 (m, 2H), 2.10 (m, 3H), 2.18 (s, 3H), 2.38 (m, 1H), 3.50 (m, 2H), 3.65 (m, 2H), 3.81 (m, 2H), 4.23 (s, 1H), 5.40 (dd, 1H), 6.07 (s, 1H), 6.56 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (s) t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 502 [MH] +.

Example 72 S-6-fN-r2- (Methylthio) ethypcarbamoyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol -3-ilamino) pyrimidine Amine starting material: 2- (methylthio) ethylamine. This product was isolated with titration (147 mg, 63%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.02 (s, 3H), 2.10 (m, 3H), 2.17 (s, 3H), 2.38 (m, 1H), 2.60 (t, 2H), 3.45 (m, 2H), 3.75 (m, 1H), 3.83 (m, 1H), 5.46 ( dd, 1H), 6.07 (s, 1H), 6.70 (s, 1H), 6.89 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.61 (d, 1H); m / z 506 [MH] +.

Example 73 S-6- (N-Cyclopr opi I carbamoyl) -2-f 2 -f 3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl > -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Amine starting material: cyclopropylamine. This product was isolated with titration (113 mg, 52%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 0.50 (m, 1H), 0.60 (m, 1H), 0.67 (m, 2H), 2.10 (m, 3H), 2.19 (s, 3H) , 2.40 (m, 1H), 2.77 (m, 1H), 3.75 (m, 1H), 3.83 (m, 1H), 5.43 (dd, 1H), 6.12 (s, 1H), 6.70 (s, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.62 (d, 1H); m / z 472 [MH] +.

Example 74 S-6- (N-Cyclopentylcarbamoyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine Amine starting material: cyclopentylamine. This product was isolated with titration (162 mg, 70%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.30-1.91 (m, 8H), 2.12 (m, 3H), 2.19 (s, 3H), 2.43 (m, 1H), 3.75 (m, 1H), 3.85 (m, 1H), 4.11 (m, 1H), 5.43 (dd, 1H), 6.15 (s, 1H), 6.70 (s, 1H), 6.88 (s, 1H), 7.40 (m, 1H) ), 7.86 (t, 1H), 7.92 (d, 1H), 8.63 (d, 1H); m / z 500 [MH] +.

Example 75 S-6- (Azetidin-1-ylcarbonyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-yH-pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine Amine starting material: azetidine. This product was isolated with titration (153 mg, 70%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.10 (s, 5H), 2.40 (m, 1H), 3.70 (m, 1H), 3.85 (m, 1H), 4.02 (m, 2H), 4.40 (m, 1H), 4.57 (m, 1H), 5.45 (dd, 1H), 6.10 (s, 1H), 6.65 (s, 1H), 6.80 (s, 1H), 7.44 (m, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 472 [MH] +.

Example 76 S-6- (N-Methylcarbamoyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino ) pyrimidine This product was prepared using a 2N solution of methyamine in THF (10.0 equivalents) and and was isolated without titration (145 mg, 70%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.18 (s, 3H), 2.38 (m, 1H), 2.77 (s, 3H), 3.75 (m, 1H) , 3.85 (m, 1H), 5.47 (dd, 1H), 6.08 (s, 1H), 6.67 (s, 1H), 6.85 (s, 1H), 7.38 (m, 1H), 7.82 (t, 1H), 7.90 (d, 1H), 8.58 (d, 1H); m / z 446 [MH] +.

Example 77 6- (N-Aminocarbamoyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Hydrazine monohydrate (1.6 ml, 20.6 mmol) was added to a mixture of 6-methoxycarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-l] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 56) (1.54 g, 3.45 mmol) in methanol (20.0 ml) at room temperature. The resulting reaction mixture was heated to reflux for 1 hour then allowed to cool. The resulting solid was collected through filtration and washed with methanol to give the title compound (1058, 68.3%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.17 (s, 3H), 2.38 (m, 1H), 3.75 (m, 1H), 3.82 (m, 1H), 5.50 (dd, 1H), 6.06 (s, 1H), 6.68 (s, 1H), 6.86 (s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.61 (d, 1H); m / z 447 [MH] +.

Example 78 6-riM - (Acetyl am i no) carbamo i II -2-f 2-j "3- (pi rid -2 -yl) isoxazol-5-ill-pyrrolidin-1-yl> -4- ( 5-methyl-1H-pyrazol-3-ylamine) pyrimidine A solution of 6- [N- (acetylamino) carbamoyl] -2-. {2- 2- [3- (pip'd-2-yl) isoxazole-5- il] pyrrolidin-1-yl.} -4- (2-acetyl-5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Method 51) (170 mg, 0.32 mmol) in methanol (10 ml) and 2N Sodium hydroxide (0.5 ml, 1.0 mmol) was stirred at room temperature for 0.5 hours The resulting precipitate was collected through filtration to give the title compound (150 mg, 96%). NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.88 (s, 3H), 2.08 (m, 3H), 2.18 (s, 3H), 2.40 (m, 1H), 3.75 (m, 1H), 3.84 (m, 1H), 5.55 (dd, 1H), 6.10 (s, 1H), 6.70 ( s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 489 [MH] +.

Example 79 6- (5-Methyl-ri, 3.41-oxadiazol-2-yl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl) -4 - (5 -methyl-1 H-pyrazol-3-ylamino) pyrimidine (Methoxycarbonylsulfamoyl) thioethylammonium salt (parental salt) (90 mg, 3.76 mmol) was added to a solution of 6- [N- (acet. Lamino) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-Ll] pyrrolidin-1-yl} -4- (2-acetyl-5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Method 51) (500 mg, 0.94 mmol) in anhydrous THF (20 mL) and the reaction warmed refluxed for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol (5 ml) and a 2N aqueous sodium hydroxide solution (1.0 ml) and stirred at room temperature for 15 minutes. The methanol was removed by evaporation and the pH of the resulting solution was adjusted to a pH of 7 with 1N hydrochloric acid. The volatiles were removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10). The purification product was then titrated with diethyl ether and collected by filtration to give the title compound (200 mg, 52%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.18 (s, 3H), 2.38 (m, 1H), 2.53 (s, 3H), 3.76 (m, 1H), 3.84 (m, 1H), 5.50 (dd, 1H), 6.08 (s, 1H), 6.72 ( s, 1H), 7.02 (s, 1H), 7.39 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.61 (d, 1H); m / z 471 [MH] +.

Example 80 6-H id roxymethyl-2-f 2 -r 3 - (pyrid-2-yl) isoxazole-5-yl pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine A solution of 2M lithium borohydride in THF (22.4 ml, 44.8 mmol) was added to a mixture of 6-methoxycarbonyl-2. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) -pyrimidine (Example 56) (4.0 mg, 8.96 mmol) in anhydrous THF (200 ml). The reaction mixture was stirred at room temperature for 3 hours and then heated to reflux for 1 hour. The mixture was allowed to cool and methanol was added until the effervescence ceased, then a 4M solution of hydrogen chloride in dioxane (30 ml) was added and the mixture was heated to reflux for 1 hour. The volatiles were removed by evaporation, the residue was dissolved in water and the resulting solution was adjusted to a pH of 9 through the careful addition of a 10M solution of aqueous sodium hydroxide. The aqueous mixture was extracted with DCM and purification by chromatography on silica gel, eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (3.4 g, 91%). NMR (DMSO-de + d4-acetic acid at 100 ° C) * 2.10 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 3.70 (m, 1H), 3.77 (m, 1H), 4.23 (dd, 2H), 5.45 (dd, 1H), 6.01 (s, 1H), 6.41 ( s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.62 (d, 1H); m / z 419 [MH] +.

Example 81 6- (Morpholinomethyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 6 - [(4-methylphenylsulfonyloxy) methyl] -2-. { 2 ~ [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-Methyl-2-N- [4-methyphenylsulfonyl] -1H-pyrazol-3-ylamino) pyrimidine (Method 52) (214 mg, 0.295 mmole) and morpholine (5 ml, 83.2 mmol) was heated to reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol (10 ml) and a 10M solution of aqueous sodium hydroxide (3 ml). The mixture was heated at 60 ° C for 1 hour. The volatiles were removed by evaporation and the residue was dissolved in water, extracted with dichloromethane. The extracts were combined and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane (100%) and then diethyl ether (100%). The purified product was titrated with diethyl ether and collected by filtration to give the title compound (125 mg). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 2.57 (m, 4H), 3.40 (m, 2H) , 3.55 (m, 4H), 3.68 (m, 1H), 3.78 (m, 1H), 5.45 (dd, 1H), 6.05 (s, 1H), 6.38 (s, 1H), 6.64 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 488 [MH] +.

Example 82 6- (4-Meti I piperazin-1-ylmethyl) -2-f 2-13 - (pyrid-2-yl) isoxazol-5-yl-1-pyrrolidin-1-yl) -4- (5-methyl-1H-pyrazole- 3-ylamino) pyrimidine A mixture of 6 - [(4-methylphenylsulfonyloxy) methyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl] -4- (5-methyl-2-N- [4-methyphenylsulfonyl] -1 H- pyrazol-3-ylamino) pyrimidine (Method 52) (214 mg, 0.295 mmol) and 1-methylpiperazine (3.0 mL, 27.1 mmol) was heated to reflux for 4 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (107 mg, 71%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.18 (s, 3H), 2.35 (m, 4H), 2.60 (m, 8H), 3.34 (d, 2H) , 3.67 (m, 1H), 3.77 (m, 1H), 5.43 (dd, 1H), 6.06 (s, 1H), 6.33 (s, 1H), 6.62 (s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.92 (d, 1H), 8.63 (d, 1H); m / z 501 [MH] +.

Example 83 6- (Methalaminomethyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl > 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 6 - [(4-methylphenylsulfonyloxy) methyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-Methyl-2-N- [4-methylphenyl] -1- sulfonyl] -1H-pyrazol-3-ylamino) pyrimidine (Method 52) (190 mg, 0.26 mmol) and a solution of 2N methylamine in THF ( 5 ml, 10 mmol) was heated at 90 ° C in a sealed container under microwave irradiation for 1 hour. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (87.1 mg, 77%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 2.60 (s, 3H), 3.75 (m, 1H) , 3.82 (m, 1H), 3.92 (dd, 2H), 5.53 (dd, 1H), 6.06 (s, 1H), 6.30 (s, 1H), 6.67 (s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 432 [MH] +.

Example 84 6- (Pyrrolidin-1-ylmethyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 6 - [(4-methylphenylsulfonyloxy) methyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-2-N- [4-methylenephosphonyl] -1H-pyrazol-3-ylamino) pyrimidine (Method 52) (214 mg, 0.295 mmol) and pyrrolidine (3.0 ml) , 27 mmol) was heated at 95 ° C for 24 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (77.6 mg, 52%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.18 (s, 3H), 2.36 (m, 1H), 3.22 (m, 4H), 3.70 (m, 1H) , 3.80 (m, 1H), 4.05 (dd, 2H), 5.49 (dd, 1H), 6.07 (s, 1H), 6.35 (s, 1H), 6.67 (s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); m / z 472 [MH] +.

Example 85 6-Aminomethyl-2-f2-r3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl} -4- (5-Methyl-1H-pyrazol-3-ylamino) pyrimidine Sodium azide (44 mg, 0.68 mmol) was added to a solution of 6 - [(4-methylphenylsulfonyloxy) methyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1-N- [4-methylphenylsulfonyl] -1H-pyrazol-3-ylamino) pyrimidine (Method 52) (159 mg, 0.22 mmol) in anhydrous DMF (2.0 ml) and The mixture was heated at 110 ° C for 1.5 hours. Then triphenylphosphine (282.0 mg, 1.08 mmol) and water were added (0.10 ml) and the reaction mixture was heated at 100 ° C for 1 hour.

The mixture was allowed to cool and then passed through an SCX-2 ion exchange column of 50 g of solute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The volatiles were removed by evaporation and the residue was dissolved in methanol (5 ml) and a 10M solution of aqueous sodium hydroxide (0.5 ml) and stirred for 1 hour. The volatiles were removed by evaporation and the residue was dissolved in water, and extracted with DCM. The extracts were combined, the solvent was removed by evaporation and the residue was purified by chromatography on silica gel, eluting with DCM / methanol / aqueous ammonia (100: 0: 0 increasing in polarity to 80: 20: 1 ) to give the title compound (48.5mg, 53 ° 10) as a solid. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.08 (m, 3H), 2.19 (s, 3H), 2.35 (m, 1H), 3.75 (m, 1H), 3.82 (m, 3H), 5.55 (d, 1H), 6.05 (s, 1H), 6.32 (s, 1H), 6.69 ( s, 1H), 7.42 (m, 1H), 7.87 (t, 1H), 7.95 (d, 1H), 8.63 (d, 1H); m / z 418 [MH] +.

Example 86 S-6-Hydroxymethyl-2-f2-l * 3- (pyrid-2-yl) isoxazol-5-ylpyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine S-6-methoxycarbonyl-2 was treated. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 1-4- (5-methyl-1H-pyrazol-3-ylammon) pyrimidine (Example 62) was added via the method described in Example 80 to give the title compound. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 3.70 (m, 1H), 3.77 (m, 1H) , 4.23 (dd, 2H), 5.45 (dd, 1H), 6.01 (s, 1H), 6.41 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.62 (d, 1H); m / z 419 [MH] +.

Example 87 S-6-Ethoxymethyl-2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl > -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine A solution of 1M of lithium bis (trimethylsilli) amide in THF (5.0 ml, 5.0 mmol) was added to a mixture of S-6-chloromethyl -2-. { 2- [3- (pyrid-2-yl) -soxazoI-5-yl] pyrrolidin-1-yl} -4 (5-methyl-2-N- [4-methylphenylsulfonylamino] -1H-pyrazol-3-ylamino) pyrididine (Method 53) (240 mg, 0.41 mmol) in anhydrous ethanol (30 ml). The reaction mixture was then heated at 100 ° C for 48 hours and allowed to cool. A small volume of water was added, the volatiles were removed by evaporation. The residue was purified by chromatography on silica gel, eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (29 mg, 16%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.15 (t, 3H), 2.05 (m, 3H), 2.18 (s, 3H), 2.35 (s, 1H), 3.52 (q, 2H), 3.67 (m, 1H), 3.76 (m, 1H), 4.20 (dd, 2H), 5.42 (dd, 1H), 6.02 (s, 1H), 6.38 (s, 1H), 6.62 (s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.92 (m, 1H), 8.62 (d, 1H); m / z 447 [MH] +.

EXAMPLE 88 S-6-r (2-Methoxyethoxy) methyl1-2-f2-r3- (pyrid-2-yl) isoxazol-5-ip-pyrrolidin-1 -i l} -4- (5-methi 1-1 H-irazol-3 -ilamino) pyrimidine A solution of 1M bys (trimethylsilyl) amide lithium in THF (5.0 ml, 5.0 mmol) was added to a mixture of S-6-chloromethyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-2-N- [4-methyphenylsulfonylamine] -1H-pyrazol-3-ylamino) pyrimidine (Method 53) (240 mg, 0.41 mmol) in anhydrous 2-methoxyethanol (30 ml). The reaction mixture was then heated at 150 ° C for 1.5 hours in a sealed vessel under microwave irradiation. A small volume of water was added, the volatiles were removed by evaporation. The residue was purified by chromatography on silica gel, eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (69.0 mg, 43%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.18 (s, 3H), 2.35 (s, 1H), 3.25 (s, 2H), 3.48 (t, 2H) , 3.60 (t, 2H), 3.68 (m, 1H), 3.76 (m, 1H), 4.25 (dd, 2H), 5.42 (dd, 1H), 6.05 (s, 1H), 6.38 (s, 1H), 6.65 (s, 1H), 7.42 (m, 1H), 7.86 (t, 1H), 7.92 (m, 1H), 8.63 (d, 1H); m / z 477 [MH] +.

Example 89 S-5-Chloro-2-f2-r3- (pyrazin-2-yl) isoxazol-5-yH-pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 2,5-dichloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyridinimine (WO Method 20) 03/04133) (195 mg, 0.72 mmol), S-2- [3- (2-pyrazinyl) isoxazole-5yl] pyrrolidine (Method 55) (171.5 mg, 0.79 mmol), N, N-dusopropylethylamine (0.28) ml, 1.58 mmol) and n-hexanol (10.0 ml) was heated at 125 ° C for 18 hours. Then 3- (2-aminoethylamino) propyl functionalized with silica gel (500 mg) was added and the reaction mixture was heated at 140 ° C for a further 2 hours. The reaction mixture was passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10). The purified product was titrated with diethyl ether and collected by filtration to give the title compound (100 mg, 31%) NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.28 (m, 2H) , 1.48 (m, 2H), 2.68 (m, 2H), 2.78 (m, 1H), 3.01 (m, 1H), 4.27 (m, 1H), 4.41 (m, 1H), 6.05 (d, 1H), 7.29 (s, 1H), 8.60 (s, 1H), 9.25 (m, 2H), 9.73 (s, 1H); m / z 450 [MH] +.

Example 90 S-6-Methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- 2-r3- (pyrazin-2-yl) -isoxazol-5-inpyrrolidin-1-yl} pyrimidine A mixture of S-2-chloro-6-methyl-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 56) (250 mg, 1.12 mmol), S-2- [ 3- (2-pyrazinyl) isoxazol-5-yl] pyrrolidine (Method 55) (266 mg, 1.23 mmol) and N, N-düsopropylethylamine (0.22 mL, 2.52 mmol) in n-hexanol (5 mL) was heated to 150 ° C in a sealed container under microwave irradiation for 6 hours. The solvent was removed by evaporation and the residue was dissolved in methanol and poured onto a SCX-2 exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (319.6 mg, 71%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.12 (s, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.69 (m, 1H) , 3.78 (m, 1H), 5.45 (dd, 1H), 5.98 (s, 1H), 6.18 (s, 1H), 6.71 (s, 1H), 8.68 (m, 2H), 9.12 (s, 1H); m / z 404 [MH] +.

EXAMPLE 91 S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-f2-r3- (pyrazin-2-yl) isoxazole-5-y-pyrrolidin-1-yl} pyrimidine A mixture of S-2,6-d? chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamine) pyrimidine (Method 57) (1.5 g, 5.55 mmole), S-2- [3- (2-pyrazinyl) isoxazol-5-yl] pyrrolidine (Method 55) (1.32 g, 6.11 mmol) and N, N-disopropylethylamine (0.92 ml, 6.66 mmol) in n-butanol (25 ml) heated at 80 ° C for 4 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (750 mg, 30% ). NMR (DMSO-de + d4-acetic acid at 100 ° C): 0.63 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.05 (m, 2H), 2.15 (m, 1H) , 2.38 (m, 1H), 3.67 (m, 1H), 3.77 (m, 1H), 5.43 (dd, 1H), 5.92 (s, 1H), 6.35 (s, 1H), 6.72 (s, 1H), 8.68 (m, 2H), 9.12 (s, 1H); m / z 450 [NM] +.

EXAMPLE 92 S-4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -2-f 2 -T 3 - (pi reason -2-yl) -isoxazol-5-ippyrrolidin-1-yl) -6 - (2-methoxyethylamino) pyrimidine A mixture of S-6-chloro-4- (5-cyclopropyl-1 H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine (Example 91) (215 mg, 0.48 mmol) and 2-methoxyethylamine (4.0 ml, 46.1 mmol) were heated at 150 ° C in a sealed container under microwave irradiation for 2 hours. The solvent was removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (78 mg, 33%). NMR (DMSO-de + acetic diacid at 100 ° C): 0.63 (m, 2H), 0.85 (m, 2H), 1.80 (m, 1H), 2.10 (m, 3H), 2.35 (m, 1H), 3.20 (s, 3H), 3.35 (m, 4H), 3.65 (m, 1H), 3.77 (m, 1H), 5.43 (dd, 1H), 5.52 (s, 1H), 5.80 (s, 1H), 6.72 (s, 1H), 8.68 (m, 2H), 9.12 (s, 1H); m / z 489 [MH] +.

Example 93 S-6-Methylamino-f2-r3- (pyrazin-2-yl) isoxazol-5-ippi rolidin-1-yl) -4- (5-cyclopropyl-1 H -pyrazol-3-ylamide) pyrimidine One mixture of S-6-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine (Example 91) (215 mg, 0.48 mmol) and a 2M solution of methylamine in THF (5.0 ml) were heated to 150 ° C in a sealed container under microwave irradiation for 1.5 hours. The solvent was removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (100 mg, 50%).

NMR (DMSO-de + d4-acetic acid at 100 ° C: 0.63 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.10 (m, 3H), 2.36 (m, 1H), 2.68 (s, 3H), 3.67 (m, 1H), 3.75 (m, 1H), 5.44 (dd, 1H), 5.60 (s, 1H), 5.80 (s, 1H), 6.72 (s, 1H), 8.68 (m, 2H), 9.13 (s, 1H); m / z 445 [MH] +.

Example 94 S-4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -6-methoxy-f2-r3- (pyrazin-2-yl) isoxazole-5-ippyrrolidin-1-yl) pyrimidine A solution of 1.33M sodium methoxide in anhydrous methanol (3.0 ml, 2.25 mmol) was added to a mixture of S-6-chloro-4- (5-cyclopropyl-1H-plrazoi-3-ylamino) -2-. { 2- [3 (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine (Example 91) (200 mg, 0.45 mmol) in anhydrous methanol (2.0 ml) and the reaction mixture was heated to 120 ° C in a sealed container under microwave irradiation for 1.5 hours. The solvent was removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M methanolic ammonia to elute the product. The solvent was removed through evaporation to give the title compound (87.5 mg, 44%). NMR (DMSO-de + d4-acetic acid at 100 ° C: 0.64 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.10 (m, 3H), 2.40 (m, 1H ), 3.71 (m, 4H), 3.78 (m, 1H), 5.45 (dd, 1H), 5.72 (s, 1H), 5.89 (s, 1H), 6.72 (s, 1H), 8.68 (m, 2H), 9.15 (s, 1H); m / z 446 [NM] +.

Example 95 6-Pyrrolidin-1-yl-2-f2-r3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine A mixture of 6-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine (Example 17) (250 mg, 0.59 mmol), pyrrolidine (0.5 ml, 5.98 mmol) and anhydrous 1,4-dioxane (5.0 ml) was heated at 100 ° C in a sealed container under microwave irradiation for 1 hour. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an SCX-2 ion exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with diethyl ether and collected by filtration to give the title compound (145 mg, 54%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.85 (s, 4H), 2.08 (m, 3H), 2.17 (s, 3H), 2.35 (m, 1H), 3.25 (m, 2H) 3.33 (m, 2H), 3.69 (m, 1H), 3.80 (m, 1H), 5.40 (dd, 1H), 5.85 (s, 1H), 6.71 (s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.61 (d, 1H); m / z 458 [NM] +.

Example 96 S-6-C lo ro-4- (5-met i 1-1 H-pyrazole -3-i lamin o) -2-T2-f3- (pi rid-2-yl) -isoxazole-5- Pyrrolidin-1-yl pyrimidine A mixture of 2,6-dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 29) (14.36 g, 59 mmol), S -2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidine (Method 42) (12.69 g, 59 mmole) and N, N-diisopropylethylamine (14.5 ml, 83 mmole) in xylene (380 ml) it was heated at 80 ° C for 2 days. The solvent was removed by evaporation. The residue was titrated with ether and water and the crude desolid product was collected through filtration, washed with water and dried. The ether was evaporated from the filtrate and DCM was added to the aqueous mixture. An insoluble material was removed through filtration, the DCM layer was separated and dried (MgSO4). The originally isolated crude product was dissolved in DCM and added to this solution. The solution was concentrated through evaporation and allowed to stand for 2 days. The resulting solid was collected through filtration, washed with a minimum of DCM and dried to give the title compound (13.3g, 53%) as white crystals. NMR (DMSO): 2.08 (m, 2H), 2.18 (m, 4H), 3.74 (m, 2H), 5.47 (d, 1H), 5.98 (s, 1H), 6.4 (s, 1H), 6.67 (s) , 1H), 7.43 (m, 1H), 7.9 (m, 2H), 8.65 (d, 1H), 8.88 (br s, 1H), 11.44 (br s, 1H); m / z 423 [NM] +.

Example 97 S-6- (2, 2.6.6-Tetramet i I piperidin-4-i lam no) -2-f 2-T3- (p ir id -2-yl) -isoxazol-5-n-pyrrolidin-1 -il > -4- (5-methyl-1 H -pyrazol-3-yl-amino) pyrimidine A mixture of S-6-chloro-2-. { 2- [3- (pip'd-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) (200 mg, 0.47 mmol), 4-amino-2, 6,6-tetramethylpiperidine (0.4 ml, 2.33 mmol) and Anhydrous 1,4-dioxane (5.0 ml) was heated at 150 ° C in a sealed container under microwave irradiation for 4 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 exchange column of 50 g of isolute. The column was eluted with methanol to elute any neutral product, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (122 mg, 47%). NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.25-1.45 (m, 12H), 2.01 (m, 3H), 2.17 (s, 3H), 2.35 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 4.23 (m, 1H), 5.40 (dd, 1H) ), 5.89 (s, 1H), 6.60 (s, 1H), 7.40 (m, 1H), 7.87 (t, 1H), 7.93 (d, 1H), 8.63 (d, 1H); m / z 543 [MH] +.

Example 98 S-6-Iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) isoxazol-5-y-pyrrolidin-1-yl) pyrimid S-6-Chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (2.0 g, 4.7 mmol), sodium iodide (3.9 g, 26 mmol) in hydroiodic acid (25 ml) at 50 ° C for 3 days. The reaction mixture was allowed to cool and was emptied on ice and basified with a 20% aqueous sodium hydroxide solution and extracted with DCM. The extracts were combined, dried (MgSO4) and the solvent was evaporated to give the title compound (2 g, 83%). NMR (DMSO): 1.9-2.1 (m, 3H), 2.16 (s, 3H), 2.28-2.40 (m, 1H), 3.45-3.60 (m, 1H), 3.68-3.80 (m, 1H), 5.35 ( d, 1H), 5.75 (s, 1H), 5.84 (s, 1H), 6.75 (s, 1H), 7.45 (d, 1H), 7.868.0 (m, 2H), 8.63 (d, 1H), 9.52 (s, 1H); m / z 515 [MH] + Example 99 SE-6-r3- (tert-Butoxycarbonylamino) prop-1-en-1-p-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) ) isoxazol-5-yl) pyrrolidin-1-yH-pyrimidine [2,3-Dihydroxy-2,3-dimethylbutane] boronate ester of 3-tert-butoxycarbonylamino) prop-1-en-1-yl (Method 58) (938 mg, 3. 5 mmole) to a mixture of S-6-iodo-4 (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) (300 mg, O.dmmoles), tetraquiis (triphenylphosdine) palladium (O) (27 mg, 0.02 mmol) and a 2M solution of aqueous sodium carbonate (1.5 ml) in toluene (8 ml) and ethanol (4 ml) and the mixture was heated to 140 ° C in a sealed container under microwave irradiation for 15 minutes. The mixture was extracted with EtOAc and the extracts were combined, washed with water and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 96: 4) to give the title compound (188 mg, 60%). NMR (DMSO): 1.45 (s, 9H), 2.05-2.18 (m, 2H), 2.20 (s, 3H), 2. 35-2.46 (m, 1H), 2.9-53.0 (m, 2H), 3.74-3.9 (m, 4H), 5.5 (d, 1H), 6. 10 (s, 1H), 6.22 (d, 1H), 6.30 (s, 1H), 6.58-6.71 (m, 3H), 7.45 (dd, 1H), 7.90-8.0 (dd, 2H), 8.65 (d, 1H), 8.90 (s, 1H), 11.55 (s, 1H); m / z 544. [MH] + Examples 100 and 101 Examples 100 and 101 were prepared by an analogous method to that described in Example 99.

EXAMPLE 100 S-6-Ethenyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) -soxazol-5-yl1-pyrrolidin-1 -l) pyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and [2,3-dihydroxy-2,3-dimethyloltane] vinylboronate ester. The product was titrated with ether / DCM / hexane to give the title compound (82 mg, 47%). NMR (DMSO): 2.02-2.12 (m, 3H), 2.21 (s, 3H), 2.35-2.40 (m, 1H), 3.69-3.80 (m, 2H), 5.40 (d, 1H), 5.49 (dd, 1H), 6.08 (s, 1H), 6. 15 (d, 1H), 6.29 (s, 1H), 6.40-6.50 (m, 1H), 6.66 (s, 1H), 7.44 (dd, 1H), 7.95 (m, 2H), 8.61 (s, 1H), 8.90 (s, 1H), 11.50 (s, 1H); m / z 415 [MH] + Example 101 SE-6- (3-Hydroxyprop-1-en-1-yl) -4- (5-methyl-1 H -pyrazol-3 -i I amino) -2 -r 2 -f 3 - (pyrid-2 il) isoxazol-5-yl > pyrrolidin-1-ippyrimidine Starting materials: S-6-iodo-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and [2,3-dihydroxy-2,3-d-methylbutane] ester 3-acetoxyprop-1-en-1-yl] boronate. The product was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2) to give the title compound (19 mg, 7% ). NMR (DMSO): 2.05-2.16 (m, 3H), 2.19 (s, 3H), 2.34-2.42 (m, 1H), 3.70-3.85 (m, 2H), 4.16 (dd, 2H), 4.50 (t, 1H), 5.49 (d, 1H), 6.08 (s, 1H), 6.25-6.32 (m, 2H), 6.69 (s, 1H), 6.75-6.82 (m, 1H), 7.45 (dd, 1H), 7.88 -7.96 (m, 2H), 8.67 (d, 1H), 8.88 (s, 1H), 11.52 (s, 1H); m / z 445 [MH] +.

Example 102 S-6- | "3- (te r-Butoxycarbonylamino) prop-1-ill -4 - (5-methyl-1 H -pyrazol-3-ylamino) -2-f2f3- (pyrid-2-yl) isoxazol-5-yl> pyrrolidin-1-n-pyrimidine A solution of SE-6- [3-tert-butoxycarbonylamino) prop-1-en-1-y] -4- (5-methyl-1H-pyrazole- 3-ylamino) -2- [2-. {3- (pyrid-2-yl) isoxazol-5-yl.} Pyrrolidin-1-yl] pyrimidine (Example 99) (84 mg, 0.15 mmol) , p-toluenesulfoniihydrazide (259 mg, 1.4 mmol) in dimethyl ethyl ether (5 ml) was heated to reflux and sodium acetate (240 mg, 2.9 mmol) in water (5 ml for 2 hours and the mixture was heated to pH) was added. reflux for 18 hours The mixture was diluted with EtOAc and washed with water, then brine, dried (MgSO 4) and the solvent was removed by evaporation The residue was dissolved in methanol and emptied onto an exchange column of ion SCX2 (10 g) The impurities were exuted with methanol and then the product was eluted with 7M of methanolic ammonia.The solvent was removed by evaporation to give r the title compound (80 mg, 95%). NMR (DMSO): 1.38 (s, 9H), 1.68-1.78 (m, 2H), 2.04-2.18 (m, 3H), 2.20 (s, 3H), 2.30-2.40 (m, 3H), 3.65-3.80 ( m, 2H), 5.45 (d, 1H), 6.02 (s, 1H), 6.20 (s, 1H), 6.28 (s, 1H), 6.68 (s, 1H), 7.45 (dd, 1H), 7.88-7.98 (m, 2H), 8.68 (d, 1H), 8.76 (s, 1H), 11.5 (s, 1H); m / z 546 [MH] +.

Example 103 S-6 r3-Aminoprop-1-p-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) isoxazol-5-yl > pyrrolidin-1-inpyrimidine S-6- [3-tert-butoxycarbonylamino) prop-1-yl] -4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 102) (80 mg, 0.15 mmole) in DCM of about 0 to 5 ° C. Trifluoroacetic acid (TFA) (1 ml) was added and the mixture was stirred at 5 ° C for 1 hour and then for 1.5 hours at room temperature. The volatiles were removed by evaporation and the residue was dissolved in methanol and poured onto an SCX2 ion exchange column (10 g). The impurities were eluted with methanol and then the product was eluted with 7M of methanolic ammonia. The solvent was removed by evaporation to give the title compound (40 mg, 63%). NMR (DMSO): 1.62-1.70 (m, 2H), 2.04-2.15 (m, 2H), 2.19 (s, 3H), 2.32-2.48 (m, 3H), 2.50-2.60 (m, 2H), 3.68-3.80 (m, 2H), 5.49 (d, 1H), 6.05 (s, 1H), 6.20 (s, 1H) , 6.65 (s, 1H), 7.45 (dd, 1H), 7.85-7.95 (m, 2H), 8.66 (d, 1H), 8.73 (s, 1H); m / z 446 [MH] +.

EXAMPLE 104 SE-6- | "3-Aminoprop-1-en-1-iH-4- (5-methyl-1 H -pyrazol-3-yl-amino) -2-r2-f3- (pyrid-2-yl ) isoxazol-5-yl> pyrrolidin-1 -i-pyrimidine It was cooled SE-6- [3-tert-butoxycarbonylamino) prop-1-en-1-yl] -4- (5-methyl-1H- p -razol-3-ylamino) -2- [2-. {3- (pyrid-2-yl) isoxazol-5-yl.} pyrrolidin-1-yl] pyridimide Na (Example 99) (50 mg, 0.09 mmol) in DCM (5 ml) at 5 ° C. TFA (1 ml) was added and the mixture was stirred at 5 ° C for 1 hour, then at room temperature for 4 hours. The volatiles were removed by evaporation, the residue dissolved in methanol, and emptied onto SCX2 ion exchange column (10 g) .The impurities were flowed with methanol and then the product was eluted with 7M methanolic ammonia. The solvent was removed by evaporation and titrated with ether to give the title compound (25 mg, 63%). NMR (DMSO): 2.07-2.12 (m, 3H), 2.20 (s, 3H), 2.32- 2.44 (m, 1H), 3.35 (d, 2H), 3.70-3.85 (m, 2H), 5.48 (d, 1H), 6.05 (s, 1H), 6.20 - 6.28 (m, 2H), 6.68 (s, 1H), 6.75-6.82 (m, 1H), 7.45 (dd, 1H), 7.89- 7.95 (m, 2H), 8.65 (d, 1H), 8.85 (s) , 1H), 11.50 (s, 1H); m / z 444 [MH] +.

Example 105 S-6-r3-Methylaminoprop-1-yn-1-in-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) isoxazole-5 -yl pyrrolidin-1 -i II pyrimidine A mixture of S-6-iodo-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) (500 mg, 0.97 mmol), 3-methylaminoprop-1-yne (134 mg, 1.9 mmol) bis (triphenylphosphine) palladium (II) chloride (27 mg, 0.04 mmol) , copper iodide (1) (4 mg, 0.02 mmol), triethylamine (0.7 ml, 5 mmol) in acetonitrile (12 ml) was heated at 75 ° C in a sealed container under microwave irradiation for 15 minutes. The reaction mixture was extracted with EtOAc, the extracts were combined and washed with water, dried (MgSO 4) and the solvent was removed by evaporation. The residue was purified through column chromatography on silica gel eluting with DCM / methanol / aqueous ammonia (100: 0: 0 increasing in polarity to 85: 15: 1) to give the title compound (219 mg, 50%). NMR (DMSO): 2.00-2.12 (m, 3H), 2.20 (s, 3H), 2.32 (m, 2H), 2. 35 (s, 3H), 3.5 (s, 2H), 3.65-3.8 (m, 2H), 5.46 (d, 1H), 6.02 (s, 1H), 6. 45 (s, 1H), 6.65 (s, 1H), 7.45 (dd, 1H), 7.87-7.98 (m, 2H), 8.67 (d, 1H), 9.05 (s, 1H), 11.6 (s, 1H); m / z 456 [NH] +.

Examples 106 to 111 Examples 106 to 111 were prepared by an analogous method to that described in Example 105.

EXAMPLE 106 S-6-r3-Methoxy prop-1 -i n-1 -i l 1-4- (5-methyl-1 H-pyrazole-3-ylamino) -2-T2-f3- (pyrid-2) -il) issoxazole-5-yl > pyrrolidin-1-inpyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-y1] pyrimidine (Example 98) and 3-methoxyprop-1-yne. The product was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). Yield: 70 mg, 53%. NMR (DMSO): 2.0-2.18 (m, 3H), 2.19 (s, 3H), 2.30-2.42 (m, 2H), 3.33 (s, 3H), 3.63-3.70 (m, 1H), 3.73-3.80 ( m, 1H), 4.30 (s, 3H), 5.45 (d, 1H), 6.03 (s, 1H), 6.45 (s, 1H), 6.67 (s, 1H), 7.45 (dd, 1H), 7. 88-7.96 (m, 2H), 8.66 (d, 1H); m / z 457 [NH] +.

Example 107 S-6-T3 -Hydroxy prop-1 -i n-1 -i H-4- (5-methyl-1-1H-pyrazol-3-ylamino) -2 - \ 2-f3- (pyrid- 2-yl) isoxazol-5-yl) pyrrolidin-1-ippyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and prop-2-in-1-ol. The product was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). Yield: 50 mg, 30%. NMR (DMSO): 2.01-2.15 (m, 4H), 2.18 (s, 3H), 2.30-2.40 (m, 1H), 3.62-3.70 (m, 1H), 3.72-3.8 (m, 1H), 4.25 ( s, 3H), 5.04 (t, 1H), 6.04 (s, 3H), 6.45 (s, 1H), 6.65 (s, 1H), 7.45 (m, 1H), 7.88-7.97 (m, 2H), 8.65 (d, 1H), 9.08 (s, 1H), 11.55 (s, 1H); m / z 443 [NH] +.

Example 108 S-6-y2- (Trimethylsilyl) ethynyn-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) is oxazole -5 -yl) pyrrolidin-1-illpyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and trimethylsilycetylene. Yield: 225 mg, 50%. NMR (DMSO): 0.25 (s, 9H), 2.02-2.19 (m, 3H), 2.20 (s, 3H), 2.30-2.42 (m, 1H), 3.623.80 (m, 2H), 5.45 (d, 1H), 6.04 (s, 1H), 6.45 (s, 1H), 6.69 (s, 1H), 7.48 (dd, 1H), 7.85-7.98 (m, 2H), 8.65 (s, 1H), 9. 05 (s, 1H), 11.60 (s, 1H); m / z 485 [MH] +.

Example 109 S-6-r3- (N-Ethylacetamido) prop-1-in-1-in-4- (5-methyl-1H-pyrazol-3-ylamino) -2-r2-f3 (pyrid-2-yl) ) isoxazol-5-yl) pyrrolidin-1-ippyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and 3- (N-methylacetamido) prop-1-ino (Method 59). Yield: 50 mg, 26%. NMR (DMSO): 2.02-2.15 (m, 5H), 2.20 (s, 3H), 2.31-2.40 (m, 1H), 2.93 (s, 3H), 2.973.01 (m, 1H), 3.64-3.71 (m, 1H), 3.73-3.80 (m, 1H), 4.38 (s, 2H), 5.45 (d, 1H), 6.04 (s, 1H), 6.45 (s, 1H), 6.65 (s, 1H), 7.45 (dd, 1H), 7.88-7.96 (m, 2H), 8.66 (d, 1H), 9.08 (s, 1H); m / z 498 [MH] +.

Example 110 S-6-r3- (Dimethylamino) pro p-1-in-l-iH -4 - (5-methyl-1 H -pyrazol-3-ylamino) -2-r2-f3 (pyrid-2- il) issoxazol-5-yl pyrrolidin-1-n-pyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-y1] pyrimidine (Example 98) and 3- (dimethylamino) prop-1-yne. The product was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). Yield: 32 mg, 18%.

NMR (DMSO): 2.01-2.15 (m, 3H), 2.19 (s, 3H), 2.28 (s, 6H), 2.32- 2.42 (m, 1H), 3.42 (s, 2H), 3.64-3.71 (m, 1H), 3.72-3.80 (m, 1H), 5.45 (d, 1H), 6.05 (s, 1H), 6.45 (s, 1H), 6.68 (s, 1H), 7.45 (d, 1H), 7.86- 7.95 (m, 2H), 8.66 (d, 1H), 9.05 (s, 1H), 11.55 (s, 1H).

Example 111 S-6-F3-Acetamidoprop-1-en-1-in-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-r2-f3- (pyrid-2-yl) isoxazole- 5-il} pyrrolidin-1-illpyrimidine Starting materials: S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and 3-acetamidoprop-1 -in (prepared by a method analogous to that described in Method 59). Yield: 44 mg, 24%. NMR (DMSO): 1.88 (s, 3H), 2.02-2.17 (m, 3H), 2.20 (s, 3H), 2.30-2.42 (m, 1H), 3.623.70 (m, 1H), 3.72-3.80 ( m, 1H), 4.1 (d, 2H), . 45 (d, 1H), 6.05 (s, 1H), 6.45 (s, 1H), 6.65 (s, 1H), 7.45 (dd, 1H), 7. 88-7.96 (m, 2H), 8.05 (s, 1H), 8.75 (d, 1H), 9.08 (s, 1H), 11.55 (s, 1 HOUR); m / z 484 [MH] +.

Example 112 S-6-f2- (Ethoxycarbon I) eti n-4- (5-methi 1-1 H-pyrazol-3-yl am i no) -2-y2-f 3- (pyrid-2 il) isoxazol-5-yl) pyrrolidin-1-yl-1-pyrimidine. S-6-iodo-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) (70 mg, 0.14 mmol), 3- (ethoxycarbonyl) ethyl chloride (0.82 ml of 1M solution in ether), bis (triphenyl) chloride lphosphine) palladium (ll) (7 mg, 0. 01 mmoles) in THF (2 ml) and dimethylacetamide (DMA) (1mi) at 70 ° C in a sealed container under microwave irradiation for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried (MgSO 4) and the volatiles were removed by evaporation. The residue was purified by chromatography on silica gel eluting with methanol / DCM (3:97) and then further purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5 : 0.2 decreasing in polarity to 0: 100: 0.2) to give the title compound (20 mg, 30%). NMR (DMSO): 1.12 (t, 3H), 2.0-2.2 (m, 3H), 2.19 (s, 3H), 2.30-2.40 (m, 1H), 2.552.60 (m, 1H), 2.66-2.70 ( m, 3H), 3.64-3.80 (m, 2H), 4.05 (q, 2H), 5.44 (d, 1H), 6.0 (s, 1H), 6.16 (s, 1H), 6.65 (s, 1H), 7.45 (dd, 1H), 7.87-7.95 (m, 2H), 8.65 (s, 1H); m / z 489 [MH] +.

EXAMPLE 113 SE-6-r2- (Methoxycarbonyl) ethene-1H-4- (5-methyl-1H-pyrrazol-3-ylamino) -2-r2-f3 (pyrid-2-yl) isoxazole- 5-il > pyrrolidin-1 -i II pyrimidine A mixture of S-6-iodo-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) (200 mg, 0.39 mmol), methyl acrylate (0.336 ml), 1,1'-bls (diphenylphosphino) ferrocene palladium (II) chloride (64 mg, 0.08 mmol) , tetrabutylammonium iodide (288 mg, 0.78 mmol) in DMF (2.5 ml), water (0.5 ml) and triethylamine (0.5 ml) was heated at 130 ° C in a sealed container under microwave irradiation for 15 minutes. The mixture was extracted with ethyl acetate, the extracts were combined and washed with water, dried (Na2SO4) and the volatiles were removed by evaporation. The residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2) to give the title compound (50 mg, 28%). NMR (DMSO): 2.05-2.18 (m, 3H), 2.20 (s, 3H), 2.38-2.45 (m, 1H), 3.73 (s, 3H), 3.753.89 (m, 2H), 5.48 (d, 1H), 6.10 (s, 1H), 6.48 (s, 1H), 6.70 (s, 1H), 6.80 (d, 1H), 7.23 (d, 1H), 7.48 (dd, 1H), 7.88-7.98 (m, 2H), 8.65 (d, 1H), 9.37 (s, 1H), 11.6 (s, 1H); m / z 473 [MH] +.

Example 114 S-6-Eti ni l-4- (5-methi 1-1 H-pi razo l-3-i lamino) -2-T2-f3- (p ir id-2-yl) -isoxazole -5 -yl) pyrrolidin-1-illpyrimidine Potassium carbonate (17 mg, 0.12 mmol) was added to a solution of S-6- [2- (trimethylsilyl) ethynyl] -4- (5-methyl-1H-pyrazole-3-) Lamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrididine (Example 108) (50 mg, 0.1 mmol) in methanol (1 ml) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried (Na2SO) and the solvent was removed by evaporation. The residue was titrated with ether and collected by filtration to give the title compound (21 mg, 50%). NMR (DMSO): 2.01-2.15 (m, 3H), 2.20 (s, 3H), 2.30-2.45 (m, 1H), 3.65-3.80 (m, 2H), 3.94 (s, 1H), 5.45 (d, 1H), 6.05 (s, 1H), 6.50 (s, 1H), 6.69 (s, 1H), 7.48 (dd, 1H), 7.857.98 (m, 2H), 8.68 (d, 1H), 9. 10 (s, 1H), 11.55 (s, 1H); m / z 413 [MH] +.

Example 115 6-Methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylammon) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1 -illipyrimidine 4-Hydroxy-6-methoxymethoxy-2- [2- [3- (pyrid-2-yl) -soxazol-5-yl was treated} pyrrolidin-1-yl] pyrimidine (Method 34) and 3-amino-5-cyclopropyl-1 H-pyrazole (Method 7 of WO 03/048133) as described in Example 26 to give the title compound (245 mg, 48%). NMR (DMSO): 0.68 (m, 2H), 0.84-0.88 (m, 2H), 1.85 (m, 1H), 2. 02-2.10 (m, 2H), 2.12-2.19 (m, 1H), 2.31-2.42 (m, 1H), 3.36 (s, 3H), 3.66-3.79 (m, 2H), 4.17 (q, 2H), 5.46 (d, 1H), 6.0 (s, 1H), 6.38 (s, 1H), 6.65 (s, 1H), 7.44 (dd, 1H), 7.89-7.95 (m, 2H), 8.65 (d, 1H), 8.94 (s, 1H); m / z 459 [MH] +.

Example 116 S -6-M-Ethoxy-methyl-4- (5-cyc-1 -propyl-1-pyrazol-3-i-amino) -2-f 2 -f 3- (pyrid-2-yl) isoxazole-5- H) pyrrolidin-1-y-pyrimidine The title compound was prepared by separating the racemic compound (Example 115) through chiral HPLC using a chiralpak AD column eluting with methanol / ethanol (85:15).

Example 117 S-6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-ippyrimidine The title compound was prepared by separating the racemic compound (Example 30) through chiral HPLC using a chiralpak AD column eluting with methanol / ethanol (85:15).

Example 118 S-6-r3-Aminoprop-1-en-1-p-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazole- 5-pyrrolidin-1-in pyrimidine Hydrazine hydrate (24 μl, 0.49 mmol) was added to S-6- [3- (N-phthalimido) prop-1-n-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Method 60) (50 mg, 0.09 mmol) in THF (1 ml) and ethanol (0.1 ml) and the mixture was stirred at room temperature for 1 hour then heated at 60 ° C for 30 minutes. The mixture was extracted with EtOAcThe extracts were combined, washed with water, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were neutralized with an aqueous sodium hydrogen carbonate solution and extracted with DCM, dried (MgSO4) and the solvent was removed by evaporation to give the title compound (15 mg, 39%). . NMR (DMSO): 1.25-1.30 (m, 2H), 1.52-1.65 (m, 1H), 2.04-2.15 (m, 3H), 2.20 (s, 3H), 3.55 (s, 2H), 3.65-3.80 ( m, 2H), 5.45 (d, 1H), 6. 05 (s, 1H), 6.42 (s, 1H), 6.65 (s, 1H), 7.44 (dd, 1H), 7.85-7.95 (m, 2H), 8.65 (s, 1H), 9.0 (s, 1H), 11.50 (s, 1H); m / z 442 [MH] +.

Example 119 S-6-f2- (N -Methyl carbamoyl) eti n-4- (5-methyl-1 H -pyrazole-3-ylamino) -2-r2-f3- (pyrid-2-yl) isoxazole -5-yl * tpyrrolidin-1-inpyrimidine A mixture of S-6- [2- (ethoxycarbonyl) ethyl] -4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 112) (80 mg, 0.16 mmol), methylamine (3 ml of a 2M solution in methanol) and 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU ) (0.1ml, 0.67 mmole) was heated at 105 ° C in a sealed container under microwave irradiation for 1.5 hours. The mixture was extracted with EtOAc, the extracts were combined, washed with water, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were neutralized with an aqueous sodium hydrogen carbonate solution and extracted with DCM, dried (MgSO) and the solvent was removed by evaporation to give the title compound (25 mg, 30%). . NMR (DMSO): 2.02-2.19 (m, 2H), 2.19 (s, 3H), 2.32-2.44 (m, 3H), 2.58 (s, 3H), 2.59-2.69 (m, 2H), 3.68-3.80 ( m, 2H), 5.45 (d, 1H), 6.04 (s, 1H), 6.20 (s, 1H), 6.68 (s, 1H), 7.30 (s, 1H), 7.45 (dd, 1H), 7.88-7.98 (m, 2H), 8.68 (d, 1H), 8.78 (s, 1H), 11.5 (s, 1H); m / z 474 [MH] +.

Example 120 S-4- (5-Eti 1-1 H-pyrazol-3-i I amino) -2-f2-f3- (2-methoxy-pyrid-3-yl) -isoxazole-5-pyrrolidin-1-pyrimidine A mixture of 4- (5-ethyl-1 H -pyrazol-3-ylamino) -2-chloropyrimidine (Method 65) (200 mg, 0.9 mmol), S-2- [3- (2-methoxypyrid-3-yl); l) isoxazol-5-yl] pyrrolidine (Method 64) (300 mg, 1.2 mmol) and diisopropylethylamine (0.22 ml, 1.4 mmol) in hexanol (10 ml) was heated at 150 ° C for 24 hours. The residue was allowed to cool and was diluted with EtOAc and washed with water. The organic solution was dried (MgSO 4) and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel eluting with EtOAc / hexane / methanol (50: 50: 0 increasing in polarity to 98: 0: 2) to give the title compound (212 mg, 55%). NMR (DMSO): 1.19 (t, 3H), 2.06-2.19 (m, 3H), 2.30-2.40 (m, 1H), 2.56 (q, 2H), 3.66-3.80 (m, 2H), 3.94 (s, 3H), 5.45 (d, 1H), 6.12 (s, 1H), 6.30 (s, 1H), 6.59 (s, 1H), 7.08 (dd, 1H), 7.89 (d, 1H), 8.10 (d, 1H) ), 8.26 (d, 1H), 8.92 (s, 1H), 11.55 (s, 1H); m / z 433 [MH] +.

Examples 121 and 122 Examples 121 and 122 were prepared by a method analogous to that described for Example 120.

Example 121 S-4- (5-Meti 1-1 H-pyrazole-3-ylamin o) -2-r2- | 3- (2-methoxy-pyrid-3-yl) -isoxazole-5-ylpiol di n-1 -MI pyrimidine Starting materials: 2-chloro-4- (5-methyl-1 H -prazole-3-ylamino) pyrimidine (Method 26) and S-2- [3 - (2-methoxypyrid-3-yl) isoxazol-5-ylpyrrolidine (Method 64). Yield: 147 mg, 49%. NMR (DMSO): 2.05-2.18 (m, 3H), 2.20 (s, 3H), 2.32-2.40 (m, 1H), 3.66-3.78 (m, 2H), 3.94 (s, 3H), 5.45 (d, 1H), 6.08 (s, 1H), 6.30 (s, 1H), 6.59 (s, 1H), 7.09 (dd, 1H), 7.88 (d, 1H), 8.09 (d, 1H), 8.28 (d, 1H) ), 8.85 (s, 1H); m / z 419 [MH] +.

Example 122 S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-r2-r3- (2-methoxypyrid-3-yl) isoxazole-5iH-pyrrolidin-1-ippyrimidine Starting materials: 2- chloro-4- (5-cyclopropyl-1 H-pyrazol-3-ylamino) pyrimidine (Method 28) and S-2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pi rrol Dyna (Method 64). Yield: 143 mg, 51%. NMR (DMSO): 0.64-0.69 (m, 2H), 0.84-0.90 (m, 2H), 1.80-1.90 (m, 1H), 2.02-2.19 (m, 3H), 2.30-2.41 (m, 1H), 3.67-3.80 (m, 2H), 3.96 (s, 3H), 5.48 (d, 1H), 6.02 (s, 1H), 6.30 (s, 1H), 6.59 (s, 1H), 7.09 (dd, 1H) , 7.89 (d, 1H), 8.10 (d, 1H), 8.29 (d, 1H), 8.90 (s, 1H), 11.60 (s, 1H); m / z 445 [MH] +.

Example 123 6- (N-tert-Butoxycarbonyl) amino-2-f2-r3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl) -4- (5-methyl-1H-pyrazole- 3-ylamino) pyrimidine 2- acid was stirred. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-Methyl-1 H -pyrazol-3-ylamino) pyridyl-6-yl carboxylic acid (Method 43) (300 mg, 0.69 mmol) in tert-butanol (30 ml) and diphenylphosphoryl azide (286 mg, 0.97 mmol) was added through triethylamine (14 μl, 0.99 mmol) and the mixture was heated and stirred at 90 ° C for 16 hours. The mixture was concentrated through evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were passed through a 20g SCX-2 column, eluting with methanol, then eluting the product with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (40 mg, 12%) as a white powder. NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.45 (s, 9H), 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.60-3.80 ( m, 2H), 5.42 (d, 1H), 6.00 (s, 1H), 6.68 (s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d , 1 HOUR); m / z 504 [MH] +.

Example 124 6- (4- (N-tert-Butoxycarbonylamino) piperidin-1-yl) -2-f2-r3- (pyrid-2-yl) isoxazol-5iH-pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) -pyrimidine A mixture of 6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H ~ pyrazol-3-ylamino) pyrimidine (Example 17) (150 mg, 0.35 mmol) and 4- (N-terbutoxycarbonylamino) piperidine (700 mg, 3.5 mmol) was added to dioxane (4 ml) and heated in a sealed container under microwave irradiation at 150 ° C for 60 minutes. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were passed through a SCX-2 column eluting with methanol and then releasing the product with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (134 mg, 64%) as a white solid. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.20-1.30 (m, 1H), 1.35 (s, 9H), 1.7 (m, 2H), 2.10 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.90 (t, 2H), 3.45 (m, 1H), 3.67 (m, 1H), 3.75 (m, 1H), 4.00 (m, 2H), 5.34 (d, 1H) ), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 587 [MH] +.

Example 124a 6- (4-Aminopiperidin-1-yl) 2-f2-r3- (pyrid-2-yl) isoxazol-5-pyrrolidin-1-yl) -4- (5-methyl-1 H -pyrazol- 3 -i lamino) pyrimidine 6- (4- (N-tert-Butoxycarbonylamino) piperidin-1-yl) -2- was added. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrrazol-3-ylamino) pyrimidine (Example 124) (120 mg, 0.20 mmol) in DCM (10ml) and trifluoroacetic acid (2ml) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated through evaporation and the residue was dissolved in methanol (10 ml) and passed through a 20 g SCX-2 ion exchange column, eluting with methanol to flow the impurities and then 2 M of methanolic ammonia. to elute the product. The solvent was removed by evaporation to give the title compound (79 mg, 81%) as a creamy powder. NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.35 (m, 1H), 1.45 (m, 1H), 1.90 (m, 2H), 2.00-2.10 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.82 (m, 2H), 3.20 (m, 1H), 3.65-3.80 (m, 2H), 4.10 (t, 2H), 5.35 (d, 1H), 6.3 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H) 8.60 (d, 1H); m / z 487 [MH] +.

Examples 125 to 132 Examples 125 to 132 were prepared by a method analogous to that described for Example 124.

EXAMPLE 125 6-Piperazin-1-yl-2-f2-r3- (pyrid-2-yl) isoxazol-5-yH-pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine Starting materials: 6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 17) and piperazine. Yield: 204mg, 73% as a white powder. NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 3.00-3.15 (m, 5H), 3.60- 3.80 (m, 6H), 5.40 (d, 1H), 5.50 (s, 1H), 6.00 (s, 1H), 6.70 (s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 473 [MH] +.

Example 126 S -6-f 4-r 2 - (2-Hydroxyethoxy) et.n piperazin-1-yl-2-f 2 -r 3 - (pi rid-2-yl) isoxazol-5-ippyrrolidin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrrazol-3-ylamino) pyrimidine (Example 96) and 2- [2- (hydroxyethoxy) ethyl] piperazine. Yield: 142 mg, 79% as a pale yellow solid. NMR (DMSO-de + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2. 15 (s, 3H), 2.35 (m, 1H), 2.70-2.90 (m, 6H), 3.45 (m, 2H), 3.35 (m, 6H), 3.65 (t, 2H), 3.68 (m, 1H) , 3.75 (m, 1H), 5.35 (d, 1H), 5.95 (s, 1H), 6.65 (s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 561 [MH] +.

Example 127 S-6- (1 -Form i I -piperazin-4-yl) -2-f 2 -T 3 - (pyrid-2-yl) is oxazol-5-illpyridin-1-yl} -4- (5methyl-1H-pyrazol-3-ylamino) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and 1-formylpiperazine. Yield: 55 mg, 31% as a pale yellow solid. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.30-3.50 (m, 8H), 3.70 ( m, 1H), 3.77 (m, 1H), 5.37 (d, 1H), 5.55 (s, 1H), 6.67 (s, 1H), 7.38 (t, 1H), 7.33 (t, 1H), 7.83 (t , 1H), 7.90 (d, 1H), 8.00 (s, 1H), 8.60 (d, 1H); m / z 501 [MH] +.

Example 128 was also isolated from the purification by HLPC of Example 127: Example 128 S -6-P i perazin-1 -i 1 -2-f 2-r 3 - (pyrid-2-yl) isoxazol-5-in pyrrolidin-1-yl-4- (5-methyl-1 H -pyrazol-3-ylamino) pyridine Yield: 64 mg, 38% as a pale yellow solid. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.05 (m, 4H), 3.60 (m, 4H), 3.65-3.80 (m, 2H), 5.35 (d, 1H), 5.95 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.60 (d , 1 HOUR); m / z 473 [MH] +.

Example 129 S-6- (4-lsopr opyl piperazin-1-yl) -2-f 2 -f 3- (pyrid-2-yl) isoxazol-5-y-pyrrolidin-1-yl-1-4- (5-methyl) -1 H -pyrazol -3 -i I to me no) pirimine dina Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-M) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methy1-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and 1-isopropylpiperazine. Yield: 94 mg, 52% as a creamy powder. NMR (DMSO-de + d4-acetic acid at 100 ° C): 1.05 (t, 6H), 2.00- 2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 2.65 ( m, 4H), 3.00 (m, 1H), 3.50 (m, 4H), 3.60-3.80 (m, 2H), 5.45 (d, 1H), 5.95 (s, 1H), 6.65 (s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 8.90 (d, 1H), 8.60 (d, 1H); m / z 515 [MH] +.

Example 130 S-6-r (4- (2-Hydroxyethyl) piperazin-1-yl) 1-2-f2-f3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl > -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 96) and 1- (2-hydroxyethyl) piperazine. Yield: 110 mg, 61% as a creamy powder. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2. 20 (s, 3H), 2.35 (m, 1H), 2.80-2.95 (m, 6H), 3.55 (t, 2H), 3.65 (t, 2H), 3.65-3.80 (m, 2H), 5.45 (d, 1H), 5.55 (s, 1H), 5.95 (s, 1H), 6.65 (s, 1H), 7.50 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 517 [MH] +.

Example 131 S-6-r (3R) -3-Hydroxypyrrolidin-1-yn-2-f2-r3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl > -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Example 96) and (3R) -3-hydroxypyridine. Yield: 92 mg, 55% as a purple powder. NMR (DMSO-de + d4-acetic acid at 100 ° C) 1.75 (m, 1H), 1.95 (m, 1H), 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H) ), 3.25-3.45 (m, 4H), 3.65 (m, 1H), 3.75 (m, 1H), 4.30 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 6.70 (s, 1H), 7.35 (t, 1H), 7.80 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 474 [MH] +.

Example 132 S-6-f (3R) -3-Dimethylamino-pyrrolidin-1-n-2-f2-r3- (pyrid-2-yl) isoxazol-5-inpyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ilamino) -pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1H-pyrrazol-3-ylamino) pyrimidine (Example 96) and (3R) -3- (dimethylamino) pyrrolidine. Yield: 128 mg, 73% as a brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.75 (m, 1H), 2. 00-2.15 (m, 4H), 2.18 (s, 3H), 2.22 (s, 6H), 2.35 (m, 1H), 2.77 (m, 1H), 3.15 (t, 1H), 3.27 (q, 1H), 3.40-3.50 (m, 2H), 3.75 (m, 2H), 5.40 (d, 1H), 5.50 (s, 1H), 5.95 (s) , 1H), 6.20 (s, 1H), 7.45 (t, 1H), 7.90-8.00 (m, 1H), 8.65 (d, 1H); m / z 501 [MH] +.

Example 133 S-6- (4-Tetrahydropyranylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino ) pyrimidine S-6-chloro-2- was added. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 96) (150 mg, 0.35 mmol) to 4-aminotetrahydropyran (4 ml) and heated to 150 ° C in a sealed vessel under irradiation of microwave for 1 hour. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were passed through a 20 g SCX-2 column, eluting with methanol and then eluting the product with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (52 mg, 30%) as a pale brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.15 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.80 (m, 1H), 2.00-2.10 (m, 3H) 2.15 (s, 3H), 2.35 (m, 1H), 3.25 (t, 1H), 3.35 (m, 1H), 3.65 (m, 2H), 3.70-3.85 (m, 3H), 5.35 (d, 1H), 5.85 (s, 1H), 6.68 (s, 1H), 5.40 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 488 [NH] +.

Example 134 to 139 Examples 134 to 139 were prepared by a method analogous to that described for Example 133.

Example 134 S-6-Morpholino-2-f2-f3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine heading: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and morpholine. Yield: 119 mg, 71% as a pale pink powder NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H) , 3.35 (m, 4H), 3.55 (m, 4H), 3.60-3.80 (m, 2H), 5.37 (d, 1H), 5.55 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H) ), 8-85 (t, 1H), 8.90 (d, 1H), 8.60 (d, 1H); m / z 474 [NH] +.

Example 135 S-6- (2-Methoxyethyl) amino-2-f2-f3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl > -4- (5-methyl-1 H-pyrazol-3-ilamino) pyrim id i na Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and 2-methoxyethylamine. Yield: 85 mg, 53% as a pale yellow powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 3.20 (s, 3H), 3.20-3.40 ( m, 4H), 3.60-3.80 (m, 2H), 5.40 (d, 1H), 6.68 (s, 1H), 7.40 (d, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 462 [MH] +.

Example 136 S-6-r (N-2-Methoxyethyl) -N-methylamino-2-f2-r3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl > -4- (5-methyl-1 H -pyrazol-3-ylamide) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methy1-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and N- (2-methoxyethyl) methylamine. Yield: 110 mg, 66% as a creamy NMR powder (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 2.60-2.75 (m, 5H), 3.45 (t, 3H), 3.55 (t, 2H), 3.60-3.80 (m, 2H), 5.45 (d, 1H), 5.60 (s, 1H), 5.95 (s, 1H), 6.65 (s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 476 [MH] +.

Example 137 S-6 - ((2R) -2-Hydroxyprop-1-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol -3 -Mam i no) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and (2R) -2-hydroxyprop-1-ylamine. Yield: 52 mg, 32% as a brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.10 (d, 3H), 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 3.25-3.40 ( m, 2H), 3.65 (m, 1H), 3.65-3.85 (m, 2H), 5.40 (d, 1H), 5.55 (s, 1H), 6.70 (s, 1H), 7.40 (t, 1H), 8.45 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 462 [MH] +.

EXAMPLE 138 S-6-fN- (2-Hydroxyethyl) -N-et-laminol-2-f2-f3- (pyrid-2-yl) isoxazole-5-pyrrolidin-il} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Starting materials: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and N- (2-hydroxyethyl) ethylamine. Yield: 113 mg, 70% as a pale yellow powder NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.05 (t, 2H), 2.00-2.15 (m, 3H), 2.20 (s, 3H) , 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m, 2H), 3.67 (m, 1H), 3.77 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 6.70 (s, 1H0, 7.40 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H), m / z 476 [MH] +.

Example 139 S-6-Dimethylamino-2-f2-r3- (pyrid-2-yl) -soxazole-5-ippyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine heading: S-6-chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 96) and dimethylamine. Yield: 86 mg, 57% as an NMR brown powder (DMSO-d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.90 (s, 6H), 3.70 (m, 1H), 3.75 (m, 1H); 5.40 (d, 1H), 5.55 (s, 1H), 5.90 (s, 1H), 6.65 (s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 432 [MH] +.

Example 140 S-6-Methylamino-2-f2-f3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl) -4- (5-methyl-1 H -pyrazole-3-ylamino ) pyrimidine S-6-chloro-2- was added. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Example 96) (150 mg, 0.35 mmole) to 2M methylamine in methanol (4 ml) and heated to 120 ° C in a sealed container under microwave irradiation for 90 minutes. The mixture was concentrated through evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were passed through a 20 g SCX-2 column, eluting with methanol then eluting the product with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (47 mg, 32%) as a white powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.70 (s, 3H), 3.65-3.75 ( m, 2H), 5.45 (d, 1H), 5.85 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 8.85 (t, 1H), 8.90 (d, 1H), 8.65 (s) , 1 HOUR); m / z 418 M] +.

EXAMPLE 141 S-6-CI gold-2-f 2 -f 3 - (pyrazin-2-yl) isoxazole-5-yl pyrrolidin-1-yl> -4- (5-methyl-1 H -pyrazol-3-ylamino) pi rimidine A mixture of S-2- [3- (2-pyrrazinyl) isoxazol-5-yl] pyrroiidine (Method 55) ( 166 mg, 0.77 mmol), 2,6-dichloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Method 29) (170 mg, 0.70) and N, N-diisopropylethylamine (134 μl, 0.77 mmoles) in xylene was stirred and heated at 70 ° C for 2 days. A second equivalent of N, N-diisopropylethylamine (134 μl, 0.77 mmol) was added and the mixture was heated for a further 2 days. The mixture was concentrated through evaporation and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (100: 0 increasing in polarity to 0: 100) to give the title compound (109 mg, 37%) as a creamy powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2. 15 (s, 3H), 2.40 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.43 (d, 1H), . 60 (s, 1H), 6.00 (s, 1H), 6.35 (s, 1H), 6.75 (s, 1H), 8.65 (m, 2H), 9. 10 (s, 1H); m / z 424 [MH] +.

Example 142 6-Mofolino-2-f2-r3- (pyrazin-2-yl) isoxazol-5-n-pyrrolidin-1-yl > -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine S-6-chloro-2- was added. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 141) (94 mg, 0.22 mmol) to morpholine (4 ml) and heated to 150 ° C in a sealed vessel under microwave irradiation for 30 minutes. The reaction mixture was concentrated through evaporation and purified through column chromatography on silica gel eluting with DCM / 2M methanolic ammonia (100: 0 increasing in polarity to 95: 5) to give the title compound ( 75 mg, 72%) as a pale yellow powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.00-2.15 (m, 3H), 2. 15 (s, 3H), 2.35 (m, 1H), 3.35 (m, 4H), 3.55 (m, 4H), 3.65-3.80 (m, 2H), 5.37 (d, 1H), 5.55 (s, 1H), 5.80 (s, 1H), 6.70 (s, 1H), 8.65 (m, 2H), 9.10 (s, 1H); m / z 475 [MH] +.

Example 143 6-Chloro-2-f2-f3- (pyrid-2-yl) isoxazol-5-inpyrroliin-1-yl > -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine. S-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine was stirred (Method 42) (262 mg, 1.22 mmol. ) in n-butanol (40 ml) and then 2,6-dichloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (Method 57) (300 mg, 1.11 mmol) was added through of N, N-diisopropylamine (233 μl, 1.33) and the mixture was stirred at 60 ° C for 2 days. The mixture was concentrated through evaporation and a saturated aqueous sodium bicarbonate solution (50 ml) was added and the mixture was extracted with DCM (3 x 25 ml). The organic extracts were combined, washed with water (50 ml) and brine (50 ml), dried (MgSO) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (50:50 increasing in polarity to 0: 100) to give the title compound (280 mg, 56%) as a white solid. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.05 (m, 2H), 2.15 (m, 1H) , 2.35 (, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 5.90 (s, 1H0, 6.35 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); m / z 449 [MH] +.

Example 144 6- (2-Hydroxyethoxy) -2-f2-f3- (pyrid-2-yl) isoxazol-5-pyrrolidin-1-yl '> -4- (5-cyclopropyl-1 H-pyrazol-3-ylamino) pi rimdine Sodium hydride (60% dispersion in oil, 71 mg, 1.78 mmol) ethylene glycol (4 ml) was added and the mixture was stirred for 5 minutes. S-6-chloro-2- was added. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 143) (160 mg, 0.35 mmol) and the mixture was heated to 150 ° C in a sealed container under microwave irradiation for 45 minutes. minutes The crude mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were drained on a 20g SCX-2 column, eluting with methanol then with 2N methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (23 mg, 14%) as a pale yellow powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.00-2.15 (m, 3H), 2.35 (m, 1H), 3.55-3.80 (m, 4H), 4.15 (m, 2H), 5.40 (d, 1H), 5.55 (s, 1H), 5.75 (s, 1H), 5.90 (s, 1H), 6.67 (s) , 1H), 7.45 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1 HOUR). m / z 475 [MH] +.

Example 145 6- f4- (tert-Butoxycarbonyl) piperazin-1-p-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3 (pyrid-2-yl) isoxazole-5 -yl) pyrrolidin-1-ippyrimidine A mixture of 6-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 17) (250 mg, 0.6 mmol) and N-terbutoxycarbonyl) piperazine (222 mg, 6.0 mmol) in 1,4-dioxane (4 ml) was heated to 160 ° C. C in a sealed container under microwave irradiation for 90 minutes. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combiand passed through a solute ion exchange column SCX-2. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the desired product (85 mg, 25%) as a white solid. NMR (DMSO-d6 at 100 ° C): 1.43 (s, 9H), 2.09 (m, 3H), 2.19 (s, 3H), 2.37 (m, 1H), 3.34 (m, 4H), 3.40 (m, 4H), 3.73 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.97 (br s, 1H), 6.68 (s, 1H), 7.48 (dd, 1H), 7.92 (m , 2H), 8.32 (br s, 1H), 8.65 (d, 1H), 11.41 (br s, 1H); m / z 573 [MH] +.

Example 146 6- (4-Aceti Ipi er azi n -1-il) -4- (5- eti 1-1 H-pyrazol-3-ylamino) -2-f 2 -f 3- (pyrid-2-yl) ) isoxazol-5-yl) pyrrolidin-1-yl-1-pyrimidine The title compound was made by an analogous method to that described in Example 145 using 6-chloro-4- (5-methyl-1 H-pyrazole-3-) ilamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-ylpyrimidine (Example 17) and 4-acetylpiperazine. Yield: 182 mg, 60%. NMR (DMSO-d6 at 100 ° C): 1.94 (s, 3H), 2.09 (m, 3H), 2.19 (s, 3H), 2.37 (m, 1H), 3.44 (m, 8H), 3.73 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.97 (br s, 1H), 6.68 (s, 1H), 7.46 (dd, 1H), 7.92 (m, 2H), 8.30 (br s, 1H), 8.65 (d, 1H), 11.38 (br s, 1H); m / z 514 [MH] +.

EXAMPLE 147 6-f2- (tert-Butoxycarbonyl) -2,7-diazaespirof3.51nonan-7-p-4- (5-methyl-1H-pyrazole-3 -Hamino) -2-f2-f3 - (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-pyrimidine A mixture of 6-chloro-N- (3-methyl-1 H -pyrazol-5-yl) -2- [2- (3-pyridin-2-yl-isoxazol-5-yl) pyrrolidin- 1-yl] pyrimidin-4-amine (Example 17) (300 mg, 0.7 mmol) and 2-tert-butoxycarbonyl) -2,7-diazaspiro [3.5] nonane (949 mg, 4.2 mmol) in 1,4-dioxane (8 ml) was heated to 160 ° C in a sealed container under microwave irradiation for 120 minutes. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica gel eluting with DCM / methanol / aqueous ammonia (100: 0 -.0 increasing in polarity to 90: 10: 1) to give the product (235 mg, 55%) like a solid mallow. NMR (DMSO-de at 100 ° C): 1.42 (s, 9H), 1.59 (t, 4H), 2.07 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 3.37 (m, 4H), 3.52 (m, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.81 (br s, 1H), 5.94 (br s, 1H), 6.63 (s, 1H), 7.45 (dd, 1H), 7.92 (m, 2H), 8.24 (br s, 1H), 8.65 (d, 1H); m / z 614 [MH] +.

Example 148 6- (2,7-Diazaspirof3.5lnonan-7-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-F2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidine -1-illpyrimidine A mixture of 6- [2-tert-butoxycarbonyl) -2,7-diazaspiro- [3.5] nonan-7-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2 -[2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 147) (110 mg, 0.19 mmol) and TFA (2 mL) was stirred at room temperature for 60 minutes. The volatiles were removed by evaporation, the residue was dissolved in DCM and poured onto an SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the desired product as a yellow solid. (66 mg, 68%). NMR (DMSO-d6 at 100 ° C): 1.51 (t, 4H), 2.07 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 3.22 (m, 4H), 3.36 (m, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.94 (br s, 1H), 6.63 (s, 1H), 7.45 (dd, 1H), 7.92 (m , 2H), 8.24 (br s, 1H), 8.65 (d, 1H); m / z 513 [MH] +.

Example 149 S-6-f4- (2-Aminoethyl) piperazin-1-ip-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) is oxazole -5 -il} pyrrolidin-1-iH-pyrymidine A mixture of S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (100 mg, 0.24 mmol), 1- (2-aminoethyl) piperazine (186 mg, 1.4 mmol) in 1,4-dioxane (4 ml) was heated at 150 ° C in a sealed container under microwave irradiation for 120 minutes. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). Fractions containing the product were combined and passed through an SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated diethyl ether and the product was collected through filtration to give the title compound (68 mg, 55%) as a white solid. NMR (DMSO-de at 100 ° C): 2.05 (m, 3H), 2.19 (s, 3H), 2.31 (m, 1H), 2.38 (m, 6H), 2.53 (m, 2H), 3.40 (t, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.66 (s, 1H), 7.44 (dd, 1H), 7.92 (m , 2H), 8.30 (br s, 1H), 8.65 (d, 1H), 11.38 (br s, 1H); m / z 516 [MH] +.

Examples 150 to 159 Examples 150 to 159 were prepared by a method analogous to that described in Example 149.

Example 150 S-6-f4- (3-Hydroxypropyl) piperazin-1-yn-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3 (pyrid-2-yl) isoxazole- 5-il > pyrrolidin-1-inpyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 1- (3-hydroxypropyl) piperazine. Yield: 84 mg, 66%. NMR (DMSO-d6 at 100 ° C): 1.50 (m, 2H), 2.09 (m, 3H), 2.19 (s, 3H), 2.36 (m, 7H), 3.42 (t, 4H), 3.49 (t, 2H), 3.73 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), 7.44 (dd, 1H), 7.94 (m, 2H), 8.30 (br s, 1H), 8.68 ( d, 1H), 11.45 (br s, 1H); m / z 531 [MH] +.

Example 151 S-6-f4- (2-Cyanoethyl) piperazin-1-ip-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazole -5-yl) pyrrole id i n-1-yl pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 1- (2-cyanoethyl) piperazine. Yield: 69 mg, 36%. NMR (DMSO-d6 at 100 ° C): 2.08 (m, 3H), 2.19 (s, 3H), 2.39 (m, 1H), 2.42 (t, 4H), 2.59 (s, 4H), 3.42 (t, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br, 1H), 6.68 (s, 1H), 7.44 (dd, 1H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.68 (d, 1H), 11.40 (br s, 1H); m / z 527 [MH] +.

EXAMPLE 152 S-6-R4- (2-Methoxyethyl) piperazin-1-yn-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3 (pyrid-2-yl) isoxazole-5 -yl) pyrrolidin-1-pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 1- (2-methoxyethyl) piperazine. Yield: 84 mg, 44%. NMR (DMSO-d6 at 100 ° C): 2.08 (m, 3H), 2.19 (s, 3H), 2.36 (m, 7H), 3.25 (s, 3H), 3.43 (t, 4H), 3.46 (t, 2H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), 7.48 (dd, 1H), 7.94 (m , 2H), 8.28 (br s, 1H), 8.68 (d, 1H), 11.40 (br s, 1H); m / z 532 [MH] +.

EXAMPLE 153 S-6- (4-Acetylpiperazin-1-yl) -4- (5-methyl-1 H-irazol-3-yl amino) -2-f 2 -f3- (pyrid-2-yl) isoxazole- 5-yl) pyrrolidin-1-illpyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 Hp -razol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrro lid i n-1-I] pyrimidine (Example 96) and 1-acetylpiperazine. Yield: 66 mg, 36%. NMR (DMSO-de at 100 ° C): 2.01 (s, 3H), 2.08 (m, 3H), 2.19 (s, 3H), 2.36 (m, 1H), 3.48 (m, 8H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), 7.48 (dd, 1H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.68 (d, 1H), 11.40 (br s, 1H); m / z 515 [H] +.

EXAMPLE 154 S-6-f4- (Eti Isulf onyl) piperazin -1 -i n-4- (5-methyl-1 Hp and 3-ylamino) -2-f2-f3 (pyrid-2-yl) isoxazol-5-yl} pi rrol idin-1 -i I] pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) -soxazole-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 1- (ethylsulfonyl) piperazine. Yield: 122 mg, 60%.

NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.96 (t, 3H), 1.90 (m, 3H), 1.99 (s, 3H), 2.22 (m, 1H), 2.73 (m, 2H) , 2.96 (m, 4H), 3.33 (m, 4H), 3.55 (m, 2H), 5.17 (d, 1H), 6.48 (s, 1H), 7.21 (dd, 1H), 7.72 (m, 2H), 8.44 (d, 1H); m / z 566 [NH] +.

Example 155 S-6-f2- (2-Hydroxyethoxy) ethylamino-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3 (pyrid-2-yl) isoxazol-5-yl pyrrolidin-1-illpyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-y1] pyrimidine (Example 96) and 2- (2-hydroxyethoxy) ethylamine. Yield: 84 mg, 48%. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.06 (m, 3H), 2.16 (s, 3H), 2.33 (m, 1H), 3.40 (m, 8H), 3.71 (m, 2H), 5.40 (d, 1H), 6.67 (s, 1H), 7.38 (dd, 1H) ), 7.89 (m, 2H), 8.62 (d, 1H); m / z 496 [MH] +.

Example 156 S-6- f2- (Acetoamido) ethylamino-4 - (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3 - (pyrid-2-yl) isoxazol-5-yl} p i rrol id i n-1 -illpyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 2- (acetoamido) ethylamine. Yield: 39 mg, 22%. NMR (DMSO-de at 100 ° C): 1.80 (s, 3H), 2.07 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.19 (m, 4H), 3.71 (m, 2H), 5.42 (d, 1H), 5.52 (br s, 1H), 5.87 (br s, 1H), 6.06 (br s, 1H), 6.68 (s, 1H), 7.49 (br s, 1H), 7.43 (dd, 1H), 7.94 (m, 2H), 8.12 (br s, 1H), 8.66 (d, 1H), 11.40 (br s, 1H); m / z 489 [MH] +.

Example 157 was also isolated from the same reaction through purification by HPLC: Example 157 S-6-f2-Aminoethylaminol-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-ippyrimidine Yield: 15 mg, 9%. NMR (DMSO-de at 100 ° C): 2.10 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 2.67 (t, 2H), 3.17 (m, 2H), 3.71 (m, 2H), 5.42 (d, 1H), 5.57 (br s, 1H), 5.90 (br s, 1H), 6.06 (brs, 1H), 6.68 (s, 1H), 7.48 (dd, 1H), 7.94 ( m, 2H), 8.12 (br s, 1H), 8.68 (d, 1H); m / z 447 [MH] +.

EXAMPLE 158 S-6-r4-Methylcyclohexylamino] -4- (5-methylene-1H-pi-razo I-3 -i I amino) -2-f 2 -f3- (pyrid-2-yl) isoxazole- 5-yl-Pyrrolidin-1-ippyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2 -. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidn-1-yl] pyrimidine (Example 96) and 4-methylcyclohexylamine. Yield: 112 mg, 48%. NMR (DMSO-de at 100 ° C): 0.84 (dd, 3H), 1.40 (m, 9H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.45 (m, 1H), 3.71 (m, 2H), 5.39 (m, 1H), 5.54 (br s, 1H), 5.82 (br s, 1H), 5.89 (br s, 1H), 6.63 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.03 ( br s, 1H), 8.64 (s, 1H), 11.41 (br s, 1 HOUR); m / z 500 [MH] +.

EXAMPLE 159 S-6- f4-Hydroxycyclohexylamino-4- (5-methylene-1 H -pyrazole-3 -lamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl > pyrrolidin-1-pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazo! -5-yl} pi rrol id in- 1-yl] pyrimidine (Example 96) and 4-hydroxycyclohexylamine. The title compound was made by an analogous method to Example 149 except that the reaction was heated for 6 hours at 180 ° C. Yield: 83 mg, 35%. NMR (DMSO-d6 at 100 ° C): 1.16 (m, 4H), 1.81 (m, 4H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.38 (m, 1H), 3.50 (br s, 1H), 3.71 (m, 2H), 4.01 (d, 1H), 5.39 (d, 1H), 5.49 (br s, 1H), 5.82 (br s, 1H), 5.89 ( br s, 1H), 6.63 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.02 (br s, 1H), 8.64 (d, 1H), 11.35 (br s, 1H); m / z 502 [NH] +.

Example 160 S-6-fcis-3,4-Dihydroxypyrrolidin-1-ip-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3 (pyrid-2-yl) isoxazole-5- il) pyrrolidin-1-illpyrimidine A mixture of S-6-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (100 mg, 0.24 mmole), cis-3,3-dimethyl-2,4-dioxa-7-aza-bicyclo [3.3.0] octane (203 mg, 1.4 mmol) in 1,4-dioxane (3 ml) was added. heated to 150 ° C in a sealed container under microwave irradiation for 120 minutes. The reaction mixture was allowed to cool, the volatiles were removed by evaporation and the residue was purified by column chromatography on silica gel eluting with DCM / methanol / aqueous ammonia (100: 0: 0 increasing in polarity to 90 : 10: 1). The purified product was dissolved in methanol (4 ml) and 2M hydrochloric acid (4 ml) and stirred at room temperature for 120 minutes. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). Fractions containing the product were combined and passed through an SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with ether and collected by filtration to give the desired product (22 mg, 19%) as a white solid. NMR (DMSO-de at 100 ° C): 2.08 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.15 (m, 1H), 3.24 (m, 1H), 3.42 (m, 1H), 3.51 (m, 1H), 3.71 (m, 2H), 4.08 (s, 2H), 5.42 (d, 1H) ), 5.47 (brs, 1H, 5.90 (brs, 1H), 6.68 (s, 1H), 7.48 (dd, 1H), 7.94 (m, 2H), 8.38 (br s, 1H), 8.68 (d, 1H); m / z 491 [MH] +.

EXAMPLE 161 S-6-C LORO-4- (5-methy1-1 H -pyrazol -3-ylamino) -2-f2-f3- (pi rim id-2-yl) isoxazol-5-yl) p Rrolidin-1-yl "| pirinr? Idine A mixture of 2,6-dichloro-4- (5-methyl-1 H-pyrazole-3-ylmene) pip'midine (Method 29) (134 mg, 0.55 mmole), S-2- [3- (pyrimid-2-yl) isoxazol-5-yl] pyrrolidine (Method 66) (130 mg, 0.6 mmol), N, N-diisopropylethylamine (78 mg, 0.6 mmol) ) and xylyne (5 ml) was heated at 70 ° C for 3 days.The crude reaction was passed through a SCX-2 solute exchange column.The column was eluted with methanol to elute any material neutral, followed by 7M methanolic ammonia to elute the product.The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (0: 100 increasing in polarity to 100: 0 The purified product was titrated with ether and collected by filtration to give the title compound (110 mg, 47%) as a solid white.

NMR (DMSO-de at 100 ° C): 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.71 (m, 2H), 5.42 (d, 1H), 6.00 (s, 1H), 6.41 (s, 1H), 6.73 (s, 1H), 7.52 (dd, 1H), 8.90 (d, 2H), 9.21 (s, 1H), 11.62 (br s, 1H); m / z 424 [MH] +.

Example 162 S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-trimyrimidine A mixture of 2,6-dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrididine (Method 29) (162 mg, 0.66 mmol), S-2 - [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl] pyrrolidine (Method 68) (180 mg, 0.73 mmole), N, N-diisopropylethylamine (95 mg, 0.73 mmole) and 1-butanol ( 5 ml) was heated at 65 ° C for 16 hours and then at 80 ° C for 2 hours. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through an ion exchange column of solute SCX-2. The column was eluted with methanol to elute any neutral material, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with ether and collected by filtration to give the title compound (117 mg, 39%) as a creamy solid; m / z 454 [MH] +.

Example 163 S-6-Morph ol i no-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3- (pyrim id-2-yl) isoxazol-5-yl > pyrrolidin-1-pyrimidine A mixture of S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidn-1-yl] pyrimidine (Example 161) (100 mg, 0.24 mmol) in morpholine (3 ml) was heated at 150 ° C in a sealed container under microwave irradiation for 40 minutes. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 isolute exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with ether to give the title compound (53 mg, 46%) as a white solid. NMR (DMSO-de at 100 ° C): 2.10 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.44 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 5.42 (d, 1H), 5.57 (s, 1H), 5.90 (s, 1H), 6.68 (s, 1H), 7.52 (dd, 1H), 8.35 (br s, 1H), 8.90 (d, 2H), 11.40 (br s, 1H); m / z 476 [MH] +.

Example 164 S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (3-methoxypyrazin-2-yl) isoxazol-5-yl >pyrrolidin-1-illpyrimidine The title compound was made by an analogous method to that described in Example 163 starting from S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2 -[2-. { 3- (3-methoxy-pyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 162) and morpholine. Yield: 15 mg, 12%. NMR (DMSO-d6 at 100 ° C): 2.07 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.47 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 4.01 (s, 3H), 5.42 (d, 1H), 5.75 (br s, 1H), 5.96 (br s, 1H), 6.66 (s, 1H), 8.31 (s, 2H), 11.40 (br s, 1 H); m / z 506 [MH] +.

Example 165 was also isolated from the same reaction through purification by HPLC: Example 165 S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-ippyrimidine Yield: 32 mg, 26%. NMR (DMSO-d6 at 100 ° C): 2.07 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.47 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 5.47 (d, 1H), 5.75 (s, 1H), 5.96 (s, 1H), 6.71 (s, 1H), 7.52 (m, 2H), 8.33 (s, 1H), 11.75 (br s, 1 HOUR); m / z 492 [NH] +.

Example 166 S-6-r4-Methylpiperazin-1-in-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-illpyrimidine A mixture of S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (plrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (150 mg, 0.36 mmol) in 1-methylpiperazine (3 ml) was heated at 150 ° C in a sealed container under microwave irradiation for 40 minutes. The mixture was allowed to cool and purified directly through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 isolute exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with hexane and collected by filtration to give the title compound (152 mg, 87%) as a white solid. NMR (DMSO-d6 at 100 ° C): 2.08 (m, 3H), 2.16 (s, 3H), 2.38 (m, 1H), 3.34 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.74 (s, 1H), 5.95 (s, 1H), 6.68 (s, 1H), 7.50 (dd, 1H), 8.38 (br s, 1H), 8.92 (d, 2H); m / z 488 [MH] +.

Examples 167 to 171 Examples 167 to 171 were prepared by a method analogous to that described in Example 166.

Example 167 S-6-f Cid obu ti larn nol-4- (5-methi 1-1 H-pyrazol-3-yl amino) -2-f 2 -f 3- (pyrid-2-yl) isoxazole-5 -yl) pyrrolidin-1-pyridine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and cyclobutylamine. Yield: 79 mg, 37%. NMR (DMSO-de at 100 ° C): 1.87 (m, 6H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.71 (m, 2H), 4.14 (m, 1H), 5.39 (d, 1H), 5.49 (br s, 1H), 5.89 (br s, 1H), 6.22 (br s, 1H), 6.63 (s, 1H), 7.42 (dd, 1H), 7.90 ( m, 2H), 8.12 (br s, 1H), 8.64 (d, 1H), 11.38 (br s, 1H); m / z 458 [MH] +.

Example 168 S-6-f3-lsopropoxip rop-1 -lamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazole-5 -yl) pyrrolidin-1-pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimide (Example 96) and 3-isopropoxyprop-1-ylamine. Yield: 89 mg, 38%. NMR (DMSO-de at 100 ° C): 1.04 (d, 6H), 1.65 (m, 2H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.18 (m, 2H), 3.35 (t, 2H), 3.49 (m, 1H), 3.70 (m, 2H), 5.39 (d, 1H) ), 5.54 (br s, 1H), 5.89 (br s, 1H), 5.99 (br s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.02 (br s, 1H), 8.64 (d, 1H), 11.38 (br s, 1H); m / z 505 [MH] +.

Example 169 S-6-f2- (Morpholin-4-yl) ethylamino-4- (5-methyl-1 H -pyrazol-3-yl amino) -2 -r2-f3- (pyrid-2-yl) isoxazole- 5-il > pyrrolidin-1-pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl] pyrimidine (Example 96) and 2- (morpholin-4-yl) ethylamine. The product was titrated with ether. Yield: 100 mg, 41%. NMR (DMSO-de at 100 ° C): 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 5H), 2.41 (t, 2H), 3.26 (m, 2H), 3.54 (m, 4H), 3.70 (m, 2H), 5.40 (dd, 1H), 5.53 (br s, 1H), 5.91 (br s, 1H), 5.92 (br s, 1H), 6.64 (s, 1H), 7.42 ( dd, 1H), 7.90 (m, 2H), 8.08 (br s, 1H), 8.64 (d, 1H); m / z 518 [MH] +.

Example 170 S-6-f2- (Dimethylamino) ethylamino-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl > pyrrolidin-1-trimyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 2- (dimethylamino) ethylamine. Yield: 90 mg, 40%. NMR (DMSO-de at 100 ° C): 2.06 (m, 3H), 2.12 (s, 6H), 2.17 (s, 3H), 2.36 (m, 3H), 3.26 (m, 2H), 3.70 (m, 2H), 5.43 (dd, 1H), 5.53 (br s, 1H), 5.91 (br s, 2H), 6.64 (s) , 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.08 (br s, 1H), 8.64 (d, 1H); m / z 476 [NH] +.

Example 171 S-6-f (2S) -2-Hydroxyprop-1-ylaminol-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazole- 5-yl) pyrrolidin-1-inpyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazoi-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and (2S) -2-H-hydroxypropyl-lamine. Yield: 28 mg, 13%. NMR (DMSO-d6 at 100 ° C): 1.06 (d, 3H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.08 (m, 1H), 3.18 (m, 1H), 3.70 (m, 3H), 4.27 (s, 1H), 5.39 (dd, 1H), 5.53 (br s, 1H), 5.90 (br s, 1H), 5.95 (br s, 1H), 6.64 (s, s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.05 (br s, 1H), 8.64 (d, 1H), 11.39 (br s, 1H); m / z 463 [NH] +.

Example 172 S-6-f2-Methylprop-1-ylaminol-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidine -1-pyrimidine A mixture of S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (200 mg, 0.47 mmol) and isobutylamine (2 ml) was heated at 150 ° C in a sealed container under microwave irradiation for 30 minutes. The reaction was allowed to cool and was poured into an aqueous sodium bicarbonate solution. The resulting precipitate was collected through filtration, washed with water and dried under vacuum to give the title compound (170 mg, 79%) as an orange solid. NMR (DMSO-d6 at 100 ° C): 0.85 (dd, 6H), 1.78 (m, 1H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 2.95 (m, 2H), 3.70 (m, 2H), 5.40 (d, 1H), 5.58 (br s, 1H), 5.89 (br s, 1H), 6.08 (br s, 1H), 6.64 (s, 1H), 7. 42 (dd, 1H), 7.90 (m, 2H), 8.66 (d, 1H); m / z 460 [NH] +.

Examples 173 to 179 Examples 173 to 179 were prepared by a method analogous to that described in Example 172.

Example 173 S-6-f3-Methoxypropylamino-1-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1- npirimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 3-methoxypropylamine. Yield: 160 mg, 72%. NMR (DMSO-de at 100 ° C): 1.68 (m, 2H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.18 (m, 2H), 3.20 (s, 3H), 3.33 (t, 2H), 3.70 (m, 2H), 5.39 (dd, 1H), 5.54 (s, 1H) ), 5.86 (s, 1H), 6.01 (br s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.64 (dd, 1H); m / z 477 [MH] +.

Example 174 S-6-f4-Ethylpiperazin-1-n-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl ) pyrrolidin-1 -i I] pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyridine (Example 96) and 1-ethylpiperazine. Yield: 200 mg, 85%.

NMR (DMSO-de at 100 ° C): 0.97 (t, 3H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 7H), 3.41 (m, 4H), 3.70 (m, 2H), 5.39 (dd, 1H), 5.75 (s, 1H), 5.94 (s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.31 (br s, 1H), 8.64 (d, 1H); m / z 502 [NH] +.

Example 175 S-6-f3-Etoxipropylamino-1-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl > pyrrolidin-1-pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 3-ethoxypropylamine. Yield: 105 mg, 46%. NMR (DMSO-de at 100 ° C): 1.06 (t, 3H), 1.68 (m, 2H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.18 (m, 2H), 3.38 (m, 4H), 3.70 (m, 2H), 5.39 (dd, 1H), 5.53 (s, 1H), 5.88 (s, 1H), 6.01 (t, 1H), 6.64 (s, 1H) ), 7.42 (dd, 1H), 7.90 (m, 2H), 8.64 (d, 1H); m / z 491 [MH] +.

Example 176 S -6-f (2 R) -Tetrahydrofuran-2-ylmet-i-lamino] -4- (5-meth i 1-1 H-pyrazol-3-ylamino) -2-f2-f3- (pyrid -2-yl) isoxazol-5-yl) pyrrolidin-1-pyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2 -. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimldine (Example 96) and (2R) -tetrahydrofuran-2-ylmethylamine. Yield: 196 mg, 86%. NMR (DMSO-d6 at 100 ° C): 1.55 (m, 1H), 1.77 (m, 3H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.20 (m, 2H), 3.56 (m, 1H), 3.70 (m, 3H), 3.91 (m, 1H), 5.39 (dd, 1H), 5.56 (s, 1H), 5.88 (s, 1H), 6.00 (t, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.64 (d, 1H); m / z 488. 5 [NH] +.

Example 177 S-6- (2-lsopropoxyethylamino) -4- (5-methyl-1 H -pyrazol-3-yl amino) -2-f 2 -f3- (pyrid-2-yl) isoxazol-5-yl * cpirrolidin-1-illpyrimidine Starting materials: S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) and 2-iopropoxyethylamine. Yield: 180 mg, 78%. NMR (DMSO-de at 100 ° C): 1.03 (dd, 6H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.30 (m, 4H), 3.48 (m, 1H), 3.70 (m, 2H), 5.40 (dd, 1H), 5.53 (s, 1H), 5.89 (s, 1H), 5.95 (t, 1H), 6.64 (s, 1H), 7.42 (dd, 1H) ), 7.90 (m, 2H), 8.66 (d, 1H); m / z 490 [NH] +.

Example 178 S -6-Morfol i no-4- (5-cyclopropyl 1-1 H -pyrazol-3-yl amino) -2-f 2 -f 3- (pyrimid-2-yl) isoxazol-5-yl > pyrrolidin-1-inpyrimidine Starting materials: S-6-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamine) -2- [2-. { 3 (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 180) and morpholine. Yield: 145 mg, 66%. NMR (DMSO-de at 100 ° C): 0.65 (m, 2H), 0.86 (m, 2H), 1.84 (m, 1H), 2.09 (m, 3H), 2.39 (m, 1H), 3.39 (m, 4H), 3.57 (m, 4H), 3.72 (m, 2H), 5.42 (dd, 1H), 5.72 (s, 1H), 5.89 (s, 1H), 6.69 (s, 1H), 7.55 (dd, 1H) ), 8.89 (d, 2H); m / z 502 [NH] +.

Example 179 S-6-M and ylamino -4 - (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2 -f2-f 3- (pyrimid-2-yl) isoxazol-5-yl > pyrrolidin-1-inpyrimidine Starting materials: S-6-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylammon) -2- [2-. { 3 (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-pyridine (Example 180) and an excess of a 2M solution of methylamine in ethanol heated at 120 ° C for 90 minutes. Yield: 125 mg, 64%. NMR (DMSO-de at 100 ° C): 0.67 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.09 (m, 3H), 2.36 (m, 1H), 2.70 (d, 3H), 3.72 (m, 2H), 5.42 (dd, 1H), 5.50 (br s, 1H), 5.83 (br s, 1H), 5.97 (br s, 1H), 6.69 (s, 1H), 7. 55 (dd, 1H), 8.12 (br s, 1H), 8.94 (d, 2H), 11.51 (br s, 1H); m / z 445 [MH] +.

Example 180 S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrimid-2-yl) -soxazol-5-yl) pyrrolidin-1-illpyrimidine One mixture of 2,6-dichloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 57) (910 mg, 3.4 mmol), S-2- [3- (pyrimid-2-yl isoxazol-5-yl] pyrrolidine (Method 66) (800 mg, 0.37 mmol), N, N-diisopropylethylamine (480 mg, 0.37 mmol) and 1-butanol (20 ml) was heated at 75 ° C for 16 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2).

Fractions containing the product were combined and passed through an SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (850 mg, 55%). NMR (DMSO-de at 100 ° C): 0.71 (m, 2H), 0.91 (m, 2H), 1.88 (m, 1H), 2.09 (m, 2H), 2.18 (m, 1H), 2.43 (m, 1H), 3.72 (m, 2H), 5.47 (dd, 1H), 5.98 (s, 1H), 6.40 (s, 1H), 6.74 (s, 1H), 7.55 (dd, 1H), 8.94 (d, 2H) ), 9.27 (s, 1H), 11.72 (br s, 1H); m / z 450 [MH] +.

EXAMPLE 181 S-6-Methyl-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-f2-f3- (3-methoxyp i razin-2-yl) isoxazol-5-yl} pyrrolidin-1-ippyrimidine A mixture of 2-chloro-6-methyl-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 56) (63 mg, 0.26 mmol), S-2- [ 3- (2-methoxypyrazon-3-yl) isoxazol-5-yl] pyrrolidine (Method 68) (70 mg, 0.28 mmol), diisopropylethylamine (0.09 ml, 0.52 mmol) and 1-hexanol (3 ml) it was heated at 120 ° C for 6 hours. The crude reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a SCX-2 isolute exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with ether and collected by filtration to give the title compound (49 mg, 44%) as a white solid. NMR (DMSO-de at 100 ° C): 12.06 (m, 3H), 2.12 (s, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.70 (m, 2H), 4.00 (s, 3H), 5.45 (d, 1H), 6.01 (br s, 1H), 6.22 (br s, 1H), 6.64 (s) , 1H), 8.30 (s, 2H), 8.74 (br s, 1H), 11. 51 (br s, 1H); m / z 435 [MH] +.

EXAMPLE 182 S-6-Methoxy-4- (5-cyclopro-phenyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrimidin-2-yl) isoxazol-5-yl > pyrrolidin-1-inpyrimidine Sodium hydride (88 mg, 1.1 mmol) was added to methanol (2 ml) and the mixture was stirred for 5 minutes. S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3 (pyrimidin-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine (Example 180) (200 mg, 0.44 mmol) and the mixture was heated to 120 ° C in a sealed container under microwave irradiation for 30 minutes. The reaction mixture was allowed to cool and was poured into a cold aqueous ammonium chloride solution. The resulting precipitate was collected through filtration and dissolved in methanol. The solution was poured into water and the precipitate was collected through filtration, washed with water and dried in a vacuum oven to give the title compound (81 mg, 41%) as a white solid. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.63 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.09 (m, 3H), 2.36 (m, 1H) 3.70 (s, 3H), 3.72 (m, 2H), 5.42 (dd, 1H), 6.69 (s, 1H), 7.49 (dd, 1H), 8.88 (d, 2H); m / z 446 [MH] +.

Example 183 S -6- (2-Methoxy-ethoxy) -4- (5-cyclopropyl-1H-pyrazole-3-i-lamine o) -2-f2-f 3-pyrimidin-2-yl) isoxazole-5- il) pyrrolidin-1-yl] pyrimidine The title compound was made by an analogous method to that described in Example 182 starting from S-6-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino ) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 180) and 2-methoxyethanol.

Yield: 80 mg, 37%. NMR (DMSO-d6 at 100 ° C): 0.67 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.09 (m, 3H), 2.36 (m, 1H), 3.24 (s, 3H), 3.52 (m, 2H), 3.72 (m, 2H), 4.25 (m, 2H), 5.42 (dd, 1H) ), 5.74 (s, 1H), 5.92 (s, 1H), 6.69 (s, 1H), 7.55 (dd, 1H), 8.68 (br s, 1H), 8.91 (d, 2H), 11.5 (br s, 1H); m / z 490 [MH] +.

Example 184 S-4- (5-Et i 1-1 H-pyrazol-3-ylamino) -2-f 2 -f 3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl ) pyrimidine A mixture of 4- (5-ethyl-1 H -pyrazol-3-ylamino) -2-chloropyrimidine (Method 65) (224 mg, 1.0 mmol), S-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine (Method 42) (268 mg, 1.25 mmol) and N, N-diisopropylamine (322 mg). mg, 0.43 ml, 2.5 mmol) in 1-hexanol (10 ml) was heated at 150 ° C for 18 hours. The solvent was removed by evaporation, and the residue was suspended in a solution of aqueous sodium bicarbonate (25 ml) and extracted with EtOAc (4 x 25 ml). The organic extracts were combined, washed with brine (2 x 25 ml), dried (MgSO 4) and the solvent was removed by evaporation. The residue was titrated with ether, collected by filtration and dried to give the title compound (202 mg, 50%) as a tan solid. NMR (DMSO): 1.18 (m, 3H), 2.02 (m, 3H), 2.35 (m, 1H), 2.50 (m, 2H), 3.56 (m, 1H), 3.78 (m, 1H), 5.42 (d , 1H), 6.00 (br m, 1H), 6. 25 (br m, 1H), 6.67 (s, 1H), 7.47 (m, 1H), 7.90 (m, 3H), 8.63 (d, 1H), 9.40 (br s, 1H), 11.80 (br s, 1H); m / z 403 [MH] +.

Example 185 S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) -isoxazol-5-ippyrrolidin-1-yl) pyrimidine Were treated 4- (5- Cyclopropyl-1 H-pyrazol-3-ylamino) -2-chloropyrimidine (Method 28) (224 mg, 1.0 mmol) and S-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine (Method 42) through the method described in Example 184, to give the title compound (210 mg, 50%) as a tan crystalline crystalline solid. NMR (DMSO): 0.65 (m, 2H), 0.87 (m, 2H), 1.82 (br m, 1H), 2.02 (m, 3H), 2.35 (m, 1H), 3.55 (m, 1H), 3.80 ( m, 1H), 5.40 (d, 1H), 5.90 (brm, 1H), 6.20 (brm, 1H), 6.65 (br, 1H), 7.47 (m, 1H), 7.85 (brs, 1H), 7.95 (m, 3H), 8.65 (m, 1H), 9.40 (br s, 1H), 11.85 (br s, 1H); m / z 415 [MH] +.

Example 186 S-4- (5-Eti 1-1 H-pyrazol-3-ylamino) -5-f luoro-2-f 2 -f 3- (pyr i d-2-yl) -soxazole-5- iH-pyrrolidin-1-yl) pyrimidine 2-Chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -5-fluoropyrimidine (Method 69) and S2- (3- (2-pyridyl) isoxazole- 5-yl) pyrrolidine (Method 42) by the method described in Example 184. The product was purified through silica gel column chromatography eluting with a mixture of EtOAc / hexane (50:50 increasing in polarity to 100: 0) to give the title compound (221 mg, 53%) as a pale yellow solid. NMR (DMSO): 1.17 (t, 3H), 2.08 (m, 3H), 2.38 (m, 1H), 2.57 (q, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.37 (d , 1H), 6.18 (br s, 1H), 6.62 (s, 1H), 7.42 (m, 1H), 7.90 (m, 3H), 8.62 (d, 1H), 8.80 (br s, 1H), 11.60 ( br s, 1H); m / z 421 [MH] +.

Example 187 S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2-f2-f3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl) pyrimidine Were treated 2-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylammon) -5-fluoropyrimidine (Method 27) and S-2- (3- (2-pyridyl) isoxazole-5-l) pyrrolidine (Method 42) by the method described in Example 184. The product was purified through silica gel column chromatography eluting with an EtOAc / hexane mixture (50:50 increasing in polarity to 100: 0) to give the title compound (192 mg, 44%) as a yellow solid. pale. NMR (DMSO): 0.67 (m, 2H), 0.87 (m, 2H), 1.85 (br m, 1H), 2.02 (m, 3H), 2.38 (m, 1H), 3.55 (m, 1H), 3.80 (m, 1H), 5.37 (d, 1H), 5.95 (br s, 1H), 6.70 (s, 1H), 7.50 (m, 1H), 7.95 (m, 3H), 8.66 (d, 1H), 9. 45 (br s, 1H), 12.00 (br s, 1H); m / z 433 [MH] +.

Example 188 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2-f2-f3- (pyrimid-2-yl) isoxazol-5-illpyrrolidin-1-yl) pyrimidine A mixture of 2 -chloro-6-methyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 70) (210 mg, 0.84 mmol), S-2- [3- (pyrimid-2 -yl) isoxazol-5-yl] pyrrolidine (Method 66) (200 mg, 0.92 mmol), N, N-diisopropylethylamine (0.16 mL, 1.18 mmol) and dry 1-hexanol (4.0 mL) was heated to 150 ° C in a sealed container under microwave irradiation for 45 minutes. The reaction mixture was allowed to cool and then purified directly through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2). The fractions containing the product were drained in an exchange column of 1 Og isolute SCX2. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with ether and collected by filtration to give the title compound (212 mg, 59%). NMR (DMSO-de at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.05 (m, 2H), 2.10 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 3.70 (m, 1H), 3.75 (m, 1H), 5.47 (dd, 1H), 5.90 (br s, 1H), 6.15 (br s, 1H), 6. 65 (s, 1H), 7.50 (t, 1H), 8.75 (br s, 1H), 8.90 (d, 2H), 11.55 (br s, 1 HOUR); m / z 430 [MH] +.

Example 189 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2-f2-f3- (pyrazin-2-yl) isoxazol-5iH-pyrrolidin-1-ippyrimidine 2-Chloro-6- were treated methyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 70) and S-2- [3- (pyrazin-2-yl) isoxazole-5-yl] pi rrol idine (Method 55) as described in Example 188 to give the title compound (218 mg, 71%). NMR (DMSO-d6 at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.83 (heptet, 1H), 2.05 (m, 2H), 2.11 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 3.67 (m, 1H), 3.75 (m, 1H), 5.48 ( dd, 1H), 5.95 (br s, 1H), 6.15 (br s, 1H), 8.65 (m, 2H), 8.75 (br s, 1H), 9.12 (br s, 1H), 11.55 (br s, 1H ); m / z 430 [MH] +.

Example 190 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2-f2-f3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl} pyrimidine 2-Chloro-6-methyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 70) and S-2- (3- (2-pyridyl) isoxazole-5-yl were treated pyrrolidine (Method 42) as described in Example 188 to give the title compound (242 mg, 66%). NMR (DMSO-de at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.83 (heptet, 1H), 2.05 (m, 2H), 2.12 (s, 3H), 2.15 (m, 1H), 2.37 (m, 1H), 3. 68 (m, 1H), 3.75 (m, 1H), 5.45 (dd, 1H), 5.95 (br s, 1H), 6.15 (br s, 1H), 7.60 (s, s, 1H), 7.43 (dd, 1H), 7.85 (dd, 1H), 7.92 (d, 1H), 8.61 (d, 1H), 8.75 (br s, 1H), 11.55 (br s, 1H); m / z 429 [MH] +.

Example 191 6- (3-H id roxiprop il) -4- (5-methi 1-1 H-pyrazol-3-yl amino) -2-f 2 -f 3- (pyrid-2-yl) isoxazole-5 -illpyrrolidin-1-yl) pyrimidine 3-Amino-1 H-5-methylpyrazole (87 mg, 0.894 mmol) was added to a stirred solution of 4-chloro-6- (3-hydroxypropyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine (Method 71) (230 mg, 0.596 mmol) in dry NMP (3 ml). 6M hydrogen chloride in dioxane (298 μl) was added, 1.19 mmoles) and the reaction was stirred under heating at 120 ° C under nitrogen for 20 hours. The reaction was allowed to cool and the reaction mixture was applied to an exchange column of 10g isolute SCX2. The column was washed with methanol to remove neutral materials and then eluted with 2M of methanolic ammonia to elute the product. The solvent of the fractions containing the product was removed by evaporation and the residue was purified by flash chromatography on silica eluting with methanol / DCM (5:95). The product was then dissolved in ethyl acetate and washed with water, dried (Na 2 SO) and the solvent was removed by evaporation.

The residue was titrated with DCM / hexane and collected by filtration to give the title compound (99 mg, 37%) as a white solid. NMR (DMSO): 1.75 (m, 2H), 2.1 (m, 3H), 2.4 (s, 3H), 3.42 (m, 2H), 3.72 (m, 2H), 4.02 (s, 1H), 5.43 (d, 1H), 6.02 (s, 1H), 6.2 (s. 1H), 6.66 (s, 1H), 7.43 (t, 1H), 7.9 (m, 2H), 8.65 (d, 1H), 8.73 (s, 1H), 11.47 (s, 1H); m / z 447 [MH] +.

EXAMPLE 192 5-66 - (3-H -hydroxy-propyl) -4- (5-methyl-1H-irazol-3 -i-lamino) -2-f 2 -f 3- (pyrid-2-yl) ) isoxazol-5-yl-1-pyrrolidin-1-yl} pyrimidine The S-enantiomer of Example 191 was separated through chiral HPLC using a chiralpak AD column with methanol as eluent.

Example 193 S-6-Propyl-2-f3- (pyrid-2-yl) isoxazol-5-illpyrrolidin-1-yl > -4- (5-m eti 1-1 H-pyrazol-3-ylamino) pyrimidine Bis (triphenylphosphine) palladium (II) chloride (34 mg) was added to a stirred solution of S-6-iodo-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-yl amino) pyrimidine (Example 98) (250 mg, 0.486 mmol) in dry dimethylacetamide (7.5 ml) and dry THF (2.5 ml). Then a 0.5M solution of n-propylzinc bromide in THF (3.9 mL, 1.94 mmol) was added and the reaction was stirred at room temperature for 24 hours. A further 0.5M solution of n-propylzinc bromide in THF (3.9 mL, 1.94 mmol) was added and the reaction was stirred an additional 24 hours. Then water and ethyl acetate were added to the reaction mixture and the mixture was filtered to remove insoluble matter. The filter layers were separated and the organic layer was washed with water and saturated brine, dried (Na2SO4), the solvent was removed by evaporation. The residue was purified through reverse phase HPLC using a column C18 eluting with water / acetonitrile / TFA (95: 5: 0.2 reducing in polarity to 0: 100: 0.2) to give the title compound (115 mg, 55%) as a white solid. NMR (DMSO-de at 373 degrees K): 0.9 (t, 3H), 1.63 (m, 2H), 2.12 (m, 3H), 2.18 (s, 3H), 2.4 (m, 3H), 3.72 (m, 1H), 3.83 (m, 1H), 5.5 (d, 1H), 6.0 (s, 1H), 6.27 (s, 1H), 6.75 (s, 1H), 7.45 (t, 1H), 7.9 (m, 2H) ), 8.65 (d, 1H), 9.43 (s, 1H); m / z 431 [MH] +.

Example 194 S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) -isoxazole-5-M) pyrrolidin-1-yl-1-pyrimidine treated 2,6-dichloro-4- (5-ethyl-1 H-pyrazol-3-ylamino) pyridin (Method 72) and S-2- (3- (2-pyridyl) isoxazol-5-yl) pyrrolidine (Method 42) as described in Example 143 to give the title compound (80 mg, 48%); NMR (DMSO-de at 100 ° C): 1.1 (t, 3H), 2.05 (m, 2H), 2.15 (m, 1H), 2.35 (m, 2H), 2.55 (q, 2H), 3.65 ( m, 1H), 3.75 (m, 1H), 5.4 (d, 1H), 6.05 (br s, 1H), 6.4 (br, 1H), 6.65 (s, 1H), 7.45 (m, 1H), 7.90 (m, 2H), 8.65 (d, 1H), 9.25 (br s, 1H), 11.65 (br s, 1H); m / z 438 [MH] +.

Example 195 S-6- (2-H idroxyethoxy) -4- (5-eti 1-1 H-pyrazol-3-yl amino) -2-f2-f 3 - (pyrid-2-yl) isoxazole-5 -il} pyrrolidin-1-yl-1-pyrimidine S-6-Chloro-4- (5-ethyl-1 H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 194) and ethylene glycol as described in Example 208 to give the title compound (80 mg, 49%). NMR (DMSO-100 ° C): 1.17 (t, 3H), 2.10 (m, 3H), 2.45 (m, 1H), 2.55 (q, 2H), 3.60 (q, 2H), 3.75 (m, 2H) ), 4.18 (m, 2H), 4.35 (t, 1H), 5.42 (d, 1H), 5.75 (br s, 1H), 6.00 (br s, 1H), 6.66 (s, 1H), 7.45 ( m, 1H), 7.92 (m, 2H), 8.65 (br s, 1H), 8.65 (d, 1H); m / z 464 [MH] +.

EXAMPLE 196 S -6- (2-Methoxyethoxy) -4- (5-eti 1-1 H-pyrazol-3-yl amino) -2-f2-f3- (pi rid-2-yl) isoxazole-5- il} pyrrolidin-1-pyrimidine S-6-chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 194) and 2-methoxyethanol as described in Example 208 to give the title compound (122 mg, 56%). NMR (DMSO-de at 100 ° C): 1.18 (t, 3H), 2.10 (m, 3H), 2.30 (m, 1H), 2.52 (q, 2H), 3.20 (s, 3H), 3.50 (q, 2H), 3.70 (m, 1H), 3.75 (m, 1H), 4.25 (t, 2H), 5.40 (d, 2H), 5.75 (br s, 1H), 6.00 (br s, 1H), 6.69 (s, 1H), 7.40 (m, 1H), 7.90 (m, 2H), 8.60 (d, 1H), 8.60 (br s, 1H), 11. 50 (br s, 1H); m / z 478 [MH] +.

Example 197 S-6-Morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-inpyrimidine Were treated S-6-chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 194) and morpholine as described in Example 166 to give the title compound (67 mg, 30%). NMR (DMSO-de at 100 ° C): 1.20 (t, 3H), 2.10 (m, 3H), 2.35 (m, 1H), 2.55 (q, 2H), 3.40 (m, 4H), '3.60 (m, 4H), 3.75 (m, 2H), 5.40 (d, 1H), 5.80 (br s, 1H), 6.00 (br s, 1H), 6.65 (s, 1H), 7.45 (m, 1H), 7.95 (m, 1H), 8.35 (br s, 1H), 8.65 ( d, 1H), 11.45 (br s, 1H); m / z 489 [MH] +.

EXAMPLE 198 S-6- (4-Methylpiperazin-1-yl) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazole-5 -il} pyrrolidin-1-ippyrimidine S-6-chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 194) and 1-methylpiperazine as described in Example 166 to give the title compound (110 mg, 49%). NMR (DMSO-de at 100 ° C): 1.15 (t, 3H), 2.00 (m, 3H), 2.25 (s, 3H), 2.35 (m, 5H), 2.55 (q, 2H), 3.30 ( m, 4H), 3.60 (m, 2H), 5.30 (q, 1H), 5.70 (br s, 1H), 5.90 (br s, 1H), 6.60 (s, 1H), 7.40 (m, 1H), 7.90 (m, 1H), 8.25 (br s, 1H), 8.65 (d, 1H), 11.30 (br s, 1H); m / z 502 [MH] +.

Example 199 S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2-f2-f3- (2-pyrazinyl) -isoxazol-5-yl) pyrrolidin-1-pyrimidine 2,6-Dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (Method 72) and S-2- [3- (2-pyrazinyl) isoxazol-5-yl] pyrrolidine were treated. (Method 55) as described in Example 141 to give the title compound (800 mg, 48%). NMR (DMSO-de at 100 ° C): 1.18 (t, 3H), 2.05 (m, 3H), 2.15 (m, 1H), 2.55 (q, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.45 (d, 1H), 6.04 (br s, 1H), 6.40 (br s, 1H), 6.78 (s, 1H), 8.70 (m, 2H), 9.14 (s, 1H), 9.25 (br s, 1 H); m / z 439 [MH] +.

Examples 200 to 207 The following individual enantiomers were prepared through separation of the racemic compound through chiral HPLC.

EXAMPLE 200 S-6-Methoxy -4- (5-methy1-1 H -pyrazol-3-ylamino) -2-r2-f3- (pyridin-2-yl) isoxazol-5-yl) pyrrolidin-1 Pyrimidine The title compound was prepared by separating the racemic compound (Example 48) through chiral HPLC using a chiralpak AD column eluting with methanol.

EXAMPLE 201 S-6- (2-Methoxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidine -1-pyrimidine The title compound was prepared by separating the racemic compound (Example 214) through qulral HPLC using a chiralpak AD column eluting with methanol.

Example 202 S-6-Pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- (2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin- 1-ippyrimidine The title compound was prepared through separation of the racemic compound (Example 95) through chiral HPLC using a Chiralpak AS column eluting with methanol.

EXAMPLE 203 S -6-Methoxymethyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2 -f2- (3-cyclopropylisoxazol-5-yl) pyrrolidin-1-pyrogimide The title compound was prepared by separating the racemic compound (Example 13) through chiral HPLC using a Chiralpak AS column eluting with methanol / ethanol (85:15).

EXAMPLE 204 S-6-Morpholinecarbonyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-illpyrimidine The title compound was prepared through separation of the racemic compound (Example 58) through chiral HPLC using a chiralpak AD column eluting with methanol / ethanol (85:15).

EXAMPLE 205 S-6-Carbamoyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl-1-pyrimidine The title compound was prepared by separating the racemic compound (Example 61) through chiral HPLC using a chiralpak AD column eluting with methanol / ethanol (85:15).

EXAMPLE 206 S-5-Fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-inpyrimidine The title compound was prepared by separating the racemic compound (Example 20) through chiral HPLC using a Chiralpak AS column eluting with methanol.

Example 207 S-4- (5-Methi 1-1 H-pyrazole-3-ylamino) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-ippyrimidine The compound of The title was prepared by separating the racemic compound (Example 23) through chiral HPLC using a Chiralpak AS column eluting with methanol.

Example 208 S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2-f2-f3- (pyrid-2-yl) isoxazole-5-ippyrrolidin-1 -iH-pyrimidine Sodium hydride (94 mg, 2.35 mmol) was added in portions to ethylene glycol (4 ml). The mixture was stirred for 10 minutes and S-6-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2 ~. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (200 mg, 0.47 mmol). The reaction was heated to 150 ° C in a sealed vessel under microwave irradiation for 1 hour. The reaction was quenched with 2M hydrochloric acid then diluted with water and extracted with DCM. The extracts were combined, washed with brine, dried (Na2SO4) and the solvent was removed by evaporation. The residue was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (70: 30: 0.2 reducing in polarity to 30: 70: 0.2). The fractions containing the product were drained on a SCX-2 column, washed with methanol to elute neutral impurities then eluted with 3N methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with ether to give the title compound (131 mg, 62%). NMR (DMSO): 2.08 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3. 61 (m, 2H), 3.71 (m, 2H), 4.18 (m, 2H), 5.4 (d, 1H), 5.75 (s, 1H), 5.95 (s, 1H), 6.68 (s, 1H), 7.4 (m, 1H), 7.88 (m, 1H), 7.94 (d, 1H), 8. 62 (d, 1H); m / z 449 [MH] +.

Examples 209 to 233 Examples 209 to 233 were prepared by an analogous method to that described for Example 208. Reaction times were between 30 minutes and 2 hours. In some cases, 10 equivalents of alcohol were used with 1 to 2 ml of 2-propanol as the solvent. The reactions could be quenched with glacial acetic acid instead of hydrochloric acid; and the reaction mixtures could be applied directly to purification by HPLC without aqueous processing. 221 Example 96 and S-4- (5-Methyl-1H-1.04 (d, 3H), 2.1 (m, 477 (2S) -2-methoxypyrazol-3-ylamino) -6- 3H), 2.19 (s, 3H), 2.39 propan-1-ol [(2S) -2-methoxyprop- (m, 1H), 3.21 (s, 3H), 1-yloxy] -2- [2-. { 3- 3.53 (m, 1H), 3.74 (m, (pyrid-2-yl) isoxazole-5- 2H), 4.11 (d, 2H), 5.39 ll} pyrrolidin-1-yl] pyrimidine (d, 1H), 5.79 (s, 1 H), 5.97 (s, 1H), 6.68 (s, 1 H), 7.45 (m, 1H), 7.91 (m, 2H), 8.65 (d, 2H), 11.5 (brs, 1H) 222 Example 96 and S-4- (5-Methyl-1H-1.88 (m, 2H), 2.01 (s, 493 3-methylthiopyrazol-3-ylamino) -6- 3H), 2.09 (m, 3H), 2.18 propan-1-ol [3- (methylthio) prop-1- (s, 3H), 2.37 (m, 1H) , iloxy] -2- [2-. { 3- (pyrid-2.5 (under DMSO 2-yl) isoxazol-5-yl.} Pyrrolidin-1-peak, 2 H), 3.72 (m, yl] pyrimidine 2 H), 4.22 (t, 2 H), 5.4 (d , 1H), 5.76 (s, 1H), 5.96 (s, 1H), 6.68 (s, 1H), 7.44 (m, 1H), 7.92 (m, 2H), 8.59 (s, 1H), 8.63 (d, 1H), 11.47 (br s, 1H) 223 Example 96 and S-4- (5-Methyl-1 H- 1.74 (m, 1H), 2.1 (m, 502 (5S) -5-hydroxypyrazol-3-ylamino ) -6- 6H), 2.18 (s, 3H), 2.39 methyl- [(2S) -5-oxopyrrolidin- (m, 1H), 3.73 (m, 3H), pyrrolidin-2-2-yl) methoxy] - 2- [2-. { 3- 4.1 (m, 2H), 5.4 (d, ona (pyrid-2-yl) isoxazole-5- 1H), 5.78 (s, 1H), 5.94 il} pyrroidin-1- (s, 1H), 6.7 (s, 1H), il] pyrimidine 7.25 (s, 1H), 7.44 (m, 1H), 7.92 (m, 2H), 8.63 (d, 2H) Sub-methods to. The reaction was quenched with a mixture of glacial acetic acid purified directly through hplc. b. The reaction was quenched with glacial acetic acid, diluted with water then extracted with DCM, dried (Na2SO4), evaporated, and then purified through hplc. c. The reaction was quenched with saturated ammonium chloride solution, then extracted with DCM, dried (Na2SO4), evaporated, then purified through hplc.

EXAMPLE 234 S-4- (5- eti 1-1 H -pyrazol-3 -ilamino) -6- (tetrah id rop ira n -4 -i I oxy) -2-T2-f3- (pyrid-2- il) isoxazol-5-yl} pyrrolidin-1-n-pyrimidine Cesium fluoride (681 mg) was heated, 3.5 mmol) and S-6-chloro-4- (5-methy1-1 H -pyrazol-3ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 96) (300 mg, 0.71 mmol) in tetrahydro-4-pyranol (3 ml) at 200 ° C in a sealed container under microwave irradiation for 2 hours. The reaction mixture was diluted with water and extracted with DCM. The extracts were combined, washed with brine, dried (Na2SO4) and the solvent was removed by evaporation. The residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (70: 30: 0.2 reducing in polarity to 30: 70: 0.2). The fractions containing the product were drained on an SCX-2 column and washed with methanol, then eluted with 7N methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (107 mg, 31%). NMR (DMSO): 1.41 (m, 1H), 1.61 (m, 2H), 1.94 (m, 1H), 2.05 (m, 3H), 2.17 (s, 3H), 2.35 (m, 1H), 3.29 (t , 1H), 3.44 (m, 1H), 3.65 (m, 2H), 3.8 (m, 2H), 4.96 (m, 1H), 5.33 (d, 1H), 5.7 (s, 1H), 5.96 (s, 1H), 6.65 (s, 1H), 7.4 (m, 1H), 7.84 (m, 1H), 7.91 (d, 1H), 8.61 (d, 1 HOUR); m / z 489 [MH] +.

Example 235 S-5-Fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidin-1-pyrimidine One mixture of 2-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -5-fluoropyrimidine (Method 27 (b)) (175 mg, 0.77 mmol), S-2- (3- (thiazole) -2-yl) isoxazol-5-yl) pyrrolidine (Method 77) (187 mg, 0.85 mmol) and diisopropylethylamine (0.28 mL, 1.6 mmol) in 1-hexanol (3 mL) was heated at 130 ° C for 48 hours. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with EtOAc / hexane (1: 1 increasing in polarity to 2: 1). The purified product was titrated with diethyl ether and collected by filtration to give the title compound (79 mg, 25%) NMR (DMSO): 2.06 (m, 3H), 2.18 (s, 3H), 2.38 (m , 1H), 3.64 (m, 1H), 3.76 (m, 1H), 5.36 (d, 1H), 6.11 (s, 1H), 6.62 (s, 1H), 7.85 (d, 1H), 7.9 (d, 1H), 7.98 (d, 1H), 8.82 (br s, 1H), 11.64 (br s, 1H); m / z 413 [MH] +.

Examples 236 to 241 Examples 236 to 241 were prepared by an analogous method to that described in Example 235. Sub-methods Sub-method d. The crude product was purified through hplc, the fractions containing the product were emptied onto an SCX2 ion exchange column, eluted with methanol to remove neutral impurities and then with methanolic ammonia to elute the product.

Example 242 S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidin-1-ippyrimidine Were treated 2,6-dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 29) and S-2- (3 (thiazol-2-yl) isoxazole-5-i) pi Preparation (Method 77) as described in Example 96. The crude product was purified by column chromatography on silica gel eluting with EtOAc / hexane (7: 3). The purified product was titrated with diethyl ether and collected by filtration to give the title compound (0.89 g, 57%) as a white solid. NMR (DMSO): 2.09 (m, 3H), 2.18 (s, 3H), 2.39 (m, 1H), 3.66 (m, 1H), 3.75 (m, 1H), 5.42 (d, 1H), 5.97 (s) , 1H), 6.39 (s, 1H), 6.71 (s, 1H), 7.85 (d, 1H), 7.98 (d, 1H), 9.22 (s, 1H), 11.62 (s, 1H); m / z 429 [MH] +.

Example 243 S-6-C parrot-4- (5-cyclopropyl 1-1 H-pyrazole-3-ilamino) -2-f 2 -f 3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidin-1-illpyrmidin 2,6-dichloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 57) and S2- (3- (thiazol-2-yl) were treated Soxazol-5-yl) pyrrolidine (Method 77) as described in Example 242 to give the title compound (183 mg, 29%) as a white solid. NMR (DMSO 373K + d4AcOH): 0.65 (m, 2H), 0.88 (m, 2H), 1.8 (m, 1H), 2.04 (m, 2H), 2.13 (m, 1H), 2.37 (m, 1H), 3.65 (m, 1H), 3.72 (m, 1H), 5.42 (d, 1H), 5.94 (s, 1H), 6.38 (s, 1H), 6.67 (s, 1H), 7.81 (d, 1H), 7.97 (s, 1H); m / z 455 [MH] +.

Example 244 S-6-Morpholin-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3- (thiazol-2-yl) isoxazo1-5-yl) pyrrolidin-1- Pyrimidine S-6-Chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 242) (150 mg, 0.35 mmole) and morpholine (3 ml) at 120 ° C in a sealed container under microwave irradiation for 30 minutes. The reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (97.5: 2.5: 0.2 reducing in polarity to 60: 40: 0.2). The fractions containing the product were drained on a SCX-2 column, washed with methanol to elute neutral impurities, then with 3.5N methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with ether and collected by filtration to give the title compound (72 mg, 43%) as a creamy solid. NMR (DMSO): 2.07 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 3.35 (m, 4H), 3.57 (m, 4H), 3.71 (m, 2H), 5.37 (d, 1H), 5.75 (s, 1H), 5.94 (s, 1H), 6.64 (s, 1H), 7.85 (d, 1H), 7.99 (d, 1H), 8.34 (s, 1H), 11.42 (s, 1 HOUR); m / z 480 [MH] +.

Examples 245 to 248 Examples 245 to 248 were prepared by a method analogous to that described in Example 244.

Sub-Methods e. It was heated at 150 ° C for 90 minutes. F. Solution of methylamine in ethanol. It was heated at 130 ° C during 90 minutes g. Reaction processing: -diluted with water, extracted with EtOAc, dried (Na2SO4) and the volatiles were evaporated. The residue was purified by column chromatography on silica gel eluting with methanol / DCM / aqueous ammonia (5: 95: 0 and then 5: 94: 1).

Example 249 S-6-M eti l-4- (5-methi 1-1 H-pyrrazol-3-ylamino) -2-f 2 -f 3 - (thiazo I-2-yl) isoxazol-5-yl > pyrrolidin-1-n-pyrimidine 2-Chloro-6-methyl-4- (5-methyl-1 H -pyrazol-3-ylamino) -pyrimidine (Method 56) (200 mg, 0.89 mmol), S-2- was suspended (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine (Method 77) (218 mg, 0.98 mmol) and N, N-diisopropylethylamine (0.37 mL, 2.1 mmol) in 1-hexanol (4 mL) and they were heated to 150 ° C in a sealed container under microwave irradiation for 3 hours. The reaction mixture was purified through reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (97.5: 2.5: 0.2 reducing in polarity to 60: 40: 0.2). The fractions containing the product were drained on an SCX-2 ion exchange column and washed with methanol to remove the neutral materials and then with 3.5N methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with ether and collected by filtration to give the title compound (164 mg, 45%) as a white solid. NMR (DMSO): 2.07 (m, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 2.36 (m, 1H), 3.71 (m, 2H), 5.43 (d, 1H), 5.99 (s) , 1H), 6.19 (s, 1H), 6.64 (s, 1H), 7.85 (d, 1H), 7.98 (d, 1H), 8.73 (s, 1H), 11.5 (s, 1H); m / z 409 [MH] +.

Example 250 S-6-f 3- (Methylsulfonyl) propy 1-1 -oxi l-4- (5-methylated 1-1 H -pyrazole-3-ylamino) -2-f 2 -f 3 (pyrid-2 il) soxazol-5-yl} pyrrolidin-1-yl-1-pyrimidine A solution of potassium peroxymonosulfate, potassium acid sulfate, potassium sulfate complex (oxone ™) (227 mg, 0.37 mmol) in water (1.3 ml) was added dropwise to a stirred solution of S -4- (5-met il-1H-p-razo l-3-ylamino) -6- [3- (m ethy lthio) pro p-1-yloxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 222) (130 mg, 0.26 mmol) in THF (1.3 ml). The mixture was stirred at room temperature for 2 hours then diluted with water and adjusted to a pH of 8 with 1M of an aqueous potassium hydroxide solution. The mixture was extracted with ethyl acetate (x3) and the organic extracts were combined, washed with brine and dried (Na2SO). The solvent was removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water / acetonitrile / TFA (70: 30: 0.2 reducing in polarity to 30: 70: 0.2). The fractions containing the product were drained on an SCX-2 ion exchange column, which was washed with methanol then eluted with 3.5N of methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue was titrated with diethyl ether and collected by filtration to give the title compound (45 mg, 33%) as a creamy solid. NMR (DMSO): 2.09 (m, 5H), 2.17 (s, 3H), 2.37 (m, 1H), 2.94 (s, 3H), 3.13 (t, 2H), 3.72 (m, 2H), 4.28 (m, 2H), 5.4 (d, 1H), 5.78 (s, 1H), 5.95 (s, 1H), 6.7 (s, 1H), 7.44 (m, 1H), 7.92 (m, 2H), 8.66 (d, 2H), 11.5 (br s, 1H); m / z 525 [MH] +.

Example 251 S-6- (2-Methoxyethoxy) -2-f2-r3- (pyrazin-2-yl) isoxazol-5-pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine S-6-chloro-2- was treated. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (Example 91) and 2-methoxyethanol through an analogous method to that described in Example 208 except that the crude product was purified at through column chromatography on silica gel eluting with hexane / EtOAc (80:20 increasing in polarity to 0: 100) to give the title compound (70 mg, 21%) a pale yellow powder. NMR (DMSO-de + d4-acetic acid at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.00-2.15 (m, 3H), 2.40 (m, 1H), 3.20 (s, 3H), 3.50 (m, 2H), 3.70 (m, 1H), 3.75 (m, 1H), 4.25 (t, 2H), 5.40 (d, 1H), 5.55 (s, 1H) ), 5.70 (s, 1H), 5.90 (s, 1H), 6.70 (s, 1H), 8.65 (m, 2H), 9.10 (s, 1H); m / z 490 [MH] +.

Example 252 S-6-Chloro-2-f2-f3- (pyrimid-2-yl) isoxazol-5-yl-1-pyrrolidin-1-yl) -4- (5-ethyl-1 H -pyrazol-3-ylamino) pyr midina 2,6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (Method 72) and S-2- [3 (pyrimid-2-yl) were treated isoxazol-5-yl] pyrrolidine (Method 66) by an analogous method to that described in Example 161 to give the title compound (364 mg, 49%) as a white powder. NMR (DMSO-d6 + d4-acetic acid at 100 ° C): 1.15 (m, 3H), 2.00-2.20 (m. 3H), 2.40 (m, 1H), 2.55 (m, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.45 (d, 1H), 6.05 (br s, 1H), 6.47 (s, 1H), 6.70 (s, 1H), 7.48 (t, 1H), 8.85 (d, 2H); m / z 438 [MH] +.

Example 253 S-6-Methoxy-2-f2-f3- (pyrimid-2-yl) isoxazol-5-illpyrrolidin-1-yl > -4- (5-ethyl-1 H-pyrazol-3-ylamino) pyrimidine S-6-chloro-2- was treated. { 2- [3- (pyrimid-2-yl) isoxazol-5-yl] -pyrrolidin-1-yl} -4- (5-ethyl-1H-pyrazol-3-ylamine) pyrimidine (Example 252) through a method analogous to that described in Example 94 to give the title compound (118 mg, 80%) as a powder pink.

NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.15 (t, 3H), 2.00-2.15 (m, 3H), 2.35 (m, 1H), 2.55 (q, 2H), 3.70 (m, 4H), 3.75 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 6.67 (s, 1H), 7.45 (t, 1H), 8.85 (d, 2H); m / z 434 [MH] +.

Example 254 S-6-Ethyl-2-f2-r3- (pyrimid-2-yl) isoxazol-5-inpyrrolidin-1-yl-4- (5-etl-1H-pyrazol-3-ylamino) pyrimidine A mixture of S-2- [3- (pyrimid-2-yl) -soxazol-5-yl] pyrrolidine (Method 66) (198 mg, 0.91 mmol), 6-ethyl-2-chloro-4- (5- ethyl-1 H-pyrazol-3-ylamino) pyrimidine (Method 79) (210 mg, 0.83 mmol), and diisopropylethylamine was heated in hexanol (4 ml) at 150 ° C for 60 minutes under microwave irradiation. The crude reaction mixture was transferred to a 10g SCX column, eluting with methanol and then eluting the product with 2M methanolic ammonia and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with DCM / 2M methanolic ammonia (100: 0 increasing in polarity to 90:10) to give the title compound (78 mg, 22%) as a pale brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.00-1.20 (m, 6H), 2. 00-2.15 (m, 3H), 2.35-2.45 (m, 3H), 2.55 (q, 2H), 3.65-3.80 (m, 2H), 5.45 (d, 1H), 5.60 (s, 1H), 6.10 ( s, 1H), 6.20 (s, 1H), 6.70 (s, 1H), 7.50 (t, 1H), 8.90 (d, 2H); m / z 432 [MH] +.

Example 255 S-6-Aminomethyl-2-f2-f3- (pyrimid-2-yl) isoxazol-5-pyrrolidin-1-yl > -4- (5-ethi 1-1 H-pi I-3 -i lamino) pyrimtdine S-6-chloro-2- was treated. { 2- [3- (pyrimid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-ethyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 252) by an analogous method to that described in Example 140 to give the title compound (20 mg, 13%) as a solid coffee. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.15 (t, 3H), 2.00- 2.15 (m, 3H), .35 (m, 1H), 2.55 (q, 2H), 2.65 (s) , 3H), 3.60-3.80 (m, 2H), 5.45 (d, 1H), 5.60 (s, 1H), 5.90 (s, 1H), 6.70 (s, 1H), 7.45 (m, 1H), 8.85 (d, 2H); m / z 433 [MH] +.

EXAMPLE 256 S-6-Ethyl-2-f 2-f 3- (pyrimid-2-yl) isoxazole-5-yl pyrrolidin-1 -i l > -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine 6-Ethyl-2-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylammon) pyrimidine (Method 80) was treated and S-2- [3- (pirlmid-2-yl) isoxazole-5-i] pyrrolidone (Method 66) by an analogous method to that described in Example 254 to give the title compound ( 230 mg, 68%) as a brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.65 (m, 2H), 0.85 (m, 2H), 1.10 (t, 3H), 1.80 (m, 1H), 2.05 (m, 2H), 2.15 (m, 1H), 2.30-2.45 (m, 3H), 3.67 (m, 1H), 3.75 (m, 1H), 5.45 (dd, 1H), 5.55 (s, 1H), 5.95 (s, 1H), 6.15 (s, 1H), 7.48 (t, 1H), 8.85 (d, 2H); m / z 444 [MH] +.

Example 257 S-6-Cyclopropyl-2-f2-f3- (pyrimid-2-yl) isoxazole-5-pyrrolidin-1-yl > -4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine 6-Cyclopropyl-2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (Method 81) and S were treated. -2- [3- (pyrimid-2-yl) isoxazole-5-y1] pi-roline (Method 66) by an analogous method to that described in Example 254 to give the title compound (89 mg , 27%) as a brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.65-0.90 (m, 7H), 0. 95 (m, 1H), 1.70 (m, 1H), 1.85 (m, 1H), 2.00-2.15 (m, 3H), 2.35 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.35 (dd, 1H), 5.65 (s, 1H), 6.00 (s, 1H), 6.20 (s, 1H), 6.65 (s, 1H), 7.50 (t, 1H), 8.90 (d, 1H); m / z 456 [MH] +.

Example 258 S-6-Cyclopropyl-2-f2-f3- (pyrimid-2-yl) isoxazol-5-pyrrolidin-1-yl > -4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine S treated 6-cyclopropyl-2-chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 82) and S-2- [3- (pyrimid-2-yl) isoxazol-5-yl] pyrrole idine (Method 66) by an analogous method to that described in Example 254 to give the title compound (80 mg, 49%) as a brown powder. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 0.70-0.80 (m, 3H), 0.95 (m, 1H), 1.15 (t, 3H), 1.70 (m, 1H), 2.00-2.15 ( m, 3H), 2.35 (m, 1H), 2.55 (q, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.35 (dd, 1H), 5.60 (s, 1H), 6.05 (s) , 1H), 6.20 (s, 1H), 6.65 (s, 1H), 7.45 (t, 1H), 8.90 (d, 2H); m / z 444 [MH] +.

Example 259 S-6- (2-Methoxyethoxy) -2-f2-f3- (pyrimid-2-yl) isoxazol-5-inpyrrolidin-1-yl) -4- (5-ethyl-1H-pyrazole-3 -ylamino) pyrimidine S-6-chloro-2- was treated. { 2- [3- (pyrimid-2-yl) lsoxazol-5-yl] -pyrrolidin-1-yl} -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (Example 252) and 2-methoxyethanol through an analogous method to that described in Example 208 except that the crude product was purified through chromatography of column on silica gel eluting with DCM / 2M methanolic ammonia (100: 0 increasing in polarity to 95: 5) to give the title compound (118 mg, 47%) as a white solid. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.15 (t, 3H), 2.00- 2.20 (m, 3H), 2.40 (m, 1H), 2.55 (q, 2H), 3.20 (s, 3H), 3.50 (m, 2H), 3. 65 (m, 1H), 3.75 (m, 1H), 4.25 (t, 2H), 5.40 (dd, 1H), 5.55 (s, 1H), 5.70 (s, 1H), 6.00 (s, 1H), 6.70 (s, 1H), 7.45 (t, 1H), 8.85 (d, 2H); m / z 478 [MH] +.

Example 260 S-6-Methyl-2-f2-f3- (3-methoxypyrazin-2-yl) -soxazole-5-pyrrolidin-1-yl > -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 2-chloro-6-methyl-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 83 ) (105 mg, 0.44 mmol), S-2- [3- (2-methoxypyrazin-3-yl) isoxazol-5-yl] pyrrolidine (Method 68) (120 mg, 0.49 mmol), diisopropylethylamine (0.12 mL, 0.69 mmoles) and hexanol (3 ml) was heated to 150 ° C in a sealed container under microwave irradiation for 1 hour. The crude reaction mixture was emptied into an SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanoic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with DCM / 2M methanolic ammonia (100: 0 increasing in polarity to 90:10) to give the title compound (86 mg, 44%) as a yellow-brown solid. NMR (DMSO-de at 100 ° C): 1.21 (t, 3H), 2.07 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 2.58 (q, 2H), 3.71 (m, 2H), 4.01 (s, 3H), 5.50 (dd, 1H), 6.08 (s, 1H), 6.22 (s, 1H), 6.63 (s, 1H), 8.33 (s, 2H), 8.78 (br s, 1H), 11.51 (br s, 1H); m / z 449 [MH] +.

Example 261 S -6-C lo ro-2-f 2 -f 3 - (3-m ethoxy p i reason -2-yl) isoxazole-5-pyrro lid i n-1-yl} -4- (5-ethyl-1 H-pyrazole-3-ylamide) pyrimidine A mixture of 2,6-dichloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 72) ( 570 mg, 2.2 mmol), S-2- [3- (2-methoxy-pyrrazin-3-yl) isoxazol-5-yl] pyrrolidine (Method 68) (600 mg, 2.4 mmol), diisopropylethylamine (310 mg , 2.4 mmol) in 1-butanol (10 ml) was heated at 75 ° C for 16 hours. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (80:20 increasing in polarity to 0: 100) to give the title compound (450 mg, 44%) as a white foam.

NMR (DMSO-de at 100 ° C): 1.21 (t, 3H), 2.07 (m, 3H), 2.37 (m, 1H), 2.58 (q, 2H), 3.71 (m, 2H), 4.01 (s, 3H), 5.50 (dd, 1H), 6.08 (s, 1H), 6.42 (s, 1H), 6.66 (s, 1H), 8.33 (s, 2H), 9.27 (s, 1H), 11.61 (s, 1H); m / z 469 [MH] +.

Example 262 S-6-M eti I-2-f 2-f 3 - (3-methoxy pyrazin-2-yl) isoxazole-5-ill pyrro lid i n-1-yl) -4- (5-cyclopropyl- 1 H -pyrazol -3-ylamino) pyrimidine 2-Chloro-6-methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine (Method 70) and S-2- [3- (2-methoxypyrazon-3-yl) isoxazol-5-yl] pyrrolidine (Method 68) by an analogous method to that described in Example 260 to give the title compound (88 mg, 40%). NMR (DMSO-d6 at 100 ° C): 0.68 (m, 2H), 0.89 (m, 2H), 1.89 (m, 1H), 2.07 (m, 3H), 2.18 (s, 3H), 2.37 (m, 1H), 3.71 (m, 2H), 4.01 (s, 3H), 5.50 (dd, 1H), 5.97 (s, 1H) ), 6.17 (s, 1H), 6.66 (s, 1H), 8.33 (s, 2H), 8.72 (br s, 1H), 11.58 (br s, 1H); m / z 461 [NH] +.

Example 263 S-6-Morpholino-2-f2-f3- (3-methoxypyrazin-2-yl) isoxazole-5-illpyrrolidin-1-yl) -4- (5-ethyl-1 H-pyrazole-3-yl) no) pyrimidine A mixture of S-6-chloro-2-. { 2- [3- (3-methoxy-pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (Example 261) (250 mg, 0.5 mmol) in morfoiin (3 mL) was heated at 70 ° C in a sealed vessel under microwave irradiation for 2 hours. hours.

The crude reaction mixture was purified through phase HPLC Reverse using a C18 column eluting with water / acetonitrile / TFA (95: 5: 0.2 decreasing in polarity to 0: 100: 0.2). The fractions containing the product were combined and passed through a solute ion exchange column SCX-2. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was titrated with hexane and collected by filtration to give the title compound (81 mg, 31%) as a white solid. NMR (DMSO-de at 100 ° C): 1.20 (t, 3H), 2.07 (m, 3H), 2.37 (m, 1H), 2.58 (q, 2H), 3.39 (m, 4H), 3.59 (m, 4H), 3.71 (m, 2H), 4.01 (s, 3H), 5.44 (dd, 1H), 5.77 (br s, 1H), 6.01 (br s, 1H), 6.62 (s, 1H), 8.27 (s) , 3H), 11.42 (br s, 1H); m / z 520 [MH] +.

Example 264 S-6-Morpholino-2-f2-f3- (3-hydroxypyrazin-2-yl) isoxazol-5-yl > pyrrolidin-1-yl-1-4- (5-ethyl-1 H -pyrazol-3-ylamino) -pyridomidine The title compound was isolated as a by-product from the preparation of Example 263 (30). mg, 11%). NMR (DMSO-d6 at 100 ° C): 1.20 (t, 3H), 2.07 (m, 3H), 2.37 (m, 1H), 2.58 (q, 2H), 3.39 (m, 4H), 3.59 (m, 4H), 3.71 (m, 2H), 5.40 (dd, 1H), 5.81 (s, 1H), 6.03 (s, 1H), 6.71 (s, 1H), 7.58 (s, 2H), 8.31 (s, 1H) ), 11.42 (br s, 1H); m / z 505 [MH] +.

Example 265 S-6-Methyl-2-f2-f3- (2-methoxypyrid-3-yl) isoxazol-5-n-pyrrolidin-1-yl) -4- (5-met i 1-1 H-pyrazole -3 -i lamino) pirim id i na A mixture of 6-methyl-2-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Method 56) (200 mg, 0.9 mmol) , S-2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidine (Method 64) (262 mg, 1.1 mmol) and diisopropylethylamine (0.22 mL, 1.25 mmol), in hexanol (5 mL) ) was heated to 150 ° C in a sealed vessel under microwave irradiation for 105 minutes. The volatiles were removed by evaporation, the residue was dissolved in EtOAc, washed with water, dried (MgSO 4), and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (1: 1) to give the title compound (160 mg, 42%). NMR (DMSO): 2.0-2.2 (m, 9H), 2.30-2.40 (m, 1H), 3.65-3.70 (m, 2H), 3.90 (s, 3H), 5.40 (dd, 1H), 6.0 (s, 1H), 6.19 (s, 1H), 6.60 (s, 1H), 7.10 (dd, 1H), 8.10 (dd, 1H) ), 8.25 (d, 1H), 8.70 (s, 1H), 11.45 (s, 1H); m / z 433 [MH] +.

Example 266 S-5-Fluoro-2-f2-f3- (2-methoxypyrid-3-yl) isoxazol-5-yl-1-pyrrolidin-1-yl) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine A mixture of 2-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -5-fluoropyrimidine (Method 27) (150 mg, 0.6 mmol), S-2- [3- (2-methoxypyrid -3-ii) isoxazol-5-yl] pyrrolidine (Method 64) (194 mg, 0.8 mmol), diisopropylethylamine (0.29 mL, 1.6 mmol) in hexanol (10 mL) was heated at 150 ° C for 24 hours. The mixture was allowed to cool, the volatiles were removed by evaporation, the residue was dissolved in EtOAc, washed with water, dried (MgSO 4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (50:50 increasing in polarity to 70:30) to give the title compound (95 mg, 35%). NMR (DMSO): 0.65 (m, 2H), 0.89 (m, 2H), 1.85 (s, 1H), 1.98-2.10 (m, 3H), 2.30-2.40 (m, 1H), 3.50-3.60 (m, 1H), 3.70-3.80 (m, 1H), 3.90 (s, 3H), 5.35 (d, 1H), 6.00 (s, 1H), 6.60 (s, 1H), 7.10 (dd, 1H), 7.90 (s, 1H), 8.20 (dd, 1H), 8.30 (d, 1H), 9.45 (s, 1H), 12.0 (s, 1 HOUR); m / z 463 [MH] +.

Example 267 S-5-Fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2-r2-f3- (2-methoxypyrid-3-yl) isoxazol-5-illpyrrolidin-1-n-pyrimidine treated 2-chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -5-fluoropyrimidine (Method 69) and S-2 [3- (2-methoxy-3-yl) isoxazole- 5-yl] pyrrolidine (Method 64) by an analogous method to that described in Example 266 to give the title compound (67 mg, 24%). NMR (DMSO): 1.40 (t, 3H), 2.02-2.20 (m, 3H), 2.32-2.40 (m, 1H), 2.50-2.60 (m, 2H), 3.63-3.70 (m, 1H), 3.73-3.80 (m, 1H), 3.95 (s, 3H), 5.38 (dd, 1H), 6.20 (s, 1H) , 6.65 (s, 1H), 7.06 (dd, 1H), 7.90 (s, 1H), 8.10 (d, 1H), 8.28 (d, 1H), 8.80 (s, 1H), 11.70 (s, 1H); m / z 451 [MH] +.

Example 268 S-5-Fluoro-4- (5-Meti 1-1 H-pi razo I -3-ylamino) -2-r2-r3- (2-methoxy-pyrid-3-yl) isoxazole-5-pyrrolidin-1 -iH-pyrimidine 2-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine (Method 27 (b)) and S-2- [3- (2-methoxypyrid-3- il) isoxazol-5-yl] idrol (Method 64) by an analogous method to that described in Example 266 to give the title compound (140 mg, 37%). NMR (DMSO): 2.01-2.15 (m, 3H), 2.20 (s, 3H), 2.30-2.40 (m, 1H), 3.61-3.69 (rn, 1H), 3.70-3.78 (m, 1H), 3.95 ( s, 3H), 5.38 (d, 1H), 6.18 (s, 1H), 6.58 (s, 1H), 7.08 (dd, 1H), 7.90 (s, 1H), 8.10 (dd, 1H), 8.28 (d , 1H), 8.82 (s, 1H), 11.65 (s, 1H); m / z 437 [MH] +.

Example 269 S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-f2-f3- (2-methoxypyrid-3-yl) isoxazole-5-yl! llpyrrolidin-1-n-pyrimidine A mixture of 2,6-dichloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 57) (300 mg, 1.1 mmol), S- 2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidine (Method 64) (299 mg, 1.22 mmol), diisopropylethylamine (0.46 ml) in xylyne (10 ml) was heated to 80 °. C for 18 hours. The solvent was removed by evaporation, the residue was dissolved in EtOAc, washed with water, dried (MgSO) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (45:55) to give the title compound (300 mg, 57%). NMR (DMSO): 0.62-0.70 (m, 2H), 0.86-0.90 (m, 2H), 1.80-1.89 (m, 1H), 2.05-2.20 (m, 2H), 2.31-2.42 (m, 1H), 3.62-3.78 (m, 2H), 3. 95 (s, 1H), 5.44 (dd, 1H), 6.00 (s, 1H), 6.39 (s, 1H), 6.65 (s, 1H), 7. 08 (dd, 1H), 8.10 (d, 1H), 8.28 (dd, 1H), 9.25 (s, 1H); m / z 479 [MH] +.

Example 270 S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2-f2-f3- (2-methoxypyrid-3-yl) isoxazole-5-inpyrrolidin-1-pyrimidine treated 2,6-dichloro-4- (5-ethyl-1H-pyrazol-3-ylamino) pyrimidine (Method 72) and S-2- [3- (2-methoxy-pyrid-3-yl) isoxazol-5-yl] pyrrolidine (Method 64) by an analogous method to that described in Example 269 to give the title compound (240 mg, 44%). NMR (DMSO): 1.2 (t, 3H), 2.02-2.20 (m, 3H), 2.32-2.45 (m, 1H), 2.55 (q, 2H), 3.623.80 (m, 2H), 3.95 (s, 3H), 5.45 (dd, 1H), 6.08 (s, 1H), 6.40 (s, 1H), 6.65 (s, 1H), 7.09 (dd, 1H), 9.10 (d, 1H), 8.28 (d, 1H) ), 9.35 (s, 1H), 11.65 (s, 1H); m / z 467 [MH] +.

Example 271 S-6-C lo ro-4- (5-meti 1-1 H-pi razo I -3 -i lamino) -2-f 2 -f 3 - (2-met oxy pyrid-3-yl) isoxazol-5-pyrrolidin-1-inpyrimidine 2,6-dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -pyrimidine (Method 29) and S-2- [3 (2- methoxypyrid-3-yl) isoxazol-5-yl] idrrol id (Method 64) by an analogous method to that described in Example 269 to give the title compound (240 mg, 44%). m / z 463 [MH] +.

Example 272 S -6- (2-H idr oxy-ethoxy) -4- (5-methi 1-1 H- i-l-3-i lamino) -2-f 2 -f3- (2-methoxypyrid-3) il) isoxazol-5-illpyrrolidin-1-illpyrimidine Sodium hydride (106 mg, 2.65 mmol) ethylenic glycol (4 ml) was added and the mixture was stirred for 10 minutes. Added S-6-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1 -yl] pyrimidine (Example 271) (180 mg, 0.4 mmol) and the mixture was heated to 150 ° C in a sealed container under microwave irradiation for 30 minutes. The mixture was allowed to cool, diluted with a solution of aqueous ammonium chloride and extracted with EtOAc. The extracts were combined, dried (MgSO4), and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (50:50 increasing in polarity to 90:10) to give the title compound (60 mg, 32%).

NMR (DMSO): 2.01-2.18 (m, 3H), 2.14 (s, 3H), 2.35-2.42 (m, 1H), 3.64 (s, 2H), 3.683.77 (m, 2H), 3.96 (s, 3H), 4.10-4.18 (m, 1H), 4. 19-4.28 (m, 1H), 4.34 (s, 1H), 5.41 (dd, 1H), 5.79 (s, 1H), 6.00 (s, 1H), 6.65 (s, 1H), 7.10 (dd, 1H), 8.10 (dd, 1H), 8.28 (d, 1H), 8.62 (s, 1H); m / z 479 [NH] +.

Example 273 S-6- (2-Hydroxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2-f2-f3- (2-methoxypyrid-3-yl) isoxazole-5-inpyrrolidin-1 -ipyrimidine S-6-chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl] pyrimidine (Example 269) and ethylenic glycol through an analogous method to that described in Example 272 to give the title compound (50 mg, 20%). NMR (DMSO): 0.62-0.70 (m, 2H), 0.82-0.90 (, 2H), 1.30-1.35 (m, 1H), 1.81-1.90 (m, 1H), 2.05-2.20 (m, 2H), 2.37-2.45 (m, 1H), 3.45 (s, 2H), 3.59-3.65 (m, 1H), 3.65 -3.75 (m, 1H), 3.95 (s, 3H), 4.14-4.25 (m, 2H), 4.35 (t, 1H), 5.40 (d, 1H), 5.75 (s, 1H), 5.91 (s, 1H) ), 6.62 (s, 1H), 7.10 (s, 1H), 7.70 (dd, 1H), 8.10 (dd, 1H), 8.25 (d, 1H), 8.60 (s, 1H), 11.55 (s, 1H); m / z 505 [MH] +.

EXAMPLE 274 S-6- (2-Hydroxyethoxy) -4- (5-et i 1-1 H-pi I-3 -i lamino) -2-f2-f 3- (2-methoxypyrid-3-y-Isoxazole -5-ippyrrolidin-1-ip pyrimidine S-6-Chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) -2- [2- [3- (2-methoxy-3-yl) -yl) isoxazol-5-yl] pyrrolidin-1-yl] pyrimidine (Example 270) and ethylene glycol by an analogous method to that described in Example 272 to give the title compound (37 mg, 16%). NMR (DMSO): 1.15 (t, 3H), 2.02-2.18 (m, 3H), 2.32-2.42 (m, 1H), 3.60-3.65 (m, 2H), 3.68-3.77 (m, 2H), 3.96 (s, 3H), 4.10-4.18 (m, 1H), 4.18-4.25 (m, 1H), 4.33 (s, 1H), 5.40 (d, 1H), 5.80 (s, 1H), 6. 00 (s, 1H), 6.61 (s, 1H), 7.08 (dd, 1H), 8.10 (d, 1H), 8.28 (d, 1H), 8. 65 (s, 1H), 11.5 (s, 1H); m / z 493 [MH] +.

Example 275 S-6-M ethyl -4- (5-et i 1-1 H-pi razo l-3-i lamino) -2-f2-f 3 - (pyrim id-2-i I) -isoxazole- 5-yl * ipyrrolidin-1-inpyrimidine 2-Chloro-6-methyl-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine (Method 83) and S-2- [3- (pyrimidine -2-yl) isoxazol-5-yl] pyrrolidine (Method 66) by an analogous method to that described in Example 260 to give the title compound (77 mg, 56%). NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.15 (t, 3H), 2.00-2.15 (m, 6H), 2.35 (m, 1H), 2.55 (q, 2H), 3.65 (, 1H) ), 3.75 (m, 1H), 5.40 (dd, 1H), 5.60 (s, 1H), 6.05 (s, 1H), 6.20 (s, 1H), 6.65 (s, 1H), 7.40 (t, 1H) 8.90 (t, 2H); m / z 418 [M] +.

Example 276 S-6-Meti l-4- (5-ethyl-1 H -pyrazol-3-yl amino) -2-f2-f3- (pyrid-2-yl) -isoxazol-5-yl > pi rol i di n-1-yl pyrimidine 2-Chloro-6-methyl-4- (5-ethyl-1 H -pyrazol-3-ylamino) -pyrimidine (Method 83) and S2- (3- (2) were treated. -pyridyl) isoxazol-5-yl) pyrrolidine (Method 42) through a method analogous to that described in Example 260 to give the title compound (134 mg, 51%). NMR (DMSO-de at 100 ° C): 1.15 (t, 3H), 2.00-2.15 (m, 6H), 2.35 (m, 1H), 2.55 (q, 2H), 2.65-3.80 (m, 2H), 5.45 (dd, 1H), 6.05 (br s, 1H), 6.20 (br s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.90 (m, 2H), 8.65 (d, 1H), 8.70 (br s, 1H), 11.50 (br s, 1H); m / z 417 [MH] +.

Example 277 S-6- (3-Methoxypropyl) -2-f2-r3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine 2-Chloro-6- (3-methoxypropyl) -4- (5-methyl-1 H -pyrazol-3-ylamino) pyridinimine was treated (Method 87) and S-2- (3- (2-pyridyl) lsoxazole-5-i) pi idro (Method 42 as described in Example 249 to give the title compound (60 mg, 19%) NMR (DMSO): 1.75-1.81 (m, 2H), 2.03-2.20 (m, 3H), 2.21 (s, 3H), 2.30-2.42 (m, 3H), 3.20 (s, 3H), 3.30 (t, 2H), 3.65-3.80 (m, 2H), . 44 (dd, 1H), 6.01 (s, 1H), 6.18 (s, 1H), 6.65 (s, 1H), 7.43, (dd, 1H), 7. 88-7.97 (m, 2H), 8.65 (d, 1H), 8.74 (s, 1H), 11.45 (s, 1H); m / z 461 [MH] +.

METHODS Preparation of Starting Materials The starting materials for the above Examples are either commercially available or are readily prepared through standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials used in the above reactions.

Methods 1 and 2 The following compounds were prepared by an analogous method to that described for the 3-methoxybenzaldehyde oxime in method 35 of WO 03/048133. to about 3: 1 mixture of E / Z isomers # comerciaimente available b approximate 3: 2 mixture of E / Z isomers Method 3 5- (tert-Butoxycarbonylaminomethyl) -3-cyclopropylisoxazole The title compound was prepared starting from cyclopropylcarboxaldehyde oxime ( Method 1) by a method analogous to that described for Method 69 of WO 03/048133 and used without purification.

Method 4 i 5- (tert-Butoxycarbon and Iamyl ethyl) -3- (ti azo I -2-yl) isoxazole The title compound was prepared starting from thiazole-2-ylcarboxaldehyde oxime (Method 2) in two steps through methods analogous to those described in Methods 22 and 43 of WO 03/048133. NMR: 1.40 (s, 9H), 4.35 (d, 2H), 6.77 (s, 1H), 7.60 (br t, 1H), 7.98 (d, 1H), 8.07 (d, 1H); m / z 226 [MH-C4H8] +.

Method 5 5-Am i nometil ciclopropi I-3-isoxazole 5-tert-butox¡carbonilaminometil) -3-cicloprop¡lisoxazol crude (Method 3) (37.4 g, 0.157 mol) and 3M hydrochloric acid (80 ml) heated in methanol (100 ml) at 50 ° C mixture about 2 hours. The methanol was removed by evaporation and the aqueous residue was washed with DCM. The aqueous layer was adjusted to a pH of 12 through the careful addition of a 40% aqueous sodium hydroxide solution and then extracted with DCM (x4). The extracts were combined, washed with brine, then dried (Na2SO4) and the volatiles were removed by evaporation to give the title compound (11.5 g, 53%) as an oil. NMR (CDCl 3): 0.80 (m, 2H), 1.00 (m, 2H), 2.00 (m, 1H), 3.90 (s, 2H), 5.78 (s, 1H); m / z 277 [2M + H] +.

Method 6 5-Am i nometi I -3- (thiazol-2-yl) isoxazole The title compound was prepared starting from 5- (tert-butoxycarbonylaminomethyl) 3- (thiazol-2-yl) -soxazole (Method 4) through a method analogous to that described in Method 56 of WO 03/048133. NMR: 4.41 (s, 2H), 7.14 (s, 1H), 8.03 (d, 1H), 8.11 (d, 1H), 8.62 (s, 3H); m / z 182 [MH] +.

Method 7 F3- (Pyridin-2-yl) isoxazol-5-inmetilf (1E) -fenilmetilen1 amine was added freshly distilled benzaldehyde (373 mg, 3.5 mmol) to a solution of 5-aminomethyl-3- (pyrid-2-yl isoxazole (Method 70 of WO 03/048133) (0.614 mg, 3.5 mmol) in dry DCM (18 ml). Then 4A molecular sieves (1.75 g) were added and the mixture was stirred moderately under nitrogen for 20 hours. The molecular sieve was removed by filtration and the filtrate was evaporated. The residue was dissolved in toluene and the solution was concentrated by evaporation. The product was crystallized and collected by filtration to give the title compound (900 mg, 97%). NMR (CDCl 3): 4.97 (s, 2H), 6.87 (s, 1H), 7.32 (m, 1H), 7.43 (m, 3H), 7.77 (m, 3H), 8.06 (d, 1H), 8.44 (s, 1H), 8.67 (d, 1H); m / z 264 [MH] +.

Methods 8 to 11 Examples 8 to 11 were prepared using the same method as Example 7: ## described in Method 68 of WO03 / 048133 # commercially available Method 12 2-f3- (Pyrid-2-yl) isoxazole-5-ip pyrrolidine n-Butyl lithium (7.5 ml of a 1.82M solution in hexane, 13.74 mmol) was added to a solution of 2.2.6, 6-tetramethylpiperidine (2.5 mL, 14.9 mmol) in THF (99 mL) was stirred at -78 ° C under nitrogen, so that the temperature was maintained below -78 ° C for 15 minutes. A solution of [3- (pyridin-2-yl) isoxazol-5-yl] methy1 [(1 E) phenalmethyl] amine (Method 7) (3.0 g, 11.45 mmol) in dry THF (51 ml) was then added for 5 minutes, maintaining the temperature at or below -70 ° C, and the mixture was stirred at -78 ° C for 15 minutes. Then 1-chloro-3-iodopropane (1.53 ml, 14.31 mmol) was added dropwise over 1 minute, the mixture was then stirred at -78 ° C for 15 minutes, then allowed to warm to room temperature and stirred at room temperature. environment for 18 hours. Diethyl ether was added, followed by water to the reaction mixture and the mixture was stirred vigorously for 5 minutes. The layers were separated, the organic layer was washed with water and then brine, dried (Na2SO4), and evaporated to give the crude alkylated imine. This imine was dissolved directly in ethanol (24 ml) and 2 M hydrochloric acid (48 ml) was added. The mixture was stirred 18 hours at room temperature. The ethanol was removed by evaporation and more water was added and the aqueous layer was washed with diethyl ether (x2). The aqueous solution was adjusted to a pH of 11.5 through the addition of solid sodium carbonate and a 40% aqueous sodium hydroxide solution near the end point. This aqueous solution was stirred for 2 hours at room temperature, during this period more 40% sodium hydroxide was added to maintain the solution at a pH of 11.5. The resulting solution of the crude product was purified through one of two procedures: Purification Procedure A DCM (70 ml) and d-t-butyl dicarbonate (2.74 g, 12.57 mmol) were then added to the aqueous solution of the crude product and the mixture was stirred vigorously at room temperature for 2.5 hours. The layers were separated and the organic layer was washed with water and then brine, dried (Na2SO4), and the volatiles were removed by evaporation. The residue was purified through column chromatography on a Biotage 40M silica cartridge eluting with DCM / EtOAc (93: 7) to give 1- (tert-butoxycarbonyl) -2- [3- (pyrid-2-yl) isoxazole. -5-yl] pyrrolidine (1.81 g, 50%) as a waxy solid. NMR (mixture of rotamers - assigned peaks for major rotamer): 1.24 (s, 9H), 1.95 (m, 3H), 2.28 (m, 1H), 3.35 (m, 1H), 3.5 (m, 1H), 5.0 ( m, 1H), 6.76 (s, 1H), 7.5 (m, 1H), 7.97 (m, 2H), 8.68 (d, 1H); m / z 316 [MH] +. 1-tert-butoxycarbonyl) -2- [3- (pyrid-2-yl) isoxazol-5-ylpyrrolidine (0.56 g, 1.78 mmol) was stirred at room temperature in a mixture of ethanol (5 ml) and 2M of acid hydrochloric (1.5 ml) for 18 hours and then heated at 60 ° C for 2 more hours. The reaction was concentrated through evaporation and water was added. The solution was adjusted to a pH of 12.5 through the addition of solid sodium carbonate and 40% of an aqueous sodium hydroxide solution near the end point. The aqueous solution was extracted with DCM (x4), the organic extracts were combined, dried (Na2SO4) and evaporated to give the title compound (183 mg, 48%) as a brown solid. NMR: 1.8 (m, 3H), 2.13 (m, 1H), 2.9 (t, 2H), 4.35 (t, 1H), 6.8 (s, 1H), 7.48 (t, 1H); 7.96 (m, 2H), 8.67 (d, 1H); m / z 216 [M] +.

Purification Procedure B The aqueous solution of the crude product was extracted with DCM (x4), the organic extracts were combined, dried (Na2SO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel with diethyl ether and then DCM / Methanol (100: 0 increasing in polarity to 95: 5) to give the title compound.

Methods 13 to 16a Examples 13 to 16a were prepared using the same method as Example 12: a purified by purification procedure A b purified through purification procedure B c purified by chromatography eluting with diethyl ether and then DCM / methanol (100: 0 increasing in polarity to 90:10) d prepared through 1- (tert-butoxycarbonyl) -2- [3- (pyrid-3-yl) isoxazol-5-yl] pyrrolidine-NMR (Mixture of rotamers - peaks assigned to the major rotamer): 1.27 (s, 9H), 1.93 ( m, 3H), 2.27 (m, 1H), 3.35 (m, 2H), 5.0 (m, 1H), 7.0 (s, 1H), 7.53 (t, 1H), 8.23 (d, 1H), 8. 07 (d, 1H), 9.05 (s, 1H); m / z 316 [MH] +. f prepared using 4-chloro-1-iodobutane and prepared through 1- (tert-butoxycarbonyl) -2- [3- (pyrid-3-yl) -soxazol-5-ylpiperidine-NMR 1.36 (m, 11H), 1.62 (m, 2H), 1.8 (m, 1H), 2.17 (d, 1H), 2.72 (t, 1H), 3.92 (d, 1H), 6.88 (s, 1H), 7.47 (dd, 1H), 7.9 (t, 1H), 8.0 (d, 1H), 8.07 (d, 1H); m / z 330 [MH] +.

Method 17 2- (3-Cyclopropylisoxazol-5-yl) pyrrolidine-1-carboximidamide A mixture of 2- (3-cyclopropylisoxazol-5-yl) pyrrolidine (Method 14) (2.05 g, 11.5 mmol) and acid Formamidine sulfonic acid (1425 g, 11.5 mmol) in dry methanol (30 mL) was heated at 60 ° C for 18 hours. The solvent was removed by evaporation and the residue was dissolved in water. The aqueous solution was washed with water and then the water was removed by evaporation. The residue was titrated with ether / DCM, the solid product was collected and dried under vacuum at 50 ° C for 18 hours to give the monosulfate salt of the title compound (1839 mg, 41%); m / z 221 [MH] +.

Method 18 2-f 2 - (3-C-cyclopropyl isoxazole-5-ill pyrro lid i n-1 -i H-4-hydroxy-6-methoxymethylpyrimidine Sodium bis- (trimethylsilyl) amide (3.65 ml from a solution of 2M in THF, 7.3 mmol) to a solution of 2- (3-cyclopropylisoxazol-5-yl) pyrrolidine-1-carboximidamide monosulfate (Method 17) (1.83 g, 6.09 mmol) and methyl 4-methoxyacetoacetate (0.867 mL, 6.7 mmol) in methanol (30 mL) and the mixture was refluxed for 4 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / Methanol (100: 0 increasing in polarity to 95: 5). The purified product was titrated with ether and the solid was then recrystallized from methanol to give the title compound (565 mg, 29%) as a white solid. NMR (DMSO-d6 + d4-acetic acid): 0.67 (m, 2H), 0.90 (m, 2H), 1.93 (m, 4H), 3.25 (s, 3H), 3.40 (m, 1H), 3.64 (m , 1H), 3.98 (dd, 2H), 5.24 (d, 1H), 5.61 (s, 1H), 5.95 (s, 1H); m / z 317 [MH] +.

Method 19 4-Chloro-2-f2- (3-cyclopropylisoxazol-5-inpyrrolidin-1-yl-1-6-methoxymethylpyrimidine A mixture of 2- [2- (3-cyclopropylisoxazol-5-yl] pyrrolidin-1-yl] - 4-hydroxy-6-methoxymethylpyrimidine (Method 18) (563 mg, 1.78 mmol) and phosphoryl chloride (1 ml, 10.7 mmol) was heated to reflux for 45 min.The volatiles were removed by evaporation, the residue was dissolved in DCM, it was washed with a saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated The residue was purified by chromatography on silica gel eluting with DCM / diethyl ether (100: 0 and then 80 : 20) to give the title compound (511 mg, 81%) as a yellow oil, NMR: 0.67 (m, 2H), 0.95 (m, 2H), 1.95 (m, 4H), 2.25 (m, 1H) , 3. 30 (m, 3H), 3.52 (m, 1H), 3.65 (m, 1H), 4.30 (m, 2H), 5.25 (d, 1H), 6. 00 (s, 1H), 6.70 (s, 1H); m / z 335 [MH] +.

Method 21 5-Am i nom eti-3- (tetrahydrofuran-3-i) isoxazole This compound was prepared by an analogous method to that described in Methods 3 and 5 using the appropriate starting materials. NMR (DMSO): 1.88 (m, 3H), 2.25 (m, 1H), 3.44 (, 1H), 3.62 (m, 1H), 3.7-3.82 (m, 4H), 3.96 (m, 1H), 6.25 ( s, 1 H); m / z 169 [MH] +.

Method 22 f3- (Tetrahydrofuran-3-yl) isoxazol-5-inmethylf (1 E) -phenylmethylene-1-amine This compound was prepared by an analogous method to that described in Method 7 starting from the compound of method 21. NMR (DMSO): 1.99 (m, 1H), 2.25 (m, 1H), 3.45 (m, 1H), 3.65 (m, 1H), 3.8 (, 2H), 3.96 (m, 1H), 4.85 (s, 2H), 6.37 (s, 1H), 7.47 (m, 3H), 7.75 (m, 2H), 8.51 ( s, 1H).

Method 23 f3- (2-Methoxypyrid-3-yl) isoxazole-5-inmethyl (1 E) -phenylmethylene-1-amino This compound was prepared by an analogous method to that described in Method 7, starting from 5-aminomethyl-3- ( 2-methoxypyrid-3-yl) isoxazole (prepared as described in WO 03/048133). NMR (DMSO): 4.02 (s, 3H), 4.95 (s, 2H), 6.8 (s, 1H), 7.0 (t, 1H), 7.45 (m, 2H), 7.8 (m, 2H), 8.24 (m, 2H), 8.45 (s, 1H); m / z 294 [MH] +.

Method 24 2-f3- (Tetrahydrofuran-3-yl) isoxazol-5-n-pyrrolidine This compound was prepared by an analogous method to that described in Method 12, starting from the compound of Method 22. NMR (DMSO): 1.7 (m, 3H), 1.9-2.15 (m, 2H), 2.15 (m, 1H), 2.84 (m, 2H), 3.18 (br s, 1H), 3.45 (m, 1H), 3.62 (m, 1H) , 3.78 (m, 2H), 3.97 (m, 2H), 4.2 (t, 1H), 6.04 (s, 1H).

Method 25 2-f3- (2-Methoxypyrid-3-yl) isoxazole-5-inpyrrolidine This compound was prepared by an analogous method to that described in Method 12, starting from the compound of Method 23. NMR (DMSO): 1.75 (m, 3H), 2.13 (m, 1H), 2.9 (m, 2H), 3.96 (s, 3H), 4.3 (t, 1H), 6.69 (s, 1H), 7.1 (t, 1H), 8.13 (d, 1H), 8.28 (d, 1H); m / z 246 [MH] +.

Method 26 2-Chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 3-amino-5-methyl-1 H-pyrazole (2.14 g, 22 mmol), and N, N-diisopropylethylamine (2.82 g, 22 mmol) in dry THF (75 ml) was stirred at 50 ° C for 18 hours. The solvent was removed by evaporation, and the residue was partitioned DCM (75 ml) and water (50 ml). The resulting precipitate was collected through filtration, washed with water and then ether, and dried under vacuum at 50 ° C to give the title compound (1.08 g, 26%) as a colorless crystalline solid.

NMR (DMSO): 2.20 (s, 3H), 6.05 (s, 1H), 7.10 (d, 1H), 8.10 (d, 1H), 9.80 (br s, 1H), 11.85 (br s, 1H); m / z 210 [MH] +.

Methods 27.27 (b) and 28 The compounds of Methods 27, 27 (b) and 28 were prepared by methods analogous to those described in Method 26 using the appropriate starting materials.

Method 27 2-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoropyrimidine Yield: 546 mg, 23%. NMR (DMSO): 0.7 (m, 2H), 0.93 (m, 2H), 1.9 (m, 2H), 6.22 (s, 1H), 8.2 (d, 1H), 10.3 (s, 1H), 12.2 (s) , 1 HOUR); m / z 254 [MM] +.

Method 27 (b) 2-Chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -5-fluoropyrimidine Yield: 3.02 g, 66%. NMR (DMSO): 2.2 (s, 3H), 6.3 (s 1H), 8.2 (d, 1H), 10.3 (br s, 1H), 12.2 (br s, 1H); m / z 228 [MH] +.

Method 28 2-Chloro-4- (5-cyclopropyl-1 H-pyrazol-3-ylamino) pi rimdine Yield: 323 mg, 14%. NMR (DMSO): 0.66 (m, 2H), 0.92 (m, 2H), 1.86 (m, 1H), 5.90 (br m 1H), 8.14 (d, 1H), 10.22 (br s, 1H), 12.14 ( br s, 1 H); m / z 236 [NH] +.

Method 29 2,6-Dichloro-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine A mixture of 2,4,6-trichloropyrimidine (1.0 g, 5.4 mmol), 3-amino-5-methyl -1 H-pyrazole (0.53 g, 5.4 mmol), and sodium carbonate (0.57 g, 5.4 mmol) in ethanol (25 mL) was stirred at room temperature for 18 hours. Water was added and the resulting precipitate was collected through filtration, washed with water and a small amount of methanol, and dried to give the title compound (1.15 g, 88%) as a colorless crystalline solid. NMR (DMSO) 2.23 (s, 3H), 6.01 (s, 1H), 7.24 (s, 1H), 10.25 (br s, 1H), 11.9 (br s, 1H); m / z 244 [MM] +.

Method 30 4-Hydroxy-6-methyl-2-r2-f3- (pyrid-2-yl) isoxazol-5-yl > pyrrolidin-1-illpyrimidine A mixture of 4-hydroxy-6-methyl-2-thiomethylpyrimidine (362 mg, 2.3 mmol) and 2 [3- (2-pyridyl) isoxazol-5-yl] pyrrolidine (500 mg, 2.3 mmol) it was placed under a nitrogen atmosphere and heated at 150 ° C for 18 hours. The mixture was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 96: 4) to give the title compound (420 mg, 56%). NMR (DMSO): 1.94-2.1 (m, 6H), 2.10-2.14 (m, 1H), 3.45 (q, 1H), 3.75 (q, 1H), 5.42-5.55 (m, 2H), 2.74 (s, 1H), 7.50 (t, 1H), 7.88-7.99 (m, 2H), 8.64 (d, 2H); m / z 324 [MH] + Method 31 4-H id roxy-6-m eti I -2-f 2 - (3-met i I isoxazol-5-yl) pyrrolidin-1-yl-pyrimidine This compound was prepared by a method analogous to that described in Method 30 using the appropriate starting materials to give the title compound (270 mg, 81%). NMR (DMSO): 1.84-2.0 (m, 6H), 2.16 (s, 3H), 2.20-2.28 (m, 1H), 3.38-3.45 (m, 1H), 3.62-3.72 (m, 1H), 5.39 ( d, 1H), 5.54 (s, 1H), 6.10 (s, 1H); m / z 261 [MH] +.

Method 32 6-Ethyl-4-hydroxy-2-f2-f3- (pyrid-2-yl) isoxazol-5-yl > pyrrolidin-1-illpyrimidine A mixture of ethyl propionylacetate (350 mg, 2.4 mmol), trifluoroacetate salt of 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidn-1- carboximidamide (Method 38) (901 mg, 2.43 mmol), sodium methoxide (144 mg, 7.7 mmol), in butanol (10 mL) was heated at 120 ° C for 18 hours. The mixture was allowed to cool and an SColu2 isolute ion exchange column was directly emptied. The column was eluted with DCM / methanol (4: 1) to remove the neutral materials and then with 7M of methanolic ammonia to elute the product. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with DCM / methanol (98: 2 increasing in polarity to 95: 5) to give the title compound (360 mg, 46%). NMR (DMSO): 0.99 (t, 3H), 2.0-2.1 (m, 3H), 2.2-2.3 (m, 3H), 3.48 (m, 1H), 3.743.80 (m, 1H), 5.43 (d, 1H), 5.49 (s, 1H), 6.76 (s, 1H), 7.48 (dd, 1H), 7.88-7.99 (m, 2H), 8.64 (d, 1H), 11.0 (s, 1H); m / z 338 [MH] +.

Methods 33 to 35 The compounds of Methods 33 to 35 were prepared by method analogous to those described in Method 32 using the appropriate starting materials.

Method 33 4-Hydroxy-6- (3-methoxypropyl) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-ippyrimidine Yield: 575 mg, 35%. NMR (DMSO): 1.60-1.68 (m, 1H), 2.0-2.1 (m, 2H), 2.20-2.35 (m, 2H), 3.08 (s, 3H), 3.10-3.15 (m, 1H), 3.50 ( q, 1H), 3.78 (t, 1H), 5.40 (d, 1H), 5.49 (s, 1H), 6.76 (s, 1H), 7.50 (dd, 1H), 7.89-7.99 (m, 2H), 8.64 (d, 1H), 11.10 (s, 1H); m / z 382 [MH] +.

Method 34 4-H id roxi-6- (methoxy metí D-2-f2-f3- (pyr i d-2-i I) isoxazol-5-yl) -pyrrolidin-1-ippyrimidine Yield: 1 g, 48% . NMR (DMSO): 2.0-2.14 (m, 3H), 2.13-2.38 (m, 1H), 3.28 (s, 3H), 3.46 (q, 1H), 3.78 (t, 1H), 4.01 (q, 2H) , 5.42 (d, 1H), 5.62 (s, 1H), 6.78 (s, 1H), 7.50 (dd, 1H), 7.9-8.0 (m, 2H), 8.64 (d, 1H); m / z 354 [M] +.

Method 35 4-Hydroxy-6- (pent-3-en-1-yl) -2-f2-f3- (pyrid-2-yl) isoxazol-5-yl > -pyrrolidin-1-illpyrimidine Yield: 1 g, 33%. NMR (DMSO): 1.42 (s, 3H), 2.0-2.15 (m, 5H), 2.2-2.38 (m, 3H), 3. 52 (q, 1H), 3733.80 (m, 1H), 5.22 (s, 2H), 5.42 (d, 1H), 5.48 (s, 1H), 6.75 (s, 1H), 7.48 (dd, 1H) 7.89-7.99 (m, 2H), 8.63 (d, 1H), 11.05 (s, 1H); m / z 378 [MH] +.

Methods 35 (a) through 37 The compounds of Methods 35 (a) through 37 were prepared by the method analogous to those described in Method 30 using the appropriate starting materials.

Method 35 (a) 4-Hydroxy-6- (methoxymethyl) -2-f2-f3- (pyrid-3-yl) isoxazol-5-yl > pyridin-1-illpyrimidine was made using 4-hydroxy-6-methoxymethyl-2-methylthiopyrimidine as the starting material. Yield: 804 mg, 61%. NMR (DMSO): 2.02 (m, 3H), 2.27 (m, 1H), 3.30 (s, 3H), 3.50 (m, 1H), 3.73 (m, 1H), 4.00 (q, 2H), 5.42 (d , 1H), 5.43 (d, 1H), 5.65 (s, 1H), 6.79 (s, 1H), 7.50 (dd, 1H), 8.22 (d, 1H), 8.65 (d, 1H), 9.02 (s, 1 HOUR); m / z 354 [MH] +.

Method 36 4-Hydroxy-6-methoxymethyl-2-f2-f3- (thiazol-2-yl) isoxazol-5-yl > pyrrolidin-1-ylpyrimidine Made using 4-hydroxy-6-methoxymethyl-2-methylthiopyrimidine as a starting material. Yield: 451 mg, 31%. NMR (DMSO): 2.04 (m, 3H), 2.28 (m, 1H), 3.25 (s, 3H), 3.47 (m, 2H), 3.75 (m, 1H), 4.0 (m, 1H), 5.41 (d , 1H), 5.62 (s, 1H), 6.8 (s, 1H), 7.95 (d, 1H), 8.02 (d, 1H); m / z 360 [MH] +.

Method 37 4-Hydroxy-2-f2-f3- (pyrid-2-yl) isoxazol-5-yl) pyrrolidin-1-yl-1-6-trifluoromethylpyrimidine Made using 2-ethylthio-4-hydroxy-6-trifluoromethylpyrimidine as Starting material. Yield: 710 mg, 30%. NMR (CDCl 3): 2.30 (m, 4H), 3.65 (m, 1H), 3.94 (m, 1H), 5.60 (m, 1H), 6.10 (s, 1H), 6.80 (s, 1H), 6.80 (s) , 1H), 7.34 (t, 1H), 7.78 (t, 1H), 8.02 (d, 1H), 8.64 (d, 1H); m / z 378 [MH] +.

Method 38 2-y3- (Pyrid-2-yl) isoxazole-5-ippyrrolidine-1-carboximidamide (trifluoroacetate salt) TFA (30 ml) was added to a cooled solution of N, N'-di (tert-butyloxycarbonyl) -2- [3 (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-carboximidamide (Method 39) in DCM (150 ml) at 0 ° C. The mixture was stirred at 0 ° C for one hour, allowed to warm to room temperature and stirred for a further 18 hours. The volatiles were removed by evaporation and the residue was titrated from DCM / ether / hexane. The product was collected by filtration to give the title compound (2.2 g, > 100%). NMR (DMSO): 1.9-2.2 (m, 3H), 2.3-2.4 (m, 1H), 3.42 (q, 1H), 3.72 (t, 1H), 5.35 (d, 1H), 6.95 (s, 1H) 7.41 (s, 2H), 7.50 (t, 1H), 7. 92-8.02 (m, 2H), 8.7 (d, 1H); m / z 258 [MH] +.

Method 39 N.N'-Difterbuty I oxycarbonyl) -2- (3- (pyrid-2-yl) isoxazole -5-i-Jipi-rrolidine-1-carboximidamide 2- [3- (pyrid-2-yl) was added isoxazol-5-yl] pyrrolidine (Method 12) (1.5 g, 7 mmol) to a solution of N, N'-di (tert-butyloxycarbonyl) -N "- (trifluoromethylsulfonyl) guanidine (2.59 g, 6.6 mmol) and triethylamine (0.975 ml) in DCM and the mixture was stirred at room temperature for 8 hours.The mixture was then washed with water, dried (MgSO.sub.0) and the volatiles were removed by evaporation.The residue was purified by chromatography on silica gel. silica eluting with DCM / methanol (100: 0 increasing in polarity to 98: 2) to give the title compound (2.3 g, 70%). NMR (DMSO): 1.32 (s, 18H), 1.9-2.1 (m, 3H), 2.25-2.35 (m, 1H), 3.41-3.50 (m, 1H), 3.72-3.80 (m, 1H), 5.41 (s, 1H), 6.79 (s, 1H), 7.50 (dd, 1H) , 7.9-8.0 (m, 2H), 8.68 (d, 1H), 9.48 (s, 1H).

Method 40 S-2- (3-Methylisoxazol-5-yl) pyrrolidine n-Butyl lithium (6.29 ml of a 1.6M solution in hexanes, 10.1 mmoies) was added to a solution of acetone oxime (368 mg, . 0 mmol) in anhydrous THF (20 ml) under nitrogen cooled to -5 ° C., so that the reaction temperature was kept below 0 ° C. At the end of the addition, the mixture was stirred at 0 ° C for one hour. Then N- (tert-butoxycarbonyl) -l-proline (1.0 g, 3.87 mmol) in anhydrous THF (30 ml) was added at such a rate to maintain the temperature of the reaction by adding N'-methoxy-N'-methylamide to the solution. below 0 ° C. At the end of the addition, the mixture was stirred at 0 ° C for 3.5 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution, the organic solvent was removed by evaporation and the aqueous residue was extracted with dichloromethane. The extracts were combined and the solvent was removed by evaporation. The residue was titrated with iohexane to give a solid intermediate oxime (617 mg). This oxime (617 mg, 2.28 mmole) and triethylamine (0.41 ml, 2.96 mmole) were dissolved in anhydrous THF (20 ml) and methanesulfonyl chloride (0.19 ml, 2.54 mmole) was added at room temperature and the mixture was stirred at room temperature. environment for 30 minutes. The volatiles were removed by evaporation, the residue was dissolved in water and extracted with dichloromethane. The extracts were combined and the solvent was removed by evaporation to give the mesylate intermediate as an oil. This mesylate was added to 4M hydrogen chloride in 1,4-dioxane (15 ml, 90 mmol) and the mixture was heated to reflux for 30 minutes. The mixture was allowed to cool and then emptied at 50 g SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel eluting with DCM / methanol (100: 0 increasing in polarity to 90:10) to give the title compound (273 mg, 46% ) as an oil. NMR (CDCl 3): 1-90 (m, 3H), 2.17 (m, 1H), 3.05 (m, 1H), 3.10 (m, 1H), 4.30 (m, 1H), 5.95 (s, 1H); m / z 153 [MH] +.

Method 41 SN-ter-B useful oxycarbon i l-2-f 3- (2-pi ri di I) isoxazol-5 -i I) pyrrolidine A solution of 13% sodium hypochlorite in water (4.6 ml) added for 2 hours to a vigorously stirred solution of SN-tert-butoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr. 1997,134,141-144 and J. Med. Chem. 1994, 37, 44554463 ) (1.0 g, 5.2 mmol) and pyrid-2-ylcarboxaldehyde oxime (577 mg, 4.72 mmol) in dichloromethane (15 ml) at -3 ° C. After the addition was complete, the reaction was stirred at 0 ° C for 2.5 hours. The mixture was then diluted with water and dichloromethane and the layers were partitioned and separated. The organic layer was washed in turn with water and brine, dried (Na 2 SO 4) and the volatiles were removed by evaporation. The residue was purified by chromatography on silica gel eluting with 10% isohexane / ethyl acetate (90:10 increasing in polarity to 75:25) to give the title compound (0.69 g, 47%) as a waxy solid . NMR (DMSO) (major rotamer): 1.4 (s, 9H), 1.95 (m, 3H), 2.28 (m, 1H), 3.35 (m, 1H), 3.5 (m, 1H), 5.0 (s, 1H) , 6.76 (s, 1H), 7.5 (m, 1H), 7.97 (m, 2H), 8.68 (d, 1H); m / z 316 [MH] +. Rotation aD = -104.8 (c = 1.0, methanol).

Method 42 S-2- (3- (2-Pyridyl) isoxazol-5-yl) pyrrolidine Trifluoroacetic acid (2.3 ml) was added over 10 minutes to a stirred solution of SN-tert-butyloxycarbonyl-2- (3- (2 -pyridyl) isoxazol-5-yl) pyrrolidine (Method 41) (0.744 g, 2.36 mmol) in dichloromethane (12 ml) at 0 ° C. The reaction was stirred at 0 ° C for 1 hour and then at room temperature for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in distilled water (23 ml). The solution was adjusted to a pH of 10.5 through the careful addition of solid sodium carbonate and then a 40% solution of aqueous sodium hydroxide near the end point. The aqueous solution was extracted with dichloromethane (x4), the organic extracts were combined, dried (Na2SO4) and the solvent was removed by evaporation to give the title compound (0.446 g, 88%) as a gum. NMR (DMSO): 1.8 (m, 3H), 2.13 (m, 1H), 2.9 (t, 2H), 4.35 (t, 1H), 6.8 (s, 1H), 7.48 (t, 1H); 7.96 (m, 2H), 8.67 (d, 1H); m / z 216 [MH] +. Rotation aD = -15.2 (c = 1.0, methane!).

Method 43 Acid 2-f2-r3- (pyrid-2-yl) isoxazol-5-ippyrrolidin-1-yl} -4- (5-methyl-1H-pyrolol -3-ylamino) pyrimidin-6-yl carboxylic acid A solution of the sodium salt of 2-chloro-4- (5-methyl-1 H-pyrazole-3-acid ilamino) pyrimidin-6-yl carboxylic acid (Method 44) (58 mg, 0.21 mmol) and 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidine (Method 12) (54 mg, 0.25 mmoies) in water (4 ml) was heated at 110 ° C for 18 hours. The solid product was isolated through filtration from the hot reaction mixture, washed with cold water and dried. The product was then titrated with diethyl ether to give the title compound (48.1 mg, 53%). NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.17 (s, 3H), 2.35 (m, 1H), 3.75 (m, 1H), 3.85 (m, 1H) , 5.50 (dd, 1H), 6.07 (s, 1H), 6.70 (S, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 433 [MH] +.

Method 44 Sodium salt of 2-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid A mixture of 2,4-dichloropyridin-6-yl carboxylic acid (Method 45) (528 mg, 2.73 mmol), 3-amino-5-methylpyrazole (279 mg, 2.87 mmol) and sodium carbonate (578 mg, 5.46 mmol) was heated in water (10 ml) at 50 ° C for 18 hours. The mixture was allowed to cool and the product was collected by filtration, washed with water and dried to give the title compound (430 mg, 77%).

NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.20 (s, 3H), 6.03 (s, 1H), 7.28 (s, 1H); m / z 254 [MH] +.

Method 45 2,4-Dichloropyrimidine-6-carboxylic acid A mixture of 2,4-dihydroxypyrimidine-6-carboxylic acid (50 g, 0.32 mol), phosphoryl chloride (298 ml, 3.2 mol) and N, N-dimet Laniline (44.7 ml, 0.35 mol) was heated to reflux for 5 hours. The mixture was allowed to cool, the volatiles were removed by evaporation and the residue was poured into an ice-water mixture. The aqueous mixture was extracted with diethyl ether, treated with decolorizing carbon, filtered and the volatiles were removed from the filtrate through evaporation. The residue was treated with hot iso-hexane, the insoluble material was removed by filtration and the solvent was removed by evaporation of the filtrate to give the title compound. (29.05 g, 47.6%). NMR (DMSO-de): 8.15 (s, 1H); m / z 191 [MH] -.

Method 46 1-tert-Butyloxy-2- (2-methyl-2H-tetrazol-5-yl) pyrrolidine A mixture of 1-tert-butyloxy-2- (2H-tetrazol-5-yl) pyrrolidine (Method 47) (500 mg, 2.2 mmol), cesium carbonate (1.43 g, 4.4 mmol), methyl iodide (0.41 mL, 6.6 mmol) in acetonitrile (15 mL) was stirred at room temperature for 12 hours. The solution was decanted from the solid material and the solution was then partitioned between water and ethyl acetate. The organics were separated, dried (MgSO 4) and the volatiles were removed by evaporation. The residue was purified by chromatography on silica gel eluting with isohexane / ethyl acetate (100: 0 increasing in polarity to 0: 100) to give the title compound (175 mg, 33%) as a clear oil. NMR (CDCl 3): 1-35 (d, 9H), 2.03 (m, 3H), 2.31 (m, 1H), 3.50 (m, 1H), 3.66 (m, 1H), 4.31 (s, 3H), 5.17 (m, 1H).

Method 47 1-ter-Buti I oxy-2 - (2 H -tethrocyte I-5-yl) pyrrolidine A mixture of tert-butyloxy-2-cyanopyrrolidine (3g, 15.3 mmol), sodium azide (1.49 g, 23.0) mmoles) and ammonium chloride (1.22 g, 23 mmol) in DMF (15 ml) was heated at 95 ° C for 48 hours. The reaction was then partitioned between ethyl acetate and water. The organics were separated, dried (MgSO 4) and the volatiles were removed by evaporation. The residue was titrated with diethyl ether and collected by filtration to give the title compound (0.79 g, 22%) as a white solid. NMR (CDCl 3): 1.50 (s, 9H), 2.06 (m, 2H), 2.34 (m, 1H), 2.94 (m, 1H), 3.43 (m, 2H), 5.07 (dd, 1H).

Method 48 2, 6-Dibromo-4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine A mixture of 2,4,6-tribromopyrimidine (3.5 g, 11 mmol), 5-methyl-1 H- pyrazole (1077 g, 11 mmol), sodium carbonate (1 g) in ethanol (50 ml) was stirred at room temperature under nitrogen for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in DCM and the minimum methanol. The resulting solution was washed with water, dried (Na 2 SO) and the volume of solvent was reduced through evaporation. The product was precipitated and collected by filtration to give the title compound (1.7 g, 47%). NMR (DMSO): 2.20 (s, 3H), 5.80 (s, 1H), 7.92 (s, 1H); m / z 334 [MH] +.

Method 49: 6-Bromo-4- (5-methyl-1H-pyrazol-3-ylamino) -2 - (2 - (3- (pyrid-2-yl) -isoxazol-5-yl) pyrrolidine) pyrimidine A mixture of 2,6-dibromo-4- (5-methyl-1 H-pyrazol-3-ylmene) pyrimidine (Method 48) (235 mg, 0.7 mmol), 2- (3- (2 -pyridyl) isoxazol-5-yl) pyrrolidine (Method 12) (167 mg, 0.77 mmol) and DIPEA (0.272 mL, 1.55 mmol) in xylene (2.5 mL) was heated at 80 ° C for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in ethyl acetate and the minimum methanol. The resulting solution was washed with water, dried (MgSO) and the solvent was removed by evaporation. The residue was dissolved in the minimum DCM and stored at -10 ° C for 18 hours. The resulting precipitate was collected through filtration to give the title compound (140 mg, 50%).

NMR (DMSO): 1.98-2.40 (m, 7H), 3.50-3.60 (m, 1H), 3.64-3.80 (m, 1H), 5.38 (d, 1H), 5.85 (s, 1H), 6.75 (s, 1H), 7.50 (t, 1H), 7.88- 8.0 (m, 2H), 8.64 (s, 1H), 9.68 (s, 1H); m / z 468 [MH] +.

Method 50: Acid S-2-f 2-f 3- (pyrid-2-y1) isoxazol-5-in pyrrolidin-1-l} -4- (5-methyl I-1 H-pyrazol-3-ylamino) pyrimidin-6-yl carboxylic acid The sodium salt of 2-chloro-4- (5-methyl-1 H-pyrazole-3-acid was treated ilamino) pyrimidin-6-yl carboxylic acid (Method 44) and S-2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidine (Method 42) as described in Method 43 to give the title compound. NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.17 (s, 3H), 2.35 (m, 1H), 3.75 (m, 1H), 3.85 (m, 1H) , 5.50 (dd, 1H), 6.07 (s, 1H), 6.70 (S, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); m / z 433 [MH] +.

Method 51 6-fN- (Aceti lam i no) carbamoin -2-f 2 -f 3- (pyrid-2-yl) isoxazol-5-yl-1-pyrrolidin-1-yl) -4- (2-acetyl-5) -methyl-1H-pyrazol-3-ylamino) -pyrimidine Acetyl chloride (0.28 ml) was added, 3.94 mmole) to a mixture of 6-hydrazide-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-ii} 4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 77) (800 mg, 1.79 mmol) and triethylamine (0.6 ml, 4.13 mmol) in anhydrous THF (20 ml) at 0 ° C. The reaction was allowed to warm to room temperature and stirred for a further 1 hour. The volatiles were removed by evaporation and the residue was titrated with water and collected by filtration to give the title compound (911 mg, 96%). NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 1.90 (s, 3H), 2.10 (m, 3H), 2.18 (s, 3H), 2.42 (m, 1H), 2.52 (s, 3H), 3.76 (m, 1H), 3.85 (m, 1H), 5.55 (dd, 1H), 6.50 (s, 1H), 6.70 (s, 1H), 7.05 (s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.61 (d, 1H); m / z 531 [NH] +.

Method 52 6-f (4-Meti If enylsulfonyl oxy) methanol -2-f 2 -f 3- (py i d-2-yl) isoxazol-5-illpyrrolidin-1-yl) -4- (5 -methyl-2-N-f4-methylphenylsulfonin-1H-pyrazole-3-ylamin o) pyrimidine p-Toluenesulfonyl chloride (3.0 g, 15.7 mmol) was added to a mixture of 6-hydroxymethyl-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine (Example 80) (3.13 g, 7.49 mmol), triethylamine (2.5 mL, 18 mmol) in anhydrous THF (50 mL). The resulting mixture was stirred at room temperature for 1 hour then heated to reflux for 4 hours. The volatiles were removed by evaporation and the residue was dissolved in water and extracted with DCM. The organic extracts were combined and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel, eluting with DCM (100%) and then with diethyl ether (100%) to give the title compound (contaminated with 31% of the 6-chloromethyl derivative) (1.69 g, 31%).

NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.10 (m, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.35 (s, 3H), 2.38 (m, 1H), 3.70 (m, 1H), 3.75 (m, 1H), 4.40 (s, 2H), 5.45 (dd, 1H), 6.45 (s, 1H), 6.68 (s, 1H), 6.75 (s, 1H), 7.10 (d, 2H), 7.38 (d, 2H), 7.42 (m, 1H), 7.55 (d, 2H), 7.75 (d, 2H), 7.90 (m, 2H), 8.62 (d, 1H); m / z 727 [MH] +.

Method 53 S-6-Chloromethyl-2-f2-f3- (pyrid-2-yl) isoxazol-5-n-pyrrolidin-1-yl > -4- (5-M ethyl -2-N-f4-methyl phenyl n-sulfonyl-1 H-pyrazol-3-ylamino) pyrimidine p-Toluenesulfonyl chloride (624 mg, 3.26 mmol) was added to a mixture of S-6 -hydroxymethyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine (Example 86) (570.4 mg, 1.36 mmol) and N, N-diisopropylethylamine (0.467 ml, 3.40 mmol) in anhydrous THF (20 ml) . The mixture was stirred at room temperature for 1 hour, then heated to reflux for 4 hours. The volatiles were removed by evaporation, the residue was dissolved in water and extracted with DCM. The extracts were combined, the solvent was removed by evaporation and the residue was purified by chromatography on silica gel, eluting with dichloromethane (100%) and then diethyl ether (100%) to give the title compound (403 mg, 50%). NMR (DMSO- d6 + d4-acetic acid at 100 ° C): 2.05 (m, 3H), 2.20 (s, 3H), 2.35 (s, 3H), 2.38 (m, 1H), 3.65 (m, 1H) , 3.76 (m, 1H), 4.35 (s, 2H), 5.40 (dd, 1H), 6.43 (s, 1H), 6.50 (s, 1H), 6.65 (s, 1H), 7.35 (d, 2H), 7.42 (m, 1H), 7.72 (d, 2H), 7.85 (t, 1H), 7.90 (m, 1H), 8.62 (d, 1H); m / z 591 [MH] +.

Method 54 Pyrazin-2-carboxaldehyde oxime A 1N solution of lithium-aluminum hydride in THF (73.8 ml, 73.8 mmol) was added to a suspension of methyl pyrazine-2-carboxylate (20 g, 145 mmol) in THF anhydrous (300.0 ml) at -78 ° C keeping the reaction temperature below -72 ° C. At the end of the addition, the reaction mixture was allowed to stir at -78 ° C for a further 20 minutes and then quenched with glacial acetic acid (20.0 ml). The resulting mixture was warmed to room temperature and the volatiles were removed by evaporation. The residue was dissolved in 3N hydrochloric acid (116 ml) and extracted with DCM. The extracts were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and the solvent was evaporated. The residue was purified by chromatography on silica gel eluting with DCM / diethyl ether (100: 0 then 80:20 and then 0: 100) to give pyrazin-2-carboxaldehyde (15.67 g, 100%). This was immediately dissolved in chloroform (200 ml), cooled to 0 ° C and hydroxylamine monohydrochloride (11.02 g, 159.5 mmol) and triethylamine (24.2 ml, 117.4 mmol) were added. The reaction mixture was then stirred at room temperature for 0.5 hour, and the solvent was removed by evaporation. The residue was suspended in diethyl ether (500 ml) and the insolubles were removed by filtration. The filtrate was evaporated and the residue purified by chromatography eluting with DCM / diethyl ether (100: 0 then 80:20 and then 0: 100) to give the title compound (5.5 g, 31%) as a solid. - NMR (DMSO-de): 8.15 (s, 1H), 8.62 (dd, 2H), 8.99 (s, 1H).

Method 55 S-2-f3- (2-Pyrazinyl) isoxazole-5-in-pyrrolidine A 13% solution of sodium hypochlorite in water (5.95 ml, 12.51 mmol) was added to a mixture of SN-tert-butoxycarbonyl-2 -etinylpyrrolidinane (1344 g, 6.88 mmol), pyrazine-2-carboxaldehyde oxime (770 mg, 6.26 mmol) and DCM (50 ml) keeping the reaction temperature below -3 ° C. The reaction mixture was then stirred at room temperature for 5 hours. Water was added and the organic layer was separated and the solvent was evaporated. The residue was dissolved in 4M of hydrogen chloride in 1,4-dioxane (20 ml) and methanol (30 ml) the mixture was heated to reflux for 1 hour. The mixture was allowed to cool, the volatiles were removed by evaporation, the residue was dissolved in water and the solution was adjusted to a pH of 12 with 10M of an aqueous sodium hydroxide solution. The reaction mixture was extracted with DCM, the extracts were combined and evaporated and the residue was purified by chromatography on silica gel, eluting with DCM and then with diethyl ether / DCM (20:80) and finally with methanol / DCM (2:98 increasing in polarity to 10:90). The purified product was then titrated with diethyl ether and collected by filtration to give the title compound (344 mg, 25%). NMR (DMSO-de): 1.78 (m, 3H), 2.17 (m, 1H), 4.38 (dd, 1H), 6. 87 (s, 1H), 8.78 (dd, 2H), 9.21 (s, 1H); m / z 217 [NH] +.

Method 56 2-Chloro-6-methyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine Solid sodium carbonate (1.2 g, 11.3 mmol) was added to a solution of 2,4-dichloro-6 methylpyrimidine (1.7 g, 10.3 mmol) and 5-amino-3-methyl-1 H-pyrazole (1.0 g, 10.3 mmol) in dry ethanol (50 ml) and the mixture was heated and stirred at 42 ° C for 3 hours. days. The mixture was allowed to cool, the insoluble material was removed by filtration and the filter pad was washed with ethanol (10 ml). The volatiles were removed from the filtrate through evaporation, keeping the bath temperature below 40 ° C. The residue was purified immediately by chromatography on silica gel eluting with methanol / DCM (5:95 Increasing in polarity to 20:80) to give the title compound (758 mg, 33%) as a white solid. NMR (CDCl 3): 2.17 (s, 3H), 2.11 (s, 3H), 5.88 (br s, 1H), 7.85 (br s, 1H), 8.80 (br s, 1H); m / z 224 [MH] +.

Method 57 2,6-Dichloro-4- (5-cyclopropyl-1 H-pi-razo I -3-i lam i) pyrimidine 2,4,6-trichloropyrimidine and 3-amino-5-cyclopropyl-1 H were treated -pirazol (Method 7 of WO 03/048133) as described in Method 29 to give the title compound (12 g, 55%). NMR (DMSO): 0.75 (m, 2H), 0.95 (m, 2H), 1.95 (m, 1H), 1.35 (m, 1H), 5.65 (br s, 1H), 7.70 (br s, 1H), 10.60 (s, 1H), 12.20 (s, 1H); m / z 270 [MH] +.

Method 58 3- (tert-Butoxycarbonylamino) prop-1-en-1-yl boronate f2,3-dihydroxy-2,3-dimethylbutane ester A complex of borane methyl sulfide (8.4 ml of a 2M solution in THF) was added. ) dropwise to a solution of a-pinene (5.4 ml, 34 mmol) in THF (10 ml) at 0 ° C and the mixture was stirred for 1 hour. The mixture was allowed to warm to room temperature, stirred for 2 hours, then cooled to 0 ° C. Then a solution of 3-tert-butoxycarbonylamino) prop-1-yne (2.0 g, 13 mmol) in THF (5 ml) was added slowly and the mixture was stirred at room temperature for 18 hours. The mixture was cooled to 0 ° C and acetaldehyde (14.3 ml, 0.25 mmol) was added dropwise. The mixture was stirred for 5 hours and then an excess of acetaldehyde and solvent was removed by evaporation. 2,3-Dihydroxy-2,3-dimethylbutane (2.4 g, 20 mmol) was added in heptane and the mixture was stirred at room temperature for 18 hours. The mixture was washed with water, dried (Na 2 SO) and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (10:90 increasing in polarity to 18:82) to give the title compound, which was used directly.

Method 59 3- (N-Methylacetamido) prop-1-ino Acetic anhydride (1.2 ml) was added dropwise, 12.7 mmol) was added to a solution of N-methyl propargylamine (400 mg, 5.8 mmol) and 4-dimethylaminopyridine (70 mg, 0.67 mmol) in pyridine (15 ml). The mixture was stirred at room temperature for 18 hours and the solvent was removed by evaporation. The residue was dissolved in EtOAc, washed with water and dried (MgSO 4) and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel eluting with methanol / DCM (5:95 and then 10:90) to give the title compound (136 mg, 22%). NMR (DMSO): 1.99 (s, 3H), 2.98 (s, 3H), 4.12 (s, 2H), 4.15 (s, 1H).

Method 60 S-6-f3- (N-Pphthalimido) pro? -1-en-1-n-4- (5-methyl-1H-pyrazol-3-ylamino) -2-f2-f3 (pyrid-2) -yl) isoxazol-5-yl) pyrrolidin-1-ylpyrimidine S-6-iodo-4- (5-methyl-1 H -pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine (Example 98) and 3- (N-phthalimido) prop-1-yne through the method described for Example 105 to give the title compound (150 mg, 45%).

NMR (DMSO): 2.00-2.12 (m, 3H), 2.18 (s, 3H), 2.32-2.41 (m, 1H), 3.61-3.69 (m, 1H), 3.70-3.78 (m, 1H), 4.61 (s, 2H), 5.45 (s, 1H), . 68 (s, 1H), 6.01 (s, 1H), 6.45 (s, 1H), 6.65 (s, 1H), 7.44 (dd, 1H), 7.84-7.96 (m, 7H), 8.65 (d, 1H) , 9.05 (s, 1H), 11.55 (s, 1H); m / z 572 MH] +.

Method 61 2-Chloropyrid-3-ylcarboxaldehyde oxime A solution of hydroxylamine hydrochloride (533 mg, 7.6 mmol) in water (1.8 ml) was added dropwise to sodium hydroxide (708 mg, 17 mmol) in water (2 mg). ml). The resulting solution was then added to a solution of 2-chloroplrld-3-carboxyl-aldehyde (1 g, 7 mmol) in ethanol (7 ml), water (7 ml) and ice (15 g). The mixture was stirred at room temperature for 18 hours. The mixture was neutralized to a pH of 7 with 6M hydrochloric acid. The solid product was collected by filtration, washed with water and dried to give the title compound (800 mg, 73%). NMR (DMSO): 7.45 (dd, 1H), 8.18 (dd, 1H), 8.32 (s, 1H), 8.42 (dd, 1H); m / z 157 [MH] +.

Method 62 SN- (tert-Butoxycarbonyl) -2-r3- (2-chloropyrid-3-yl) isoxazole-5-in-pyrrolidine Sodium hypochlorite (5.3 ml of an aqueous 13% solution) was added dropwise to a vigorously stirred suspension of 2-chloropyrid-3-ylcarboxaldehyde oxime (Method 61) (800 mg, 5.1 mmol) and SN-tert-butoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bu II. Soc. Chim. Fr. 1997, 134, 141-144 and J. Med. Chem. 1994, 37, 4455-4463) (1.99 g, 10.2 mmol) in DCM (20 ml) at about 0 to 5 ° C. The mixture was allowed to warm and stirred at room temperature for 18 hours. The volatiles were removed by evaporation and the residue was purified by chromatography on silica gel eluting with EtOAc / hexane (20:80) to give the title compound (955 mg, 54%). NMR (DMSO): 1.22-1.42 (m, 9H), 1.95-2.0 (m, 3H), 2.22-2.38 (m, 1H), 3.30-3.40 (m, 1H), 3.43-3.55 (m, 1H), 5.0 (s, 1H), 6.78 (s, 1H), 7.58 (s, 1H), 8.12 (d, 1H), 8.55 (dd, 1H); m / z 350 [MH] +.

Method 63 SN- (tert-Butoxycarbonyl) -2-f3- (2-methoxypyrid-3-yl) isoxazole-5-n-pyrrolidine A mixture of SN-tert-butoxycarbonyl) -2- [3- (2 chloropyrid-3-yl) isoxazol-5-yl] pyrrolidine (Method 62) (950 mg, 2.7 mmol) and sodium methoxide (740 mg, 13.7 mmol) in methanol (25 ml) was heated to reflux for 18 hours. The reaction mixture was allowed to cool, diluted with EtOAc. The solution was washed with water, dried (Na 2 SO 4) and the solvent was removed by evaporation. The residue was purified by chromatography on silica gel eluting with EtOAc / hexane (15:85) to give the title compound (675 mg, 72%). NMR (DMSO): 1.22-1.42 (m, 2H), 1.88-2.0 (m, 3H), 2.22-2.34 (m, 1H), 3.34-3.42 (m, 1H), 3.42-3.53 (m, 1H), 3.95 (s, 3H), 4.98 (s, 1H), 6.67 (s, 1H), 7.12 (dd, 1H), 8.14 (dd, 1H), 8.30 (dd, 1H); m / z 346 [MH] +.

Method 64 S-2-f3- (2-Methoxypyrid-3-yl) isoxazol-5-yl-1-pyrrolidine 2M hydrochloric acid (25 ml) was added to a solution of SN-tert-butoxycarbon I) -2- [3- (2-m-ethoxy-pyrid-3-yl) isoxazo-1-5-11] pyrrolefin (Method 63) (670 mg, 2 mmol) in methanol (25 ml) and the mixture was stirred at room temperature environment for 2.5 days. The mixture was concentrated through evaporation, adjusted to a pH of 7 with a 40% aqueous sodium hydroxide solution and extracted with DCM. The extracts were combined, dried (MgSO) and the solvent was removed by evaporation to give the title compound (300 mg, 65%) as an oil. NMR (DMSO): 1.70-1.82 (m, 3H), 1.98-2.07 (m, 1H), 2.86-2.91 (m, 2H), 3.96 (s, 3H), 4.29-4.38 (m, 1H), 6.70 ( s, 1H), 7.10 (dd, 1H), 8.13 (dd, 1H), 8.28 (dd, 1H); m / z 246 [MH] +.

Method 65 4- (5-Ethyl-1 H -pyrazol-3-ylamino) -2-chloropyrimidine A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 5-amino-3-ethyl-1 H-pyrazole (2.44 g, 22 mmol) and N, N-diisopropylethylamine (3.8 ml, 22 mmol) in dry THF (75 ml) was heated at 60 ° C for 18 hours. The volatiles were removed by evaporation, and the residue was titrated with a mixture of DCM and water. The solid product was collected by filtration, washed with water and ether, and dried to give the title compound (1.55 g, 35%) as a colorless crystalline solid.

NMR (DMSO): 1.20 (t, 3H), 2.60 (q, 2H), 6.06 (s, 1H), 7.15 (s, 1H), 8.10 (d, 1H), 9.80 (s, 1H), 11.83 (br s, 1H); m / z 224 [MH] +.

Method 66 S-2-f3- (Pyrimid-2-yl) isoxazole-5-pyrrolidine A 13% solution of aqueous sodium hypochlorite (4.25 ml, 7.45 mmole) was added slowly to a mixture of SN-tert-butoxycarbonyl -2-etinlpyrrolidine (prepared as described in Bul. Soc. Chim. Fr. 1997, 134, 141-144 and J. Med. Chem. 1994, 37, 4455-4463) (1.45 g, 7.45 mmol) and pyrimidine-2-carbaldehyde oxime (0.47 g, 3.82 mmol, Khimiya Geterotsikllcheskikh Soedinenii (1972), 10, 1422-4) in DCM (15 ml) cooled to 0 ° C. The reaction mixture was allowed to warm to room temperature and then stirred for 12 hours. The mixture was diluted with ethyl acetate, the layers were separated, the solvent was removed from the organic layer through evaporation. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (0: 100 increasing in polarity to 100: 0). The product fractions were evaporated to give a golden oil, which was solidified to a solid at rest (250 mg, 20%). This solid was then dissolved in TFA (2 ml) and stirred at room temperature for 45 minutes. The reaction was evaporated to dryness and the residue was dissolved in DCM and voided on an SCX-2 isolute ion exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to elute the product. The fractions containing the product were evaporated to give the title compound (125 mg, 15%) as an orange solid. NMR (DMSO-d6): 1.78 (m, 3H), 2.14 (m, 1H), 2.92 (t, 2H), 4.36 (t, 1H), 6.82 (s, 1H), 7.60 (t, 1H), 8.96. (d, 2H); m / z 217 [NH] +.

Method 67 3-Methoxypyrazine-2-carboxaldehyde oxime A mixture of 3-methoxypyrazine-2-carboxaldehyde (Tetrahedron (1999), 56 (2), 265273) (2.1 g, 15 mmol), hydroxyl-1-hydrochloride (1.27 g, mmoles), ethanol (20 ml) and triethylamine (4.17 ml, 30 mmol) was heated at 60 ° C for 90 minutes. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (100: 0 increasing in polarity to 0: 100) to give the title compound (740 mg, 32%) as a white solid. NMR (DMSO-de): 3.96 (s, 3H), 8.22 (s, 2H), 8.23 (m, 1H), 11.89 (s, 1H).

Method 68 S-2-f3- (2-Methoxypyrazin-3-yl) isoxazole-5-pyrrolidine Sodium hypochlorite (5.23 ml of an aqueous 13% solution, 9.16 mmole) was added slowly to a stirred mixture of SN- tert-butoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr. 1997, 134, 141-144 and J. Med. Chem. 1994, 37, 4455-4463) (1.07 g, 5.50 mmol) , 3-methoxypyrazine-2-carboxaldehyde oxime (Method 67) (0.7 g, 4.58 mmol) in DCM (40 ml) cooled to 0 ° C. The reaction was allowed to warm to room temperature and then stirred for 12 hours. The layers were separated, the solvent was removed from the organic layer and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (100: 0 increasing in polarity to 0: 100). The purified product was solidified to a solid at rest and dissolved in TFA (10 ml) and the mixture was stirred at room temperature for 30 minutes. The volatiles were removed by evaporation and the residue was dissolved in DCM and poured into a SCX-2 isolute exchange column. The column was eluted with methanol to elute any neutral material, followed by 7M of methanolic ammonia to remove the product. The solvent was removed by evaporation to give the title compound (260 mg, 23%) as a brown oil. NMR (DMSO-de): 1.78 (m, 3H), 2.14 (m, 1H), 2.92 (t, 2H), 4.01 (s, 3H), 4.36 (dd, 1H), 6.78 (s, 1H), 8.36 (s, 2H); m / z 247 [MH] +.

Method 69 2-Chloro-4- (5-ethyl-1 H -pyrazole-3 -i I amino) -5-fluoro-pyrimidine 5-amino-1 H-3-ethylpyrazole and 2,4-dichloro-5 were treated fluoropyrimidine by the method described in Method 65 to give the title compound (1.89 g, 78%) as an off-white crystalline solid.

NMR (DMSO): 1.20 (t, 3H), 2.62 (q, 2H), 6.35 (s, 1H), 8.22 (d, 1H), 10.35 (s, 1H), 12.25 (br s, 1H); m / z 242 [MH] +.

Method 70 2-Chloro-6-methyl-4- (5-cyclopropyl-1 H-pyrazole-3 -lamino) pipminid sodium carbonate (2.15 g, 20.25 mmol) was added to a stirred solution of 2, 4-dichloro-6-methylpyrimidine (3 g, 18.4 mmol) and 3-amino-1 H-5-cyclopropylpyrazole (2.25 g, 18.4 mmol) in dry ethanol (40 ml) and the mixture was stirred at 40 ° C for 4 hours. days. The insoluble material was removed by filtration, the filter pad was washed with ethanol. The volatiles were removed from the filtrate through evaporation keeping the bath below 40 ° C. The residue was purified immediately by column chromatography on silica gel eluting with methanol / DCM (0: 100 increasing in polarity to 20:80) to give the title product (1.9 g, 46%) obtained as a white solid . NMR (DMSO): 0.65 (m, 2H), 0.90 (m, 2H), 2.25 (s, 3H), 5.90 (br s, 1H), 7.05 (br s, 1H), 10.15 (br s, 1H), 12.10 (br s, 1H); m / z 250 [MH] +.

Method 71 4-CI gold-6- (3-hydroxy propyl) -2-f 2 -f 3- (pi rid-2-inisoxazo l-5-iH-pyridin-1-yl.} Pi rimine A solution of 2.5% w / v osmium tetroxide in tert-butanol (0.47 ml) was added to a vigorously stirred solution of 4-chloro-6- (pent-3-en-1-yl) -2- {2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-ylpyrimidine (prepared as described in Example 34) in THF (10.5 ml) and water (2.8 ml). Solid sodium periodate (951 mg, 4.44 mmol) was then added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (Na 2 SO 4), and the solvent was removed by evaporation. The residue was dissolved in THF (13.5 ml) and distilled water (5.0 ml) and sodium borohydride (59 mg, 1.59 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and water and the layers were partitioned and separated. The ethyl acetate layer was washed with water and saturated brine, dried (Na2SO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with methanol / DCM (1.5: 98.5) to give the title compound (205 mg, 36%). NMR (DMSO-de / 300MHz): 1.67 (m, 2H), 2.06 (m, 3H), 2.42 (m, 3H), 3.35 (m, 2H), 3.58 (m, 1H), 3.78 (m, 1H) , 4.4 (d, 1H), 5.4 (d, 1H), 6.67 (s, 1H), 6.73 (s, 1H), 7.47 (t, 1H), 7.95 (m, 1H), 8.66 (d, 1H); m / z 386 [MH] +.

Method 72 2,6-Dichloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine 2,4,6-Trichloropyrimidine and 3-amino-5-ethyl-1 H-pyrazole were treated (Method 6 from WO 03/048133) as described in Method 29 to give the title compound (2.48 g, 51%). NMR (DMSO-de at 100 ° C): 1.2 (t, 3H), 2.6 (q, 2H), 6.0 (s, 1H), 7. 3 (br s, 1H), 10.2 (br s, 1H), 12.0 (br s, 1H); m / z 259 [MH] +.

Method 73 S-2- (3- (thiazol-4-yl) isoxazol-5-yl) pyrrolidine SN-tert-butyloxycarbonyl-2- (3- (thiazol-4-yl) isoxazole-5-yl was treated ) pi rrolid i na (Method 74) (334 mg, 1.04 mmol) as described in Method 42 to give the title compound (217 mg, 94%) as a yellow solid. NMR (DMSO): 1.75 (m, 3H), 2.1 (m, 1H), 2.9 (t, 2H), 4.32 (t, 1H), 6.72 (s, 1H), 8.29 (s, 1H), 9.24 (s) , 1 HOUR); m / z 222 [MH] +.

Method 74 S-N-Ter-butyloxycarbonyl -2 - (3 - (th i azo I -4-yl) isoxazol-5-yl) pyrrolidine A solution of triethylamine (0.7 ml, 5.4 mmol) in THF (2 ml) was added dropwise to a stirred solution of thiazole-4-chlorocarboxaidehyde oxime (Method 75) (730 mg, 4.5 mmol) and SN-ter- butoxycarbonyl-2-ethynyl pyrrolidine (prepared as described in Bull. Soc. Chim. Fr. 1997, 134, 141-144 and J. Med. Chem. 1994, 37, 4455-4463) (0.96 g, 4.95 mmol) in THF (20 ml) was cooled to 0 ° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed by evaporation and the residue was partitioned between DCM and water and the insoluble material was removed by filtration. The layers were separated, the solvent was removed from the organic layer and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (3: 1 increasing in polarity to 3: 2) to give the recovered acetylene. (634 mg) and the title compound (334 mg, 23%) as a white solid. NMR (DMSO): 1.25 (s, 5H), 1.38 (s, 4H), 1.93 (m, 3H), 2.26 (m, 1H), 3.37 (m, 1H), 3.48 (m, 1H), 5.0 (s, 1H), 6.71 (br d, 1H), 8.32 (s, 1H), 9.23 (s, 1H); m / z 344 [M + Na] + Method 75: Thiazole-4-chlorocarboxaldehyde oxime N-chlorosuccinimide (600 mg, 4.5 mmol) was added to a solution of thiazole-4-carboxaldehyde oxime (Method 76) (579 mg, 4.5 mmol) in DMF (4 mL) cooled to 0 ° C. The reaction was stirred at 0 ° C for 1 hour, allowed to warm to room temperature and stirred for a further 2 hours. The mixture was diluted with ether and water. The ether layer was separated, washed with water and brine, the solid product was collected through filtration and the filtrate was dried (Na2SO4) and the solvent was removed by evaporation to give the solid product. Two batches of the solid were combined to give the crude title compound (730 mg, 100%). NMR (DMSO): 8.12 (s, 1H), 9.15 (s, 1H), 12.42 (s, 1H); m / z 163 [MH] + Method 76 Thiazole-4-carboxaldehyde oxime Thiazole-4-carboxaldehyde was treated (Synthesis 1987, 998) by the method described in Method 67 to give the title compound.

NMR (DMSO): 7.93 (s, 1H), 8.22 (s, 1H), 9.13 (s, 1H), 11.28 (s, 1H).

Method 77 S -2- (3 - (Ti azo I -2 -i I) isoxazol-5-yl) pyrrolidine 3M hydrochloric acid (26 ml) was added to a solution of S-N-tert-butyloxycarbonyl-2 (3). - (tiazol-2-yl) isoxazol-5-yl) pyrrolidine (Method 78) (8.32 g, 26 mmol) in methanol (26 ml) and the mixture was stirred at room temperature for 18 hours and then at 60 C for 1 hour The volatiles were removed by evaporation, the aqueous layer was washed with DCM, adjusted to a pH of 11-12 with a 40% solution of aqueous sodium hydroxide and extracted with DCM (x6). The extracts were combined, dried (Na2SO4) and the solvent was removed by evaporation The residue was purified by column chromatography on silica gel eluting with methanol / DCM (5:95) to give the compound of the title (4.01 g, 70%) as a yellow oil, NMR (DMSO): 1.75 (m, 3H), 2.10 (m, 1H), 2.89 (t, 2H), 4.33 (m, 1H), 6.78 (s) , 1H), 7.95 (d, 1H), 8.03 (d, 1H), m / z 222 [MH] +.

Method 78 SN-tert-Butyloxycarbonyl-2- (3- (thiazol-2-yl) isoxazol-5-yl) pyrrolidine N-Chlorosuccinimide (10.6 g, 80 mmol) was added in portions to a solution of thiazole oxime -2-carboxaldehyde (Method 2) (10.35 g, 80 mmol) in DMF (30 ml) cooled to -5 ° C. The reaction was stirred at -5 ° C for 1 hour, allowed to warm slowly to room temperature for 3 hours. The mixture was diluted with ether, EtOAc and water. The solid product was collected through filtration. The organic layer was separated, washed with water and brine, dried (Na2SO4) and the solvent was removed by evaporation, keeping the bath temperature at room temperature, to give the solid product. The two batches of the solid were combined and directly dissolved in THF (200 ml) and the solution was added dropwise to a solution of SN-tert-butoxycarbonyl-2-ethynylpyrrolidine (prepared as described in Bull. Soc. Chim. Fr. 1997, 134, 141-144 and J. Med. Chem. 1994, 37, 4455-4463) (31 g, 160 mmol) and triethylamine (13.4 ml, 96 mmol) in THF (200 ml) cooled to 0 °. C, the mixture was left to slowly warm to room temperature and stirred for 18 hours. The solvent was removed by evaporation, water was added to the residue and the mixture was extracted with DCM. The extracts were combined, washed with brine, dried (Na2SO4) and the solvent was removed by evaporation. The residue was purified through column chromatography on silica gel eluting with EtOAc / hexane (1: 4 increasing in polarity to 1: 1) to elute the first acetylene recovered and then to give the title compound (8.32 g, %) as an orange oil. NMR (DMSO): 1.22 and 1.38 (2x br s, 9H), 1.85 (m, 3H), 2.15 (br m, 1H), 3.37 (m, 1H), 3.50 (m, 1H), 5.00 (br m, 1H), 6.78 and 6.83 (2x br s, 1H), 7.97 (d, 1H), 8.05 (d, 1H); m / z 266 [MH-C4H9] +.

Method 79 6-Ethyl-2-chloro-4- (5-eti 1-1 H-pyrazol-3-ilamino) pyrimidine Was stirred 2, 4-dichloro-6-etl-pyrimidine (J. Am. Chem. Soc. 1936, 58, 78) (1.33 g 7.53 mmol) in ethanol (50 ml) and 5-ethyl-1H-3- was added amino-pyrazole (Method 6 of WO 03/048133) (0.836 g, 7.53 mmol) followed by sodium carbonate (1.25 g) and the mixture was stirred at 40 ° C for 4 days thereafter at 55 ° C overnight. The insoluble inorganics were removed by filtration and the solvent was removed from the filtrate through evaporation. Water (100 ml) was added and the mixture was extracted with EtOAc (3 x 50 ml). The extracts were combined and washed with water (50 ml), brine (50 ml), dried (MgSO 4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (100: 0 increasing in polarity to 0: 100) to give the title compound (210 mg, 11%) as a white solid. NMR (DMSO-d6 at 100 ° C): 1.20 (m, 6H), 2.50-2.70 (m, 4H), 6.05 (s, 1H), 7.05 (br s, 1H), 9.70 (br s, 1H), 11.85 (br s, 1H); m / z 252 [MH] +.

Method 80 6-Ethyl-2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine 2,4-Dichloro-6-ethyl-pyrimidine (J. Am. Chem. Soc. 1936, 58, 78) and 5-cyclopropyl-1 H-3-amino-pyrazole (Method 7 of WO 03/048133) by an analogous method to that described in Method 79 to give the title compound (464 mg, 32%) as a pale yellow powder. NMR (DMSO-d6 at 100 ° C): 0.65 (m, 2H), 0.90 (m, 2H), 1.15 (t, 3H), 1.90 (m, 1H), 2.55 (q, 2H), 5.95 (br s) , 1H), 7.05 (br s, 1H), 9.70 (br s, 1H); m / z 264 [MH] +.

Method 81 6-Cyclopropyl-2-chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -pyrimidine 2,4-Dichloro-6-cyclopropylpyrimidine (Chem. Abs. 1969, 71, 61412I) and 5-cyclopropyl-1 H-3-amino-pyrazole (Method 7 of WO 03/048133) by an analogous method to that described in Method 79 to give the title compound (200 mg , 23%) as a pink solid. NMR (DMSO-de at 100 ° C): 0.85 (m, 2H), 0.95 (m, 6H), 1.90 (m, 2H), 5.90 (s, 1H), 7.05 (br s, 1H), 9.60 (br s, 1H), 11.90 (br s, 1H); m / z 276 [MH] +.

Method 82 6-Cyclopropyl-2-chloro-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine 2,4-Dichloro-6-cyclopropylpyridine (Chem. Abs. 1969, 71, 61412) ) and 5-ethyl-1 H-3-amino-pyrazole (Method 6 of WO 03/048133) by an analogous method to that described in Method 79 to give the title compound (200 mg, 23%) as a solid rose. NMR (DMSO-de at 100 ° C): 0.95 (m, 4H), 1.20 (t, 3H), 1.90 (m, 1H), 2.60 (q, 2H), 5.65 (s, 1H), 6.05 (br s) , 1H), 7.05 (br s, 1H), 9.60 (br s, 1H), 11.85 (br s, 1H); m / z 264 [MH] +.

Method 83 2-Chloro-6-methyl-4- (5-ethyl-1 H -pyrazol-3-ylamino) pyrimidine 2,4-Dichloro-6-methylpyrimidine and 5-amino-3-ethyl-1H- were treated pyrazole (Method 6 of WO 03/048133) by an analogous method to that described in Method 56 to give the title compound (450 mg, 42%). NMR (DMSO-de at 100 ° C): 1.20 (t, 3H), 2.25 (s, 1H), 3.60 (q, 2H), 6.05 (s, 1H), 7.00 (br s, 1H), 9.70 (br s, 1H), 11.85 (br s, 1H); m / z 238 [MH] +.

Method 84 4 Hydroxy-4-mercapto-6- (3-methoxypropyl) pyrimidine A solution of methyl 6-methoxy-3-oxohexanoate (5.33 g, 30.6 mmol) in ethanol (20 ml) was added to a mixture of thiourea ( 3.29 g, 43.3 mmol) and sodium ethoxide in ethanol (22.4 ml of a 21% w / w solution) heated to 80 ° C and the mixture was stirred at 75 ° C for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in water and the solution adjusted to a pH of 3 with 2M hydrochloric acid. The mixture was cooled in ice and the precipitated product was collected through filtration and dried to give the title compound (2.52 g, 43%). NMR (DMSO): 1.78 (q, 2H), 2.39 (t, 2H), 3.22 (s, 3H), 3.28 (q, 2H), 5.64 (s, 1H); m / z 201 [MH] +.

Method 85 2,4-Dihydroxy-6- (3-methoxypropyl) pyrimidine A suspension of 4-hydroxy-4-mercapto-6- (3-methoxypropyl) pyrimidine (Method 84) (3.9 g, 19.5 mmol) and chloroacetic acid ( 1.89 g, 19.9 mmol) in water (20 ml) was heated at 120 ° C for 24 hours. The mixture was allowed to cool, adjusted to a pH of 7 with a sodium hydroxide solution and extracted with EtOAc. The extracts were combined, dried (Na2SO) and the solvent was removed by evaporation to give the title compound (1.9 g, 55%) as a solid. NMR (DMSO): 1.78 (q, 2H), 2.31 (t, 2H), 3.21 (s, 3H), 3.30 (q, 2H), 5.29 (s, 1H); m / z 185 [MH] +.

Method 86 2,4-Dichloro-6- (3-methoxypropyl) pyrimidine A solution of 2,4-dihydroxy-6- (3-methoxypropyl) pyrimidine (Method 85) (1.9 g 10.2 mmole) and N, Nd. Laniline (2 ml) in phosphoryl chloride (20 ml) was heated at 90 ° C for 30 minutes. The mixture was allowed to cool, ice water was added and the mixture was extracted with EtOAc. The extracts were combined, washed with 2M hydrochloric acid, dried (Na2SO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (50:50) to give the title compound (1.5 g, 68%).

NMR (DMSO): 1.88 (q, 2H), 2.78 (t, 2H), 3.21 (s, 3H), 3.32 (t, 2H), 7.72 (s, 1H); m / z 221 [MH] +.

Method 87 2-Chloro-6- (3-methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -pyrimidine 2,4-Dichloro-6- (3-methoxypropyl) pyrimidine was treated (Method 86 ) and 3-amino-1 H-5-methylpyrazole as described in Method 70 to give the title compound (200 mg, 32%). NMR (DMSO): 1.88 (q, 2H), 2.20 (s, 3H), 2.59 (t, 2H), 3.21 (s, 3H), 3.32 (t, 2H), 3.38 (t, 2H), 6.05 (s) , 1H), 7.04, (s, 1H), 9.65 (s, 1H), 11.80 (s, 1H); m / z 282 [MH] +.

Pharmacical Analysis Methods to Detect Inhibition of Igf-1r Kinase Activity and Downstream Signaling and Selectivity Signaling of Insulin Receptor Kinase and Eqfr Abbreviations used: PBS (PBS / T) is saline regulated in its pH, pH 7.4 (with 0.95% of Tween 20) HEPES is N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid] DTT is dithiothreitol TMB is tetramethyl benzidine DMSO is dimethyl sulfoxide BSA is bovine serum albumin ATP is adenosine tri-phosphate DMEM en Eagle Medium modified with Dulbecco FBS / FCS is fetal calf / calf serum HBSS is Hanks Balanced Salts Solution HRP is horseradish peroxidase SDS is sodium dodecyl sulfate IGF-I (IGR-1R) is growth factor-l Insulin type (IGF-1 receptor) EGF is epidermal growth factor IGF-1R Kinase Assay a) Cloning, Expression and Purification of Protein A DNA molecule encoding a fusion protein containing glutathione-S-transferase, (GST), thrombin cleavage site and intracellular domain of IGF-1R (amino acids 930-1367) and subsequently named as GST-IGFR, was constructed and cloned into pFastBad (Life Technies Ltd, UK) using standard molecular biy techniques (Molecular Cloning - A, Laboratory Manual, Second Edition 1989; Sambrook, Fritsch and Maniatis; Coid Spring Harbor Laboratory Press). The production of recombinant virus was carried out following the manufacturer's protocol. Briefly, the pFastBac-1 vector containing GST-IGFR was transformed to DHIOBac cells of £. coli containing the baculovirus genome (bacmid DNA) and through a transposition event in the cells, a region of the pFastBac vector containing the gentamicin resistance gene and the GST-IGFR expression cassette including the baculovirus polyhedrin promoter, was transposed directly in the DNA bacmid. Through selection in gentamicin, kanamycin, tetracycline and X-gal, the resulting white cies must contain recombinant bacmid DNA encoding GST-IGFR. The bacmid DNA was extracted from a small scale culture of several white cies of BHIOBac and was transfected into Spodoptera frugiperda Sf21 cells grown on a TC100 medium (Life Technies Ltd, UK) containing 10% serum using the CellFECTIN reagent (Life Technies Ltd, UK), following the manufacturer's instructions. Virus particles were harvested by harvesting the cell culture medium 72 hours after transfection. 0.5 ml of the medium was used to infect a suspension culture of 100 ml of Sf21s containing 1 x 10 7 cells / ml. The cell culture medium was harvested 48 hours after infection, and virus titration was determined using a standard plaque assay procedure. Virus supplies were used to infect Sf9 and "High 5" cells at a multiplicity of infection (MOI) of 3 to determine the expression of Recombinant GST-IGFR. The GST-IGFR protein was purified by affinity chromatography on Glutathione-Sepharose followed by elution with glutathione. Briefly, the cells were used in 50mM HEPES pH 7.5 (Sigma, H3375), 200mM NaCl (Sigma, S7653), Complete Protease Inhibitor Cocktail (Roche, 1 873 580) and 1mM DTT (Sigma, D9779), from hereinafter referred to as lysis pH regulator. The clarified lysate supernatant was loaded through a chromatography column packed with Glutathione Sepharose (Amersham Pharmacia Biotech UK Ltd.). The contaminants were washed from the mixture with the pH regulator of lysis until the UV absorbance at 280 nm returned to the baseline. The elution was performed with a lysis pH regulator containing 20mM of reduced glutathione (Sigma, D2804) and the fractions containing the GST fusion protein were combined and dialysed in a pH regulator containing glycerol, comprising 50 mM HEPES, pH 7.5 , 200 mM NaCl, 10% glycerol (v / v), 3 mM reduced glutathione and 1 mM DTT. b) Kinase activity assay The activity of the purified enzyme was measured through phosphorylation of a synthetic peptide poly GluAlaTyr (EAY) 6: 3: 1 peptide (Sigma-Aldrich Company Ltd, UK, P3899) using a detection system ELISA in a 96-cavity format. b.i) Reagents used Supply solutions 200mM HEPES, pH 7.4 stored at 4 ° C (Sigma, H3375) 1M DTT stored at -20 ° C (Sigma, D9779) 100mM Na3V04 stored at 4 ° C (Sigma, S6508) 1M MnCl2 stored at 4 ° C (Sigma, M3634) 1mM ATP stored at -20 ° C (Sigma, A3377) Net Triton X-100 stored at room temperature (Sigma, T9284) 10mg / ml BSA stored at 4 ° C (Sigma, A 7888) Enzyme solution GST-IGF-1R fusion protein at 75 ng / ml in 100mM HEPES, pH 7.4, 5mM DTT, 0.25mM Na3V04, 0.25% Triton X-100, 0.25mg / ml BSA, freshly prepared.

Solution of 100mM co-factor HEPES, pH 7.4, 60mM MnCl2, 5mM ATP.

Poly EAY substrate Poly sigma substrate (Glu, Ala, Tyr) 6: 3: 1 (P3899). It was made up to 1 mg / ml in PBS and stored at -20 ° C.

Assay plates 96-well Nunc Maxisorp immunoplates were used (Life Technologies Ltd, UK).

Antibodies Upstate monoclonal anti-phosphotyrosine antibody Biotechnoiogy Inc., NY, USA (UBI 05-321). 3μl in 11ml of PBS / T + 0.5% BSA was diluted per assay plate. Secondary antibody conjugated with anti-mouse and sheep IgG HRP from Amersham Pharmacia Biotech UK Ltd. (NXA931). 20μl of the supply solution was diluted in 11ml PBS / T + 0.5% BSA per test plate.

TMB solution 1mg of the TMB tablet (Sigma T5525) was dissolved in 1ml of DMSO (Sigma, D8779) in the dark for 1 hour at room temperature. To this solution were added 9ml of pH regulator of 50mM of phosphate-citrate, pH 5.0 + 0.03% of sodium perborate [1 capsule of pH regulator (Sigma P4922) per 100ml of distilled water]. The stop solution is 1M H2S04 (Fisher Sclentific UK.

Cat. No. S / 9200 / PB08).

Test Compound DMSO was dissolved at 10mM after dilutions in distilled water to give a scale of 200 to 0.0026μM in 1-2% final concentration of DMSO in the assay cavity. b.ii) Test protocol The EAY poly substrate was diluted with 1μg / ml in PBS and then supplied in an amount of 10Oμl per well to a 96-well plate. The plate was sealed and incubated overnight at 4 ° C. The excess EAY poly solution was discarded and the plate was washed (2x PBS / T, 250μl PBS per well), stained dry between the washings. The plate was then washed again (1x 50mM HEPES, pH 7.4, 250μl per well) and dried by staining (this is important in order to remove the above phosphate levels). 10μl of the test compound solution was added with 40μl of kinase solution to each well. Then, 50μl of the cofactor solution was added to each well and the plate was incubated for 60 minutes at room temperature. The plates were emptied (ie, the contents were discarded) and washed twice with PBS / T (250μl per well), dry skin between each wash. 100μl of the diluted anti-phosphotyrosine antibody was added per well and the plate was incubated for 60 minutes at room temperature.

The plate was again emptied and washed twice with PBS / T (250μl per cavity), stained dry between each wash. They added 10Oμl of anti-mouse-sheep IgG antibody diluted per well and the plate was left for 60 minutes at room temperature. The contents were discarded and the plate was washed twice with PBS / T (250μl per cavity), stained dry between each wash. They added 1 OOμl of TMB per well and the plate was incubated for 5-10 minutes at room temperature (the solution became a blue color in the presence of horseradish peroxidase). The reaction was stopped with 50μl of H2SO4 per well (the blue-yellow solution was rotated) and the plate was read at 450nm in a Versamax plate reader (Molecular Devices Corporation, CA, USA) or the like. The compounds of the Examples were found to have an IC50 in the above test of less than 100μM. c) Inhibition of IGF-stimulated cell proliferation The construction of murine fibroblasts (NIH3T3) that overexpress the human IGF-1 receptor has been described by Lammers et al (EMBO J, 8, 1369-1375, 1989). These cells show a proliferative response to IGF-I, which was measured through incorporation of BrdU into the newly synthesized DNA. The potency of the compound was determined as the cause of the inhibition of IGF-stimulated proliferation in the following assay: c.i) Reagents used: BrdU cell proliferation ELISA (colorimetric) [Boehringer Mannheim (Diagnostics and Biochemicals) Ltd, UK. Cat no. 1 647229]. DMEM, FCS, Glutamine, HBSS (all from Life Technologies Ltd., UK). Carbon / Dextran in FBS strips (HyClone SH30068.02, Perbio Science UK Ltd). BSA (Sigma, A 7888). The animal / human recombinant IGF-1 media grade (GroPep Limited ABN 78 008 176, 298, Australia, Cat No. IU 100).

Preparation and Storage of IGF 100μg of lyophilized IGF in 100ul of 10nM HCl was reconstituted. 400μl of 1mg / ml BSA in PBS was added. Aliquots of 25μl @ 200μg / ml IGF-1. Stored at -20 ° C.

For testing: 10μl of supply IGF + 12.5ml of growth medium to give the 8X supply of 160ng / ml.

Complete growth medium 5 DMEM, 10% FCS, 2mM glutamine.

Fasting medium DMEM, carbon / dextran at 1% FCS in strips, 2mM glutamine.

Test Compound The compounds were initially dissolved in DMSO at 10mM, followed by dilutions in DMEM + 1% FCS + glutamine to give a scale of 100 to 0.0.45μM 1-0.00045% DMSO at a final concentration in the test cavity. c.ii) Day 1 Test Protocol The exponentially growing NIH3T3 / IGFR cells were harvested and seeded in a full growth medium in a 96-well flat bottom tissue ure dish (Costar 3525) at 1.2x104 in a volume of 100 μl.

Day 2 The growth medium of each cavity was carefully removed using a multichannel pipette. The wells were rinsed carefully three times with 200μl of HBSS. 10Oμl was added to each well and the plate was re-incubated for 24 hours.

Day 3 50μl of a 4X concentrate of the test compound was added to the appropriate wells. The cells were incubated for 30 minutes with only the compound before the addition of IGF. For cells treated with IGF, an appropriate volume was added (ie, 25μl) of a fasting medium to make a final volume per cavity of up to 200μl followed by 25μl of IGF-1 at 160ng / ml (to give the final concentration of 20ng / ml). Control cells not stimulated with IGF also had an appropriate volume (i.e., 50μl) of the fasting medium added to be a final volume per cavity of up to 200μl. The plate was re-incubated for 20 hours.

Day 4 The incorporation of BrdU in the cells (after an incorporation period of 4 hours) was analyzed using the BrdU Cell Proliferation Elisa analysis according to the manufacturer's protocol. It was found that the compounds of the Examples have an IC50 in the above test of less than 50μM. d) Action Assay Mechanisms The inhibition of signal transduction mediated by IGF-IR was determined by measuring the changes in the phosphorylation of IGF-IR, Akt and MAPK (ERK1 and 2) in response to the stimulation of IGF-I from MCF-7 cells (ATCC No. HTB-22). A measure of selectivity was provided through the effect on phosphorylation of MAPK in response to EGF in the same cell line. d.i) Reagents used: RPMI 1640 medium, RPMI 1640 medium without Phenol Red, FCS, Glutamine (all from Life Technologies Ltd., UK). FBS in carbon strips / dextran (HyClone SH30068.02, Perbio Science UK Ltd). SDS (Sigma, L4390). 2-mercaptoethanol (Sigma, M6250). Bromophenol blue (Sigma, B5525). Ponceau S (Sigma, P3504). Base tris (base TRIZMA ™, Sigma, T1503). Glycine (Sigma, G7403). Methanol (Fisher Scientific UK, Cat. No. M / 3950/21). Dry milk powder (Marvel ™, Premier Brands UK Ltd.). The animal / grade of recombinant human IGF-1 medium (GroPep Limited ABN 78008 176 298, Australia, Cat No. IU 100). Recombinant human EGF (Promega Corporation, Wl, USA, Cat. No. G5021).

RPMI 1640 full growth medium, 10% FCS, 2mM glutamine Means of fasting Medium RPMI1640 without Red Phenol, FCS in strips of carbon / dextran 1%, 2mM glutamine.

Test Compounds Compounds were initially dissolved in DMSO for 10mM, followed by dilutions in RPMI 1640 medium without Phenol Red + 1% FCS + 2mM glutamine to give a scale of 100 to 0. 0.45μM in 1-0,00045% DMSO final concentration in the assay cavity.

Western transfer buffer 50mM Tris base, 40mM glycine, 0.04% SDS, 20% methanol.

PH regulator of Laemmli x2: 100mM Tris-HCl pH6.8, 20% glycerol, 4% SDS.

Sample pH regulator x4: 200mM of 2-mercaptoethanol, bromophenol blue in 0.2% in distilled water.

Primary Antibodies IGF-1Rβ anti-human rabbit (Santa Cruz Biotechnoiogy Inc., USA, Cat. No sc-713) double phospho-specific aspect of rabbit anti-insulin / IGF-1R [pYpY1162 / 1163], Double Phosphospecific (BioSource International Inc, CA, USA, Cat No.44-8041).

Anti-PKBa / Mouse Akt (Transduction Laboratories, KY, USA.

Cat. No. P67220) rabbit anti-phospho-Akt (Ser473) (Cell Slgnalling Technology Inc, MA, USA. Cat. No. # 9271). Anti-p44 / MAP p42 rabbit kinase (Cell Signaling Technology Inc., MA, USA, Cat. No. # 9102). Anti-phospho p44 / MAP kinase p42 (Cell Signaling Technology Inc., MA, USA, Cat. No. # 9101). The mouse anti-actin clone AC-40 (Sigma-Aldrich Company Ltd, UK, A4700).

Secondary Antibodies Linked to HRP, goat anti-rabbit (Cell Signaling Technology Inc, MA, USA, Cat. No. # 7074). HRP of conjugated goat anti-mouse IgG (Amersham Pharmacia Biotech UK Ltd. Cat. No. NXA931).

Dilute anti-rabbit to 1: 2000 in PBST + 5% milk. Dilute anti-mouse to 1: 5000 in PBST + 5% milk. d.ii) Test Protocol Treatment of the cell MCF-7 cells were plated in a plate of 24 cavities at 1x105 / well in 1 ml of a complete growth medium. The plate was incubated for 24 hours to allow the cells to settle. The medium was removed and the plate was washed moderately 3 times with PBS 2ml / well. 1 ml of fasting medium was added to each cavity and the plate was incubated for 24 hours in serum to fasten the cells. Then, 25μl of each compound dilution was added and the cells and compound were incubated for 30 minutes at 37 ° C. After 30 minutes of compound incubation, 25, μl of IGF (for 20ng / ml final concentration) or EGF (for a final concentration of 0.1ng / m!) Were added to each well as appropriate and the cells were incubated with the IGF or EGF factor for 5 minutes at 37 ° C. The volume was removed (through a pipette) and then 1 OOμl of Laemmii 2x pH regulator was added. Plates were stored at 4 ° C until the cells were harvested. (The harvest should occur after 2 hours of the addition of the pH regulator of Laemmii to the cells). To harvest the cells, a pipette was used to repeatedly extract and expel the Laemmli pH regulator / cell mixture and transfer to a 1.5ml tube of Eppendorf. The harvested cell lysates were kept at -20 ° C until required. The protein concentration of each lysate can be determined using the DC protein assay kit (Bio-Rad Laboratories, USA according to the manufacturer's instructions).

Western staining technique Cell samples were made with 4x sample buffer, applied with a syringe with a 21 gauge needle and boiled for 5 minutes. Samples were loaded in equal volumes and a molecular weight ladder in 4.12% bis-tris gels (Invitrogen BV, The Netherlands) and the gels were processed in an Xcell SureLock ™ Mini-Cell (Invitrogen) apparatus with the provided solutions and according to the manufacturer's instructions. The gels were stained on a Hybond C Extra ™ membrane (Amersham Pharmacia Biotech UK Ltd.) for 1 hour at 30 volts in the Xcell SureLock ™ Mini-Cell apparatus, using Western transfer pH regulator. The stained membranes were stained again with 0.1% Ponceau S to visualize transferred proteins and then cut horizontally into strips for multiple antibody incubations according to molecular weight standards. Separate strips were used for the detection of IGF-IR, Akt, MAPK and the actin control. The membranes were blocked for 1 hour at room temperature in a PBST + 5% milk solution. The membranes were then placed in 3 ml of a primary antibody solution in 4 cavity plates and the plates were incubated overnight 4 ° C. The membranes were washed in 5 ml of PBST, 3 times for 5 minutes in each wash. The secondary antibody solution conjugated with HRP was prepared and 5 ml was added per membrane.

The membranes were incubated for 1 hour at room temperature with shaking. The membranes were washed in 5ml of PBST, 3 times for 5 minutes in each wash. The ECL solution (SuperSignal ECL, Pierce, Perbio Science UK Ltd) was prepared and incubated with the membranes for 1 minute (according to the manufacturer's instructions), followed by exposure to a light sensitive and developed film. It was found that the compounds of the Examples have an IC50 in the above test of less than 20μM. By way of example, the following Table illustrates the activity of the representative compounds according to the invention. Column 2 of the Table shows the IC50 data from Test (c) described above for the inhibition of IGF-stimulated proliferation in murine fibroblasts (NIH3T3) over-expressing the human IGF-1 receptor:

Claims

1. - A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups may be optionally substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms , cycloalkylcarbonyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, [alkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms, carbamoyl, alkoxycarbonyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carb amyloyl, -C (0) -OR3b, -OR3, -NHR3b, -N [alkyl of 1 to 6 carbon atoms] R3, -S (0) mR3a or -N (R3c) C (0) R3a, where R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, m is 0, 1 or 2, R3b represents a 4, 5 or 6-membered heterocyclic saturated monocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur and R3c represents hydrogen or alkyl of 1 to 6 carbon atoms , or R3 represents a 5-6 membered saturated monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a heteroaromatic ring of 5 to 6 comprising at least one heterogeneous atom of selected ring of nitrogen, oxygen and sulfur, or R3 represents a 2,7-diazaspiro group [3.5], each of these groups or rings within R3 may optionally be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms carbon, halogen, hydroxyl, trifluoromethyl, tri- [C 1-4 alkyl] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, d - [C 1-6 alkyl] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms, aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, d - [alkyl of 1 to 6 carbon atoms] amino-alkyl of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1 to 3 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, carbamoyl, alkylcarbamoi 1 to 6 carbon atoms, di- [C 1-6 alkylcarbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkyl Isulf in 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c) C (0) R3a, wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen sulfur, any of these substituents may be optionally substituted by one or more alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano; -NQ1 represents an N-linked saturated monocyclic 5 to 6 membered ring containing a heterogeneous nitrogen atom and optionally comprises one or more additional heterogeneous ring atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro , cyano-NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonylammon of 1 to 4 carbon atoms, phenylcarbonyl, -S (0) palquyl of 1 to 4 atoms of carbon, -C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently forms a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkion of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated 5 to 6 membered monocyclic ring or unsaturated, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR 10 R 11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, feni lcarbonyl, -S (0) nalkyl of 1 to 6 carbon atoms, -C (O) NR12R13 and -SO2NR14R15, wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10, R11, R12, R13, R14 and R15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and n is 0, 1 or 2; and where any saturated monocyclic ring optionally carries 1 or 2 oxo or thioxo substituents.

2. A compound according to claim 1, wherein: R1 represents trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl from 1 to 6 carbon atoms, each of these groups may optionally be substituted by one or more substituents independently selected from halogen and alkoxy of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkium of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl from 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alko] uilo of 1 to 6 carbon atoms] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms - alkylamlamine of 1 to 6 carbon atoms, alkoxyamido of 1 to 6 carbon atoms, carbamoyl, alkanoylamino from 2 to 6 carbon atoms, -C (O) R3b, -OR3b, -SR3b, NHR3b, -N [alkyl from 1 to 6 ato carbon atoms] R3b or -S (0) mR3a wherein R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms -alkyl of 1 6 carbon atoms carbon or alkoxy of 1 to 6 carbon atoms m is 0, 1 or 2, and R3b represents a saturated 5 to 6 membered monocyclic ring containing one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, or R3 represents a ring saturated monocyclic 5 to 6 membered heterocyclic ring, this ring comprises at least one heterogeneous ring atoms selected from nitrogen, oxygen and sulfur, each of these groups or rings within R3 optionally - may be substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, cyano, amino, alkylamino of 1 to 6 atoms carbon, di- [C 1-6 alkyl] amino, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkylamino of 1-3 carbon atoms, alkoxycarbonyl of 1 to 6 atoms carbon, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio or of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl alkanoylamino of 1 to 6 carbon atoms, or a saturated monocyclic ring of 4, 5, 6 or 7 members, said ring may optionally comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, - NQ1 represents a saturated monocyclic ring N-linked from 5 to 6 members containing a heterogeneous nitrogen atom and optionally comprises one or more additional heterogeneous ring atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, at any available ring atom, by one or more additional substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano -NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, fenifcarbonyl, - S (0) palquil of 1 to 4 carbon volumes, -C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently forms a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by one or more substituents independently selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR 10 R 11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, -S (0) nalkyl of 1 to 6 carbon atoms, -C (0) NR12R13 and - SOzNR14R15, wherein R10, R11, R12, R13, R14 and R5 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10, R11, R12, R13, R14 and R15, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring, and n is 0, 1 or 2.

3. A compound according to claim 1, wherein: R1 represents trifluoromethyl, or an alkyl group of 1 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, each of these groups can optionally be substituted by halogen or an alkoxy group of 1 to 6 carbon atoms; R 2 represents hydrogen, halogen or trifluoromethyl; R3 represents hydrogen or an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms or -S (0) mR3a, each of these groups within R3 can optionally be substituted by at least one substituent selected from alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, halogen, hydroxyl, trifluoromethyl, or a saturated monocyclic ring of 4, 5, 6 or 7 member, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, where R3a represents an alkyl group of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, and is 0, 1 or 2; -NQ1 represents an N-eniazado saturated monocyclic ring of 5 to 6 members which contains a heterogeneous nitrogen atom and optionally comprises one or more additional ring heterogeneous atoms selected from nitrogen, oxygen and sulfur; Q2 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, said ring is substituted by Q3 and is optionally substituted, on any available ring atom, by one or more additional substituents, which may be the same or different, of alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of which may be optionally substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR4R5, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, alkylcarbonylamino of 1 to 4 carbon atoms, phenylcarbonyl, -S (0) palquil of 1 to 4 carbon atoms, - C (0) NR6R7 and -S02NR8R9, wherein R4, R5, R6, R7, R8 and R9 each independently represents hydrogen or alkyl of 1 to 6 carbon atoms, or R4 and R5 or R6 and R7 or R8 and R9, when taken together with the nitrogen atom to which they are attached, each independently can form a saturated heterocyclic ring and p is 0, 1 or 2; Q3 represents an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, or a saturated or unsaturated monocyclic ring of 5 to 6 members, which may comprise at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and wherein Q3 is optionally substituted by at least one substituent selected from alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms (any of these may optionally be substituted by at least one substituent selected from halogen, amino, hydroxyl and trifluoromethyl), halogen, nitro, cyano-NR 10 R 11, carboxyl, hydroxyl, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, phenylcarbonyl, -S (0) nalkyl of 1 to 6 atoms of carbon, -C (0) NR12R13 and -S02NR14R15, wherein R10, R11, R12, R13, R14 and R15 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, or R10, R11, R12, R13, R, 1144 and R, 1150, when taken together with the nitrogen atom to which they are attached, independently each can form a saturated heterocyclic ring, and n is 0, 1 or 2.

4. A compound according to any of the preceding claims, wherein R 1 represents an alkyl group of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.

5. A compound according to any of the preceding claims, wherein R2 represents hydrogen or halogen.

6. A compound according to claim 5, wherein R2 represents halogen.

7. A compound according to any of the preceding claims, wherein R3 represents hydrogen, hydroxyl or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms-alkoxy from 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 3 to 8 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino , cycloalkylamino of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms- alkylamino of 1 to 6 carbon atoms, alkoxyamino of 1 to 6 carbon atoms ,, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di - [C 1-6 alkylcarbamoyl, C (0) R 3b, -OR 3b, -NHR 3b, -N [alkyl from 1 to 6 carbon atoms] R3, -S (0) mR3a or -N (R3c) C (0) R3a, wherein R3a represents an alkyl group of 1 to 6 carbon atoms or an alkoxy group of 1 to 6 carbon atoms, m is 0, 1 or 2, R3b represents a saturated 4, 5 or 6 membered monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, and R3c represents hydrogen or alkyl from 1 to 6 carbon atoms, or R3 represents a saturated 5- to 6-membered monocyclic heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 5-6 membered heteroaromatic ring comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur, or R3 represents a 2,7-diazaspiro [3.5] nonane group. Each of these groups or rings within R3 optionally may be substituted by one or more (for example one or two, particularly one) substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, C 1-6 alkoxy-C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkoxy, halogen, hydroxyl, trifluoromethyl, tri- [C 1-4 alkyl] silyl, cyano, amino, alkylamino of 1 to 6 carbon atoms, di- [C 1-6 alkyl] amino, amino-alkyl of 1 to 6 atoms carbon, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino-alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 atoms carbon, carbamoyl, alkylcarbamoyl of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] carbamoyl, alkylthio of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, an alkanoylamino group -N (R3c) C (0) R3a wherein R3a and R3c are as defined above, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, said ring optionally may comprise one or more heterogeneous atoms selected from nitrogen, oxygen and sulfur, any of these substituents It can be substituted by one or more (for example one or two, particularly one) alkyl groups of 1 to 4 carbon atoms, hydroxyl or cyano. Any saturated monocyclic ring within R3 optionally carries 1 or 2 oxo or thioxo substituents.

8. A compound according to claim 5, wherein R3 represents hydrogen or halogen, or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1- to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms ] amino, carbamoyl, -C (0) R3b, -OR3b, -SR3b, -NHR3, -N [alkyl of 1 to 6 carbon atoms] R3b or -S (0) mR3a, wherein R3a and R3b are as defined in the claim 1, or R3 represents a saturated or monocyclic 5 or 6 membered heterocyclic ring, which comprises at least one heterogeneous atom selected from nitrogen, oxygen and sulfur, each of these groups or rings may be optionally substituted by one or more substituents as defined in claim 1.

9. A compound according to any of the preceding claims, wherein R3 represents hydrogen or an alkyl group of 1 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, or R3 represents a saturated, monocyclic 5- to 6-membered heterocyclic ring comprising at least one heterogeneous ring atom selected from nitrogen or oxygen, each of these groups or rings may be optionally substituted by one or more substituents independently selected from hydroxyl and alkoxy of 1 to 3 carbon atoms.

10. A compound according to any of the preceding claims, wherein R3 represents hydrogen.

11. A compound according to any of the preceding claims, wherein NQ1 represents a saturated 5 to 6 membered monocyclic ring containing a heterogeneous atom and optionally at least one additional heterogeneous atom, which may be the same or different, selected nitrogen, oxygen and sulfur.

12. A compound according to claim 11, wherein NQ1 is pyrrolidinyl or piperidinyl.

13. A compound according to any of the preceding claims, wherein Q2 represents a 5-6 membered heteroaromatic ring comprising one or two heterogeneous ring atoms, which may be the same or different, selected from nitrogen and oxygen, said ring is substituted by Q3 and optionally by at least one substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen and cycloalkyl of 3 to 8 carbon atoms.

14. A compound according to claim 13, wherein the heteroaromatic ring is selected from isoxazolyl and tetrazolyl.

15. A compound according to claim 14, wherein the heteroaromatic ring is isoxazolyl.

16. A compound according to any of the preceding claims, wherein Q3 represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or an optionally substituted saturated or unsaturated 5 to 6 membered monocyclic ring optionally comprising at least one heterogeneous ring atom selected from nitrogen, oxygen and sulfur.

17. A compound according to claim 16, wherein Q3 represents an alkyl group of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms or an optionally substituted unsaturated monocyclic ring of 5 to 6 members comprising one or two heterogeneous atoms, which may be the same or different, selected from nitrogen, oxygen and sulfur.

18. A compound according to claim 16 or 17, wherein Q3 represents an optionally substituted unsaturated 5 to 6 membered monocyclic ring comprising one or two heterogeneous atoms, which may be the same or different, selected from nitrogen, oxygen and sulfur.

19. A compound according to claim 18, wherein Q3 represents thiazolyl, pyrazinyl, pyrimidinyl or pyridyl.

20. A compound according to claim 1, wherein R1 represents an alkyl group of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; R2 represents halogen; R3 represents hydrogen; -NQ1 represents a saturated five or six membered monocyclic ring containing a heterogeneous nitrogen atom and optionally at least one heterogeneous additional ring atom selected from nitrogen, oxygen and sulfur; Q2 represents a substituted 5 to 6 membered heteroaromatic ring comprising one or two heterogeneous ring atoms, which may be the same or different, selected from nitrogen and oxygen; and Q3 represents an alkyl group of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms or an optionally substituted unsaturated 5 to 6 membered monocyclic ring comprising one or two heterogeneous ring atoms, which may be the same or different, selected from nitrogen, oxygen and sulfur.

21. A compound according to claim 20, wherein -NQ1 represents pyrrolidyl or piperidinyl; Q2 represents isoxazolyl or tetrazolyl; and Q3 represents methyl, cyclopropyl, thiazolyl, tetrahydrofuranyl, pyrazinyl, thiazolyl, pyrimidinyl or pyridyl.

22. A compound according to claim 20 or 21, wherein -NQ1 represents pyrrolidinyl; Q2 represents isoxazolyl; Y Q3 represents thiazolyl, pyrazinyl, pyrimidinyl or pyridyl.

23. A compound according to claim 20 or 21, wherein -NQ1 represents pyrrolidinyl or piperidiniio; Q2 represents isoxazolyl; and Q3 represents methyl, cyclopropyl, thiazolyl or pyridyl.

24. A compound of the formula (I) according to claim 1, selected from one or more of: 5-Chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-Ll] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- [2- (3-methylisoxazol-5-yl] pyrrolidin-1-yl] -4- (5-tert-butyl-1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- [2- (3-methylisoxazol-5-yl] pyrrolidin-1-yl] -4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- [2- (3-cyclopropylisoxazole -5-ll] pyrrolidin-1-yl] -4- (5-cylpropyl-1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- [2- (3-cyclopropylsoxazol-5-yl] pyrrolidin-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; 5-Chloro- 2- [2- (3-methylisoxazoi-5-yl] pyrrolidin-1-yl] -4- (5-methyl-1 H-pi-razo I-3-ylamino) pyrimidine; 5-Chloro-2- {2- [3- (thiazol-2-y) isoxazole-5-yl] pyrrolidin-1-yl.} -4- (5-methyl-1H-1-l-3-i-lamyl) no) pyrimidine, 5-chloro-2- { 2- [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-yl.} -4- (5-cyclopropyl) -1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2-. {2- [3- (pyrid-2-yl) isoxazol-5-yl] plrrolidin-1-yl .}. -4- (5-Clclopropyl-1H-pyrrazol-3-ylamino) pyrimidine; 5-Chloro-2-. {2- [3- (pyrid-3-yl) lsoxazole-5- L] pyrrolidin-1-yl.} -4- (5-methy1-1H-pyrazol-3-ylamino) pyrimidine; 5-chloro-2-. {2- 2- [3- (plrid-3 il) isoxazol-5-yl] pyrrolidin-1-yl.} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; 2- [2- (3-Cyclopropylisoxazol-5-yl) pyrrolidin-1-yl] ~ 6-methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 2- [2- (3-Cyclopropyl isoxazole-5-yl) pi rrol id n-1-yl] -6-methoxy meti l-4- ( 5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- (2- (3- (pyrid-2-yl) isoxazol-5-yl) piperidin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 5-Chloro-2- [2- (3. {Tetrahydrofuran-3-yl}. Isoxazol-5-yl] pyrrolidin-1-yl] -4- (5-methyl-1 H -pyrazole- 3-ylamino) pyrimidine; 5-Chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2- (3 { Tetrahydrofuran-3-yl.} Isoxazole-5 -yl] pyrrolidin-1-yl] pyrimidine; 6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. {2- 2- [3- (pyrid-2- il) isoxazoi-5-y!] pyrrolidin-1-yl] pyrimidine; 5-Chloro-4- (5-cyclopropyl-1 Hp -razol-3-ylamino) -2- { 2- [3- (pyrid -2- l) isoxazol-5-yl] piperidin-1-yl.}. Pyrimidine; 5-Chloro-2- { 2- [3- (2-methoxypyrid-3-yl) isoxazole -5-yl] pyrrolidn-1-yl.} -4- (5-methyl-1 Hp -razol-3-ylamino) pyrimidine; 5-Fluoro-4- (5-methyl-1H -pyrazol-3-ylammon) -2-. {2- 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrroiidin-1-yl} - pyrimidine; (5-Cyclopropyl-1 H -pyrazol-3-ylammon) -5-fluoro-2-. {2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1- il.) pyrimidine; S-5-Chloro-2- {2- [3-methy1-oxazol-5-yl] pyrrolidin-1-yl} -4- (5- cyclopropyl-1H-p-arazoi-3-ylamino) pyrimidine; 4- (5-Methoxy-1H-pyrrazol-3) -ylamino) -2- { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrro lidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamine) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] plrrolidin-1-yl} plurality; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2- (3-ethylisoxazol-5-yl) pyrrolidin-1-yl] pyrimidine; 6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6- (3-Methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) Soxazol-5-il} pyrrolidin-1-yl] pyrimidine; 4- (5-Cyclopropyl-1 H-pi razo l-3-l lamí no) -6-metoxim eti l-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-3-yl) isoxazol-5-yl} p i rrol din-1-yl] pirim id ina; 4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (pent-3-en-1-yl) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -6-trifluoromethylpyrimidine: 4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (plrid-2-yl) isoxazol-5-l] pyrrolidin-1-yl} -6-trifluoromethylpyrimidine; S-6-Ethyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1] pyrimidine; S-5-Chloro-2-. { 2- [3- (thiazol-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methi I- 1 H-pi razol-3 -lamino) pyrimidine; S-5-Chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-methyl-2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Chloro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] plrroli in-1-yl} -4- (5-methyl-1H-pyrazol-3-llamino) pyrimidine; S-5-Chloro-2-. { 2- [3- (2-methoxypyrid-3-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (3-N, N-Dimethylaminopropyl) -4- (5-methyl-1H-pyrazolo-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5'il} pyrrolidin-1-yl] pyrimidine; 6- (3-Pyrrolidol-1-ylpropyl) -4- (5-methy1-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; 6-Methoxycarbonyl-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-y) I) soxazol-5-i I] prolid id in-1-ylpyrimidine; 6- (2-Hydroxyethylcarbamoyl) -4- (5-methyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Met.l-1H-pyrazole-3-llamno) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-ii} -6 (pyrrolidin-1-ylcarbonyl) pyrimidine; 6-Methoxy-4- (5-methy1-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl)) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 5-Chloro-4- (3-cyclopropyl-1H-pyrazol-5-ylamino) -2- [2- (2-methyl-2H-tetrazol-5-yl) pyrrolidin-1-yl] pyrimidine; 6-N-Eti I piperazin i l-4- (5-meti 1-1 H-pi razol-3-i mi no) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6-N-Methylpiperazyl-2-. { 2- [3- (pyrid-2-yl) isoxazoi-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pi-razo l-3-ylammon) pyrimidine; 6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6- (3- (N, N-Dimethylamino) propin-1-yl) -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- (2- (3- (pyrid-2) -yl) isoxazol-5-yl) pyrrolidin-1-yl) pyrimidine; 6-Methylamino-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2- (3-pyridin-2-illsoxazol-5-yl) pyrrolidin-1-yl] pyrimidine; 6- (2-Methoxyethyl) amino-4- (5-methyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) iso xa zol5-ii] pyrrolidin-1-ylpyrimidine; 6- Methoxy carbon i l-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin- 1 -i l} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (N-Methylcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pi-razo l-3-ylamino) pyrimidine; 6-Morpholinocarbonyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolldin-1-yl} -4 ~ (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (N- (2-Methoxyethyl) carbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrro lidin-1-yl} -4- (5-methyl-1 H-pi-razo l-3-ylamino) pyrimidine; 6- (N-Hydroxycarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-Carbamoyl-2-. { 2- [3- (pyrid-2-y) I) soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methy1- 1H-pyrazol-3-ylamino) pyrididine; S-6-Methoxycarbon-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pi-razo l-3-ylamino) pyrimidine; S-6- (N- (2-Methoxyethyl) carbamol) -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-metii-1 H -pyrazol-3-ylamino) pyrimidine; S-6- [N- (2-Methoxyethyl) -N-methylcarbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6- [N- (2- (Acetylamino) ethyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidine; S-6- [N- [2- (2-Hydroxyethoxy) ethyl] carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-p i razol-3-i lamino) pyrimidine; S-6- [N - ((R) -2-Hydroxypropyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrro! Idin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- [N- (4-Hydroxybutyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrrazol-3-ylamino) pyrimidine; S-6- [N - ((2R) -2,3-D¡h¡droxypropyl) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6- [N- (Carbamoylmethyl) carbamoyl-2-J. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4 (5-methy1-1H-pyrazol-3-ylamino) pyrimidine; S-6 - ((3R) -3-Hydroxypyrrolidin-1-ylcarbonyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-. { N- [2- (Methoxy) ethyl] carbamoyl} -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-l] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6- (N-Cyclopro? Ilcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrro lidin-1-yl} -4- (5-methyl-1 H-pi-1-3-ylamino) pyrimidine; S-6- (N-Cyclopentylcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- (Azetidin-1-ylcarbonyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-ll] pyrrolidin-1-yl} -4- (5-methyll-1H-pyrazol-3-ylamino) pyrimidine; S-6- (N-Methylcarbamoyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (N-Aminocarbamoyl) -2-. { 2- [3- (pyrid-2-ll) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- [N- (Acetylamino) carbamoyl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (5-Methyl- [1,3,4] -oxadiazol-2-yl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-Hydroxymethyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (Morpholinomethyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (4-Methylpiperazin-1-ylmethyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (Methylaminomethyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (Pyrrolidin-1-ylmethyl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5- methyl-1 H-pi razol-3-ylamino) pyrimidine; 6-Aminomethyl-2-. { 2- [3- (p i rid-2-i I) isoxazol-5-i I] pyrrolidin-1-1 l} -4- (5-methyI-1H-pyrazol-3-ylamino) pyrimidine; S-6-Hydroxymethyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pi-razo l-3-ylamino) pyrimidine; S-6-Ethoxymethyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6 - [(2-Methoxyethoxy) methyl] -2-. { 2- [3- (pyrid-2-yl) isoxazoI-5-yl] pyrrolidin-1-yl} -4- (5-methyI-1H-pyrazol-3-llamno) pyrimidine; S-5-Chloro-2-. { 2- [3- (p -razin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazolo-3-ylamino) pyrimidine; S-6-Methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-ylpyrimidine; S-6-Chloro-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrazin-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -6- (2-methoxyethylamino) pyrimidine; S-6-Methylamino-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; S-4- (5-Cyclopropyl-1 H-pyrrazol-3-ylamino) -6-methoxy-. { 2- [3- (pyrazin-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6-Pyrrolidin-1-ll-2-. { 2- [3- (pyrid-2-yl) -soxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Chloro-4- (5-rnetll-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin1-i I] pyrimidine; S-6- (2,2,6,6-Tetramethylpiperidin-4-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazsl-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6-lodo-4- (5-metii-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-E-6- [3-tert-Butoxycarbonylamino) prop-1-en-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamine) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Ethenyl-4- (5-methyl-1H-p-arazoi-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-E-6- (3-H id roxiprop-1-en-1-yl) -4- (5-methi 1-1 H-pi razoi-3-lamin o) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} plrroldin-1-1] pyrmidin; S-6- [3-tert-Butoxycarbonylamino) prop-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamide) -2- [2-. { 3 (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Aminoprop-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1- i I] pyrimidine; S-E-6- [3-Aminoprop-1-en-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Methylammoprop-1-yn-1-yl] -4- (5-methylene-1 H-p-razo l-3-i lamie) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Methoxyprop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-M} pyrrolidin-1-yl] pyrimidine; S-6- [3-Hydroxyprop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (Trimethylsilyl) ethynyl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- (N-Methylacetamido) prop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3 (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- (Dimethylamino) prop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Acetamidoprop-1-yn-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (Ethoxycarbon I) ethyl] -4- (5-methi 1-1 H-pi razo l-3-i lamí no) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-ll} pyrrolidin-1-yl] pyrimidine; S-E-6- [2- (Methoxycarbonyl) eten-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Ethinyl-4- (5-methy1-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6- Methoxymethyl-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-i) isoxazol-5-yl} pyrroli din-1-yl] pyrimidine; S-6- Methoxy methyl-4- (5-cyclopropyl 1-1 H-pi-3-ylamine) -2- [2-. { 3- (pyrid-2-yl) lsoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- Metoxy metí l-4- (5-met¡ 1-1 H-pi razol-3-ilam i no) -2- [2-. { 3- (p-irid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-Aminoprop-1-ln-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (N -Methyl carbamoyl) ethyl] -4- (5-methyl-1H-pyrazole-3-ylamine) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-ylpyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxa zol-5-i I] pyrro lidin-1-ylpyrimidine; S-4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl] pyrim dyne; 6- (N-tert-Butoxycarbonyl) amino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6- (4-Aminopiperidin-1-yl) 2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrrazol-3-llamino) pyrimidine; 6- (4- (N-tert-Butoxycarbonylamino) piperadin-1-yl) -2-. { 2- [3- (pyrid-2-yl) isoxa zol-5-yl] pyrrolidin-1-yl} -4- (5- methyl-1 H-pi razol-3-ylamino) pyrimidine; 6-Piperazin-1-yl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pi-razo-l-3-ylamino) pyrimidine; S-6-. { 4- [2- (2-Hydroxyethoxy) ethyl] piperazin-1-yl} -2-. { 2- [3- (pyrid-2-y1) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyll-1 H-pyrazol-3-ylamino) pyrimidine; S-6- (1-Formyl-piperazin-4-yl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1 -ii} -4- (5-methyl-1 H -pyrazol-3-ylamino) pyrimidine; S-6-Piperazin-1-yl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- (4-Isopropylpiperazin-1-yl) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6 - [(4- (2-Hydroxyethyl) piperazin-1-yl)] - 2-. { 2- [3- (pyrid-2-yl) isoxazol-5-l] pyrrolidin-1-yl} 4- (5-methyl-1 H-pyrrazol-3-ylamino) pyrimidine; S-6 - [(3R) -3-Hydroxypyrrolidin-1-yl] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyll-1H-pyrazol-3-ylammon) pyrimidine; S-6 - [(3R) -3-Dimethylamino-pyrroidin-1-yl] -2-. { 2- [3- (pyrid-2-yl) -soxazol-5-I] pyrro I id i n-1 -i l} -4- (5-methyl I- 1 H-pyrazol-3-ylamino) pyrimidine; S-6- (4-Tetrahydropyranylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Morpholino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1 H-pi-razol-3-ylammon) pyrimidine; S-6- (2-Methoxyethyl) amino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} 4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6 - [(N-2-Methoxyethyl) -N-methylamino] -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-plrazol-3-ylammon) pyrimidine; S-6 - ((2R) -2-Hydroxyprop-1-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4 (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6- [N- (2-Hydroxyethyl) -N-et -lamino] -2-. { 2- [3- (pyrid-2-y1) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Dimethylamino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5- methyl-1 H -pyrazol-3-ylamino) plrimidine; S-6-Methylamino-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1 - [} -4- (5-methyl-1H-pyrrazol-3-ylamino) pyrimidine; S-6-Chloro-2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidi-1-ll} -4- (5-methyl-1H-pyrazolo-3-ylamino) pyrimidine; 6-Mofolino-2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; 6-C parrot-2-. { 2- [3- (pyrid-2-y1) isoxazole-5-y1] pyrrolidin-1-y1} -4- (5-cyclop ropl I-1H-pyrazol-3-ylamino) pyrimidine; 6- (2-Hydroxyethoxy) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) pyrimidine; 6- [4-tert-Butoxycarbonyl] piperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3 (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; 6- (4-Acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3 ~ (pyrid-2-yl) isoxazol5-ll} pyrrolidin-1-yl] pyrimidine; 6- [2-tert-Butoxycarbonyl) -2,7-diazaspiro [3.5] nonan-7-yl] -4- (5-methyl-1H-p-aceol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 6- (2,7-Diazaspiro [3.5] nonan-7-yl) -4- (5-methyl-1H-p¡razol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4- (2-Aminoethyl) piperazin-1-1] -4- (5-methyl-1 H-pi-3-ylamyl) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-ylpyrimidine; S-6- [4- (3-Hydroxypropyl) piperazin-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid2-yl) isoxazole-5-iI} pyrrolidin-1-yl] pyrimidine; S-6- [4- (2-Cyanoethyl) p.perazin-1-yl] -4- (5-methyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-ii} pyrrolidin-1-yl] pyrimidine; S-6- [4- (2-Methoxyethyl) piperazin-1-yl] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (4-Acetylpiperazin-1-yl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) i soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4- (Ethylsulfonyl) piperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (2-Hydroxyethoxy) ethylamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (Acetoamido) ethylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-ll} pyrrolidin-1-yl] pyrimidine; S-6- [2-Aminoethylamino] -4- (5-methy1-1H-pyrazol-3-ylammon) -2- [2-. { 3- (p i rid-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6- [4-Methylcyclohexylamino] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4-Hydroxycyclohexylamino] -4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [cs-3,4-Dihydroxypyrrolidin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-methi 1-1 H-pi razo l-3-í lamin o) -2- [2-. { 3- (pyrim id -2-yl) isoxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; S-6-Chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazn-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-methy1-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-hydroxypyrazin-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4-Met i] piperazin-1 -i l] -4- (5-methi 1-1 H-pi razo l-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [Cyclobutylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3-lsop-ropoxiprop-1-ylamino] -4- (5-methyl-1 H-pi-razo-l-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (Morpholin-4-yl) ethylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [2- (Dimethylamino) et.lamino] -4- (5-methy1-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6 - [(2S) -2-Hydroxyprop-1-ylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pirro lid i n-1- i l] pyrimidine; S-6- [2-Methylprop-1-ylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- Methoxy propylamino] -4- (5-m eti 1-1 H-pi razol-3-i min) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [4-Ethyl-pperazin-1-yl] -4- (5-methyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; S-6- [3-Ethoxypropylamino] -4- (5-methyl-1 H -pyrazole-3-i lamin or) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6 - [(2R) -Tetrahydrofuran-2-ylmethylamino] -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3 (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-lsopropoxyethylamino) -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methylamino-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1 H-pi-reazo-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxy-pyrazin-2-yl) i soxazol-5-yl} pyrrolidin-1-ylpyrimidine; S-6-Methoxy-4- (5-cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrimidin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrrmidin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylammon) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrro lidin-1-yl} pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidi-1-yl} plrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -5-fluoro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1 H-pi-reazo l-3-i-iiam not) -6-methyl-2-. { 2- [3- (pi rim id-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2-. { 2- [3- (pyrazin-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6-methyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; 6- (3-Hydroxypropyl) -4- (5-methyl-1H-pyrazole = 3-ylamino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-6- (3-H¡d roxiprop i I) -4- (5-methi 1-1 H-pi razol-3-ilam ino) -2-. { 2- [3- (pyrid-2-yl) isoxazol-5-yl] pyrrolidin-1-yl} pyrimidine; S-6-Propyl-2-. { 2- [3- (pyrid-2-yl) isoxazol-5-ii] pyrrolidin-1-yl} -4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidine; S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-H idioxyethoxy) -4- (5-ethyl-1 H-pi-l-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (4-Methylpiperazin-1-yl) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2 i) iso xa zol5-il} pyrrolidin-1-ylpyrimidine; S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (2-pyrazinyl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methoxy-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) lsoxazol-5-yl} pirro lid i n-1-l] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-methyl-1 H-pi-3-ylamyl) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolid i n-1-ylpyrimidine; S-6-Pyrrolidin-1-yl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methoxymethyl-4- (5-methyl-1H-pyrazol-3-yl) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholinocarbonyl-4- (5-methyl-1 H-p-arazoi-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Carbamoyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Fluoro-4- (5-methy1-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) -soxazol-5-yl} pyrrolidin-1] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-l! pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-4- (5-Methyl-1 H-pyrrazol-3-ylamino) -6- (2- {N- [2-hydroxyethyl] -N-methyl-amino} ethoxy) 2- [2-. { 3- (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-morpholinoethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidi n-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (methylthio) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} p i rrol din-1-yl] pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (tetrahydrofuran-3-ylmethoxy) -2- [2-. { 3- (p i rid-2-i I) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2- (2-hydroxyethoxy) ethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; 4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-methoxylethoxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1- i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (3-hydroxypropyloxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- [2- (2-methoxyethoxy) ethoxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrroiidin-1-yl] pyrimidine; S-4- (5- Methyl-1H-pyrazo l-3-ylamino) -6- (2-ethoxyethoxy) -2- [2-. { 3 ~ (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-plrazol-3-ylamino) -6- (3-morpholinoprop-1-yloxy) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidin; S-4- (5-Meti 1-1 H-plrazol-3-yla min) -6- (3-methoxyprop-1-yloxy) -2- [2-. { 3- (pyrid-2-i) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- [2- (2-oxopyrrolidin-1-yl) ethoxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6 - [(2S) -2-methoxyprop-1-yloxy] -2- [2-. { 3- (pyrid-2-yl) iso xa zol-5-yl} pyrrolidin-1-ylpyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- [3- (methylthio) prop-1-yloxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6 - [(2S) -5-oxopyrrolidin-2-yl) methoxy] -2- [2-. { 3 (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrididine; S-4- (5-Methyl-1H-pyrazol-3-ylamine) -6 - [(2R) -5-oxopyrrolidin-2-yl) methoxy] -2- [2-. { 3 (pyrid-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- [2- (imidazolid-2-on-1-yl) ethoxy] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pi rrol id in- 1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-ethoxy-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6-hydroxy-2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1 H-pi-l-3-ylamino) -6- (2-methoxy-ethoxy) -2- [2-. { 3- (thiazol-2-i i) iso xa zol-5-il} pyrrolidin-1-i I] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2-. { 3- (thiazol-2- l) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-M eti 1-1 H-pyrazol-3-yla min) -6 - [(2R) -2-h id roxiprop-1-i loxi] -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2-. { 3- (Plrazin-2-yl) isoxazol-5-yl} p i Rrolidin- -iljpyrimidine; S-4- (5-Ethyl-1H-pyrazol-3-ylamino) -6-methoxy-2- [2-. { 3- (pyrazin-2-yl) So xa zol-5-il} pyrrolidin-1-i I] pyrimidine; S-4- (5-Cyclopropyl-1H-pyrazol-3-ylamino) -6- (2-hydroxyethoxy) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-M ethyl-1 H-pi-3-ylamino) -6- (tetrah id ro pira n-4-lloxi) -2- [2-. { 3- (pyrid-2-yl) isoxa2? L-5-yl} pyrrolidin-1-yl] pyrimidine; S-5-Fluoro-4- (5-methyl-1 H -py2? L-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxa zol-5-yl} pyrrolidin-1-i I] pyrimidine; S-5-Chloro-4- (5-methyl-1H-pyrazo) -3-ylamino) -2- [2-. { 3- (t-azole-4-yl) -soxazol-5-yl} pyrrolidin-1 -i I] pyrimidine; S-5-Fluoro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazole-5-l} pyrrolidin-1-yl] pyrimidine; S-4- (5-Ethyl-1H-pyrazole-3-llamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pi rrol din-1-il] pirim id i na; S-4- (5-Cyclopropyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (t.azol-2-yl) isoxazole-5-i I.). pi rroi id i n- 1 -yljpyrimidine; S-4- (5-Cyclopropropyl-1H-pyrazol-3-ylamino) -5-Fuoro-2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-methy1-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazole-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morph olino-4- (5-ethyl-1 H-pi razol-3-i licked) -2- [2-. { 3- (p irazi n-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethylamino) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methalamino-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- (4- Methyl piperazin-1-yl) -4- (5-methyl-1 H-pi-razol-3-i m ino) -2- [2-. { 3- (thiazol-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (thiazol-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6- [3- (Methylsulfonyl) propyl-1-oxy] -4- (5-methyl-1 H -pyrazol-3-ylamino) -2- [2-. { 3- (pyrid2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-4- (5-Cyclopropyl-1 H-plrazol-3-ylamino) -6- (2-methoxyethoxy) -2- [2-. { 3- (pyrazin-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyra my dyne; S-6-Methyl-4- (5-Ethyl-1 H-pyrrazol-3-ylamino) -2- [2-. { 3- (3-meioxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-Ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazin-2-yl) i soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yi) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methoxy-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-11] pyrimidine; S-6-Ethyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methylamino-4- (5-ethyl-1 H-pi-razol-3-i lamí) -2- [2-. { 3- (p rim id-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Ethyl-4- (5-cyclopropyl-1H-pyrazol-3-llamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-i I] pyrimidine; S-6-Cyclopropyl-4- (5-cyclopropyl-1 H -pyrazol-3-ylammon) -2- [2-. { 3- (pyrimid-2-y1) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Cyclopropyl-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-iI} pyrrolidin-1-yl] pyrimidine; S-6- (2-Methoxyethoxy) -4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Metii-4- (5-Methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl ] pyrimidine; S-5- FI uoro-4- (5-cyclopropyl-1 H-pi-razol-3-i mi) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazole-5 -i I] pyrrolidin-1-yl] pyrimidine; S-5-Fluoro-4- (5-ethyl-1H-pyrazol-3-llamino) -2- [2- [3- (2-methoxypridrid-3-yl) isoxazol-5-yl] pyrrolidin-1-ylpyrimidine; S-6- (2-Hydroxyethoxy) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidine -1-yl] pyrimidine; S-6-Chloro-4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl ] pyrimidine; S-6-Chloro-4- (5-eti 1-1 H -pyrazol-3-yl-amino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin- 1-yl] pyrimidine; S-6- (2-Hydroxyethoxy) -4- (5-cyclopropyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidine - 1-yl] pyrimidine; S-5-Fluoro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazol-5-yl] pyrrolidin-1-yl ] pyrimidine; S-6- (2-H id roxietox¡) -4- (5-eti 1-1 H-pyrazole-3-i lamin o) -2- [2- [3- (2-methoxypyrid-3-yl) iso xa zol-5-yl] pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-cyclopropyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (3-methoxypyrazin-2-yl) -soxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Morpholino-4- (5-ethyl-1 H-plrazol-3-ylamino) -2- [2-. { 3- (3-methoxypyrazin-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Chloro-4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2- [3- (2-methoxypyrid-3-yl) isoxazole-5-ii] pyrrolidin -1-yl] pyrimidine; S-6-Met l-4- (5-ethyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrimid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; S-6-Methyl-4- (5-ethyl-1H-pyrazol-3-ylammon) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-pyrimidine; S-6-Morpholino-4- (5-etii-1H-pyrazol-3-ylamino) -2- [2-. { 3- (3-h id roxi p i razln-2-yl) isoxazol-5-yl} p r-R-din-1-yl] pyrimidine; and S-6- (3-Methoxypropyl) -4- (5-methyl-1H-pyrazol-3-ylamino) -2- [2-. { 3- (pyrid-2-yl) isoxazol-5-yl} pyrrolidin-1-yl] pyrimidine; and pharmaceutically acceptable salts thereof.

25. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24, in association with a pharmaceutically acceptable auxiliary, diluent or carrier.

26. A method for pre-processing a pharmaceutical composition according to claim 25, which comprises mixing a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24 with a pharmaceutically acceptable auxiliary, diluent or vehicle.

27. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24 for use in therapy.

28. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24 for use in the modulation of the insulin-like growth factor-1 receptor activity in a human or animal

29. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24 in the manufacture of a medicament for use in the treatment of cancer.

30. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24 in the manufacture of a medicament for use in the modulation of the receptor activity of the Insulin-like growth factor 1

31. A method for treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 24.

32. - A process for preparing a compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises: (i) reacting a compound of the formula (II) wherein L1 represents a leaving group (eg, halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R1, R2 and R3 are as defined in formula (I) except that any functional group is protected if necessary , with a compound of the formula (III), wherein Q1 and Q2 are as defined in formula (I) except that any functional group is protected if necessary; or (ii) reacting a compound of the formula (IV) wherein L2 represents a leaving group (eg, halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R2, R3, Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of the formula (V), wherein R is as defined in formula (I) except that any functional group is protected if necessary; or (iii) reacting a compound of the formula (VI) where Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of the formula (VII) wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, R21 independently represents an alkyl group of 1 to 6 carbon atoms and R2 and R3 are as defined in formula (I), except that any functional group is protected if necessary; or (iv) reacting a compound of the formula (VIII) wherein R1, R2, R3, NQ1 and Q2 are as defined in formula (I) except that any functional group is protected if necessary with hydrazine; or (v) for compounds of the formula (I) wherein R3 is an alkoxy group of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- [alkyl of 1 to 6 carbon atoms] amino, amino, -OR3b, SR, 3Cb • NHR-N-C 1-6 -alkyl] R 3b -S (0) mR3a wherein m is 0 and R3a and R3b are as defined above (and the group R3 is optionally substituted by at least one group as defined above), reacting a compound of the formula (IX) wherein L3 represents a leaving group (for example halogen or sulfonyloxy such as methanesulfonyloxy or toluene-4-sulfonyloxy) and R1, R2, Q1 and Q2 are as defined in the formula (I), except that any functional group is protected if necessary, as a compound of the formula H-Xa, wherein Xa is selected from OR22, NH2, NHR22, N (R22) 2, NH2, OR3b, SR3b, NHR3b , N [alkyl of 1 to 6 carbon atoms] R3b and SR3b, wherein R22 is an alkyl group of 1 to 6 carbon atoms, optionally substituted, and R3a and R3b are each as defined above, except that any group functional is protected if necessary; or (vi) for compounds of the formula (I) wherein R3 is an optionally substituted 5 or 6 membered saturated monocyclic heterocyclic ring comprising at least one nitrogen in the ring and, optionally, one or more additional heterogeneous atoms selected from nitrogen, oxygen and sulfur, reacting a compound of the formula (IX) with a compound of the formula (Xb) wherein Q 4 is an optionally substituted 5 or 6 membered saturated monocyclic heterocyclic ring, comprising one or more additional heterogeneous atoms selected from nitrogen, oxygen and sulfur, in addition to the nitrogen atom shown above, said ring is optionally substituted by at least one ring as defined above, or with an optionally substituted 2,7- diazaspiro [3,5] nonato group; or (vii) for compounds of the formula (I) wherein R3 is an alkylene group of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms and the group R3 is optionally substituted by at least one group as defined above, by reacting a compound of the formula (IX), with a compound of the formula (Xc) or the formula (Xc ') H. C- R, 23 / H H l (XC) wherein R23 is selected from hydrogen and an alkyl group of 1 to 4 carbon atoms or alkoxycarbonyl of 1 to 4 carbon atoms, optionally substituted; (viii) for the compounds of the formula (I) wherein R3 is attached to the pyrimidine ring through a carbon atom, reacting a compound of the formula (IX), with a compound of the formula M-R3, in wherein R3 is appropriately selected from the groups R3 as defined above, and M is a metal group, such as ZnBr, B (OH) 2, CuCN or SnBu3; (ix) for the compounds of the formula (I) wherein R3 is an alkoxycarbonyl group of 1 to 6 carbon atoms (and the group R3 is optionally substituted by at least one group as defined above), by reacting a compound of the formula (X) wherein R1, R2, Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of the formula HO-alkyl of 1 to 6 carbon atoms, wherein the alkyl group of 1 to 6 carbon atoms is optionally substituted by at least one group as defined above and any functional group is protected if necessary; or (x) for compounds of the formula (I), wherein R3 is a 5-membered heteroaromatic ring comprising at least one heterogeneous atom selected from nitrogen, oxygen and sulfur (and the group R3 is optionally substituted by at least one group as defined above), conduct an internal condensation reaction using an appropriate starting material and a suitable dehydrating agent. For example, for the compounds of the formula (I), wherein R3 is a group 1, 3,4-oxadlazole, reacting a compound of the formula (XI) wherein Z represents any suitable substituent for R3 as defined above , and R1, R2, Q1 and Q2 are as defined in formula (I) except that any functional group is protected if necessary, with a suitable dehydrating agent, such as (methoxycarbonylsulfanoyl) triethylammonium hydroxide; or (xi) for compounds of the formula (I) wherein R3 is an alkyl group of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms substituted by at least one group as defined above, reacts a compound of the formula (XII) wherein L3 represents a leaving group as defined above, W represents an alkyl group of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms optionally substituted carbon, and R1, R2, Q1 and Q2 are as defined in formula (I), except that any functional group is protected if necessary, with a compound of formula H-Xa, (Xb), (Xc ), (Xc '), or M-R3 as defined above; and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x) or (xi) performing one or more of the following: converting the obtained compound to a further compound of the invention, forming a pharmaceutically acceptable salt of the compound.